Topic Editors

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata, Italy

Compounds with Medicinal Value

Abstract submission deadline
closed (31 December 2021)
Manuscript submission deadline
closed (31 March 2022)
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Topic Information

Dear Colleagues,

In industrialized countries over the last few decades, there has been a significant increase in infectious; cardiovascular, inflammatory, and neurodegenerative diseases; as well as different forms of cancer, diabetes, and so on.

Between them, microbial infections and cancer are still the major causes of death among the world’s population due to increased bacterial resistance phenomena and the development of resistance to chemotherapeutics. For these reasons, there is an urgent need to design and synthesize new antimicrobial agents, particularly those with antibacterial activity, and particularly against Gram-negative pathogens that could be used to fight drug resistance, and also for new antineoplastic drugs with higher selectivity on tumoral cells, which are able to overcome cancer cells’ resistance with minimal side effects.

Recently, some delivery systems have proved particulary effective as antimicrobial and anticancer carriers due to targeted drug delivery at the action sites, reduced drug-resistance and side effects, and an increased therapeutic index.

Potential topics for manuscripts include the following:

  • The design, synthesis, and biological evaluation of anticancer agents;
  • The design, synthesis, and biological evaluation of antimicrobial agents;
  • Delivery systems and nanosystems for targeted cancer and antimicrobial therapy...

Prof. Dr. Maria Stefania Sinicropi
Topic Editor

Keywords

  • molecular modeling
  • synthesis
  • anticancer compounds
  • antimicrobial compounds
  • targeted therapy
  • delivery systems

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Applied Sciences
applsci
2.7 4.5 2011 16.9 Days CHF 2400
Biomolecules
biomolecules
5.5 8.3 2011 16.9 Days CHF 2700
Pharmaceuticals
pharmaceuticals
4.6 4.7 2004 14.6 Days CHF 2900
Biomedicines
biomedicines
4.7 3.7 2013 15.4 Days CHF 2600
Antibiotics
antibiotics
4.8 5.5 2012 13.7 Days CHF 2900

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Published Papers (117 papers)

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18 pages, 645 KiB  
Article
Antimicrobial and Cytotoxic Cyathane-Xylosides from Cultures of the Basidiomycete Dentipellis fragilis
by Winnie Chemutai Sum, Nico Mitschke, Hedda Schrey, Kathrin Wittstein, Harald Kellner, Marc Stadler and Josphat Clement Matasyoh
Antibiotics 2022, 11(8), 1072; https://doi.org/10.3390/antibiotics11081072 - 08 Aug 2022
Cited by 11 | Viewed by 2361
Abstract
In our continued search for biologically active metabolites from cultures of rare Basidiomycota species, we found eight previously undescribed cyathane-xylosides from submerged cultures of Dentipellis fragilis, which were named dentifragilins A–H. In addition, the known cyathane derivatives striatal D and laxitextine A [...] Read more.
In our continued search for biologically active metabolites from cultures of rare Basidiomycota species, we found eight previously undescribed cyathane-xylosides from submerged cultures of Dentipellis fragilis, which were named dentifragilins A–H. In addition, the known cyathane derivatives striatal D and laxitextine A were isolated. All compounds were characterized by high-resolution electrospray ionization mass spectrometry (HR-ESIMS) as well as by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Several of the compounds exhibited significant activities in standardized cell-based assays for the determination of antimicrobial and cytotoxic effects. The discovery of cyathanes in the genus Dentipellis has chemotaxonomic implications, as this class of diterpenoids has already been shown to be characteristic for mycelial cultures of the related genera Hericium and Laxitextum, which are classified as Dentipellis in the family Hericiaceae. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 3787 KiB  
Article
Astaxanthin Carotenoid Modulates Oxidative Stress in Adipose-Derived Stromal Cells Isolated from Equine Metabolic Syndrome Affected Horses by Targeting Mitochondrial Biogenesis
by Malwina Mularczyk, Nabila Bourebaba, Krzysztof Marycz and Lynda Bourebaba
Biomolecules 2022, 12(8), 1039; https://doi.org/10.3390/biom12081039 - 27 Jul 2022
Cited by 6 | Viewed by 2794
Abstract
Astaxanthin is gaining recognition as a natural bioactive component. This study aimed to test whether astaxanthin could protect adipose-derived stromal stem cells (ASCs) from apoptosis, mitochondrial dysfunction and oxidative stress. Phaffia rhodozyma was used to extract astaxanthin, whose biocompatibility was tested after 24, [...] Read more.
Astaxanthin is gaining recognition as a natural bioactive component. This study aimed to test whether astaxanthin could protect adipose-derived stromal stem cells (ASCs) from apoptosis, mitochondrial dysfunction and oxidative stress. Phaffia rhodozyma was used to extract astaxanthin, whose biocompatibility was tested after 24, 48 and 72 h of incubation with the cells; no harmful impact was found. ASCs were treated with optimal concentrations of astaxanthin. Several parameters were examined: cell viability, apoptosis, reactive oxygen levels, mitochondrial dynamics and metabolism, superoxide dismutase activity, and astaxanthin’s antioxidant capacity. A RT PCR analysis was performed after each test. The astaxanthin treatment significantly reduced apoptosis by modifying the normalized caspase activity of pro-apoptotic pathways (p21, p53, and Bax). Furthermore, by regulating the expression of related master factors SOD1, SOD2, PARKIN, PINK 1, and MFN 1, astaxanthin alleviated the oxidative stress and mitochondrial dynamics failure caused by EMS. Astaxanthin restored mitochondrial oxidative phosphorylation by stimulating markers associated with the OXPHOS machinery: COX4I1, COX4I2, UQCRC2, NDUFA9, and TFAM. Our results suggest that astaxanthin has the potential to open new possibilities for potential bio-drugs to control and suppress oxidative stress, thereby improving the overall metabolic status of equine ASCs suffering from metabolic syndrome. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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39 pages, 7183 KiB  
Article
Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations
by Nahed N. E. El-Sayed, Magdi E. A. Zaki, Sami A. Al-Hussain, Abir Ben Bacha, Malika Berredjem, Vijay H. Masand, Zainab M. Almarhoon and Hanaa S. Omar
Pharmaceuticals 2022, 15(7), 891; https://doi.org/10.3390/ph15070891 - 19 Jul 2022
Cited by 8 | Viewed by 2294
Abstract
Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant [...] Read more.
Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC50 values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC50 values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski’s rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 6685 KiB  
Article
Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives
by Vincent Montero, Marc Montana, Omar Khoumeri, Florian Correard, Marie-Anne Estève and Patrice Vanelle
Pharmaceuticals 2022, 15(7), 781; https://doi.org/10.3390/ph15070781 - 23 Jun 2022
Cited by 4 | Viewed by 1987
Abstract
The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane [...] Read more.
The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC50 = 2.49 ± 1.33 μM and IC50 = 3.96 ± 2.03 μM for compound 11a and IC50 = 5.3 ± 2.12 μM and IC50 = 7.12 ± 1.59 μM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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13 pages, 1326 KiB  
Article
Purification, Characterization and Evaluation of the Antitumoral Activity of a Phospholipase A2 from the Snake Bothrops moojeni
by Breno Emanuel Farias Frihling, Ana Paula de Araújo Boleti, Caio Fernando Ramalho de Oliveira, Simone Camargo Sanches, Pedro Henrique de Oliveira Cardoso, Newton Verbisck, Maria Lígia Rodrigues Macedo, Paula Helena Santa Rita, Cristiano Marcelo Espinola Carvalho and Ludovico Migliolo
Pharmaceuticals 2022, 15(6), 724; https://doi.org/10.3390/ph15060724 - 07 Jun 2022
Cited by 7 | Viewed by 2191
Abstract
Nature presents a wide range of biomolecules with pharmacological potential, including venomous animal proteins. Among the protein components from snake venoms, phospholipases (PLA2) are of great importance for the development of new anticancer compounds. Thus, we aimed to evaluate the PLA [...] Read more.
Nature presents a wide range of biomolecules with pharmacological potential, including venomous animal proteins. Among the protein components from snake venoms, phospholipases (PLA2) are of great importance for the development of new anticancer compounds. Thus, we aimed to evaluate the PLA2 anticancer properties from Bothrops moojeni venom. The crude venom was purified through three chromatographic steps, monitored by enzymatic activity and SDS-PAGE (12%). The purified PLA2 denominated BmPLA2 had its molecular mass and N-terminal sequence identified by mass spectrometry and Edman degradation, respectively. BmPLA2 was assayed against human epithelial colorectal adenocarcinoma cells (Caco-2), human rhabdomyosarcoma cells (RD) and mucoepidermoid carcinoma of the lung (NCI-H292), using human fibroblast cells (MRC-5) and microglia cells (BV-2) as a cytotoxicity control. BmPLA2 presented 13,836 Da and a 24 amino acid-residue homologue with snake PLA2, which showed a 90% similarity with other Bothrops moojeni PLA2. BmPLA2 displayed an IC50 of 0.6 µM against Caco-2, and demonstrated a selectivity index of 1.85 (compared to MRC-5) and 6.33 (compared to BV-2), supporting its selectivity for cancer cells. In conclusion, we describe a new acidic phospholipase, which showed antitumor activity and is a potential candidate in the development of new biotechnological tools. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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16 pages, 985 KiB  
Review
Phytotherapy: A Solution to Decrease Antifungal Resistance in the Dental Field
by Katherine Cuenca-León, Edisson-Mauricio Pacheco-Quito, Yanela Granda-Granda, Eleonor Vélez-León and Aránzazu Zarzuelo-Castañeda
Biomolecules 2022, 12(6), 789; https://doi.org/10.3390/biom12060789 - 04 Jun 2022
Cited by 4 | Viewed by 3646
Abstract
The pathologies produced by fungi in the oral cavity in recent decades have become a health problem, with factors such as an imbalance of the local microbiota being the cause for their propagation. Conventional antifungal treatments, instead of being beneficial, have generated alterations [...] Read more.
The pathologies produced by fungi in the oral cavity in recent decades have become a health problem, with factors such as an imbalance of the local microbiota being the cause for their propagation. Conventional antifungal treatments, instead of being beneficial, have generated alterations that have led to antifungal resistance. The aim of this study was to investigate and describe phytotherapy resources as a possible solution to oral antifungal resistance. A bibliographic search was carried out on platforms such as PubMed, Scopus, ScienceDirect, Web of Science, and Google scholar. A total of 248 scientific articles were obtained, of which 108 met the inclusion criteria. Microorganisms of fungal origin currently show resistance to the different antifungals of conventional use, which is undoubtedly altering the oral health of human beings, but there are new therapeutic possibilities such as the active principles of various natural species. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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20 pages, 4332 KiB  
Article
Dopamine D2 and Serotonin 5-HT1A Dimeric Receptor-Binding Monomeric Antibody scFv as a Potential Ligand for Carrying Drugs Targeting Selected Areas of the Brain
by Agata Kowalik, Mateusz Majerek, Krzysztof Mrowiec, Joanna Solich, Agata Faron-Górecka, Olga Woźnicka, Marta Dziedzicka-Wasylewska and Sylwia Łukasiewicz
Biomolecules 2022, 12(6), 749; https://doi.org/10.3390/biom12060749 - 26 May 2022
Cited by 2 | Viewed by 2378
Abstract
Targeted therapy uses multiple ways of ensuring that the drug will be delivered to the desired site. One of these ways is an encapsulation of the drug and functionalization of the surface. Among the many molecules that can perform such a task, the [...] Read more.
Targeted therapy uses multiple ways of ensuring that the drug will be delivered to the desired site. One of these ways is an encapsulation of the drug and functionalization of the surface. Among the many molecules that can perform such a task, the present work focused on the antibodies of single-chain variable fragments (scFvs format). We studied scFv, which specifically recognizes the dopamine D2 and serotonin 5-HT1A receptor heteromers. The scFvD2–5-HT1A protein was analyzed biochemically and biologically, and the obtained results indicated that the antibody is properly folded and non-toxic and can be described as low-immunogenic. It is not only able to bind to the D2–5-HT1A receptor heteromer, but it also influences the cAMP signaling pathway and—when surfaced on nanogold particles—it can cross the blood–brain barrier in in vitro models. When administered to mice, it decreased locomotor activity, matching the effect induced by clozapine. Thus, we are strongly convinced that scFvD2–5-HT1A, which was a subject of the present investigation, is a promising targeting ligand with the potential for the functionalization of nanocarriers targeting selected areas of the brain. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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20 pages, 4302 KiB  
Article
Anti-Inflammatory Effects of GM1 Ganglioside on Endotoxin-Induced Uveitis in Rats
by Tzu-Heng Weng, Chang-Chih Ke and Yuahn-Sieh Huang
Biomolecules 2022, 12(5), 727; https://doi.org/10.3390/biom12050727 - 21 May 2022
Cited by 2 | Viewed by 2611
Abstract
Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide [...] Read more.
Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide (LPS). GM1 was injected intraperitoneally for three consecutive days prior to the LPS injection. Twenty-four hours after the LPS injection, the integrity of the blood-aqueous barrier was evaluated by determining the protein concentration and number of infiltrating cells in the aqueous humor (AqH). Immunohistochemical and Western blot analyses of the iris-ciliary body (ICB) were performed to evaluate the effect of GM1 on the LPS-induced expression of cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1). The effect of GM1 on proinflammatory mediators and signaling cascades was examined in LPS-stimulated RAW 264.7 cells using Western blotting and immunofluorescence staining to further clarify the underlying anti-inflammatory mechanism. Results: GM1 significantly reduced the protein concentration and number of infiltrating cells in the AqH of rats with EIU. GM1 also decreased the LPS-induced expression of the ICAM-1 and COX-2 proteins in the ICB. In RAW 264.7 cells, GM1 inhibited the proinflammatory mediators induced by LPS, including inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and this inhibitory effect was potentially mediated by suppressing reactive oxygen species (ROS)-mediated activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Conclusions: Based on this study, GM1 may be a potential anti-inflammatory agent for ocular inflammatory diseases. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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17 pages, 3594 KiB  
Article
Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity
by Kelsey E. Huntington, Lindsey Carlsen, Eui-Young So, Matthias Piesche, Olin Liang and Wafik S. El-Deiry
Pharmaceuticals 2022, 15(5), 618; https://doi.org/10.3390/ph15050618 - 17 May 2022
Cited by 14 | Viewed by 2996
Abstract
As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with [...] Read more.
As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. Because integrins activate transforming growth factor beta (TGF-β) signaling, we compared the plasma levels of active and total TGF-β in COVID-19+ patients. The plasma TGF-β1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. Moreover, the inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and it may mitigate COVID-19 severity through decreased TGF-β1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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13 pages, 5005 KiB  
Article
ZnO/Ag Nanocomposites with Enhanced Antimicrobial Activity
by Jaime Gonzalez Cuadra, Loredana Scalschi, Begonya Vicedo, Maxim Guc, Víctor Izquierdo-Roca, Samuel Porcar, Diego Fraga and Juan B. Carda
Appl. Sci. 2022, 12(10), 5023; https://doi.org/10.3390/app12105023 - 16 May 2022
Cited by 13 | Viewed by 2457
Abstract
In this study, ZnO/Ag nanocomposites were synthesized using a facile chemical route involving metallic precursors of zinc acetate dehydrate and silver acetate, and dissolving the two metallic precursors in EtOH. The final concentration of the solution was 0.4 M. The different nanocomposites were [...] Read more.
In this study, ZnO/Ag nanocomposites were synthesized using a facile chemical route involving metallic precursors of zinc acetate dehydrate and silver acetate, and dissolving the two metallic precursors in EtOH. The final concentration of the solution was 0.4 M. The different nanocomposites were synthesized using different atomic percentages of silver to compare the amount of silver nanoparticles with the bactericidal power of the nanocomposites. They were prepared at concentrations of 0, 1, 3, 5, 7, and 10 at%. The as-prepared nanocomposites were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM) and scanning transmission electron microscopy (STEM) to study their structural and morphological properties. SEM showed that there is a clear effect of Ag on the size of the ZnO particles, since when silver percentages of 1 at% are included, the grain size obtained is much smaller than that of the ZnO synthesis. The effect is maintained for 3, 5, 7, and 10 at% silver. Transmission electron microscopy (TEM) compositional mapping confirms the presence of spherical nanoparticles in the synthesized samples. The size of the nanoparticles ranges from about 10 to about 30 nm. In addition, UV-Vis and Raman spectroscopy were performed to obtain structural details. The different samples show an increase in the absorption in the visible range due to the incorporation of the silver NPs. Measurement of the antimicrobial activity was tested against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) It is shown that zinc oxide has bactericidal power for these two groups of bacteria and also that when it is used together with silver NP, this effect improves, eliminating more than 90% of inoculated bacteria. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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13 pages, 2105 KiB  
Article
Artemisia dracunculus L. Ethanolic Extract and an Isolated Component, DMC2, Ameliorate Inflammatory Signaling in Pancreatic β-Cells via Inhibition of p38 MAPK
by Peter Smoak, Susan J. Burke, Thomas M. Martin, Heidi M. Batdorf, Z. Elizabeth Floyd and J. Jason Collier
Biomolecules 2022, 12(5), 708; https://doi.org/10.3390/biom12050708 - 15 May 2022
Cited by 1 | Viewed by 1776
Abstract
Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. [...] Read more.
Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. Herein, we described the use of 2′,4′-dihydroxy-4-methoxydihydrochalcone (DMC2), a bioactive molecule isolated from an ethanolic extract of Artemisia dracunculus L., as a novel anti-inflammatory agent. The ethanolic extract, termed PMI 5011, reduced IL-1β-mediated NF-κB activity. DMC2 retained this ability, indicating this compound as the likely source of anti-inflammatory activity within the overall PMI 5011 extract. We further examined NF-κB activity using promoter-luciferase reporter constructs, Western blots, mRNA abundance, and protein secretion. Specifically, we found that PMI 5011 and DMC2 each reduced the ability of IL-1β to promote increases in the expression of the Ccl2 and Ccl20 genes. These genes encode proteins that promote immune cell recruitment and are secreted by β-cells in response to IL-1β. Phosphorylation of IκBα and the p65 subunit of NF-κB were not reduced by either PMI 5011 or DMC2; however, phosphorylation of p38 MAPK was blunted in the presence of DMC2. Finally, we observed that while PMI 5011 impaired glucose-stimulated insulin secretion, insulin output was preserved in the presence of DMC2. In conclusion, PMI 5011 and DMC2 reduced inflammation, but only DMC2 did so with the preservation of glucose-stimulated insulin secretion. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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10 pages, 3854 KiB  
Brief Report
Significant Sex Differences in the Efficacy of the CSF1R Inhibitor-PLX5622 on Rat Brain Microglia Elimination
by Aviv Sharon, Hadas Erez and Micha E. Spira
Pharmaceuticals 2022, 15(5), 569; https://doi.org/10.3390/ph15050569 - 02 May 2022
Cited by 9 | Viewed by 2368
Abstract
Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor [...] Read more.
Microglia play pivotal roles in central nervous system development, homeostasis, responses to trauma, and neurodegenerative and neuropsychiatric disorders with significant sex-bias in their symptoms and prevalence. Survival of the microglia in adult brains depends on the expression of the colony-stimulating factor 1 receptor (CSF1R). The inhibition of CSF1R by brain-permeant PLX5622 in the chow eliminates, within 5–10 days, ~90% of the microglia in female and male mice, thereby enabling the investigation of the roles of the microglia in health and pathological mice models. Because of a prevailing “impression” that PLX5622 is ineffective in rats, it has hardly been used in studies of adult rats. Here, we report that effective microglia elimination by PLX5622-chow in rats is highly sex-dependent. Our observations provide missing information for the limited use and interpretation of PLX5622 in biomedical studies of the microglia in rat models. The sex differences that are too often overlooked must be carefully considered and clearly emphasized. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 3297 KiB  
Article
Antifungal Thiazolidines: Synthesis and Biological Evaluation of Mycosidine Congeners
by Igor B. Levshin, Alexander Y. Simonov, Sergey N. Lavrenov, Alexey A. Panov, Natalia E. Grammatikova, Alexander A. Alexandrov, Eslam S. M. O. Ghazy, Nikita A. Savin, Peter V. Gorelkin, Alexander S. Erofeev and Vladimir I. Polshakov
Pharmaceuticals 2022, 15(5), 563; https://doi.org/10.3390/ph15050563 - 01 May 2022
Cited by 10 | Viewed by 2738
Abstract
Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity [...] Read more.
Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity in vitro. Some of the synthesized compounds exhibit high antifungal activity, both fungistatic and fungicidal, and lead to morphological changes in the Candida yeast cell wall. Based on the use of limited proteomic screening and toxicity analysis in mutants, we show that Mycosidine activity is associated with glucose transport. This suggests that this first-in-class antifungal drug has a novel mechanism of action that deserves further study. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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26 pages, 5935 KiB  
Article
Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2
by Povilas Kavaliauskas, Felipe Stambuk Opazo, Waldo Acevedo, Ruta Petraitiene, Birutė Grybaitė, Kazimieras Anusevičius, Vytautas Mickevičius, Sergey Belyakov and Vidmantas Petraitis
Pharmaceuticals 2022, 15(5), 541; https://doi.org/10.3390/ph15050541 - 27 Apr 2022
Cited by 11 | Viewed by 2425
Abstract
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing [...] Read more.
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 916 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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17 pages, 6203 KiB  
Article
Administration of Hookworm Excretory/Secretory Proteins Improves Glucose Tolerance in a Mouse Model of Type 2 Diabetes
by Zainab Khudhair, Rafid Alhallaf, Ramon M. Eichenberger, Matt Field, Lutz Krause, Javier Sotillo and Alex Loukas
Biomolecules 2022, 12(5), 637; https://doi.org/10.3390/biom12050637 - 26 Apr 2022
Cited by 6 | Viewed by 2482
Abstract
Diabetes is recognised as the world’s fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to [...] Read more.
Diabetes is recognised as the world’s fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to understand the molecular mechanisms that underlie the development of T2D-induced insulin resistance, we treated mice fed on normal or diabetes-promoting diets with excretory/secretory products (ES) from the gastrointestinal helminth Nippostrongylus brasiliensis. We demonstrated that treatment with crude ES products from adult worms (AES) or infective third-stage larvae (L3ES) from N. brasiliensis improved glucose tolerance and attenuated body weight gain in mice fed on a high glycaemic index diet. N. brasiliensis ES administration to mice was associated with a type 2 immune response measured by increased eosinophils and IL-5 in peripheral tissues but not IL-4, and with a decrease in the level of IL-6 in adipose tissue and corresponding increase in IL-6 levels in the liver. Moreover, treatment with AES or L3ES was associated with significant changes in the community composition of the gut microbiota at the phylum and order levels. These data highlight a role for N. brasiliensis ES in modulating the immune response associated with T2D, and suggest that N. brasiliensis ES contain molecules with therapeutic potential for treating metabolic syndrome and T2D. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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14 pages, 1900 KiB  
Article
Cobalt Bis-Dicarbollide Enhances Antibiotics Action towards Staphylococcus epidermidis Planktonic Growth Due to Cell Envelopes Disruption
by Eva Vaňková, Kristýna Lokočová, Petra Kašparová, Romana Hadravová, Ivana Křížová, Olga Maťátková, Jan Masák and Václav Šícha
Pharmaceuticals 2022, 15(5), 534; https://doi.org/10.3390/ph15050534 - 26 Apr 2022
Cited by 5 | Viewed by 1960
Abstract
The emergence of antibiotic resistance in opportunistic pathogens represents a huge problem, the solution for which may be a treatment with a combination of multiple antimicrobial agents. Sodium salt of cobalt bis-dicarbollide (COSAN.Na) is one of the very stable, low-toxic, amphiphilic boron-rich sandwich [...] Read more.
The emergence of antibiotic resistance in opportunistic pathogens represents a huge problem, the solution for which may be a treatment with a combination of multiple antimicrobial agents. Sodium salt of cobalt bis-dicarbollide (COSAN.Na) is one of the very stable, low-toxic, amphiphilic boron-rich sandwich complex heteroboranes. This compound has a wide range of potential applications in the biological sciences due to its antitumor, anti-HIV-1, antimicrobial and antibiofilm activity. Our study confirmed the ability of COSAN.Na (in the concentration range 0.2–2.48 µg/mL) to enhance tetracycline, erythromycin, and vancomycin action towards Staphylococcus epidermidis planktonic growth with an additive or synergistic effect (e.g., the combination of 1.24 µg/mL COSAN.Na and 6.5 µg/mL TET). The effective inhibitory concentration of antibiotics was reduced up to tenfold most efficiently in the case of tetracycline (from 65 to 6.5 µg/mL). In addition, strong effect of COSAN.Na on disruption of the cell envelopes was determined using propidium iodide uptake measurement and further confirmed by transmission electron microscopy. The combination of amphiphilic COSAN.Na with antibiotics can therefore be considered a promising way to overcome antibiotic resistance in Gram-positive cocci. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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19 pages, 2221 KiB  
Article
Possible Association between the Use of Proton Pump Inhibitors and H2 Receptor Antagonists, and Esophageal Cancer: A Nested Case–Control Study Using a Korean National Health Screening Cohort
by Hyo Geun Choi, Hong Kyu Lee, Ho Suk Kang, Hyun Lim, Joo-Hee Kim, Ji Hee Kim, Nan Young Kim, Seong-Jin Cho, Eun Sook Nam, Kyueng-Whan Min and Mi Jung Kwon
Pharmaceuticals 2022, 15(5), 517; https://doi.org/10.3390/ph15050517 - 22 Apr 2022
Cited by 7 | Viewed by 2740
Abstract
Although safety concerns regarding proton pump inhibitor (PPI)/H2-receptor antagonists (H2RA) in the incident esophageal cancer have been raised, the Asian-based report is unclear. We investigated the estimated likelihood of incident esophageal cancer—its mortality depending on prior history of PPI/H2RA use—and gastroesophageal reflux disease [...] Read more.
Although safety concerns regarding proton pump inhibitor (PPI)/H2-receptor antagonists (H2RA) in the incident esophageal cancer have been raised, the Asian-based report is unclear. We investigated the estimated likelihood of incident esophageal cancer—its mortality depending on prior history of PPI/H2RA use—and gastroesophageal reflux disease (GERD) in Koreans. Using the Korean National Health Insurance Service-Health Screening Cohort data (2002–2015), a case–control study was retrospectively conducted, including 811 patients with incident esophageal cancer and 3244 controls matched with sex, age, income, and residence. Propensity score overlap weighting was adjusted to balance the baseline covariates. Overlap propensity score-weighted logistic regression analyses were assessed to determine associations of the prior exposure of PPI/H2RA (current vs. past) and the medication duration (<30-, 30–90-, vs. ≥90-days) with incident esophageal cancer and its mortality among the total participants or those with/without the GERD episodes, after adjusting for multiple covariates including PPI/H2RA. The current exposure to either PPI or H2RA showed higher odds for incident esophageal cancer than the nonuser group ([13.23; 95%CI 10.25–17.06] and [4.34; 95%CI 3.67–5.14], respectively), especially in all adults over the age of 40 years without GERD. Both current and past exposures to PPI showed a decreased probability of mortality compared with those of the nonuser group ([0.62; 95%CI 0.45–0.86] and [0.41; 95%CI 0.25–0.67], respectively). However, current or past exposure to H2RA harbored the mutually different likelihoods for mortality depending on the presence of GERD and old age. This study carefully speculates on the possible link between PPI/H2RA and incident esophageal cancer in the Korean population. Mortality appears to be affected by certain risk factors depending on drug types, exposure history, old age, and the presence of GERD. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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22 pages, 4477 KiB  
Article
Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest
by Eun-Sil Lee, Nayeon Kim, Joon Hee Kang, Aizhan Abdildinova, Seon-Hyeong Lee, Myung Hwi Lee, Nam Sook Kang, Tae-Sung Koo, Soo-Youl Kim and Young-Dae Gong
Pharmaceuticals 2022, 15(5), 502; https://doi.org/10.3390/ph15050502 - 20 Apr 2022
Cited by 3 | Viewed by 2323
Abstract
Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its [...] Read more.
Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound DGG200064 was tested in vivo through a xenograft mouse model of colorectal cancer using HCT116 cells. The in vivo results showed high cell growth inhibition efficacy. Our results confirmed that the newly synthesized DGG200064 inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, DGG200064 (GI50 = 12 nM in an HCT116 cell-based assay) induced G2/M arrest by selectively inhibiting the interaction of FBXW7 and c-Jun proteins. Additionally, the physicochemical properties of the lead compounds were analyzed. Based on the results of the study, we suggested further development of DGG200064 as a novel oral anti-colorectal cancer drug. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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22 pages, 10315 KiB  
Article
Comparative Studies on the Antioxidant, Antifungal, and Wound Healing Activities of Solenostemma arghel Ethyl Acetate and Methanolic Extracts
by Fatma F. Abdel-Motaal, Zainab M. Maher, Samah F. Ibrahim, Amany El-Mleeh, Maged Behery and Asmaa A. Metwally
Appl. Sci. 2022, 12(9), 4121; https://doi.org/10.3390/app12094121 - 19 Apr 2022
Cited by 9 | Viewed by 4658
Abstract
Various herbal compounds are used for medical purposes due to their safety, as there are no or minimal side effects. This study was performed to assess the wound healing and antioxidant activities of ethyl acetate (EtOAc) and methanolic extract (MeoH) of Solenostemma arghel [...] Read more.
Various herbal compounds are used for medical purposes due to their safety, as there are no or minimal side effects. This study was performed to assess the wound healing and antioxidant activities of ethyl acetate (EtOAc) and methanolic extract (MeoH) of Solenostemma arghel (S. arghel). Their antifungal activities were also evaluated against isolated swabs of equine wounds. They underwent GC-MS analysis for the characterization of both extracts. For wound healing evaluation, forty-five male albino rats were divided into three groups; the control group was treated with normal saline, and the other two groups were treated with S. arghel EtOAc and MeoH extract gels, respectively. The wounds were examined clinicopathologically and immunohistochemistry on the 3rd, 7th, and 14th days post-wounding. GC-Ms analysis of S. arghel recorded fifty-one volatile organic compounds (VOCs) within EtOAc extraction and thirty VOCs in MeoH extract. VOCs represented in EtOAc extract showed higher antioxidant activity and better and faster wound healing than VOCs of MeOH extract. The treated groups showed improved wound healing clinically and pathologically in comparison with the control group as they decreased the wound surface area (WSA) and percent (WSA%) and increased the wound contraction percent (WC%), epithelization, fibroblast proliferation with neovascularization, and reduced the inflammatory reaction. Moreover, the treated groups showed higher expression of vascular endothelial growth factor (VEGF) compared with the control. The EtOAc extract showed higher antifungal activity against Penicillium funiculosum, P. jensenii, M. cinctum, and Candida albicans, which were isolated from infected clinical equine wounds, than MeOH extract. The treated groups showed improved wound healing clinically and pathologically in comparison with the control group as they decreased the wound surface area (WSA) and percent (WSA%) and increased the wound contraction percent (WC%), epithelization, fibroblast proliferation with neovascularization, and reduced the inflammatory reaction. Moreover, the treated groups showed higher expression of vascular endothelial growth factor (VEGF) compared with the control. Additionally, the two extract gels showed promising healing of equine wounds. In conclusion, the study recommended the use of S. arghel EtOAc extract as it was proven to promote wound healing compared with MeoH extract. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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18 pages, 4342 KiB  
Article
Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway
by Dandan Chen, Yanan Duan, Shuxiang Yu, Xinwen Zhang, Ni Li and Jingya Li
Pharmaceuticals 2022, 15(4), 469; https://doi.org/10.3390/ph15040469 - 13 Apr 2022
Cited by 3 | Viewed by 2339
Abstract
Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, [...] Read more.
Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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20 pages, 1135 KiB  
Review
Recent Advances in Green Synthesis, Characterization, and Applications of Bioactive Metallic Nanoparticles
by Shabaaz J. P. Begum, S. Pratibha, Janhvi M. Rawat, Divya Venugopal, Prashant Sahu, Abhilash Gowda, Kamal A. Qureshi and Mariusz Jaremko
Pharmaceuticals 2022, 15(4), 455; https://doi.org/10.3390/ph15040455 - 08 Apr 2022
Cited by 46 | Viewed by 4865
Abstract
Nanoparticles (NPs) are elements derived from a cluster of atoms with one or more dimensions in the nanometer scale in the range of 1–100 nm. The bio nanofabrication of metallic NPs is now an important dynamic area of research, with major significance in [...] Read more.
Nanoparticles (NPs) are elements derived from a cluster of atoms with one or more dimensions in the nanometer scale in the range of 1–100 nm. The bio nanofabrication of metallic NPs is now an important dynamic area of research, with major significance in applied research. Biogenic synthesis of NPs is more desirable than physical and chemical synthesis due to its eco-friendliness, non-toxicity, lower energy consumption, and multifunctional nature. Plants outperform microorganisms as reducing agents as they contain large secondary biomolecules that accelerate the reduction and stability of the NPs. The produced NPs can then be studied spectroscopically (UV-Visible, XRD, Raman, IR, etc.) and microscopically (SEM, TEM, AFM, etc.). The biological reduction of a metallic ion or its oxide to a nanoparticle is quick, simple, and may be scaled up at room temperature and pressure. The rise in multi-drug resistant (MDR) microbes due to the immoderate use of antibiotics in non-infected patients is a major cause of morbidity and mortality in humans. The contemporary development of a new class of antibiotics with different mechanisms of action to kill microbes is crucial. Metals and their oxides are extremely toxic to microbes at unprecedentedly low concentrations. In addition, prevailing infections in plants and animals are raising significant concerns across the globe. NPs’ wide range of bioactivity makes them ideal antimicrobial agents in agricultural and medical fields. The present review outlines the synthesis of metallic NPs from botanicals, which enables the metals to be in a stabilized form even after ionization. It also presents a valuable database on the biofunctionalization of synthesized NPs for further drug development. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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7 pages, 1672 KiB  
Article
Biosynthesis of (±)-Differolide, an Antioxidant Isolate from Streptomyces qaidamensis S10T
by Yujie Wu, Wei Zhang, Kan Jiang, Xue Yu, Shiyu Wu, Guangxiu Liu and Tuo Chen
Appl. Sci. 2022, 12(8), 3741; https://doi.org/10.3390/app12083741 - 08 Apr 2022
Viewed by 1309
Abstract
Streptomyces from unexplored or underexplored environments may be an essential source of discoveries of bioactive molecules. One such example is Streptomyces qaidamensis S10T, which was isolated from a sand sample collected in Qaidam Basin, Qinghai Province, China. Here, we report [...] Read more.
Streptomyces from unexplored or underexplored environments may be an essential source of discoveries of bioactive molecules. One such example is Streptomyces qaidamensis S10T, which was isolated from a sand sample collected in Qaidam Basin, Qinghai Province, China. Here, we report on (±)-differolide, an antioxidant isolated from S. qaidamensis, and verified with scavenging experiments on 2,2-diphenyl-1-picrylhydrazyl (DPPH). The biosynthetic gene cluster responsible for synthesizing the compound was also identified using comparative genomic methods. These results provide a basis for further study of the biological activities of (±)-differolide, which also make it possible to develop as an antioxidant medicine. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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15 pages, 3778 KiB  
Article
Synthesis, Characterization and Biological Activities of New Schiff Base Compound and Its Lanthanide Complexes
by Abdel-Aziz Abu-Yamin, Maisa Siddiq Abduh, Sultan Ayesh Mohammed Saghir and Naif Al-Gabri
Pharmaceuticals 2022, 15(4), 454; https://doi.org/10.3390/ph15040454 - 07 Apr 2022
Cited by 31 | Viewed by 2763
Abstract
The thermal condensation of 3-(2-Furyl)acrolein with 2-Amino-6-ethoxybenzothiazole generated a new Schiff base, (1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-imine (L), with general formula of C16H14N2O2S. Also, a series of lanthanide complexes of gadolinium, samarium, and neodymium (La [...] Read more.
The thermal condensation of 3-(2-Furyl)acrolein with 2-Amino-6-ethoxybenzothiazole generated a new Schiff base, (1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-imine (L), with general formula of C16H14N2O2S. Also, a series of lanthanide complexes of gadolinium, samarium, and neodymium (LaLc) were synthesized utilizing acetonitrile as the solvent and triethylamine as a buffer and catalyst. Based on elemental analysis, mass spectroscopy, and FTIR analysis, all of the Bis-(1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-iminetri-nitratolanthanide(III) complexes with the general formula [LnL2(NO3)3]·H2O are solids with a 2:1 molar ratio (ligand: metal). Based on conductivity estimates, they are nonelectrolytes and monoatomic paramagnetic according to the magnetic moment measurements, and one mole of lattice water was found after thermal gravimetric measurements and FTIR analysis. Therefore, the lanthanide complexes show a ten-coordination structure with a deformed bicapped square antiprismatic. The Schiff base and its complexes were screened for their antimicrobial, antifungal, antioxidant, and antitumor properties. Their antimicrobial and antifungal activities were strong, and they also produced good antioxidant and antitumor effects. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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17 pages, 1929 KiB  
Article
Antibacterial Fractions from Erodium cicutarium Exposed—Clinical Strains of Staphylococcus aureus in Focus
by Vanja Ljoljić Bilić, Uroš M. Gašić, Dušanka Milojković-Opsenica, Hrvoje Rimac, Jadranka Vuković Rodriguez, Josipa Vlainić, Diana Brlek-Gorski and Ivan Kosalec
Antibiotics 2022, 11(4), 492; https://doi.org/10.3390/antibiotics11040492 - 06 Apr 2022
Cited by 2 | Viewed by 2242
Abstract
Followed by a buildup of its phytochemical profile, Erodium cicutarium is being subjected to antimicrobial investigation guided with its ethnobotanical use. The results of performed in vitro screening on Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans strains, show that E. cicutarium [...] Read more.
Followed by a buildup of its phytochemical profile, Erodium cicutarium is being subjected to antimicrobial investigation guided with its ethnobotanical use. The results of performed in vitro screening on Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans strains, show that E. cicutarium has antimicrobial activity, with a particular emphasis on clinical S. aureus strains—both the methicillin sensitive (MSSA) and the methicillin resistant (MRSA) S. aureus. Experimental design consisted of general methods (the serial microdilution broth assay and the agar well diffusion assay), as well as observing bactericidal/bacteriostatic activity through time (the “time-kill” assay), investigating the effect on cell wall integrity and biofilm formation, and modulation of bacterial hemolysis. Observed antibacterial activity from above-described methods led to further activity-guided fractionation of water and methanol extracts using bioautography coupled with UHPLC-LTQ OrbiTrap MS4. It was determined that active fractions are predominantly formed by gallic acid derivatives and flavonol glycosides. Among the most active phytochemicals, galloyl-shikimic acid was identified as the most abundant compound. These results point to a direct connection between galloyl-shikimic acid and the observed E. cicutarium antibacterial activity, and open several new research approaches for future investigation. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 1600 KiB  
Article
Discovery of 5,7-Dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one with Lipid Lowering Effects in Hepatocytes
by Yi-Han Chang, Chia-Hung Yen, Chih-Chung Lai, Hsuan-Yu Lai and Hsin-Yi Hung
Pharmaceuticals 2022, 15(4), 449; https://doi.org/10.3390/ph15040449 - 04 Apr 2022
Cited by 1 | Viewed by 1863
Abstract
The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a [...] Read more.
The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a 2-phenoxychromone originating from Artemisia capillaris Thunb., is well-known for its liver-protective effects. As a result, a series of 2-phenoxychromones was prepared and evaluated for its protective activity against lipid droplet formation in oleic acid (OA)-treated Huh7 cells by means of high-content screening. In the light of the results, the compounds with trimethoxy groups on the phenyl ring possessed better inhibitory properties against lipid accumulation in Huh7 cells, compared to other functional groups on the same ring. Nonetheless, the compounds with a hydroxy group at the C-5 position of the chromone exhibited apparent cytotoxicity. Finally, the active compound, 5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (7e), with an IC50 value of 32.2 ± 2.1 μM against lipid accumulation and no significant cytotoxicity, reduced the accumulation of lipid droplets by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) to facilitate the catabolism of fat, which shows promise for further optimization to manage NAFLD and NASH. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 3755 KiB  
Article
Preclinical Efficacy and Toxicity Analysis of the Pan-Histone Deacetylase Inhibitor Gossypol for the Therapy of Colorectal Cancer or Hepatocellular Carcinoma
by Mascha Mayer, Alexander Berger, Christian Leischner, Olga Renner, Markus Burkard, Alexander Böcker, Seema Noor, Timo Weiland, Thomas S. Weiss, Christian Busch, Ulrich M. Lauer, Stephan C. Bischoff and Sascha Venturelli
Pharmaceuticals 2022, 15(4), 438; https://doi.org/10.3390/ph15040438 - 01 Apr 2022
Cited by 5 | Viewed by 2696
Abstract
Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors [...] Read more.
Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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16 pages, 2700 KiB  
Article
A Novel Allosteric Inhibitor Targets PLK1 in Triple Negative Breast Cancer Cells
by Jankiben R. Patel, Prasad Thangavelu, Renee M. Terrell, Bridg’ette Israel, Arindam Basu Sarkar, A. Michael Davidson, Kun Zhang, Rahul Khupse and Syreeta L. Tilghman
Biomolecules 2022, 12(4), 531; https://doi.org/10.3390/biom12040531 - 31 Mar 2022
Cited by 3 | Viewed by 2312
Abstract
While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 [...] Read more.
While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 allosteric inhibitor targeting the PLK1 T-loop (a switch responsible for activation) and evaluate its effects in triple-negative breast cancer cells. A novel compound, RK-10, was developed based on an in silico model, and its effects on specificity, viability, migration, and cell cycle regulation in MCF-10A and MDA-MB 231 cells were evaluated. When MDA-MB 231 cells were treated with 0–50 µg/mL RK-10, phospho-PLK1 (Thr-210) was decreased in cells cultured adherently and cells cultured as mammospheres. RK-10 significantly inhibited viability after 24 h; however, by 48 h, 25–50 µM RK-10 caused >50% reduction. RK-10 attenuated wound healing by up to 99.7% and caused S and G2/M cell cycle arrest, which was associated with increased p21 expression. We developed a novel allosteric inhibitor which mediates anti-proliferative and anti-migratory properties through targeting phospho-PLK1 (Thr-210) in mammospheres and causing S phase and G2/M cell cycle arrest. Further development of PLK1 allosteric inhibitors may be a promising approach for TNBC treatment. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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10 pages, 1633 KiB  
Article
Rosmarinic Acid Attenuates the Lipopolysaccharide-Provoked Inflammatory Response of Vascular Smooth Muscle Cell via Inhibition of MAPK/NF-κB Cascade
by Ching-Pei Chen, You-Cian Lin, Yu-Hui Peng, Han-Min Chen, Jiun-Tsai Lin and Shao-Hsuan Kao
Pharmaceuticals 2022, 15(4), 437; https://doi.org/10.3390/ph15040437 - 31 Mar 2022
Cited by 8 | Viewed by 2289
Abstract
Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflammatory and antioxidant activities. Here, we further investigate the anti-inflammatory effect of RA on rat A7r5 aortic smooth muscle cells with exposure to lipopolysaccharide (LPS). Our findings showed that low-dose [...] Read more.
Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflammatory and antioxidant activities. Here, we further investigate the anti-inflammatory effect of RA on rat A7r5 aortic smooth muscle cells with exposure to lipopolysaccharide (LPS). Our findings showed that low-dose RA (10–25 μM) did not influence the cell viability and morphology of A7r5 cells and significantly inhibited LPS-induced mRNA expression of the pro-inflammatory mediators TNFα, IL-8, and inducible NO synthase (iNOS). Consistently, RA reduced the production of TNFα, IL-8, and NO by A7r5 cells with exposure to LPS. Signaling cascade analysis showed that LPS induced activation of Erk, JNK, p38 mitogen-activated protein kinase (MAPK), and NF-κB, and RA treatments attenuated the activation of the three MAPKs and NF-κB. Moreover, cotreatment with RA and Erk, JNK, p38 MAPK, or NF-κB inhibitors further downregulated the mRNA expression of TNFα, IL-8, and iNOS, and decreased the production of TNFα, IL-8, and NO by A7r5 cells. Taken together, these findings indicate that RA may ameliorate the LPS-provoked inflammatory response of vascular smooth muscle cells by inhibition of MAPK/NF-κB signaling. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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14 pages, 3436 KiB  
Article
ZLN005 Alleviates In Vivo and In Vitro Renal Fibrosis via PGC-1α-Mediated Mitochondrial Homeostasis
by Pengfei Zhu, Haijian Ma, Shichao Cui, Xiqiao Zhou, Weilong Xu, Jiangyi Yu and Jingya Li
Pharmaceuticals 2022, 15(4), 434; https://doi.org/10.3390/ph15040434 - 31 Mar 2022
Cited by 7 | Viewed by 2763
Abstract
Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the [...] Read more.
Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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34 pages, 1758 KiB  
Review
Insights into Recent Studies on Biotransformation and Pharmacological Activities of Ginsenoside Rd
by Xiaoping Song, Lina Wang and Daidi Fan
Biomolecules 2022, 12(4), 512; https://doi.org/10.3390/biom12040512 - 28 Mar 2022
Cited by 12 | Viewed by 3591
Abstract
It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities [...] Read more.
It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities of Rd—as a potential treatment for a variety of diseases—have been published. However, no specific, comprehensive reviews have been documented to date. The present review not only summarizes the in vitro and in vivo studies on the health benefits of Rd, including anti-cancer, anti-diabetic, anti-inflammatory, neuroprotective, cardioprotective, ischemic stroke, immunoregulation, and other pharmacological effects, it also delves into the inclusion of potential molecular mechanisms, providing an overview of future prospects for the use of Rd in the treatment of chronic metabolic diseases and neurodegenerative disorders. Although biotransformation, pharmacokinetics, and clinical studies of Rd have also been reviewed, clinical trial data of Rd are limited; the only data available are for its treatment of acute ischemic stroke. Therefore, clinical evidence of Rd should be considered in future studies. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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13 pages, 1162 KiB  
Article
The Novel Analogue of Modafinil CE-158 Protects Social Memory against Interference and Triggers the Release of Dopamine in the Nucleus Accumbens of Mice
by Karl Ebner, Simone B. Sartori, Rita Murau, Fabian Kopel, Predrag Kalaba, Vladimir Dragačević, Johann J. Leban, Nicolas Singewald, Mario Engelmann and Gert Lubec
Biomolecules 2022, 12(4), 506; https://doi.org/10.3390/biom12040506 - 27 Mar 2022
Cited by 4 | Viewed by 2527
Abstract
Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male [...] Read more.
Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male mice. Systemic administration of CE-158 1 h before the social learning event prevented the impairment of social-recognition memory following retroactive interference 3 h after the learning session of a juvenile conspecific. This effect was dose-dependent, as mice treated with 10 mg/kg, but not with 1 mg/kg CE-158, were able to discriminate between the novel and familiar conspecific despite the presentation of an interference stimulus, both 3 h and 6 h post learning. However, when 10 mg/kg of the drug was administered after learning, CE-158 failed to prevent social memory from interference. Paralleling these behavioral effects, the systemic administration of 10 mg/kg CE-158 caused a rapid and sustained elevation of extracellular dopamine in the nucleus accumbens, a brain area where dopaminergic signaling plays a key role in learning and memory function, of freely moving mice, while 1 mg/kg was not sufficient for altering dopamine levels. Taken together, our findings suggest promnestic effects of the novel dopamine-transporter-inhibitor CE-158 in a social recognition memory test that may be in part mediated via increased dopamine-neurotransmission in the nucleus accumbens. Thus, selective-dopamine-transporter-inhibitors such as CE-158 may represent interesting drug candidates for the treatment of memory complaints observed in humans with cognitive impairments and dementia. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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15 pages, 1550 KiB  
Article
Natural Phaeosphaeride A Derivatives Overcome Drug Resistance of Tumor Cells and Modulate Signaling Pathways
by Victoria Abzianidze, Natalia Moiseeva, Diana Suponina, Sofya Zakharenkova, Nadezhda Rogovskaya, Lidia Laletina, Alvin A. Holder, Denis Krivorotov, Alexander Bogachenkov, Alexander Garabadzhiu, Anton Ukolov and Vyacheslav Kosorukov
Pharmaceuticals 2022, 15(4), 395; https://doi.org/10.3390/ph15040395 - 24 Mar 2022
Cited by 2 | Viewed by 2088
Abstract
In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds [...] Read more.
In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds on the activation of intracellular kinase cascades in A431 cells. MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex was used, which allowed for the simultaneous detection of the following nine phosphorylated protein markers of the main intracellular signaling pathways: a universal transcription factor that controls the expression of immune-response genes, apoptosis and cell cycle NFκB (pS536); cAMP-dependent transcription factor (CREB (pS133); mitogen-activated kinase p38 (pT180/pY182); stress-activated protein kinase JNK (pT183/pY185); ribosomal SK; transcription factors STAT3 (pS727) and STAT5A/B (pY694/699); protein kinase B (Akt) (pS473); and kinase regulated by extracellular signals ERK1/2 (pT185/pY187). The effect of various concentrations of PPA derivatives on the cell culture was studied using xCelligence RTCA equipment. The compounds were found to modulate JNK, ERK1/2, and p38 signaling pathways. The set of activated kinase cascades suggests that oxidative stress is the main probable mechanism of the toxic action of PPA derivatives. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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9 pages, 1102 KiB  
Article
Juniper communis L. Essential Oils from Western Romanian Carpathians: Bio-Structure and Effective Antibacterial Activity
by Eugenia Dumitrescu, Florin Muselin, Carmen S. Dumitrescu, Sergiu A. Orasan-Alic, Răzvan F. Moruzi, Alexandru O. Doma, Erieg A. Mohamed and Romeo T. Cristina
Appl. Sci. 2022, 12(6), 2949; https://doi.org/10.3390/app12062949 - 14 Mar 2022
Cited by 5 | Viewed by 2688
Abstract
The antibacterial activity of four bacterial standard strains that are naturally encountered in humans and animals was investigated by using bioactive compounds from commercial essential oils of Juniperus communis that were collected from the Western Romanian Carpathians. The Juniper communis essential oils, volatile [...] Read more.
The antibacterial activity of four bacterial standard strains that are naturally encountered in humans and animals was investigated by using bioactive compounds from commercial essential oils of Juniperus communis that were collected from the Western Romanian Carpathians. The Juniper communis essential oils, volatile compounds, were recognized through the GC–MS methodology by comparing identified spectra with those held in the NIST 02, Wiley 275 library. The ratio of each component was calculated based on the peak areas of the GC, without utilizing correction factors. The CLSI standardized micro-dilution was used to determine antimicrobial activity, employing 10−3 dilutions of fresh culture, with inoculums equivalent to a standard of 0.5 McFarland being prepared for testing. Four bacterial strains, Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Streptococcus pyogenes (ATCC 19615), were investigated, using 96-well micro-dilution plates. Over each micro-dilution well, the essential oils were poured, introducing gradually 2, 4, 8, and 10 µL/well, respectively. The results were expressed as ±SEM and analyzed by one-way ANOVA with Bonferroni’s multiple comparison test, considering the differences statistically provided when p < 0.05 or lower. The juniper essential oil originating from the Western Romanian Carpathians is rich in four main volatile compounds: β-pinene (34.02%), 1α-pinene (30.43%), p-cymol (20.25%), and β-myrcene (10.20%). The juniper communis essential oil reduced bacterial density for all four strains tested, but compared to Gram-negative bacteria, in our case; a considerably higher antibacterial effectiveness was detected for Gram-positives, with peak reduction of Staphylococcus aureus, recommending the Romanian essential oil as a beneficial antibacterial resource. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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18 pages, 4861 KiB  
Article
Discovery of APL-1030, a Novel, High-Affinity Nanofitin Inhibitor of C3-Mediated Complement Activation
by Joshua Garlich, Mathieu Cinier, Anne Chevrel, Anaëlle Perrocheau, David J. Eyerman, Mark Orme, Olivier Kitten and Lukas Scheibler
Biomolecules 2022, 12(3), 432; https://doi.org/10.3390/biom12030432 - 11 Mar 2022
Cited by 6 | Viewed by 3832
Abstract
Uncontrolled complement activation contributes to multiple immune pathologies. Although synthetic compstatin derivatives targeting C3 and C3b are robust inhibitors of complement activation, their physicochemical and molecular properties may limit access to specific organs, development of bifunctional moieties, and therapeutic applications requiring transgenic expression. [...] Read more.
Uncontrolled complement activation contributes to multiple immune pathologies. Although synthetic compstatin derivatives targeting C3 and C3b are robust inhibitors of complement activation, their physicochemical and molecular properties may limit access to specific organs, development of bifunctional moieties, and therapeutic applications requiring transgenic expression. Complement-targeting therapeutics containing only natural amino acids could enable multifunctional pharmacology, gene therapies, and targeted delivery for underserved diseases. A Nanofitin library of hyperthermophilic protein scaffolds was screened using ribosome display for C3/C3b-targeting clones mimicking compstatin pharmacology. APL-1030, a recombinant 64-residue Nanofitin, emerged as the lead candidate. APL-1030 is thermostable, binds C3 (KD, 1.59 nM) and C3b (KD, 1.11 nM), and inhibits complement activation via classical (IC50 = 110.8 nM) and alternative (IC50 = 291.3 nM) pathways in Wieslab assays. Pharmacologic activity (determined by alternative pathway inhibition) was limited to primate species of tested sera. C3b-binding sites of APL-1030 and compstatin were shown to overlap by X-ray crystallography of C3b-bound APL-1030. APL-1030 is a novel, high-affinity inhibitor of primate C3-mediated complement activation developed from natural amino acids on the hyperthermophilic Nanofitin platform. Its properties may support novel drug candidates, enabling bifunctional moieties, gene therapy, and tissue-targeted C3 pharmacologics for diseases with high unmet need. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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14 pages, 2154 KiB  
Review
Assessment of Avermectins-Induced Toxicity in Animals
by Muhammad Salman, Rao Zahid Abbas, Khalid Mehmood, Riaz Hussain, Sehar Shah, Mehwish Faheem, Tean Zaheer, Asghar Abbas, Bernardo Morales, Ina Aneva and José L. Martínez
Pharmaceuticals 2022, 15(3), 332; https://doi.org/10.3390/ph15030332 - 09 Mar 2022
Cited by 20 | Viewed by 5544
Abstract
Macrocyclic lactones, particularly the avermectins, have completely revolutionized the approaches aimed at control of parasites. These avermectins are the most widely used anti-parasitic drugs in veterinary field with sales exceeding one billion US dollars annually. However, before clinical usage, their safety evaluation in [...] Read more.
Macrocyclic lactones, particularly the avermectins, have completely revolutionized the approaches aimed at control of parasites. These avermectins are the most widely used anti-parasitic drugs in veterinary field with sales exceeding one billion US dollars annually. However, before clinical usage, their safety evaluation in the animals is a major critical factor that must be considered. Many studies have reported the negative effects of avermectins like ivermectin, abamectin, doramectin, and eprinomectin on the host animals. These harmful effects arise from avermectins targeting GABA and glutamate-gated chloride channels present both in the parasites and the host animals. In this review, various modes of avermectins action along with the negative effects on the host like nephrotoxicity, hepatotoxicity, neurotoxicity, reproductive toxicity, and endocrine disruption were discussed in detail. Furthermore, other important issues like ecotoxicity, drug resistance, and drug residues in milk associated with avermectins usage were also discussed, which need special attention. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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11 pages, 1483 KiB  
Article
Investigation of the Quality of the 12 Most-Used Antibiotics Available in Retail Private Pharmacies in Rwanda
by Thomas Bizimana, Védaste Kagisha, Jean Baptiste Nyandwi, Alain Katembezi Nyirimigabo, Raymond Muganga, Marie Françoise Mukanyangezi and Egide Kayitare
Antibiotics 2022, 11(3), 329; https://doi.org/10.3390/antibiotics11030329 - 02 Mar 2022
Cited by 2 | Viewed by 3697
Abstract
Using poor-quality antibiotics leads to increased risk of the development of microorganism-resistant strains, treatment failure, loss of confidence in health systems, and associated socio-economic impacts. The prevalence of poor-quality antibiotics has been found to be high in some of the Low and Middle-Income [...] Read more.
Using poor-quality antibiotics leads to increased risk of the development of microorganism-resistant strains, treatment failure, loss of confidence in health systems, and associated socio-economic impacts. The prevalence of poor-quality antibiotics has been found to be high in some of the Low and Middle-Income Countries (LMICs), but no data were available on the situation in Rwanda. This study was conducted to obtain data and inform health professionals on the quality of the 12 most-used selected antibiotics from private retail pharmacies in Rwanda. The investigation was conducted on 232 batches collected from randomly selected private retail pharmacies in all provinces of Rwanda, and concerned only with visual inspection and assay tests. Visual inspection was performed using a tool adopted by the International Pharmaceutical Federation (FIP) to identify manufacturing defects. An assay test quantified the Active Pharmaceutical Ingredient (API) in each collected batch using high-performance liquid chromatography (HPLC) coupled with an ultraviolet-visible (UV) detector, and the results were reported as the percentage content of the amount of APIs stated on the label. A total of 232 batches were analyzed, manufactured in 10 countries; the main country of manufacture was Kenya, with almost half of the batches (49.6%). The results of the visual inspection did not show the presence of counterfeit/ falsified antibiotics on the Rwandan market in this study but revealed weaknesses in labeling: more than 90% of the analyzed batches of the 12 antibiotics did not present the dosage statement on their label, and the complete list of excipients was missing in more than 20% of the analyzed batches. The assay test using HPLC confirmed the presence of APIs in 100% of the analyzed batches. However, moderate deviations from acceptable ranges of the API content defined by M. M. Nasr & C. M. Stanley in 2006 for erythromycin and the United States Pharmacopoeia 2018 for the other 11 molecules were found. The failure rate to meet the quality requirements in terms of the percentage content of active pharmaceutical ingredients declared on the labels was estimated at 8.2% in total, with 3.9% and 4.3% containing more and less than the amount of APIs stated on the labels respectively. The most-represented antibiotics on the Rwandan market were amoxicillin, co-trimoxazole and cloxacillin. No counterfeit antibiotics were found in this study. However, substandard batches with moderate deviations were found, suggesting that regular quality control of antibiotics is needed in Rwanda. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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25 pages, 11596 KiB  
Review
Staphyloxanthin as a Potential Novel Target for Deciphering Promising Anti-Staphylococcus aureus Agents
by Rana A. Elmesseri, Sarra E. Saleh, Heba M. Elsherif, Ibrahim S. Yahia and Khaled M. Aboshanab
Antibiotics 2022, 11(3), 298; https://doi.org/10.3390/antibiotics11030298 - 23 Feb 2022
Cited by 17 | Viewed by 3322
Abstract
Staphylococcus aureus is a fatal Gram-positive pathogen threatening numerous cases of hospital-admitted patients worldwide. The emerging resistance of the pathogen to several antimicrobial agents has pressurized research to propose new strategies for combating antimicrobial resistance. Novel strategies include targeting the virulence factors of [...] Read more.
Staphylococcus aureus is a fatal Gram-positive pathogen threatening numerous cases of hospital-admitted patients worldwide. The emerging resistance of the pathogen to several antimicrobial agents has pressurized research to propose new strategies for combating antimicrobial resistance. Novel strategies include targeting the virulence factors of S. aureus. One of the most prominent virulence factors of S. aureus is its eponymous antioxidant pigment staphyloxanthin (STX), which is an auspicious target for anti-virulence therapy. This review provides an updated outline on STX and multiple strategies to attenuate this virulence factor. The approaches discussed in this article focus on bioprospective and chemically synthesized inhibitors of STX, inter-species communication and genetic manipulation. Various inhibitor molecules were found to exhibit appreciable inhibitory effect against STX and hence would be able to serve as potential anti-virulence agents for clinical use. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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19 pages, 3223 KiB  
Article
Solids Turn into Liquids—Liquid Eutectic Systems of Pharmaceutics to Improve Drug Solubility
by Mafalda C. Sarraguça, Paulo R. S. Ribeiro, Cláudia Nunes and Catarina Leal Seabra
Pharmaceuticals 2022, 15(3), 279; https://doi.org/10.3390/ph15030279 - 23 Feb 2022
Cited by 7 | Viewed by 2291
Abstract
The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is [...] Read more.
The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non-toxicity, biodegradability, and being non-expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes mellitus and have low solubility in water. To prepare the THELES, several coformers were tested, namely, tromethamine, L(+)-arginine, L-tryptophan, citric acid, malic acid, ascorbic acid, and p-aminobenzoic acid, in molar ratios of 1:1 and 1:2. To improve viscosity, water was added in different molar ratios to all systems. THELES were characterized by mid-infrared spectroscopy (MIR), and differential scanning calorimetry. Their viscosity, solubility, and permeability were also determined. Their stability at room temperature and 40 °C was accessed by MIR. Cytocompatibility was performed by metabolic activity and cell lysis evaluation, according to ISO10993-5:2009, and compared with the crystalline APIs. THELES with TRIS were successfully synthesized for both APIs. Results showed an increased solubility without a decrease in the permeability of the APIs in the THELES when compared with the pure APIs. The THELES were also considered stable for 8 weeks at ambient temperature. The cells studied showed that the THELES were not toxic for the cell lines used. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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35 pages, 9600 KiB  
Article
Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition
by Mater H. Mahnashi, Fardous F. El-Senduny, Mohammed Abdulrahman Alshahrani and Mahrous A. Abou-Salim
Pharmaceuticals 2022, 15(2), 246; https://doi.org/10.3390/ph15020246 - 18 Feb 2022
Cited by 7 | Viewed by 2432
Abstract
Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 [...] Read more.
Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12ac and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC50 values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC50 = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC50 = 0.049 µM). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic BCL-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer’s rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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19 pages, 2733 KiB  
Article
Zinc-Substituted Pheophorbide A Is a Safe and Efficient Antivascular Photodynamic Agent
by Milena J. Szafraniec, Monika Toporkiewicz and Andrzej Gamian
Pharmaceuticals 2022, 15(2), 235; https://doi.org/10.3390/ph15020235 - 16 Feb 2022
Cited by 4 | Viewed by 1917
Abstract
The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to [...] Read more.
The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to cancer cells, which may necessitate the use of relatively high doses. Here we show that zinc pheophorbide a is very effective against vascular endothelial cells, even in its albumin-complexed form. Albumin complexation increases the lysosomal accumulation of the drug, thus enhancing its efficiency. Zinc pheophorbide a at nanomolar concentrations induces endothelial cell death via apoptosis, which in many cases is considered a desirable cell death mode because of its anti-inflammatory effect. Additionally, we demonstrate that in comparison to tumor cells, endothelial cells are much more susceptible to photodynamic treatment with the use of the investigated compound. Our findings demonstrate that zinc pheophorbide a is a very promising photosensitizer for use in vascular-targeted photodynamic therapy against solid tumors, acting as a vascular shutdown inducer. It can also possibly find application in the treatment of a range of vascular disorders. Numerous properties of zinc pheophorbide a are comparable or even more favorable than those of the well-known photosensitizer of a similar structure, palladium bacteriopheophorbide (TOOKAD®). Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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14 pages, 3961 KiB  
Article
Carpaine Promotes Proliferation and Repair of H9c2 Cardiomyocytes after Oxidative Insults
by Suhaini Sudi, Yee-Zheng Chin, Nur Syafinaz Wasli, Siat-Yee Fong, Sadia Choudhury Shimmi, Siew-Eng How and Caroline Sunggip
Pharmaceuticals 2022, 15(2), 230; https://doi.org/10.3390/ph15020230 - 15 Feb 2022
Cited by 3 | Viewed by 2410
Abstract
Carpaine has long been identified as the major alkaloid in Carica papaya leaves that possess muscle relaxant properties. Limited study on the molecular signaling properties of carpaine urges us to conduct this study that aims to elucidate the mechanism underlying the cardioprotective effect [...] Read more.
Carpaine has long been identified as the major alkaloid in Carica papaya leaves that possess muscle relaxant properties. Limited study on the molecular signaling properties of carpaine urges us to conduct this study that aims to elucidate the mechanism underlying the cardioprotective effect of carpaine in embryonic cardiomyocytes of the H9c2 cell line. The 50% inhibitory concentration (IC50) of carpaine was first determined using a colorimetric MTT assay to establish the minimum inhibitory concentration for the subsequent test. Using a 1 µM carpaine treatment, a significant increase in the H9c2 proliferation rate was observed following 24 and 48 h of incubation. A Western blot analysis also revealed that carpaine promotes the upregulation of the cell cycle marker proteins cyclin D1 and PCNA. Carpaine-induced H9c2 cell proliferation is mediated by the activation of the FAK-ERK1/2 and FAK-AKT signaling pathways. In the setting of ischemia-reperfusion injury (IRI), carpaine provided a significant protective role to recover the wounded area affected by the hydrogen peroxide (H2O2) treatment. Furthermore, the oxidative-stress-induced reduction in mitochondrial membrane potential (MMP) and overproduction of reactive oxygen species (ROS) were attenuated by carpaine treatment. The current study revealed a novel therapeutic potential of carpaine in promoting in vitro cardiomyocyte proliferation and repair following injury. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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16 pages, 2309 KiB  
Review
Novel Nutraceutical Compounds in Alzheimer Prevention
by Ricardo Benjamin Maccioni, Camila Calfío, Andrea González and Valentina Lüttges
Biomolecules 2022, 12(2), 249; https://doi.org/10.3390/biom12020249 - 03 Feb 2022
Cited by 21 | Viewed by 6547
Abstract
Alzheimer’s disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative [...] Read more.
Alzheimer’s disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean shilajit. Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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13 pages, 1496 KiB  
Article
Myricetin Increases Circulating Adropin Level after Activation of Glucagon-like Peptide 1 (GLP-1) Receptor in Type-1 Diabetic Rats
by Ying-Xiao Li, Kai-Chun Cheng, I-Min Liu and Ho-Shan Niu
Pharmaceuticals 2022, 15(2), 173; https://doi.org/10.3390/ph15020173 - 31 Jan 2022
Cited by 5 | Viewed by 2883
Abstract
Myricetin is a common plant-derived flavonoid, considered an agonist of glucagon-like peptide 1 (GLP-1) receptor. It improves glycemic control and helps reduce body weight in diabetic subjects. The potential mechanisms of action of myricetin in this context might be enhancing the secretion of [...] Read more.
Myricetin is a common plant-derived flavonoid, considered an agonist of glucagon-like peptide 1 (GLP-1) receptor. It improves glycemic control and helps reduce body weight in diabetic subjects. The potential mechanisms of action of myricetin in this context might be enhancing the secretion of β-endorphin (BER) to activate peripheral μ-opioid receptors. Moreover, adropin is a nutritionally regulated peptide hormone, which regulates energy metabolism, and plays a role in ameliorating diabetes. Because their mechanisms of insulin sensitivity are closely related, we hypothesized that myricetin may interact with adropin and plasma BER. The present study investigated the glucose-lowering effect of acute and chronic treatments of myricetin in type-1 diabetic rats. Plasma BER and adropin levels were determined by enzyme-linked immunosorbent assay (ELISA). The secretion of BER was measured in rats who received adrenalectomy. The changes in adropin gene (Enho) or mRNA level of GLP-1 receptor were measured using qPCR analysis. The results showed that myricetin dose-dependently increased plasma BER and adropin levels like the reduction of hyperglycemia after bolus injection as acute treatment. In addition, these effects of myricetin were inhibited by the antagonist of GLP-1 receptor. Moreover, in HepG2 cell line, myricetin induced GLP-1 receptor activation, which modulated the expression of adropin. In diabetic rats, the plasma adropin increased by myricetin is mainly through endogenous β-endorphin after activation of GLP-1 receptor via bolus injection as acute treatment. Additionally, chronic treatment with myricetin increased adropin secretion in diabetic rats. In conclusion, our results provide a new finding that activation of opioid μ-receptor in the liver may enhance circulating adropin in animals. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 60464 KiB  
Article
Two Red Sea Sponge Extracts (Negombata magnifica and Callyspongia siphonella) Induced Anticancer and Antimicrobial Activity
by Hussein A. El-Naggar, Mansour A. E. Bashar, Islam Rady, Mohammad S. El-Wetidy, Waleed B. Suleiman, Fatimah O. Al-Otibi, Sara A. Al-Rashed, Lamiaa M. Abd El-Maoula, El-Sayed S. Salem, Enas M. H. Attia and Sayed Bakry
Appl. Sci. 2022, 12(3), 1400; https://doi.org/10.3390/app12031400 - 28 Jan 2022
Cited by 12 | Viewed by 3238
Abstract
Bioactive compounds extracted from marine organisms showed several biological activities. The present study is an extension of our earlier studies where we assessed the antiproliferative and pro-apoptotic activities of ethanol, methylene chloride, ethyl acetate, acetone, and chloroform crude extracts of sponges: Negombata magnifica [...] Read more.
Bioactive compounds extracted from marine organisms showed several biological activities. The present study is an extension of our earlier studies where we assessed the antiproliferative and pro-apoptotic activities of ethanol, methylene chloride, ethyl acetate, acetone, and chloroform crude extracts of sponges: Negombata magnifica (NmE) and Callyspongia siphonella (CsE) against cancer cells. Herein, we are extending our previous findings on both sponge species depending on an alternative methanol extraction method with more advanced molecular biochemical insights as additional proof for anticancer and antimicrobial activity of N. magnifica and C. siphonella. Therefore, sponge specimens were collected during winter 2020 from the Dahab region at the Gulf of Aqaba. Each sponge was macerated with methanol to obtain the crude extracts; NmE and CsE. GC–MS analysis presented a total of 117 chemical compounds; 37 bioactive, 11 represented previously as constituents for a natural organism, and 69 had no biological activities. NmE dose-dependently inhibited the growth of HepG2, MCF-7, and Caco-2 carcinoma cell lines compared to CsE, which unfortunately has no antiproliferative activity against the same cancer cells. NmE was found to induce G0/G1 cell cycle arrest in HepG2 cells with its inhibition for CDK6, Cyclins D1, and E1 in HepG2, MCF-7, and Caco-2 cells. NmE also activated ROS production in HepG2 cells and induced apoptosis in HepG2, MCF-7, and Caco-2 cells via an increase in pro-apoptotic protein Bax, caspase-3, and cleavage PARP, and a decrease in anti-apoptotic protein BCL2. Unlike its anticancer potential, CsE exhibited clear superior results as an antimicrobial agent with a wider range against six microbial strains, whereas NmE showed a positive antibacterial activity against only two strains. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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10 pages, 7939 KiB  
Article
Treatment of Bone Defects Resulted after Excision of Enchondroma of the Hand in 15 Patients, Comparing the Techniques of Autologous Bone Graft, Injectable Bone Substitute and Spontaneous Healing
by Petru Ciobanu, Andrian Panuta, Iulian Radu, Norin Forna, Stefanita Arcana, Razvan Tudor, Alexandru Covaciu, Victor Niculescu, Vladimir Poroch and Bogdan Puha
Appl. Sci. 2022, 12(3), 1300; https://doi.org/10.3390/app12031300 - 26 Jan 2022
Cited by 3 | Viewed by 5054
Abstract
Background: Enchondroma is the most common benign bone tumor of the hand. Surgical excision of the tumor using curettage is the treatment of choice. The management of the resulting defects is still a controversial topic in the literature. Methods: This retrospective study includes [...] Read more.
Background: Enchondroma is the most common benign bone tumor of the hand. Surgical excision of the tumor using curettage is the treatment of choice. The management of the resulting defects is still a controversial topic in the literature. Methods: This retrospective study includes 15 patients diagnosed with solitary enchondroma in the hand bones: eight cases with type A, three cases with type B and four cases with type D according to Takigawa classification. The aim of this study was to compare the course and outcome in the three patient groups treated by curettage associated with natural consolidation of the bone defect, autologous bone graft or injectable synthetic bone substitute in association with plate and screw osteosynthesis. Results: Outcomes were assessed using the DASH score (mean score 2.5) and TAM score (excellent in all patients) with no significant functional differences between the three groups. Defects managed with k-IBS® injectable bone substitute were associated with shorter operating time, simpler surgical technique and less postoperative pain assessed by VAS score. Conclusion: The use of k-IBS® bone substitute is efficient and less technically demanding than autologous bone grafting. The Takigawa classification could be a good indicator for treatment choice. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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19 pages, 3039 KiB  
Article
Aescin Protects against Experimental Benign Prostatic Hyperplasia and Preserves Prostate Histomorphology in Rats via Suppression of Inflammatory Cytokines and COX-2
by Mohamed Raafat, Amr A. Kamel, Alaa H. Shehata, Al-Shaimaa F. Ahmed, Asmaa M. A. Bayoumi, Rabab A. Moussa, Mohammed A. S. Abourehab and Mahmoud El-Daly
Pharmaceuticals 2022, 15(2), 130; https://doi.org/10.3390/ph15020130 - 22 Jan 2022
Cited by 13 | Viewed by 4347
Abstract
Background: Benign prostatic hyperplasia (BPH) is the most common urogenital condition in aging males, while inflammation and tissue proliferation constitute the main pathophysiological factors. The adverse effects of currently available BPH medications limit patient compliance. We tested the protective effect of aescin against [...] Read more.
Background: Benign prostatic hyperplasia (BPH) is the most common urogenital condition in aging males, while inflammation and tissue proliferation constitute the main pathophysiological factors. The adverse effects of currently available BPH medications limit patient compliance. We tested the protective effect of aescin against the development of BPH in rats. Methods: A total of 18 male Wistar rats were divided into 3 groups: control (sesame oil 1 mL/kg, s.c.); BPH (testosterone oenanthate 3 mg/kg, s.c., in sesame oil), and BPH-aescin rats (testosterone oenanthate 3 mg/kg, s.c. + aescin 10 mg/kg/day, p.o.). All treatments continued for 4 weeks. Serum and prostatic samples were harvested for biochemical and histopathological examination. Results: Induction of BPH by testosterone increased the prostate weight and prostate weight index, serum testosterone, prostate expression of inflammatory (IL-1β, TNF-α, and COX-2), and proliferative markers (PCNA and TGF-β1). Concurrent treatment with aescin decreased the testosterone-induced increase in prostatic IL-1β, TNF-α, and COX-2 expression by 47.9%, 71.2%, and 64.4%, respectively. Moreover, aescin reduced the prostatic proliferation markers TGF-β1 and PCNA by 58.3% and 71.9%, respectively, and normalized the prostate weight. Conclusion: The results of this study showed, for the first time, that aescin protected against the development of experimental BPH in rats via its anti-inflammatory and antiproliferative effects. These findings warrant further studies to clinically repurpose aescin in the management of BPH. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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15 pages, 2790 KiB  
Article
Benzaldehyde Attenuates the Fifth Stage Larval Excretory–Secretory Product of Angiostrongylus cantonensis-Induced Injury in Mouse Astrocytes via Regulation of Endoplasmic Reticulum Stress and Oxidative Stress
by Kuang-Yao Chen, Yi-Ju Chen, Chien-Ju Cheng, Kai-Yuan Jhan and Lian-Chen Wang
Biomolecules 2022, 12(2), 177; https://doi.org/10.3390/biom12020177 - 21 Jan 2022
Cited by 3 | Viewed by 2382
Abstract
Excretory–secretory products (ESPs) are the main research targets for investigating the hosts and helminths interaction. Parasitic worms can migrate to parasitic sites and avoid the host immune response by secreting this product. Angiostrongylus cantonensis is an important food-borne zoonotic parasite that causes severe [...] Read more.
Excretory–secretory products (ESPs) are the main research targets for investigating the hosts and helminths interaction. Parasitic worms can migrate to parasitic sites and avoid the host immune response by secreting this product. Angiostrongylus cantonensis is an important food-borne zoonotic parasite that causes severe neuropathological damage and symptoms, including eosinophilic meningitis or meningoencephalitis in humans. Benzaldehydes are organic compounds composed of a benzene ring and formyl substituents. This compound has anti-inflammatory and antioxidation properties. Previous studies showed that 3-hydroxybenzaldehyde (3-HBA) and 4-hydroxybenzaldehyde (4-HBA) can reduce apoptosis in A. cantonensis ESP-treated astrocytes. These results on the protective effect underlying benzaldehyde have primarily focused on cell survival. The study was designed to investigate the molecular mechanisms of endoplasmic reticulum stress (ER stress) and oxidative stress in astrocytes in A. cantonensis ESP-treated astrocytes and to evaluate the therapeutic consequent of 3-HBA and 4-HBA. First, we initially established the RNA-seq dataset in each group, including normal, ESPs, ESPs + 3-HBA, and ESPs + 4-HBA. We also found that benzaldehyde (3-HBA and 4-HBA) can stimulate astrocytes to express ER stress-related molecules after ESP treatment. The level of oxidative stress could also be decreased in astrocytes by elevating antioxidant activity and reducing ROS generation. These results suggested that benzaldehyde may be a potential therapeutic compound for human angiostrongyliasis to support brain cell survival by inducing the expression levels of ER stress- and oxidative stress-related pathways. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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15 pages, 2931 KiB  
Article
Synthesis and Anti-Hepatoma Activities of U12 Derivatives Arresting G0/G1 Phase and Inducing Apoptosis by PI3K/AKT/mTOR Pathway
by Renjing Yang, Chunchun Du, Ting Cao, Guanghui Wang, Xin Jiang, Jun Gao, Ting Lin, Cuiling Sun, Rong Ding, Wenjing Tian and Haifeng Chen
Pharmaceuticals 2022, 15(1), 107; https://doi.org/10.3390/ph15010107 - 17 Jan 2022
Cited by 3 | Viewed by 2418
Abstract
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural [...] Read more.
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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14 pages, 1682 KiB  
Article
Antifungal Activity of Natural Compounds vs. Candida spp.: A Mixture of Cinnamaldehyde and Eugenol Shows Promising In Vitro Results
by Ilaria Maria Saracino, Claudio Foschi, Matteo Pavoni, Renato Spigarelli, Maria Chiara Valerii and Enzo Spisni
Antibiotics 2022, 11(1), 73; https://doi.org/10.3390/antibiotics11010073 - 08 Jan 2022
Cited by 19 | Viewed by 2711
Abstract
Candida spp. are commensal organisms of the skin, mucous membranes, gastrointestinal tract, blood, and vagina of animals and humans. In recent decades, the incidence of human fungal infections has increased, with Candida spp. (mainly C. albicans) infections being the most frequent, and [...] Read more.
Candida spp. are commensal organisms of the skin, mucous membranes, gastrointestinal tract, blood, and vagina of animals and humans. In recent decades, the incidence of human fungal infections has increased, with Candida spp. (mainly C. albicans) infections being the most frequent, and the treatment of fungal infections is still a clinical challenge. Colonization of the human gastrointestinal tract by Candida spp. is significant because infections (e.g., candidemia and vulvovaginal candidiasis) frequently arise from commensal microorganisms. The aim of this study was to test in vitro the antifungal activity and the eventual synergistic effect of five pure components of essential oils: cinnamaldehyde, α-pinene, limonene, eucalyptol, and eugenol. These compounds were tested on 18 Candida strains (15 C. albicans, 2 C. glabrata, and 1 C. lusitaniae) derived from a culture collection of vaginal clinical strains. Methods: Fungistatic activity was evaluated using the disk diffusion method. For fungicidal activity, microdilution and time–kill curve protocols were set up. The checkerboard method was chosen to evaluate a possible synergistic effect of these compounds when mixed. Results: Cinnamaldehyde and eugenol gave the best results, inhibiting all the Candida strains and showing a highly additive effect (FICI 0.625). The cinnamaldehyde inhibition zone (IZ), MIC, and MFC means were 69 mm, 50.05 mg/L, and 109.26 mg/L respectively. Cinnamaldehyde led to the total loss of viable Candida cells within 4 h. Eugenol IZ, MIC, and MFC means were 35.2 mm, 455.42 mg/L, and 690.09 mg/L, respectively. Eugenol led to the total loss of viable fungal cells within 1 h. Treatment with α-pinene inhibited 88.9% of Candida strains, with an IZ mean of 21.2 mm, a MIC mean of 195.41 mg/L, and a MFC mean of 251.27 mg/L; this compound led to the total loss of viable fungal cells only after 24 h. Limonene inhibited only 33.3% of the tested strains and eucalyptol did not produce an inhibition halo, so these compounds were not tested further. Conclusions: These characteristics, together with the well-known safety of cinnamaldehyde and eugenol for human use, make these two natural compounds the perfect candidates for the treatment of candidiasis. This was a pilot study, the purpose of which was to evaluate the best composition of a mixture to be used against intestinal and vulvovaginal candidiasis; in vivo studies are needed to confirm these very encouraging results. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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11 pages, 2344 KiB  
Article
Persimmon Leaves (Diospyros kaki) Extract Enhances the Viability of Human Corneal Endothelial Cells by Improving Na+-K+-ATPase Activity
by Ramsha Afzal and Hyung Bin Hwang
Pharmaceuticals 2022, 15(1), 72; https://doi.org/10.3390/ph15010072 - 06 Jan 2022
Cited by 2 | Viewed by 1972
Abstract
The Na+/K+-ATPase, present in the basolateral membrane of human corneal endothelial cells (HCECs), is known to play an important role for corneal transparency. Na+/K+-ATPase dysfunction is one of the major causes of corneal decompensation. The [...] Read more.
The Na+/K+-ATPase, present in the basolateral membrane of human corneal endothelial cells (HCECs), is known to play an important role for corneal transparency. Na+/K+-ATPase dysfunction is one of the major causes of corneal decompensation. The ethanol extract of Diospyros kaki (EEDK) has been reported to increase corneal cell viability. Thus, we treated HCECs with EEDK and studied its effects on HCECs survival and Na+/K+-ATPase against cytotoxic drugs like staurosporine (ST) and ouabain (OU). Firstly, survival assays, (MTT assay and live dead-imaging) showed that decreased HCECs viability by ST and OU was significantly recovered by EEDK co-treatment. Secondly, Na+/K+-ATPase activity assays revealed that EEDK enhanced Na+/K+-ATPase enzymatic activity (* p < 0.01) with/without ST and OU. Finally, Na+/K+-ATPase expression analysis (Western Blot and confocal microscopy) demonstrated that EEDK treatment with/without ST and OU facilitates Na+/K+-ATPase expression in HCECs. Taken together, our findings led us to the conclusion that EEDK might aid HCECs survival in vitro by increasing the activity and expression of Na+/K+-ATPase enzyme. Since Na+/K+-ATPase activity is important to maintain cellular function of HCECs, we suggest that EEDK can be a potential effective agent against corneal edema and related corneal disorders. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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26 pages, 36015 KiB  
Review
FDA-Approved Oximes and Their Significance in Medicinal Chemistry
by Jyothi Dhuguru, Eugene Zviagin and Rachid Skouta
Pharmaceuticals 2022, 15(1), 66; https://doi.org/10.3390/ph15010066 - 04 Jan 2022
Cited by 37 | Viewed by 9334
Abstract
Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their [...] Read more.
Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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25 pages, 3614 KiB  
Review
Some Common Medicinal Plants with Antidiabetic Activity, Known and Available in Europe (A Mini-Review)
by Monika Przeor
Pharmaceuticals 2022, 15(1), 65; https://doi.org/10.3390/ph15010065 - 04 Jan 2022
Cited by 23 | Viewed by 4984
Abstract
Diabetes is a metabolic disease that affected 9.3% of adults worldwide in 2019. Its co-occurrence is suspected to increase mortality from COVID-19. The treatment of diabetes is mainly based on the long-term use of pharmacological agents, often expensive and causing unpleasant side effects. [...] Read more.
Diabetes is a metabolic disease that affected 9.3% of adults worldwide in 2019. Its co-occurrence is suspected to increase mortality from COVID-19. The treatment of diabetes is mainly based on the long-term use of pharmacological agents, often expensive and causing unpleasant side effects. There is an alarming increase in the number of pharmaceuticals taken in Europe. The aim of this paper is to concisely collect information concerning the few antidiabetic or hypoglycaemic raw plant materials that are present in the consciousness of Europeans and relatively easily accessible to them on the market and sometimes even grown on European plantations. The following raw materials are discussed in this mini-review: Morus alba L., Cinnamomum zeylanicum J.Presl, Trigonella foenum-graecum L., Phaseolus vulgaris L., Zingiber officinale Rosc., and Panax ginseng C.A.Meyer in terms of scientifically tested antidiabetic activity and the presence of characteristic biologically active compounds and their specific properties, including antioxidant properties. The characteristics of these raw materials are based on in vitro as well as in vivo studies: on animals and in clinical studies. In addition, for each plant, the possibility to use certain morphological elements in the light of EFSA legislation is given. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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20 pages, 5218 KiB  
Article
Immobilized Bisphosphonates as Potential Inhibitors of Bioprosthetic Calcification: Effects on Various Xenogeneic Cardiovascular Tissues
by Irina Y. Zhuravleva, Anna A. Dokuchaeva, Elena V. Karpova, Tatyana P. Timchenko, Anatoly T. Titov, Svetlana S. Shatskaya and Yuliya F. Polienko
Biomedicines 2022, 10(1), 65; https://doi.org/10.3390/biomedicines10010065 - 29 Dec 2021
Cited by 3 | Viewed by 1531
Abstract
Calcification is the major factor limiting the clinical use of bioprostheses. It may be prevented by the immobilization of bisphosphonic compounds (BPs) on the biomaterial. In this study, we assessed the accumulation and structure of calcium phosphate deposits in collagen-rich bovine pericardium (Pe) [...] Read more.
Calcification is the major factor limiting the clinical use of bioprostheses. It may be prevented by the immobilization of bisphosphonic compounds (BPs) on the biomaterial. In this study, we assessed the accumulation and structure of calcium phosphate deposits in collagen-rich bovine pericardium (Pe) and elastin-rich porcine aortic wall (Ao) and bovine jugular vein wall (Ve) cross-linked with glutaraldehyde (GA) or diepoxy compound (DE). These tissues were then modified with pamidronic (PAM) acid or 2-(2′-carboxyethylamino)ethylidene-1,1-bisphosphonic (CEABA) acid. Tissue transformations were studied using Fourier-transform infrared spectroscopy. After subcutaneous implantation of the biomaterials in 220 rats, calcification dynamics were examined using atomic absorption spectrophotometry, light microscopy after von Kossa staining, and scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy The calcium content in all GA-cross-linked tissues and DE-cross-linked Ao increased to 100–160 mg/g on day 60 after implantation. BPs prevented the accumulation of phosphates on the surface of all materials and most effectively inhibited calcification in GA-cross-linked Ao and DE-cross-linked Pe. PAM containing -OH in the R1 group was more effective than CEABA containing -H in R1. The calcification-inhibitory effect of BPs may be realized through their ability to block nucleation and prevent the growth of hydroxyapatite crystals. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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37 pages, 1911 KiB  
Review
Nigella sativa L. Phytochemistry and Pharmacological Activities: A Review (2019–2021)
by Mohammed Dalli, Oussama Bekkouch, Salah-eddine Azizi, Ali Azghar, Nadia Gseyra and Bonglee Kim
Biomolecules 2022, 12(1), 20; https://doi.org/10.3390/biom12010020 - 23 Dec 2021
Cited by 33 | Viewed by 6968
Abstract
Medicinal and aromatic plants are mainly characterized by the presence of different bioactive compounds which exhibit various therapeutic activities. In order to investigate the different pharmacological properties of different Nigella sativa extracts, a multitude of research articles published in the period between 2019 [...] Read more.
Medicinal and aromatic plants are mainly characterized by the presence of different bioactive compounds which exhibit various therapeutic activities. In order to investigate the different pharmacological properties of different Nigella sativa extracts, a multitude of research articles published in the period between 2019 and 2021 were obtained from different databases (Scopus, Science Direct, PubMed, and Web of Science), and then explored and analyzed. The analysis of the collected articles allows us to classify the phytochemicals and the pharmacological activities through their underlying molecular mechanisms, as well as to explore the pharmacological activities exhibited by several identified compounds in Nigella sativa which allow a better understanding, and better elucidation, of the bioactive compounds responsible for the pharmacological effects. Also shown are the existence of other bioactive compounds that are still unexplored and could be of great interest. This review could be taken as a guide for future studies in the field. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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19 pages, 1963 KiB  
Article
Screening of the Promising Direct Thrombin Inhibitors from Haematophagous Organisms. Part I: Recombinant Analogues and Their Antithrombotic Activity In Vitro
by Maria A. Kostromina, Elena A. Tukhovskaya, Elvira R. Shaykhutdinova, Gulsara A. Slashcheva, Alina M. Ismailova, Victor A. Palikov, Yuliya A. Palikova, Igor A. Dyachenko, Irina N. Kravchenko, Elena S. Sadovnikova, Nadezhda I. Novikova, Natalia A. Perepechenova, Evgeniy A. Zayats, Yuliya A. Abramchik, Dmitry D. Lykoshin, Andrey N. Mamaev, Elena V. Grigorieva, Andrey P. Momot, Arkady N. Murashev and Roman S. Esipov
Biomedicines 2022, 10(1), 11; https://doi.org/10.3390/biomedicines10010011 - 22 Dec 2021
Cited by 4 | Viewed by 3046
Abstract
The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most [...] Read more.
The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis(desirudin), being the first-known and most well-studied natural anticoagulant, along with recombinant analogs of haemadin from the leech Haemadipsa sylvestris, variegin from the tick Amblyomma variegatum, and anophelin from Anopheles albimanus. These polypeptides were chosen due to their high specificity and affinity for thrombin, as well as their distinctive inhibitory mechanisms. We have developed a universal scheme for the biotechnological production of these recombinant peptides as pharmaceutical substances. The anticoagulant activities of these peptides were compared using the thrombin amidolytic activity assay and prolongation of coagulation time (thrombin time, prothrombin time, and activated partial thromboplastin time) in mouse and human plasma. The preliminary results obtained suggest haemadin as the closest analog of recombinant hirudin-1, the active substance of the medicinal product Iprivask (Aventis Pharmaceuticals, USA) for the prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery. In contrast, variegin can be regarded as a natural analog of bivalirudin (Angiomax, The Medicines Company), a synthetic hirudin-1 derivative certified for the treatment of patients undergoing percutaneous coronary intervention and of patients with unstable angina pectoris after percutaneous transluminal coronary angioplasty. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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