Pharmaceuticals

26 pages, 5371 KiB

Open AccessArticle

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

by Junbo Zhu, Yabin Duan, Delong Duo, Jianxin Yang, Xue Bai, Guiqin Liu, Qian Wang, Xuejun Wang, Ning Qu, Yang Zhou and Xiangyang Li

Pharmaceuticals 2022, 15(10), 1303; https://doi.org/10.3390/ph15101303 - 21 Oct 2022

Cited by 5 | Viewed by 2160

Abstract

(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs [...] Read more.

(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs are limited. (2) Methods: The aim of this study was to evaluate the pharmacokinetics of nifedipine, bosentan, simvastatin, sildenafil, and their respective main metabolites, dehydronifedipine, hydroxybosentan, simvastatin hydroxy acid, and N-desmethyl sildenafil, in rats exposed to high-altitude hypoxia. Additionally, the protein and mRNA expression of cytochrome P450 3A1 (CYP3A1), a drug-metabolizing enzyme, were examined. (3) Results: There were significant changes in the pharmacokinetic properties of the drugs in rats exposed to high-altitude hypoxia, as evidenced by an increase in the area under the curve (AUC) and the half-life (t_1/2z) and a decrease in total plasma clearance (CL_z/F). However, most of these changes were reversed when the rats returned to a normoxic environment. Additionally, there was a significant decrease in CYP3A1 expression in rats exposed to high-altitude hypoxia at both the protein and mRNA levels. (4) Conclusions: High-altitude hypoxia suppressed the metabolism of the drugs, indicating that the pharmacokinetics of the drugs should be re-examined, and the optimal dose should be reassessed in patients living in high-altitude areas. Full article

(This article belongs to the Special Issue Pharmacokinetics (PK)/Pharmacodynamics (PD) Study in Drug Discovery and Development)

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24 pages, 862 KiB

Open AccessReview

Overview on Strategies and Assays for Antibiotic Discovery

by Anika Rütten, Teresa Kirchner and Ewa Maria Musiol-Kroll

Pharmaceuticals 2022, 15(10), 1302; https://doi.org/10.3390/ph15101302 - 21 Oct 2022

Cited by 5 | Viewed by 4987

Abstract

The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections [...] Read more.

The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents 2022)

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15 pages, 3143 KiB

Open AccessArticle

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity

by Ebru Koçak Aslan, Muhammed İhsan Han, Vagolu Siva Krishna, Rasoul Tamhaev, Cagatay Dengiz, Şengül Dilem Doğan, Christian Lherbet, Lionel Mourey, Tone Tønjum and Miyase Gözde Gündüz

Pharmaceuticals 2022, 15(10), 1301; https://doi.org/10.3390/ph15101301 - 21 Oct 2022

Cited by 7 | Viewed by 2822

Abstract

Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In [...] Read more.

Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1–SIH13). Following structural characterization by FTIR, ¹H NMR, ¹³C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1–SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1–SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1–SIH13 adhered to Lipinski’s rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Tuberculosis 2021)

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18 pages, 2515 KiB

Open AccessArticle

Valorisation of the Inhibitory Potential of Fresh and Dried Fruit Extracts of Prunus spinosa L. towards Carbohydrate Hydrolysing Enzymes, Protein Glycation, Multiple Oxidants and Oxidative Stress-Induced Changes in Human Plasma Constituents

by Anna Magiera, Joanna Kołodziejczyk-Czepas, Karolina Skrobacz, Monika Ewa Czerwińska, Magdalena Rutkowska, Aleksandra Prokop, Piotr Michel and Monika Anna Olszewska

Pharmaceuticals 2022, 15(10), 1300; https://doi.org/10.3390/ph15101300 - 21 Oct 2022

Cited by 4 | Viewed by 1835

Abstract

Prunus spinosa fruits (sloes), both fresh and dried, are underexplored dietary components and ethno-phytotherapeutic remedies applied to treat chronic oxidative-stress-related diseases, including diabetes. The present study aimed to evaluate drying-related changes in the antidiabetic potential of sloe extracts and some bioactivity mechanisms, which [...] Read more.

Prunus spinosa fruits (sloes), both fresh and dried, are underexplored dietary components and ethno-phytotherapeutic remedies applied to treat chronic oxidative-stress-related diseases, including diabetes. The present study aimed to evaluate drying-related changes in the antidiabetic potential of sloe extracts and some bioactivity mechanisms, which might be connected with their traditional application. The polyphenol-enriched extracts, prepared by fractionated extraction and phytochemically standardised, i.a., by LC-MS/MS, were tested in vitro using a set of biological and chemical models. The experiments revealed the significant extracts’ ability to counteract the generation of advanced glycation end products (AGEs) and inhibit the activity of key glycolytic enzymes, i.e., α-glucosidase and α-amylase. Moreover, they were proved to effectively scavenge multiple oxidants of physiological importance (O₂^•−, HO^•, H₂O₂, NO^•, HOCl), increase the non-enzymatic antioxidant capacity of human plasma (NEAC) under oxidative stress conditions induced by peroxynitrite, and protect plasma proteins and lipids against peroxidation and nitration at in vivo-relevant levels (1–50 µg/mL, equivalent to 0.03–6.32 µg polyphenols/mL). In most cases, the activity of fresh fruit extracts surpassed that of dried-based products. The correlation studies and tests on model compounds proved polyphenols as dominant contributors to the observed effects. Furthermore, the co-occurring representatives of various polyphenolic classes were found to contribute to the biological activity of sloes through additive and synergistic effects. Considering the extraction yield and activity parameters, especially the superior outcomes compared to anti-diabetic drugs aminoguanidine and acarbose in the anti-glycation and α-glucosidase inhibition tests, the methanol–water (75:25, v/v) extract of fresh fruits and its phenolic-enriched fractions revealed the most advantageous potential for functional application. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus)

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29 pages, 5887 KiB

Open AccessArticle

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells

by Gustavo Moreno-Quintero, Wilson Castrillón-Lopez, Angie Herrera-Ramirez, Andrés F. Yepes-Pérez, Jorge Quintero-Saumeth and Wilson Cardona-Galeano

Pharmaceuticals 2022, 15(10), 1299; https://doi.org/10.3390/ph15101299 - 21 Oct 2022

Cited by 9 | Viewed by 1997

Abstract

A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against [...] Read more.

A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC₅₀ values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC₅₀ value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations. Full article

(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)

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12 pages, 3078 KiB

Open AccessArticle

An Algae-Made RBD from SARS-CoV-2 Is Immunogenic in Mice

by Dania O. Govea-Alonso, Ashwini Malla, Omayra C. Bolaños-Martínez, Sornkanok Vimolmangkang and Sergio Rosales-Mendoza

Pharmaceuticals 2022, 15(10), 1298; https://doi.org/10.3390/ph15101298 - 21 Oct 2022

Cited by 3 | Viewed by 1560

Abstract

Despite the current advances in global vaccination against SARS-CoV-2, boosting is still required to sustain immunity in the population, and the induction of sterilizing immunity remains as a pending goal. Low-cost oral immunogens could be used as the basis for the design of [...] Read more.

Despite the current advances in global vaccination against SARS-CoV-2, boosting is still required to sustain immunity in the population, and the induction of sterilizing immunity remains as a pending goal. Low-cost oral immunogens could be used as the basis for the design of affordable and easy-to-administer booster vaccines. Algae stand as promising platforms to produce immunogens at low cost, and it is possible to use them as oral delivery carriers since they are edible (not requiring complex purification and formulation processes). Herein, a Chlamydomonas-made SARS-CoV-2 RBD was evaluated as an oral immunogen in mice to explore the feasibility of developing an oral algae-based vaccine. The test immunogen was stable in freeze-dried algae biomass and able to induce, by the oral route, systemic and mucosal humoral responses against the spike protein at a similar magnitude to those induced by injected antigen plus alum adjuvant. IgG subclass analysis revealed a Th2-bias response which lasted over 4 months after the last immunization. The induced antibodies showed a similar reactivity against either Delta or Omicron variants. This study represents a step forward in the development of oral vaccines that could accelerate massive immunization. Full article

(This article belongs to the Section Biopharmaceuticals)

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20 pages, 722 KiB

Open AccessReview

Targeting NMDA Receptor Complex in Management of Epilepsy

by Shravan Sivakumar, Mehdi Ghasemi and Steven C. Schachter

Pharmaceuticals 2022, 15(10), 1297; https://doi.org/10.3390/ph15101297 - 21 Oct 2022

Cited by 7 | Viewed by 4102

Abstract

N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology [...] Read more.

N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology of seizure disorders and epilepsy. Accordingly, NMDAR modulators have been shown to exert anticonvulsive effects in various preclinical models of seizures, as well as in patients with epilepsy. In this review, we provide an update on the pathologic role of NMDARs in epilepsy and an overview of the NMDAR antagonists that have been evaluated as anticonvulsive agents in clinical studies, as well as in preclinical seizure models. Full article

(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)

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14 pages, 10403 KiB

Open AccessArticle

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

by Mohamed A. Morsy, Rania Abdel-Latif, Sara Mohamed Naguib Abdel Hafez, Mahmoud Kandeel and Seham A. Abdel-Gaber

Pharmaceuticals 2022, 15(10), 1296; https://doi.org/10.3390/ph15101296 - 21 Oct 2022

Cited by 7 | Viewed by 1884

Abstract

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for [...] Read more.

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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26 pages, 1433 KiB

Open AccessReview

Potential Application of Small Interfering RNA in Gastro-Intestinal Tumors

by Pasquale Losurdo, Nicolò de Manzini, Silvia Palmisano, Mario Grassi, Salvatore Parisi, Flavio Rizzolio, Domenico Tierno, Alice Biasin, Chiara Grassi, Nhung Hai Truong and Gabriele Grassi

Pharmaceuticals 2022, 15(10), 1295; https://doi.org/10.3390/ph15101295 - 20 Oct 2022

Cited by 2 | Viewed by 2292

Abstract

Despite the progress made in the diagnoses and therapy of gastrointestinal cancers, these diseases are still plagued by a high mortality. Thus, novel therapeutic approaches are urgently required. In this regard, small interfering RNA (siRNA), double-stranded RNA molecules able to specifically target the [...] Read more.

Despite the progress made in the diagnoses and therapy of gastrointestinal cancers, these diseases are still plagued by a high mortality. Thus, novel therapeutic approaches are urgently required. In this regard, small interfering RNA (siRNA), double-stranded RNA molecules able to specifically target the mRNA of pathological genes, have the potential to be of therapeutic value. To be effective in the human body, siRNAs need to be protected against degradation. Additionally, they need to target the tumor, leaving the normal tissue untouched in an effort to preserve organ function. To accomplish these tasks, siRNAs have been formulated with smart delivery systems such has polymers and lipids. While siRNA protection is not particularly difficult to achieve, their targeting of tumor cells remains problematic. Here, after introducing the general features of gastrointestinal cancers, we describe siRNA characteristics together with representative delivery systems developed for gastrointestinal cancers. Afterward, we present a selection of research papers employing siRNAs against upper- and lower- gastrointestinal cancers. For the liver, we also consider papers using siRNAs to combat liver cirrhosis, a relevant risk factor for liver cancer development. Finally, we present a brief description of clinical trials employing siRNAs for gastrointestinal cancers. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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14 pages, 2764 KiB

Open AccessArticle

Ginkgo biloba Extract Stimulates Adipogenesis in 3T3-L1 Preadipocytes

by Fernanda Malanconi Thomaz, Jussara de Jesus Simão, Viviane Simões da Silva, Meira Maria Forcelini Machado, Lila Missae Oyama, Eliane Beraldi Ribeiro, Maria Isabel Cardoso Alonso Vale and Monica Marques Telles

Pharmaceuticals 2022, 15(10), 1294; https://doi.org/10.3390/ph15101294 - 20 Oct 2022

Cited by 4 | Viewed by 1937

Abstract

Smaller adipocytes are related to the reversal of metabolic disorders, suggesting that molecules that can act in the adipogenesis pathway are of great interest. The objective of this study was to investigate the effect of Ginkgo biloba extract (GbE) in modulating the differentiation [...] Read more.

Smaller adipocytes are related to the reversal of metabolic disorders, suggesting that molecules that can act in the adipogenesis pathway are of great interest. The objective of this study was to investigate the effect of Ginkgo biloba extract (GbE) in modulating the differentiation in preadipocytes. 3T3-L1 preadipocytes were differentiated for 7 days into adipocytes without (control group) and with GbE at 1.0 mg/mL. Lipid content and gene expression were analyzed on day 7 (D7) by Oil Red O staining and PCR Array Gene Expression. Western blotting analysis of the key adipogenesis markers was evaluated during the differentiation process at days 3 (D3), 5 (D5), and 7 (D7). GbE increased lipid content and raised the gene expression of the main adipogenesis markers. Key proteins of the differentiation process were modulated by GbE, since C/EBPβ levels were decreased, while C/EBPα levels were increased at D7. Regarding the mature adipocytes’ markers, GbE enhanced the levels of both FABP4 at D5, and perilipin at D3 and D5. In summary, the present findings showed that GbE modulated the adipogenesis pathway suggesting that the treatment could accelerate the preadipocyte maturation, stimulating the expression of mature adipocyte proteins earlier than expected. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Obesity)

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24 pages, 4406 KiB

Open AccessArticle

The Probiotic Strains Bifidοbacterium lactis, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Saccharomyces boulardii Regulate Wound Healing and Chemokine Responses in Human Intestinal Subepithelial Myofibroblasts

by Gesthimani Tarapatzi, Eirini Filidou, Leonidas Kandilogiannakis, Michail Spathakis, Maria Gaitanidou, Konstantinos Arvanitidis, Ioannis Drygiannakis, Vassilis Valatas, Katerina Kotzampassi, Vangelis G. Manolopoulos, George Kolios and Stergios Vradelis

Pharmaceuticals 2022, 15(10), 1293; https://doi.org/10.3390/ph15101293 - 20 Oct 2022

Cited by 10 | Viewed by 3124

Abstract

Bifidobacterium lactis, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Saccharomyces boulardii are common probiotic supplements. Colonic subepithelial myofibroblasts (cSEMFs) are actively involved in mucosal wound healing and inflammation. cSEMFs, isolated from healthy individuals, were stimulated with 10² or 10⁴ cfu/mL of these [...] Read more.

Bifidobacterium lactis, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Saccharomyces boulardii are common probiotic supplements. Colonic subepithelial myofibroblasts (cSEMFs) are actively involved in mucosal wound healing and inflammation. cSEMFs, isolated from healthy individuals, were stimulated with 10² or 10⁴ cfu/mL of these probiotic strains alone and in combination, and their effect on chemokine and wound healing factor expression was assessed by qRT-PCR, ELISA and Sircol Assay, and on cSEMFs migration, by Wound Healing Assay. These strains remained viable and altered cSEMFs’ inflammatory and wound healing behavior, depending on the strain and concentration. cSEMFs treated with a combination of the four probiotics had a moderate, but statistically significant, increase in the mRNA and/or protein expression of chemokines CXCL1, CXCL2, CXCL4, CXCL8, CXCL10, CCL2 and CCL5, and healing factors, collagen type I and III, fibronectin and tissue factor. In contrast, when each strain was administered alone, different effects were observed, with greater increase or decrease in chemokine and healing factor expression, which was balanced by the mixture. Overall, this study highlights that the use of multiple probiotic strains can potentially alert the gut mucosal immune system and promote wound healing, having a better effect on mucosal immunity than the use of single probiotics. Full article

(This article belongs to the Special Issue Gut Microbiota, Inflammatory Bowel Diseases, and Therapeutic Targets)

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13 pages, 1018 KiB

Open AccessReview

[¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^TM): The First FDA-Approved Radiotherapeutical for Treatment of Prostate Cancer

by Ute Hennrich and Matthias Eder

Pharmaceuticals 2022, 15(10), 1292; https://doi.org/10.3390/ph15101292 - 20 Oct 2022

Cited by 66 | Viewed by 10613

Abstract

In March 2022, [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^TM) was approved by the FDA for the treatment of prostate cancer patients. Until now, the approval has been limited to patients with PSMA-positive metastatic castration-resistant prostate cancer who have previously received other therapy options [...] Read more.

In March 2022, [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^TM) was approved by the FDA for the treatment of prostate cancer patients. Until now, the approval has been limited to patients with PSMA-positive metastatic castration-resistant prostate cancer who have previously received other therapy options (such as inhibition of the androgen receptor pathway and taxane-based chemotherapy). [¹⁷⁷Lu]Lu-PSMA-617, which combines a PSMA-specific peptidomimetic with a therapeutical radionuclide, is used in a radioligand therapy that selectively delivers ionizing radiation to tumor cells, causing their death, while sparing the surrounding healthy tissue. In numerous clinical trials, the efficacy of [¹⁷⁷Lu]Lu-PSMA-617 was demonstrated. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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22 pages, 3983 KiB

Open AccessReview

Pimarane Diterpenes from Fungi

by Ke Ye and Hong-lian Ai

Pharmaceuticals 2022, 15(10), 1291; https://doi.org/10.3390/ph15101291 - 20 Oct 2022

Cited by 2 | Viewed by 1987

Abstract

Pimarane diterpenes are a kind of tricyclic diterpene, generally isolated from plant and fungi. In nature, fungi distribute widely and there are nearly two to three million species. They provide many secondary metabolites, including pimarane diterpenes, with novel skeletons and bioactivities. These natural [...] Read more.

Pimarane diterpenes are a kind of tricyclic diterpene, generally isolated from plant and fungi. In nature, fungi distribute widely and there are nearly two to three million species. They provide many secondary metabolites, including pimarane diterpenes, with novel skeletons and bioactivities. These natural products from fungi have the potential to be developed into clinical medicines. Herein, the structures and bioactivities of 197 pimarane diterpenes are summarized and the biosynthesis and pharmacological researches of pimarane diterpenes are introduced. This review may be useful improving the understanding of pimarane diterpenes from fungi. Full article

(This article belongs to the Special Issue Discovery, Metabolism and Potential Bio-Activities of Natural Products in Traditional Medicine)

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12 pages, 3110 KiB

Open AccessArticle

In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer

by Ghazi Aljabal and Beow Keat Yap

Pharmaceuticals 2022, 15(10), 1290; https://doi.org/10.3390/ph15101290 - 20 Oct 2022

Cited by 2 | Viewed by 1485

Abstract

14-3-3 sigma is a vital negative cell cycle regulator. Its expression is consistently downregulated in many types of cancer through gene promoter hypermethylation or proteasomal degradation. 14-3-3 sigma needs to form a homodimer to be functional, while dimers are less prone to degradation [...] Read more.

14-3-3 sigma is a vital negative cell cycle regulator. Its expression is consistently downregulated in many types of cancer through gene promoter hypermethylation or proteasomal degradation. 14-3-3 sigma needs to form a homodimer to be functional, while dimers are less prone to degradation than monomers. This suggests that a homodimer stabilizer may increase the tumor suppressive activities of 14-3-3 sigma. However, no known homodimer stabilizer of 14-3-3 sigma has been reported to date. Therefore, this study attempts to test the potential capability of GCP-Lys-OMe (previously reported to bind at the dimer interface of 14-3-3 zeta isoform), to bind and stabilize the 14-3-3 sigma homodimer. In silico docking of GCP-Lys-OMe on 14-3-3 sigma showed more favorable interaction energy (−9.63 kcal/mole) to the dimer interface than 14-3-3 zeta (−7.73 kcal/mole). Subsequent 100 ns molecular dynamics simulation of the GCP-Lys-OMe/14-3-3 sigma complex revealed a highly stable interaction with an average root-mean-square deviation of 0.39 nm (protein backbone) and 0.77 nm (ligand atoms). More contacts between residues at the homodimer interface and a smaller coverage of conformational space of protein atoms were detected for the bound form than for the apo form. These results suggest that GCP-Lys-OMe is a potential homodimer stabilizer of 14-3-3 sigma. Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 5130 KiB

Open AccessArticle

Chromatographic Techniques and Pharmacological Analysis as a Quality Control Strategy for Serjania triquetra a Traditional Medicinal Plant

by A. Berenice Aguilar-Guadarrama, Guadalupe Yáñez-Ibarra, Martha Edith Cancino-Marentes, Paola González-Ibarra, Rolffy Ortiz-Andrade, Amanda Sánchez-Recillas, Javier-German Rodríguez-Carpena, Yoshajandith Aguirre-Vidal, Irma-Martha Medina-Diaz and Gabriela Ávila-Villarreal

Pharmaceuticals 2022, 15(10), 1289; https://doi.org/10.3390/ph15101289 - 20 Oct 2022

Cited by 3 | Viewed by 2734

Abstract

Serjania triquetra is a medicinal plant widely used in traditional medicine for the treatment of urinary tract diseases, renal affections, and its complications. The population can buy this plant in folk markets as a raw material mixed with several herbal remedies or as [...] Read more.

Serjania triquetra is a medicinal plant widely used in traditional medicine for the treatment of urinary tract diseases, renal affections, and its complications. The population can buy this plant in folk markets as a raw material mixed with several herbal remedies or as a health supplement. On the market, two commercial presentations were found for the vegetal material; one had a bulk appearance and the other was marketed wrapped in cellophane bags (HESt-2, HESt-3). Nevertheless, the plant has not been exhaustively investigated and quality control techniques have not been developed. This research aimed to realize a phytochemical study using an authentic, freshly collected sample as a reference for S. triquetra (HESt-1), using the compounds identified. A method for the determination of preliminary chromatographic fingerprinting was developed. Additionally, the vasorelaxant effect from three samples was evaluated with ex vivo rat models. Thus, three hydroalcoholic extracts (HESt-1, HESt-2, and HESt-3) were prepared by maceration. A total of nine compounds were fully identified from HESt-1 after the extract was subjected to open-column chromatography. Seven metabolites were detected by gas chromatography, while ursolic acid (UA) and allantoin were isolated and identified using UPLC-MS and NMR, respectively. Three extracts were analyzed for their chromatographic fingerprint by UPLC-MS. Biological activity was explored by ex vivo rat aorta ring model to evaluate vasorelaxant activity. All extracts showed a vasorelaxant effect in a concentration-dependent and endothelium-dependent manner. S. triquetra vascular activity may be attributed to UA and allantoin compounds previously described in the literature for this activity. Full article

(This article belongs to the Section Natural Products)

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12 pages, 3613 KiB

Open AccessArticle

Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile

by Ayesha Naseer, Faisal Abdulrhman Osra, Asia Naz Awan, Aqeel Imran, Abdul Hameed, Syed Adnan Ali Shah, Jamshed Iqbal and Zainul Amiruddin Zakaria

Pharmaceuticals 2022, 15(10), 1288; https://doi.org/10.3390/ph15101288 - 19 Oct 2022

Cited by 6 | Viewed by 2405

Abstract

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide [...] Read more.

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide derivatives which also have some novel structures were synthesized via condensation reaction and investigated against urease for their inhibitory action. Among the series, 5-chloropyridine-2 yl-methylene hydrazine carbothioamide (Rx-6) and pyridine 2-yl-methylene hydrazine carboxamide (Rx-7) IC50 = 1.07 ± 0.043 µM, 2.18 ± 0.058 µM both possessed significant activity. Furthermore, molecular docking and kinetic studies were performed for the most potent inhibitors to demonstrate the binding mode of the active pyridine carbothioamide with the enzyme urease and its mode of interaction. The ADME profile also showed that all the synthesized molecules present oral bioavailability and high GI absorption. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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17 pages, 3087 KiB

Open AccessArticle

Brain Microvascular Endothelial Cell-Derived Exosomes Protect Neurons from Ischemia–Reperfusion Injury in Mice

by Jin Sun, Qing Yuan, Lichen Guo, Guangxu Xiao, Tong Zhang, Bing Liang, Rongmei Yao, Yan Zhu, Yue Li and Limin Hu

Pharmaceuticals 2022, 15(10), 1287; https://doi.org/10.3390/ph15101287 - 19 Oct 2022

Cited by 5 | Viewed by 1914

Abstract

Stroke often results in neurological and neuropsychiatric sequela. Exosomes derived from brain endothelial cells (EC-Exo) protect neurons from hypoxic injury. However, the biological role of exosomes in apoptosis and synaptic plasticity remains unclear. This research aimed to assess whether cerebral microvascular endothelial cells [...] Read more.

Stroke often results in neurological and neuropsychiatric sequela. Exosomes derived from brain endothelial cells (EC-Exo) protect neurons from hypoxic injury. However, the biological role of exosomes in apoptosis and synaptic plasticity remains unclear. This research aimed to assess whether cerebral microvascular endothelial cells inhibit apoptosis and promote synaptic remodeling through exosome-mediated cell–cell interaction after the ischemic attack. The effects of EC-Exo on primary neuronal apoptosis and synapses in oxyglucose deprivation reoxygenation (OGD/R) injury were first assessed in vitro. Animal experiments were performed using C57BL/6J mice, divided into three groups: a sham group, a model (middle cerebral artery occlusion/reperfusion, MCAO/R) group, and an EC-Exo group (tail vein injection of EC-Exo, once/2 days for 14 days) to evaluate the neuromotor and exploratory abilities of mice after MCAO/R. Apoptosis and synaptic protein expression levels were detected. The results demonstrated that EC-Exo inhibited neuronal apoptosis and increased synaptic length after OGD/R. In vivo, EC-Exo not only improved neural motor behavior and increased regional cerebral blood flow (rCBF) in MCAO/R-injured mice but also promoted the expression of synaptic regulatory proteins and inhibited apoptosis in the brain. These results suggest that EC-Exo may provide neuroprotection against stroke by promoting synaptic remodeling and inhibiting apoptosis from protecting neurons. Full article

(This article belongs to the Special Issue Natural Products for Potential Use of Neuroprotective and Neurorestorative Effects in Stroke)

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16 pages, 1375 KiB

Open AccessReview

Nanotechnology-Based Dressings for Wound Management

by Janaína A. Ataide, Beatriz Zanchetta, Érica M. Santos, Ana Laura M. Fava, Thais F. R. Alves, Letícia C. Cefali, Marco V. Chaud, Laura Oliveira-Nascimento, Eliana B. Souto and Priscila G. Mazzola

Pharmaceuticals 2022, 15(10), 1286; https://doi.org/10.3390/ph15101286 - 19 Oct 2022

Cited by 8 | Viewed by 2929

Abstract

Wound healing is known to be a complicated and intricate process and commonly classified as chronic or acute. Patients with chronic wounds are of public health concern, and require more attention onto skin lesions, including atopic dermatitis. Despite being a natural process, healing [...] Read more.

Wound healing is known to be a complicated and intricate process and commonly classified as chronic or acute. Patients with chronic wounds are of public health concern, and require more attention onto skin lesions, including atopic dermatitis. Despite being a natural process, healing can be impaired by existing chronic de diseases such as diabetes, for example. Recently, wound dressings based in nanotechnology systems have emerged as a viable option to improve the healing process. Current advances in nanotechnology-based systems to release growth factors and bioactive agents represent a great opportunity to develop new therapies for wound treatments. It is essential that healthcare professionals understand the key processes involved in the healing cascade, to maximize care with these patients and minimize the undesirable outcomes of non-healing wounds. Therefore, this review aims to summarize the healing process phases and provide a general overview of dressings based in nanotechnology using biomaterials for the release of active agents in wound site. Full article

(This article belongs to the Section Pharmaceutical Technology)

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18 pages, 3622 KiB

Open AccessArticle

Speciation Analysis Highlights the Interactions of Auranofin with the Cytoskeleton Proteins of Lung Cancer Cells

by Monika Kupiec, Agnieszka Tomaszewska, Wioletta Jakubczak, Maja Haczyk-Więcek and Katarzyna Pawlak

Pharmaceuticals 2022, 15(10), 1285; https://doi.org/10.3390/ph15101285 - 19 Oct 2022

Cited by 3 | Viewed by 1913

Abstract

Two types of lung cells (epithelial cancer lung cells, A-549 and lung fibroblasts MRC-5) were exposed to the clinically established gold drug auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC₅₀). Collected cells were subjected to speciation analysis using [...] Read more.

Two types of lung cells (epithelial cancer lung cells, A-549 and lung fibroblasts MRC-5) were exposed to the clinically established gold drug auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC₅₀). Collected cells were subjected to speciation analysis using inductively coupled plasma mass spectrometry (ICP-MS). Auranofin showed better affinity toward proteins than DNA, RNA, and hydrophilic small molecular weight compounds. It can bind to proteins that vary in size (~20 kDa, ~75 kDa, and ≥200 kDa) and pI. However, the possibility of dimerization and protein–protein complex formation should also be taken into account. µRPLC/CZE-ESI-MS/MS studies on trypsinized proteins allowed the indication of 76 peptides for which signal intensity was influenced by auranofin presence in cells. Based on it, identity was proposed for 20 proteins. Except for thioredoxin reductase (TrxR), which is directly targeted by gold complex, the proteins were found to be transformed. Five indicated proteins: myosin, plectin, talin, two annexins, and kinase M3K5, are responsible for cell–cell, cell–protein interactions, and cell motility. A wound healing test confirmed their regulation by auranofin as cell migration decreased by 40% while the cell cycle was not interrupted. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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16 pages, 1049 KiB

Open AccessReview

A Comprehensive Study of Therapeutic Applications of Chamomile

by Amit Sah, Punnoth Poonkuzhi Naseef, Mohammed S. Kuruniyan, Gaurav K. Jain, Foziyah Zakir and Geeta Aggarwal

Pharmaceuticals 2022, 15(10), 1284; https://doi.org/10.3390/ph15101284 - 19 Oct 2022

Cited by 13 | Viewed by 11981

Abstract

Chamomile has a long history of traditional medicinal uses. The two commonly used varieties with therapeutic applications are German chamomile known as Matricaria chamomilla L. and Roman chamomile or Chamaemelum nobile L. The plant contains many components, namely, flavonoids, terpenoids, and coumarins, which [...] Read more.

Chamomile has a long history of traditional medicinal uses. The two commonly used varieties with therapeutic applications are German chamomile known as Matricaria chamomilla L. and Roman chamomile or Chamaemelum nobile L. The plant contains many components, namely, flavonoids, terpenoids, and coumarins, which are responsible for its medicinal properties. The review discusses recent developments that help in establishing its role as a therapeutic agent in various areas as an anti-inflammatory, antioxidant, analgesic, antimicrobial, hepatoprotective, anti-allergic, anticancer, and anti-hypertensive agent. Not much is known about its role in the treatment of CNS disorders and metabolic syndromes, which are also discussed. The chemical components responsible for the therapeutic activity and the respective mechanism of action are also elaborated. Full article

(This article belongs to the Section Natural Products)

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33 pages, 3554 KiB

Open AccessReview

Strategies for Improving Peptide Stability and Delivery

by Othman Al Musaimi, Lucia Lombardi, Daryl R. Williams and Fernando Albericio

Pharmaceuticals 2022, 15(10), 1283; https://doi.org/10.3390/ph15101283 - 19 Oct 2022

Cited by 28 | Viewed by 5700

Abstract

Peptides play an important role in many fields, including immunology, medical diagnostics, and drug discovery, due to their high specificity and positive safety profile. However, for their delivery as active pharmaceutical ingredients, delivery vectors, or diagnostic imaging molecules, they suffer from two serious [...] Read more.

Peptides play an important role in many fields, including immunology, medical diagnostics, and drug discovery, due to their high specificity and positive safety profile. However, for their delivery as active pharmaceutical ingredients, delivery vectors, or diagnostic imaging molecules, they suffer from two serious shortcomings: their poor metabolic stability and short half-life. Major research efforts are being invested to tackle those drawbacks, where structural modifications and novel delivery tactics have been developed to boost their ability to reach their targets as fully functional species. The benefit of selected technologies for enhancing the resistance of peptides against enzymatic degradation pathways and maximizing their therapeutic impact are also reviewed. Special note of cell-penetrating peptides as delivery vectors, as well as stapled modified peptides, which have demonstrated superior stability from their parent peptides, are reported. Full article

(This article belongs to the Special Issue Feature Reviews in Biopharmaceuticals)

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25 pages, 5676 KiB

Open AccessReview

4D Printing of Hydrogels: Innovation in Material Design and Emerging Smart Systems for Drug Delivery

by Tuan Sang Tran, Rajkamal Balu, Srinivas Mettu, Namita Roy Choudhury and Naba Kumar Dutta

Pharmaceuticals 2022, 15(10), 1282; https://doi.org/10.3390/ph15101282 - 19 Oct 2022

Cited by 18 | Viewed by 4006

Abstract

Advancements in the material design of smart hydrogels have transformed the way therapeutic agents are encapsulated and released in biological environments. On the other hand, the expeditious development of 3D printing technologies has revolutionized the fabrication of hydrogel systems for biomedical applications. By [...] Read more.

Advancements in the material design of smart hydrogels have transformed the way therapeutic agents are encapsulated and released in biological environments. On the other hand, the expeditious development of 3D printing technologies has revolutionized the fabrication of hydrogel systems for biomedical applications. By combining these two aspects, 4D printing (i.e., 3D printing of smart hydrogels) has emerged as a new promising platform for the development of novel controlled drug delivery systems that can adapt and mimic natural physio-mechanical changes over time. This allows printed objects to transform from static to dynamic in response to various physiological and chemical interactions, meeting the needs of the healthcare industry. In this review, we provide an overview of innovation in material design for smart hydrogel systems, current technical approaches toward 4D printing, and emerging 4D printed novel structures for drug delivery applications. Finally, we discuss the existing challenges in 4D printing hydrogels for drug delivery and their prospects. Full article

(This article belongs to the Special Issue 3D Printing of Drug Formulations)

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14 pages, 1976 KiB

Open AccessArticle

In Vitro Characterization of Aerosolized Albuterol Generated by a Jet Nebulizer and Delivered through a Heated Flow Nasal Cannula System

by Ariel Berlinski and Joshua Spiva

Pharmaceuticals 2022, 15(10), 1281; https://doi.org/10.3390/ph15101281 - 18 Oct 2022

Cited by 1 | Viewed by 1677

Abstract

Pediatric patients receiving respiratory support with heated flow nasal cannula (HFNC) systems frequently receive inhaled medications. Most available data have been obtained with vibrating mesh nebulizers that are expensive. Data are lacking regarding the feasibility of using less expensive devices such as continuous [...] Read more.

Pediatric patients receiving respiratory support with heated flow nasal cannula (HFNC) systems frequently receive inhaled medications. Most available data have been obtained with vibrating mesh nebulizers that are expensive. Data are lacking regarding the feasibility of using less expensive devices such as continuous output jet nebulizers. The characteristics of the aerosols generated by jet nebulizers operated at different conditions (6 and 9 L/min) were studied alone and connected to a HFNC system and different size cannulas using a cascade impactor and spectrophotometry (276 nm). Aerosol characteristics changed while traveling through the HFNC system. Initial size selection occurred at the exit of the circuit (before connecting to the cannula) with all aerosol <5 µm. Nasal cannula size further selected aerosols and reduced drug delivery. The operating flow of the nebulizer did not affect the delivered mass but higher flows generated smaller particle size aerosols. The addition of supplemental flow significantly reduced the delivered mass. The measured aerosol characteristics would likely result in intrapulmonary deposition. The delivery of aerosolized albuterol generated by a continuous output nebulizer placed in the inlet of a HFNC system and connected to large or XXL cannulas is feasible. Full article

(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)

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14 pages, 2988 KiB

Open AccessArticle

Callicarpa dichotoma Leaf Extract Alleviates Atopic Dermatitis through the Suppression of T Cells and Keratinocytes Activation

by Eun-Nam Kim, Hyun-Su Lee and Gil-Saeng Jeong

Pharmaceuticals 2022, 15(10), 1280; https://doi.org/10.3390/ph15101280 - 18 Oct 2022

Cited by 2 | Viewed by 1832

Abstract

Atopic dermatitis (AD) is a highly recurrent chronic inflammatory skin disease, characterized by severe itching, immune imbalance, and skin barrier dysfunction. Damage to the skin barrier function is known to be the main cause of Th1/Th2 immune imbalance, due to the Th2-mediated immune [...] Read more.

Atopic dermatitis (AD) is a highly recurrent chronic inflammatory skin disease, characterized by severe itching, immune imbalance, and skin barrier dysfunction. Damage to the skin barrier function is known to be the main cause of Th1/Th2 immune imbalance, due to the Th2-mediated immune response, and pro-inflammatory cytokines, including IL-4, IL-5, IL-13 and IL-31 and it plays an important role in further eliciting the environment of AD through stimulation. Currently, the most widely used drugs for the treatment of AD are corticosteroids, antihistamines and immunosuppressants (used by more than 60% of patients), which are reported to exhibit various side effects when taken for a long time. Therefore, interest in the physiological activity of safer plant-derived natural extracts is increasing. Callicarpa dichotoma is traditionally used in oriental medicine for bruises, habitual pain, gastric and postpartum hemorrhage. Recent studies have reported that it exhibits antioxidant anti-inflammatory and anti-hepatotoxic activity, but the role and activity of C. dichotoma in AD have not yet been studied. Therefore, in this study, the new physiological activity of C. dichotoma in the AD environment was investigated, suggesting its potential as a natural therapeutic agent. Full article

(This article belongs to the Special Issue Therapeutic Candidates from Plants and the Pharmacology of Their Effects on Atopic Dermatitis)

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17 pages, 3262 KiB

Open AccessArticle

Development of Capsaicin-Containing Analgesic Silicone-Based Transdermal Patches

by Szabolcs László, István Z. Bátai, Szilvia Berkó, Erzsébet Csányi, Ágnes Dombi, Gábor Pozsgai, Kata Bölcskei, Lajos Botz, Ödön Wagner and Erika Pintér

Pharmaceuticals 2022, 15(10), 1279; https://doi.org/10.3390/ph15101279 - 18 Oct 2022

Cited by 5 | Viewed by 1883

Abstract

Transdermal therapeutic systems (TTSs) enable convenient dosing in drug therapy. Modified silicone-polymer-based patches are well-controlled and cost-effective matrix diffusion systems. In the present study, we investigated the substance release properties, skin penetration, and analgesic effect of this type of TTS loaded with low-dose [...] Read more.

Transdermal therapeutic systems (TTSs) enable convenient dosing in drug therapy. Modified silicone-polymer-based patches are well-controlled and cost-effective matrix diffusion systems. In the present study, we investigated the substance release properties, skin penetration, and analgesic effect of this type of TTS loaded with low-dose capsaicin. Release properties were measured in Franz diffusion cell and continuous flow-through cell approaches. Capsaicin was detected with HPLC-UV and UV spectrophotometry. Raman spectroscopy was conducted on human skin samples exposed to the TTS. A surgical incision or carrageenan injection was performed on one hind paw of male Wistar rats. TTSs were applied to the epilated dorsal skin. Patches were kept on the animals for 6 h. The thermal hyperalgesia and mechanical pain threshold of the hind paws were detected. Patches exhibited controlled, zero-order kinetic capsaicin release. According to the Raman mapping, capsaicin penetrated into the epidermis and dermis of human skin, where the target receptors are expressed. The thermal pain threshold drop of the operated rat paws was reversed by capsaicin treatment compared to that of animals treated with control patches. It was concluded that our modified silicone-polymer-based capsaicin-containing TTS is suitable for the relief of traumatic and inflammatory pain. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Pain)

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63 pages, 2647 KiB

Open AccessReview

Alterations of HDL’s to piHDL’s Proteome in Patients with Chronic Inflammatory Diseases, and HDL-Targeted Therapies

by Veronika Vyletelová, Mária Nováková and Ľudmila Pašková

Pharmaceuticals 2022, 15(10), 1278; https://doi.org/10.3390/ph15101278 - 18 Oct 2022

Cited by 10 | Viewed by 3066

Abstract

Chronic inflammatory diseases, such as rheumatoid arthritis, steatohepatitis, periodontitis, chronic kidney disease, and others are associated with an increased risk of atherosclerotic cardiovascular disease, which persists even after accounting for traditional cardiac risk factors. The common factor linking these diseases to accelerated atherosclerosis [...] Read more.

Chronic inflammatory diseases, such as rheumatoid arthritis, steatohepatitis, periodontitis, chronic kidney disease, and others are associated with an increased risk of atherosclerotic cardiovascular disease, which persists even after accounting for traditional cardiac risk factors. The common factor linking these diseases to accelerated atherosclerosis is chronic systemic low-grade inflammation triggering changes in lipoprotein structure and metabolism. HDL, an independent marker of cardiovascular risk, is a lipoprotein particle with numerous important anti-atherogenic properties. Besides the essential role in reverse cholesterol transport, HDL possesses antioxidative, anti-inflammatory, antiapoptotic, and antithrombotic properties. Inflammation and inflammation-associated pathologies can cause modifications in HDL’s proteome and lipidome, transforming HDL from atheroprotective into a pro-atherosclerotic lipoprotein. Therefore, a simple increase in HDL concentration in patients with inflammatory diseases has not led to the desired anti-atherogenic outcome. In this review, the functions of individual protein components of HDL, rendering them either anti-inflammatory or pro-inflammatory are described in detail. Alterations of HDL proteome (such as replacing atheroprotective proteins by pro-inflammatory proteins, or posttranslational modifications) in patients with chronic inflammatory diseases and their impact on cardiovascular health are discussed. Finally, molecular, and clinical aspects of HDL-targeted therapies, including those used in therapeutical practice, drugs in clinical trials, and experimental drugs are comprehensively summarised. Full article

(This article belongs to the Special Issue Potential Therapeutic Target for Atherosclerosis)

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19 pages, 763 KiB

Open AccessReview

Recent Advances in the Treatment of Pulmonary Arterial Hypertension

by Naoyuki Otani, Takashi Tomoe, Atsuhiko Kawabe, Takushi Sugiyama, Yasuto Horie, Hiroyuki Sugimura, Takanori Yasu and Takaaki Nakamoto

Pharmaceuticals 2022, 15(10), 1277; https://doi.org/10.3390/ph15101277 - 17 Oct 2022

Cited by 7 | Viewed by 2967

Abstract

Pulmonary arterial hypertension (PAH) is a disease in which stenosis or obstruction of the pulmonary arteries (PAs) causes an increase in PA pressure, leading to right-sided heart failure and death. Basic research has revealed a decrease in the levels of endogenous vasodilators, such [...] Read more.

Pulmonary arterial hypertension (PAH) is a disease in which stenosis or obstruction of the pulmonary arteries (PAs) causes an increase in PA pressure, leading to right-sided heart failure and death. Basic research has revealed a decrease in the levels of endogenous vasodilators, such as prostacyclin, and an increase in the levels of endogenous vasoconstrictors, such as endothelin, in patients with PAH, leading to the development of therapeutic agents. Currently, therapeutic agents for PAH target three pathways that are selective for PAs: the prostacyclin, endothelin, and nitric oxide pathways. These treatments improve the prognosis of PAH patients. In this review, we introduce new drug therapies and provide an overview of the current therapeutic agents. Full article

(This article belongs to the Special Issue Recent Advances in Pharmacology of Pulmonary Hypertension)

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16 pages, 864 KiB

Open AccessReview

The Emerging Role of Extracellular Vesicles from Mesenchymal Stem Cells and Macrophages in Pulmonary Fibrosis: Insights into miRNA Delivery

by Shuang Li, Jingang Zhang, Guangjiao Feng, Lingmei Jiang, Zhihong Chen, Wenqiang Xin and Xiuru Zhang

Pharmaceuticals 2022, 15(10), 1276; https://doi.org/10.3390/ph15101276 - 17 Oct 2022

Cited by 5 | Viewed by 2228

Abstract

Pulmonary fibrosis is a type of chronic, progressive, fibrotic lung disease of unclear cause with few treatment options. Cell therapy is emerging as a promising novel modality for facilitating lung repair. Mesenchymal stem cell (MSC)-based and macrophage-based cell therapies are regarded as promising [...] Read more.

Pulmonary fibrosis is a type of chronic, progressive, fibrotic lung disease of unclear cause with few treatment options. Cell therapy is emerging as a promising novel modality for facilitating lung repair. Mesenchymal stem cell (MSC)-based and macrophage-based cell therapies are regarded as promising strategies to promote lung repair, due to incredible regenerative potential and typical immunomodulatory function, respectively. Extracellular vesicles (EVs), including exosomes and microvesicles, are cell-derived lipid-bilayer membrane vesicles that are secreted from virtually every cell and are involved in intercellular communication by delivering expansive biological cargos to recipients. This review provides a deep insight into the recent research progress concerning the effects of MSC and macrophage-associated EVs on the pathogenesis of pulmonary fibrosis. In addition to discussing their respective vital roles, we summarize the importance of cross-talk, as macrophages are vital for MSCs to exert their protective effects through two major patterns, including attenuating macrophage activation and M1 phenotype macrophage polarization. Moreover, miRNAs are selectively enriched into EVs as essential components, and consideration is given to the particular effects of EV-associated miRNAs. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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14 pages, 3602 KiB

Open AccessArticle

Chemical Composition and Antimicrobial Potential of Essential Oil of Acritopappus confertus (Gardner) R.M.King & H.Rob. (Asteraceae)

by Rafael Pereira da Cruz, José Walber Gonçalves Castro, Débora Odília Duarte Leite, Natália Kelly Gomes de Carvalho, José Weverton Almeida-Bezerra, Raimundo Luiz Silva Pereira, Fázia Fernandes Galvão Rodrigues, José Jailson Lima Bezerra, Adrielle Rodrigues Costa, Edna Mori, Pablo Antonio Maia de Farias, Henrique Douglas Melo Coutinho, Maria Flaviana Bezerra Morais-Braga, Marcello Iriti, José Galberto Martins da Costa and Fabíola Fernandes Galvão Rodrigues

Pharmaceuticals 2022, 15(10), 1275; https://doi.org/10.3390/ph15101275 - 17 Oct 2022

Cited by 1 | Viewed by 2049

Abstract

Microbial resistance has become a worrying problem in recent decades after the abusive use of antibiotics causing the selection of resistant microorganisms. In order to circumvent such resistance, researchers have invested efforts in the search for promising natural substances, such as essential oils. [...] Read more.

Microbial resistance has become a worrying problem in recent decades after the abusive use of antibiotics causing the selection of resistant microorganisms. In order to circumvent such resistance, researchers have invested efforts in the search for promising natural substances, such as essential oils. Thus, the objective of this work was to determine the chemical composition of the essential oil of Acritopappus confertus leaves, to evaluate its intrinsic effect and its effects in combination with drugs against pathogenic fungi and bacteria, in addition to verifying the inhibition of virulence in Candida strains. To this end, the oil was verified by gas chromatography coupled with mass spectrometry (GC/MS). Candida strains were used for antifungal assays by means of the serial microdilution technique, in order to determine the average inhibitory concentration (IC₅₀), and for the modification assays, sub-inhibitory concentrations (MIC/8) were used. Finally, the natural product’s ability to inhibit the formation of filamentous structures was evaluated. In antibacterial tests, the MIC of the oil against strains of Staphylococcus aureus and Escherichia coli and its modifying effects in association with gentamicin, erythromycin, and norfloxacin were determined. The major constituent of the essential oil was the monoterpene myrcene (54.71%). The results show that the essential oil has an antifungal effect, with C. albicans strains being the most susceptible. Furthermore, the oil can potentiate the effect of fluconazole against strains of C. tropicalis and C. albicans. Regarding its effect on micromorphology, the oil was also able to inhibit the filaments in all strains. In combination with antibiotics, the oil potentiated the drug’s action by reducing the MIC against E. coli and S. aureus. It can be concluded that the essential oil of A. confertus has potential against pathogenic fungi and bacteria, making it a target for the development of an antimicrobial drug. Full article

(This article belongs to the Special Issue Application of Gas Chromatography to Detect Volatile Secondary Metabolites from Natural Products of Pharmacological Interest)

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16 pages, 851 KiB

Open AccessReview

The Potential Therapeutic Role of Metformin in Diabetic and Non-Diabetic Bone Impairment

by Wei Mu, Guoqiang Liang, Yue Feng, Yunyun Jiang and Falin Qu

Pharmaceuticals 2022, 15(10), 1274; https://doi.org/10.3390/ph15101274 - 17 Oct 2022

Cited by 3 | Viewed by 2846

Abstract

Metformin is a widely-used anti-diabetic drug in patients with type 2 diabetic mellitus (T2DM) due to its safety and efficacy in clinical. The classic effect of metformin on lowering blood glucose levels is to inhibit liver gluconeogenesis that reduces glucose production as well [...] Read more.

Metformin is a widely-used anti-diabetic drug in patients with type 2 diabetic mellitus (T2DM) due to its safety and efficacy in clinical. The classic effect of metformin on lowering blood glucose levels is to inhibit liver gluconeogenesis that reduces glucose production as well as increases peripheral glucose utilization. However, the factors such as hyperglycemia, insulin deficiency, reduced serum levels of insulin-like growth factor-1 (IGF-1) and osteocalcin, accumulation of advanced glycation end products (AGEs), especially in collagen, microangiopathy, and inflammation reduced bone quality in diabetic patients. However, hyperglycemia, insulin deficiency, reduced levels of insulin-like growth factor-1 (IGF-1) and osteocalcin in serum, accumulation of advanced glycation end products (AGEs) in collagen, microangiopathy, and inflammation, reduce bone quality in diabetic patients. Furthermore, the imbalance of AGE/RAGE results in bone fragility via attenuating osteogenesis. Thus, adequate glycemic control by medical intervention is necessary to prevent bone tissue alterations in diabetic patients. Metformin mainly activates adenosine 5′ -monophosphate-activated protein kinase (AMPK), and inhibits mitochondrial respiratory chain complex I in bone metabolism. In addition, metformin increases the expression of transcription factor runt-related transcription factor2 (RUNX2) and Sirtuin protein to regulate related gene expression in bone formation. Until now, there are a lot of preclinical or clinical findings on the application of metformin to promote bone repair. Taken together, metformin is considered as a potential medication for adjuvant therapy in bone metabolic disorders further to its antidiabetic effect. Taken together, as a conventional hypoglycemia drug with multifaceted effects, metformin has been considered a potential adjuvant drug for the treatment of bone metabolic disorders. Full article

(This article belongs to the Special Issue Pharmacological Targets of Bone Homeostasis: Osteoclasts and Osteoblasts)

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