Topic Editors

Chair and Department of Biology with Genetics, Medical University of Lublin, Chodźki Str. 4a, 20-093 Lublin, Poland
Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chodźki St., 20-093 Lublin, Poland
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska Str. 69, 79010 Lviv, Ukraine
Chair, Department of Organic Chemistry, Medical University of Lublin, Chodźki 4a (Collegium Pharmaceuticum), 20-093 Lublin, Poland

New Compounds Discovery and Development in Medicine — Advances in Research on Potential Therapeutic Agents and Drug Candidates

Abstract submission deadline
closed (31 October 2023)
Manuscript submission deadline
closed (31 December 2023)
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Topic Information

Dear Colleagues,

Despite the enormous progress of science and technology, we are not able to cure many diseases. Recent years' research shows that there is a great need for new, safe drugs in almost every field of medicine and pharmacy, including in cardiology, neurology, oncology, microbiology, parasitology, virology, dermatology, hematology, endocrinology and others. Therefore, the search for new compounds and substances of potential therapeutic importance is an important and urgent challenge for modern medicine. Publications that would be of special interest in our Special Topic may include research and future perspectives on various compounds exhibiting a broad spectrum of biological activity (in vitro, in vivo and in silico studies). Research aimed at determining the molecular mechanism of action of new compounds for their potential application in therapy will also be interesting.

The search for new, active compounds is a tedious and lengthy process. The recent advances in research conducted towards the discovery of potential therapeutic agents and drug candidates, presented as part of this Special Topic, will allow the medical community to be provided with the latest knowledge in this field.

In this Special Topic, will publish original experimental research, reviews and preclinical observations regarding new biologically active compounds discovery and development in medicine.

Prof. Dr. Anna Bogucka-Kocka
Dr. Przemysław Kołodziej
Prof. Dr. Monika Wujec
Prof. Dr. Roman Lesyk
Dr. Jacek Bogucki
Topic Editors

Keywords

  • new bioactive compound
  • new drug candidates
  • potential therapeutic agents
  • molecular mechanisms
  • molecular targets, molecular docking
  • cell growth and differentiation
  • genetic therapy
  • treatment of civilization diseases
  • antioxidants
  • anti-infective activities (antiparasitic, antimicrobial, antiviral, and antifungal activity), anticancer activity
  • apoptosis
  • autophagy
  • clinical pharmacology
  • medicinal chemistry

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
4.7 3.7 2013 15.4 Days CHF 2600
Journal of Clinical Medicine
jcm
3.9 5.4 2012 17.9 Days CHF 2600
Journal of Personalized Medicine
jpm
3.4 2.6 2011 17.8 Days CHF 2600
Medicina
medicina
2.6 3.6 1920 19.6 Days CHF 1800
Pharmaceutics
pharmaceutics
5.4 6.9 2009 14.2 Days CHF 2900
Molecules
molecules
4.6 6.7 1996 14.6 Days CHF 2700

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Published Papers (17 papers)

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18 pages, 2205 KiB  
Article
New Thiosemicarbazide Derivatives with Multidirectional Biological Action
by Patryk Lasek, Urszula Kosikowska, Przemysław Kołodziej, Grażyna Kubiak-Tomaszewska, Natalia Krzyżanowska, Tomasz Szostek, Marta Struga, Marcin Feldo, Anna Bogucka-Kocka and Monika Wujec
Molecules 2024, 29(7), 1529; https://doi.org/10.3390/molecules29071529 - 29 Mar 2024
Viewed by 524
Abstract
Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the [...] Read more.
Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the world. Therefore, laboratories all over the world are still working on finding new, effective methods of pharmacotherapy. This research work aimed to synthesize new compounds derived from 3-trifluoromethylbenzoic acid hydrazide and to determine their biological activity. The first stage of the research was to obtain seven new compounds, including six linear compounds and one derivative of 1,2,4-triazole. The PASS software was used to estimate the potential probabilities of biological activity of the newly obtained derivatives. Next, studies were carried out to determine the nematocidal potential of the compounds with the use of nematodes of the genus Rhabditis sp. and antibacterial activity using the ACCT standard strains. To determine the lack of cytotoxicity, tests were performed on two cell lines. Additionally, an antioxidant activity test was performed due to the importance of scavenging free radicals in infections with pathogenic microorganisms. The conducted research proved the anthelmintic and antibacterial potential of the newly obtained compounds. The most effective were two compounds with a 3-chlorophenyl substituent, both linear and cyclic derivatives. They demonstrated higher efficacy than the drugs used in treatment. Full article
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22 pages, 11232 KiB  
Article
Celastrol Pyrazine Derivative Alleviates Silicosis Progression via Inducing ROS-Mediated Apoptosis in Activated Fibroblasts
by Ying Bai, Chao Liang, Lu Gao, Tao Han, Fengxuan Wang, Yafeng Liu, Jiawei Zhou, Jianqiang Guo, Jing Wu and Dong Hu
Molecules 2024, 29(2), 538; https://doi.org/10.3390/molecules29020538 - 22 Jan 2024
Viewed by 790
Abstract
Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient [...] Read more.
Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07. In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-β) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis. Full article
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17 pages, 9941 KiB  
Article
Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells
by Yu-Chen Liu, Gang Wei, Zhi-Qiang Liao, Fang-Xin Wang, Chunxiao Zong, Jiannan Qiu, Yifei Le, Zhi-Ling Yu, Seo Young Yang, Heng-Shan Wang, Xiao-Bing Dou and Cai-Yi Wang
Molecules 2024, 29(1), 12; https://doi.org/10.3390/molecules29010012 - 19 Dec 2023
Viewed by 966
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9 [...] Read more.
Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 μM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy. Full article
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14 pages, 826 KiB  
Article
A Randomized Clinical Trial of Inhaled Nitric Oxide Treatment in Premature Infants Reveals the Effect of Maternal Racial Identity on Efficacy
by Jeremy D. Marks and Michael D. Schreiber
J. Clin. Med. 2023, 12(24), 7567; https://doi.org/10.3390/jcm12247567 - 08 Dec 2023
Viewed by 644
Abstract
Respiratory distress syndrome increases the risk of death and bronchopulmonary dysplasia (BPD) in premature infants. Inhaled nitric oxide (iNO) may reduce these risks. Recent meta-analyses have suggested that iNO is effective only at doses higher than 5 ppm and in infants born to [...] Read more.
Respiratory distress syndrome increases the risk of death and bronchopulmonary dysplasia (BPD) in premature infants. Inhaled nitric oxide (iNO) may reduce these risks. Recent meta-analyses have suggested that iNO is effective only at doses higher than 5 ppm and in infants born to Black mothers. In a randomized, double-blinded, controlled trial, infants born before 32 0/7 weeks gestation, weighing <1500 g, and requiring respiratory support were assigned to receive iNO for either seven days (short iNO), or until 33 0/7 weeks PMA (long iNO). The primary outcome was death or BPD. A total of 273 patients were enrolled, of whom 83 receiving long iNO (61.5%) experienced the primary outcome, compared with 65 (47.1%) receiving short iNO (relative risk (RR) 1.37; 95% confidence interval (CI), 1.06–1.79; p = 0.017). This increase was due solely to increased BPD in infants weighing 750–999 g (RR 1.33, 95% CI 1.07–1.66, p = 0.009). However, there was no difference in the numbers of infants requiring supplemental oxygen at 40 weeks PMA. Among infants < 750 g, long-iNO-treated infants had a lower cumulative probability of death (χ2 5.12, p = 0.02). Long iNO increased the primary outcome in non-Black infants (RR 1.93, 95% CI 1.20–3.24) but not in Black infants. Understanding how maternal racial identity determines responses of premature infants to iNO may help narrow the gap in health outcomes between Black and non-Black infants. Full article
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24 pages, 5567 KiB  
Article
Study of the Molecular Architectures of 2-(4-Chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic Acid Using Their Vibrational Spectra, Quantum Chemical Calculations and Molecular Docking with MMP-2 Receptor
by Mauricio Alcolea Palafox, Nataliya P. Belskaya and Irena P. Kostova
Pharmaceutics 2023, 15(12), 2686; https://doi.org/10.3390/pharmaceutics15122686 - 27 Nov 2023
Viewed by 862
Abstract
1,2,3-triazole skeleton is a valuable building block for the discovery of new promising anticancer agents. In the present work, the molecular structure of the synthesized anticancer drug 2-(4-chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic acid (1b) and its anionic form (2b) was characterized [...] Read more.
1,2,3-triazole skeleton is a valuable building block for the discovery of new promising anticancer agents. In the present work, the molecular structure of the synthesized anticancer drug 2-(4-chlorophenyl)-5-(pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylic acid (1b) and its anionic form (2b) was characterized by means of the B3LYP, M06-2X and MP2 quantum chemical methods, optimizing their monomer, cyclic dimer and stacking forms using the Gaussian16 program package. The molecular structure was found to be slightly out of plane. The good agreement between the IR and Raman bands experimentally observed in the solid state with those calculated theoretically confirms the synthesized structures. All of the bands were accurately assigned according to functional calculations (DFT) in the monomer and dimer forms, together with the polynomic scaling equation procedure (PSE). Therefore, the effect of the substituents on the triazole ring and the effect of the chlorine atom on the molecular structure and on the vibrational spectra were evaluated through comparison with its non-substituted form. Through molecular docking calculations, it was evaluated as to how molecule 1b interacts with few amino acids of the MMP-2 metalloproteinase receptor, using Sybyl-X 2.0 software. Thus, the relevance of triazole scaffolds in established hydrogen bond-type interactions was demonstrated. Full article
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16 pages, 4419 KiB  
Article
In Silico and In Vitro Exploration of Poziotinib and Olmutinib Synergy in Lung Cancer: Role of hsa-miR-7-5p in Regulating Apoptotic Pathway Marker Genes
by Salman Alamery, Anfal AlAjmi, Tanveer A. Wani and Seema Zargar
Medicina 2023, 59(11), 1923; https://doi.org/10.3390/medicina59111923 - 30 Oct 2023
Cited by 3 | Viewed by 1217
Abstract
Background and objectives: Non-small cell lung cancer (NSCLC) is often caused by EGFR mutations, leading to overactive cell growth pathways. Drug resistance is a significant challenge in lung cancer treatment, affecting therapy effectiveness and patient survival. However, combining drugs in research shows [...] Read more.
Background and objectives: Non-small cell lung cancer (NSCLC) is often caused by EGFR mutations, leading to overactive cell growth pathways. Drug resistance is a significant challenge in lung cancer treatment, affecting therapy effectiveness and patient survival. However, combining drugs in research shows promise in addressing or delaying resistance, offering a more effective approach to cancer treatment. In this study, we investigated the potential alterations in the apoptotic pathway in A549 cells induced by a combined targeted therapy using tyrosine kinase inhibitors (TKIs) olmutinib and poziotinib, focusing on cell proliferation, differential gene expression, and in silico analysis of apoptotic markers. Methods: A combined targeted therapy involving olmutinib and poziotinib was investigated for its impact on the apoptotic pathway in A549 cells. Cell proliferation, quantitative differential gene expression, and in silico analysis of apoptotic markers were examined. A549 cells were treated with varying concentrations (1, 2.5, and 5 μM) of poziotinib, olmutinib, and their combination. Results: Treatment with poziotinib, olmutinib, and their combination significantly reduced cell proliferation, with the most pronounced effect at 2.5 μM (p < 0.005). A synergistic antiproliferative effect was observed with the combination of poziotinib and olmutinib (p < 0.0005). Quantitative differential gene expression showed synergistic action of the drug combination, impacting key apoptotic genes including STK-11, Bcl-2, Bax, and the Bax/Bcl-2 ratio. In silico analysis revealed direct interactions between EGFR and ERBB2 genes, accounting for 77.64% of their interactions, and 8% co-expression with downstream apoptotic genes. Molecular docking indicated strong binding of poziotinib and olmutinib to extrinsic and intrinsic apoptotic pathway markers, with binding energies of −9.4 kcal/mol and −8.5 kcal/mol, respectively, on interacting with STK-11. Conclusions: Combining poziotinib and olmutinib therapies may significantly improve drug tolerance and conquer drug resistance more effectively than using them individually in lung cancer patients, as suggested by this study’s mechanisms. Full article
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14 pages, 390 KiB  
Review
Breastfeeding-Related Health Benefits in Children and Mothers: Vital Organs Perspective
by Julio César Muro-Valdez, Alejandra Meza-Rios, Blanca Rosa Aguilar-Uscanga, Rocio Ivette Lopez-Roa, Eunice Medina-Díaz, Esmeralda Marisol Franco-Torres and Adelaida Sara Minia Zepeda-Morales
Medicina 2023, 59(9), 1535; https://doi.org/10.3390/medicina59091535 - 25 Aug 2023
Cited by 1 | Viewed by 2626
Abstract
Breast milk (BM) is a constantly changing fluid that represents the primary source of nutrition for newborns. It is widely recognized that breastfeeding provides benefits for both the child and the mother, including a lower risk of ovarian and breast cancer, type 2 [...] Read more.
Breast milk (BM) is a constantly changing fluid that represents the primary source of nutrition for newborns. It is widely recognized that breastfeeding provides benefits for both the child and the mother, including a lower risk of ovarian and breast cancer, type 2 diabetes mellitus, decreased blood pressure, and more. In infants, breastfeeding has been correlated with a lower risk of infectious diseases, obesity, lower blood pressure, and decreased incidence of respiratory infections, diabetes, and asthma. Various factors, such as the baby’s sex, the health status of the mother and child, the mother’s diet, and the mode of delivery, can affect the composition of breast milk. This review focuses on the biological impact of the nutrients in BM on the development and functionality of vital organs to promote the benefit of health. Full article
19 pages, 8329 KiB  
Article
Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies
by Nawal Kishore Sahu, Ritu Sharma, Kshirsagar Prasad Suhas, Jyoti Joshi, Kunal Prakash, Richa Sharma, Ramendra Pratap, Xiwen Hu, Sukhbir Kaur, Mukesh Jain, Carmine Coluccini, Paolo Coghi and Sandeep Chaudhary
Molecules 2023, 28(12), 4817; https://doi.org/10.3390/molecules28124817 - 16 Jun 2023
Cited by 5 | Viewed by 1449
Abstract
Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2′-pyrrolidin]-2-one/spiro[indoline-3,3′-pyrrolizin]-2-one 23af, 24af, and [...] Read more.
Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2′-pyrrolidin]-2-one/spiro[indoline-3,3′-pyrrolizin]-2-one 23af, 24af, and 25ag were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20ah, various substituted chalcones 21af, and 22ac amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies. Full article
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31 pages, 12588 KiB  
Article
Synthesis, Characterization, DFT Studies of Novel Cu(II), Zn(II), VO(II), Cr(III), and La(III) Chloro-Substituted Schiff Base Complexes: Aspects of Its Antimicrobial, Antioxidant, Anti-Inflammatory, and Photodegradation of Methylene Blue
by Laila H. Abdel-Rahman, Maram T. Basha, Badriah Saad Al-Farhan, Walaa Alharbi, Mohamed R. Shehata, Noura O. Al Zamil and Doaa Abou El-ezz
Molecules 2023, 28(12), 4777; https://doi.org/10.3390/molecules28124777 - 15 Jun 2023
Cited by 4 | Viewed by 1575
Abstract
A new chlorobenzylidene imine ligand, (E)-1-((5-chloro-2-hydroxybenzylidene)amino) naphthalen-2-ol (HL), and its [Zn(L)(NO3)(H2O)3], [La(L)(NO3)2(H2O)2], [VO(L)(OC2H5)(H2O)2], [Cu(L)(NO3)(H2O)3], and [...] Read more.
A new chlorobenzylidene imine ligand, (E)-1-((5-chloro-2-hydroxybenzylidene)amino) naphthalen-2-ol (HL), and its [Zn(L)(NO3)(H2O)3], [La(L)(NO3)2(H2O)2], [VO(L)(OC2H5)(H2O)2], [Cu(L)(NO3)(H2O)3], and [Cr(L)(NO3)2(H2O)2], complexes were synthesized and characterized. The characterization involved elemental analysis, FT-IR, UV/Vis, NMR, mass spectra, molar conductance, and magnetic susceptibility measurements. The obtained data confirmed the octahedral geometrical structures of all metal complexes, while the [VO(L)(OC2H5)(H2O)2] complex exhibited a distorted square pyramidal structure. The complexes were found to be thermally stable based on their kinetic parameters determined using the Coats–Redfern method. The DFT/B3LYP technique was employed to calculate the optimized structures, energy gaps, and other important theoretical descriptors of the complexes. In vitro antibacterial assays were conducted to evaluate the complexes’ potential against pathogenic bacteria and fungi, comparing them to the free ligand. The compounds exhibited excellent fungicidal activity against Candida albicans ATCC: 10231 (C. albicans) and Aspergillus negar ATCC: 16404 (A. negar), with inhibition zones of HL, [Zn(L)(NO3)(H2O)3], and [La(L)(NO3)2(H2O)2] three times higher than that of the Nystatin antibiotic. The DNA binding affinity of the metal complexes and their ligand was investigated using UV-visible, viscosity, and gel electrophoresis methods, suggesting an intercalative binding mode. The absorption studies yielded Kb values ranging from 4.40 × 105 to 7.30 × 105 M−1, indicating high binding strength to DNA comparable to ethidium bromide (value 107 M−1). Additionally, the antioxidant activity of all complexes was measured and compared to vitamin C. The anti-inflammatory efficacy of the ligand and its metal complexes was evaluated, revealing that [Cu(L)(NO3)(H2O)3] exhibited the most effective activity compared to ibuprofen. Molecular docking studies were conducted to explore the binding nature and affinity of the synthesized compounds with the receptor of Candida albicans oxidoreductase/oxidoreductase INHIBITOR (PDB ID: 5V5Z). Overall, the combined findings of this work demonstrate the potential of these new compounds as efficient fungicidal and anti-inflammatory agents. Furthermore, the photocatalytic effect of the Cu(II) Schiff base complex/GO was examined. Full article
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16 pages, 826 KiB  
Systematic Review
A Review of the Characteristics of Clinical Trials and Potential Medications for Alcohol Dependence: Data Analysis from ClinicalTrials.gov
by Fahad S. Alshehri
Medicina 2023, 59(6), 1101; https://doi.org/10.3390/medicina59061101 - 07 Jun 2023
Cited by 1 | Viewed by 1385
Abstract
Objective. This study provides a comprehensive analysis of the characteristics of clinical trials related to alcohol dependence that are registered on ClinicalTrials.gov. Methods. All ClinicalTrials.gov trials registered up to 1 January 2023 were examined, focusing on trials that involved alcohol dependence. [...] Read more.
Objective. This study provides a comprehensive analysis of the characteristics of clinical trials related to alcohol dependence that are registered on ClinicalTrials.gov. Methods. All ClinicalTrials.gov trials registered up to 1 January 2023 were examined, focusing on trials that involved alcohol dependence. All 1295 trials were summarized by presenting their characteristics and results and reviewed most intervention drugs used in the treatment of alcohol dependence. Results. The study analysis identified a total of 1295 clinical trials registered on ClinicalTrials.gov that were focused on alcohol dependence. Of these, 766 trials had been completed, representing 59.15% of the total, while 230 trials were currently recruiting participants, accounting for 17.76% of the total. None of the trials had yet been approved for marketing. The majority of the studies included in this analysis were interventional studies (1145 trials, or 88.41%), which accounted for most of the patients enrolled in the trials. In contrast, observational studies represented only a small portion of the trials (150 studies, or 11.58%) and involved a smaller number of patients. In terms of geographic distribution, the majority of registered studies were located in North America (876 studies, or 67.64%), while only a small number of studies were registered in South America (7 studies, or 0.54%). Conclusions. The purpose of this review is to provide a basis for the treatment of alcohol dependence and prevention of its onset through an overview of clinical trials registered at ClinicalTrials.gov. It also offers essential information for future research to guide future studies. Full article
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29 pages, 9839 KiB  
Article
Synthesis and Biological Evaluation of Piperazine Hybridized Coumarin Indolylcyanoenones with Antibacterial Potential
by Chunmei Zeng, Srinivasa Rao Avula, Jiangping Meng and Chenghe Zhou
Molecules 2023, 28(6), 2511; https://doi.org/10.3390/molecules28062511 - 09 Mar 2023
Cited by 11 | Viewed by 1805
Abstract
A class of piperazine hybridized coumarin indolylcyanoenones was exploited as new structural antibacterial frameworks to combat intractable bacterial resistance. Bioactive assessment discovered that 4-chlorobenzyl derivative 11f showed a prominent inhibition on Pseudomonas aeruginosa ATCC 27853 with a low MIC of 1 μg/mL, which [...] Read more.
A class of piperazine hybridized coumarin indolylcyanoenones was exploited as new structural antibacterial frameworks to combat intractable bacterial resistance. Bioactive assessment discovered that 4-chlorobenzyl derivative 11f showed a prominent inhibition on Pseudomonas aeruginosa ATCC 27853 with a low MIC of 1 μg/mL, which was four-fold more effective than norfloxacin. Importantly, the highly active 11f with inconspicuous hemolysis towards human red blood cells displayed quite low proneness to trigger bacterial resistance. Preliminary explorations on its antibacterial behavior disclosed that 11f possessed the ability to destroy bacterial cell membrane, leading to increased permeability of inner and outer membranes, the depolarization and fracture of membrane, and the effusion of intracellular components. Furthermore, bacterial oxidative stress and metabolic turbulence aroused by 11f also accelerated bacterial apoptosis. In particular, 11f could not only effectively inset into DNA, but also bind with DNA gyrase through forming supramolecular complex, thereby affecting the biological function of DNA. The above findings of new piperazine hybridized coumarin indolylcyanoenones provided an inspired possibility for the treatment of resistant bacterial infections. Full article
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12 pages, 2411 KiB  
Article
Resveratrol Ameliorates Vancomycin-Induced Testicular Dysfunction in Male Rats
by Fahad S. Alshehri
Medicina 2023, 59(3), 486; https://doi.org/10.3390/medicina59030486 - 01 Mar 2023
Viewed by 1984
Abstract
Background and Objectives: Numerous studies have indicated that antibiotics may adversely affect testicular and sperm function. As an alternative to penicillin, vancomycin is a glycopeptide antibiotic developed to treat resistant strains of Staphylococcus aureus. A few studies have suggested that vancomycin could [...] Read more.
Background and Objectives: Numerous studies have indicated that antibiotics may adversely affect testicular and sperm function. As an alternative to penicillin, vancomycin is a glycopeptide antibiotic developed to treat resistant strains of Staphylococcus aureus. A few studies have suggested that vancomycin could cause testicular toxicity and apoptosis. Vancomycin, however, has not been investigated in terms of its mechanism of causing testicular toxicity. Materials and Methods: An experiment was conducted to investigate the effects of resveratrol (20 mg/kg, oral gavage) against vancomycin (200 mg/kg, i.p.) on the testicular function of Wistar rats for one week (7 days). There were three subgroups of animals. First, saline (i.p.) was administered to the control group. Then, in the second group, vancomycin was administered. Finally, vancomycin and resveratrol were administered in combination in the third group. Results: After seven days of vancomycin treatment, testosterone levels, sperm counts, and sperm motility were significantly reduced, but resveratrol attenuated the effects of vancomycin and restored the testosterone levels, sperm counts, and sperm motility to normal. In the presence of resveratrol, the vancomycin effects were attenuated, and the luteinizing hormone and follicular hormone levels were normalized after seven days of treatment with vancomycin. Histologically, vancomycin administration for seven days caused damage to testicular tissues and reduced the thickness of the basal lamina. However, the resveratrol administration with vancomycin prevented vancomycin’s toxic effects on testicular tissue. Conclusion: Resveratrol showed potential protective effects against vancomycin-induced testicular toxicity in Wistar rats. Full article
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16 pages, 2434 KiB  
Article
Synthetic Glabridin Derivatives Inhibit LPS-Induced Inflammation via MAPKs and NF-κB Pathways in RAW264.7 Macrophages
by Jaejin Shin, Leo Sungwong Choi, Hyun Ju Jeon, Hyeong Min Lee, Sang Hyo Kim, Kwan-Woo Kim, Wonmin Ko, Hyuncheol Oh and Hyung Soon Park
Molecules 2023, 28(5), 2135; https://doi.org/10.3390/molecules28052135 - 24 Feb 2023
Cited by 5 | Viewed by 2245
Abstract
Glabridin is a polyphenolic compound with reported anti-inflammatory and anti-oxidative effects. In the previous study, we synthesized glabridin derivatives—HSG4112, (S)-HSG4112, and HGR4113—based on the structure–activity relationship study of glabridin to improve its biological efficacy and chemical stability. In the present study, we investigated [...] Read more.
Glabridin is a polyphenolic compound with reported anti-inflammatory and anti-oxidative effects. In the previous study, we synthesized glabridin derivatives—HSG4112, (S)-HSG4112, and HGR4113—based on the structure–activity relationship study of glabridin to improve its biological efficacy and chemical stability. In the present study, we investigated the anti-inflammatory effects of the glabridin derivatives in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We found that the synthetic glabridin derivatives significantly and dose-dependently suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2), and decreased the level of inducible nitric oxygen synthase (iNOS) and cyclooxygenase-2 (COX-2) and the expression of pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α). The synthetic glabridin derivatives inhibited the nuclear translocation of the NF-κB by inhibiting phosphorylation of the inhibitor of κB alpha (IκB-α), and distinctively inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. In addition, the compounds increased the expression of antioxidant protein heme oxygenase (HO-1) by inducing nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) through ERK and p38 MAPKs. Taken together, these results indicate that the synthetic glabridin derivatives exert strong anti-inflammatory effects in LPS-stimulated macrophages through MAPKs and NF-κB pathways, and support their development as potential therapeutics against inflammatory diseases. Full article
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14 pages, 3240 KiB  
Article
rhTPO Ameliorates Radiation-Induced Long-Term Hematopoietic Stem Cell Injury in Mice
by Hao Luan, Jinkun Yang, Yemei Wang, Xing Shen, Xuewen Zhang, Zizhi Qiao, Shuang Xing and Zuyin Yu
Molecules 2023, 28(4), 1953; https://doi.org/10.3390/molecules28041953 - 18 Feb 2023
Cited by 1 | Viewed by 1469
Abstract
Exposure to medium and high doses of ionizing radiation (IR) can induce long-term bone marrow (BM) suppression. We previously showed that recombinant human thrombopoietin (rhTPO) significantly promotes recovery from hematopoietic-acute radiation syndrome, but its effect on long-term BM suppression remains unknown. C57BL/6 mice [...] Read more.
Exposure to medium and high doses of ionizing radiation (IR) can induce long-term bone marrow (BM) suppression. We previously showed that recombinant human thrombopoietin (rhTPO) significantly promotes recovery from hematopoietic-acute radiation syndrome, but its effect on long-term BM suppression remains unknown. C57BL/6 mice were exposed to 6.5 Gy γ-rays of total body irradiation (TBI) at a dose-rate of 63.01 cGy per minute, and the mice were treated with rhTPO (100 μg; intramuscular injection) or vehicle at 2 h after TBI. All mice were killed one or two months after TBI for analysis of peripheral blood cell counts, long-term hematopoietic stem cell (HSC) frequency, and BM-derived clonogenic activity. The HSC self-renewal capacity was analyzed by BM transplantation. The levels of reactive oxygen species (ROS) production and ratios of γH2AX+ and p16, p53, and p21 mRNA in HSCs were measured by flow cytometry and real-time polymerase chain reaction, respectively. Treatment with rhTPO reduced long-term myelosuppression by improving long-term hematopoietic reconstitution (p < 0.05) after transplantation and resting state maintenance of HSCs (p < 0.05). Moreover, rhTPO treatment was associated with a sustained reduction in long-term ROS production, reduction of long-term DNA damage, diminished p53/p21 mRNA expression, and prevention of senescence after TBI. This study suggests rhTPO is an effective agent for treating IR-induced long-term BM injury because it regulates hematopoietic remodeling and HSC cycle disorder through the ROS/p53/p21/p16 pathway long term after IR. Full article
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14 pages, 9500 KiB  
Article
Spironolactone as a Potential New Treatment to Prevent Arrhythmias in Arrhythmogenic Cardiomyopathy Cell Model
by Jean-Baptiste Reisqs, Adrien Moreau, Yvonne Sleiman, Azzouz Charrabi, Antoine Delinière, Francis Bessière, Kevin Gardey, Sylvain Richard and Philippe Chevalier
J. Pers. Med. 2023, 13(2), 335; https://doi.org/10.3390/jpm13020335 - 15 Feb 2023
Cited by 4 | Viewed by 1813
Abstract
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease associated with ventricular arrhythmias in patients. The occurrence of these arrhythmias is due to direct electrophysiological remodeling of the cardiomyocytes, namely a reduction in the action potential duration (APD) and a disturbance of Ca2+ [...] Read more.
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease associated with ventricular arrhythmias in patients. The occurrence of these arrhythmias is due to direct electrophysiological remodeling of the cardiomyocytes, namely a reduction in the action potential duration (APD) and a disturbance of Ca2+ homeostasis. Interestingly, spironolactone (SP), a mineralocorticoid receptor antagonist, is known to block K+ channels and may reduce arrhythmias. Here, we assess the direct effect of SP and its metabolite canrenoic acid (CA) in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) of a patient bearing a missense mutation (c.394C>T) in the DSC2 gene coding for desmocollin 2 and for the amino acid replacement of arginine by cysteine at position 132 (R132C). SP and CA corrected the APD in the muted cells (vs. the control) in linking to a normalization of the hERG and KCNQ1 K+ channel currents. In addition, SP and CA had a direct cellular effect on Ca2+ homeostasis. They reduced the amplitude and aberrant Ca2+ events. In conclusion, we show the direct beneficial effects of SP on the AP and Ca2+ homeostasis of DSC2-specific hiPSC-CMs. These results provide a rationale for a new therapeutical approach to tackle mechanical and electrical burdens in patients suffering from ACM. Full article
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14 pages, 1431 KiB  
Article
A Potential Therapy Using Antisense Oligonucleotides to Treat Autosomal Recessive Polycystic Kidney Disease
by Huixia Li, Chunli Wang, Ruochen Che, Bixia Zheng, Wei Zhou, Songming Huang, Zhanjun Jia, Aihua Zhang, Fei Zhao and Guixia Ding
J. Clin. Med. 2023, 12(4), 1428; https://doi.org/10.3390/jcm12041428 - 10 Feb 2023
Cited by 2 | Viewed by 1551
Abstract
(1) Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by progressively enlarged kidneys with fusiform dilatation of the collecting ducts. Loss-of-function mutations in the PKHD1 gene, which encodes fibrocystin/polyductin, cause ARPKD; however, an efficient treatment method and drug for [...] Read more.
(1) Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by progressively enlarged kidneys with fusiform dilatation of the collecting ducts. Loss-of-function mutations in the PKHD1 gene, which encodes fibrocystin/polyductin, cause ARPKD; however, an efficient treatment method and drug for ARPKD have yet to be found. Antisense oligonucleotides (ASOs) are short special oligonucleotides which function to regulate gene expression and alter mRNA splicing. Several ASOs have been approved by the FDA for the treatment of genetic disorders, and many are progressing at present. We designed ASOs to verify whether ASOs mediate the correction of splicing further to treat ARPKD arising from splicing defects and explored them as a potential treatment option. (2) Methods: We screened 38 children with polycystic kidney disease for gene detection using whole-exome sequencing (WES) and targeted next-generation sequencing. Their clinical information was investigated and followed up. The PKHD1 variants were summarized and analyzed, and association analysis was carried out to analyze the relationship between genotype and phenotype. Various bioinformatics tools were used to predict pathogenicity. Hybrid minigene analysis was performed as part of the functional splicing analysis. Moreover, the de novo protein synthesis inhibitor cycloheximide was selected to verify the degraded pathway of abnormal pre-mRNAs. ASOs were designed to rescue aberrant splicing, and this was verified. (3) Results: Of the 11 patients with PKHD1 variants, all of them exhibited variable levels of complications of the liver and kidneys. We found that patients with truncating variants and variants in certain regions had a more severe phenotype. Two splicing variants of the PKHD1 genotypes were studied via the hybrid minigene assay: variants c.2141-3T>C and c.11174+5G>A. These cause aberrant splicing, and their strong pathogenicity was confirmed. We demonstrated that the abnormal pre-mRNAs produced from the variants escaped from the NMD pathway with the use of the de novo protein synthesis inhibitor cycloheximide. Moreover, we found that the splicing defects were rescued by using ASOs, which efficiently induced the exclusion of pseudoexons. (4) Conclusion: Patients with truncating variants and variants in certain regions had a more severe phenotype. ASOs are a potential drug for treating ARPKD patients harboring splicing mutations of the PKHD1 gene by correcting the splicing defects and increasing the expression of the normal PKHD1 gene. Full article
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16 pages, 2332 KiB  
Article
CXCR2 Antagonist RIST4721 Acts as a Potent Chemotaxis Inhibitor of Mature Neutrophils Derived from Ex Vivo-Cultured Mouse Bone Marrow
by Klaudia Szymczak, Margery G. H. Pelletier, James M. Mackay, DeAnne Reid and Peter C. W. Gaines
Biomedicines 2023, 11(2), 479; https://doi.org/10.3390/biomedicines11020479 - 07 Feb 2023
Viewed by 1997
Abstract
Neutrophils act as critical mediators of innate immunity, which depends on their rapid responses to chemokines followed by their migration towards sites of infection during chemotaxis. Chemokine receptors expressed on the surface of neutrophils mediate chemotaxis by activating contractile machinery as the cells [...] Read more.
Neutrophils act as critical mediators of innate immunity, which depends on their rapid responses to chemokines followed by their migration towards sites of infection during chemotaxis. Chemokine receptors expressed on the surface of neutrophils mediate chemotaxis by activating contractile machinery as the cells escape from capillary beds and then attack pathogens. Neutrophils also contribute to inflammatory responses, which support pathogen destruction but can lead to acute and chronic inflammatory disorders. CXCR2, a G-protein-coupled chemokine receptor expressed on both myeloid and epithelial cells, is well-characterized for its capacities to bind multiple chemokines, including interleukin-8 and growth-related oncogene alpha in humans or keratinocyte chemokine (KC) in mice. Here we show that a small molecule CXCR2 antagonist termed RIST4721 can effectively inhibit KC-stimulated chemotaxis by neutrophils derived from ex vivo-cultured mouse bone marrow in a potent and dose-dependent manner. Antagonistic properties of RIST4721 are thoroughly characterized, including the maximal, half-maximal and minimum concentrations required to inhibit chemotaxis. Importantly, RIST4721-treated neutrophils exhibit robust phagocytosis and reactive oxygen species production, confirming drug specificity to chemotaxis inhibition. Together our data indicate that RIST4721 acts to inhibit inflammation mediated and potentiated by neutrophils and therefore promises to facilitate treatment of a host of inflammatory conditions. Full article
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