Current medicinal chemistry最新文献

Objective: The purpose of this scoping review is to provide researchers with a comprehensive knowledge map and identify existing knowledge gaps.

Introduction: Glaucoma is the leading cause of irreversible blindness worldwide. ROCK inhibitors are a novel class of intraocular pressure-lowering drugs that specifically target trabecular meshwork cells. Current research on ROCK inhibitors is dispersed across multiple directions, and their precise mechanisms of action in glaucoma treatment remain incompletely understood. For these reasons, we sought to integrate the existing evidence using a scoping review approach.

Methods: Relevant articles published between 2014 and 2024 were identified and screened using keywords in the PubMed and Embase databases. Articles were analyzed based on the inclusion and exclusion criteria.

Results: The collected studies were categorized into three main themes: intraocular pressure reduction, neuroprotection, and anti-fibrosis. A total of 23 articles were included in the review. We found that studies related to intraocular pressure reduction accounted for the majority (approximately 74%), while research on neuroprotection and anti-fibrosis was relatively limited (approximately 14% each). Furthermore, among the 23 included articles, only one was a systematic review or meta-analysis.

Conclusion: ROCK inhibitors directly act on the trabecular meshwork to lower IOP and have potential neuroprotective and anti-fibrotic effects. However, these potential effects require further clinical trials to validate their efficacy in humans. In the future, more systematic reviews and meta-analyses are also needed to integrate and summarize the current primary research findings.

Introduction: G-quadruplexes (G4s) are non-classical high-level structures that are formed by DNA/RNA sequences and have been a promising target for developing antitumor drugs. However, it is still a challenge to find a ligand that binds to a particular G4 with selectivity. Telomeric multimeric G4s are more accessible for screening for specific ligands due to their higher-order structure compared with telomeric monomeric G4s.

Methods: In this study, the natural product berberine was found to exhibit a higher selectivity for telomeric multimeric G4 in comparison with other G4s. The mechanism of interaction between telomeric G4s and berberine was further investigated by fluorescence spectra measurements, job plot analysis, and UV titrations. We found that there are three binding sites for berberine on telomeric dimeric G-quadruplex Tel45, which are located at the 5' and 3' terminal G-quartet surfaces and the pocket between the two quadruplex units of Tel45. It was worth noting that the berberine preferred to interact within the interfacial cavity between two G4 units.

Results: Moreover, via dynamic light scattering (DLS) and native polyacrylamide gel electrophoresis (Native-PAGE) assays, it was found that the particle size of the telomeric multimeric G4s conformation was significantly increased by the addition of berberine. In contrast, the particle sizes of Tel21 did not change significantly after the addition of berberine. An immunofluorescence assay indicated that berberine induced the formation of endogenous telomeric G4 structures along with the related telomeric DNA damage response.

Conclusion: This study provides a hypothetical basis for the development of natural products targeting telomeric G4 as antitumor drugs.

Background: Lung Squamous Cell Carcinoma (LUSC), a major subtype of non-small cell lung cancer, presents significant treatment challenges due to limited targeted therapy options. This study aims to identify novel therapeutic targets to improve therapeutic strategies for LUSC.

Methods: By employing bulk RNA sequencing, Weighted Gene Co-expression Network Analysis (WGCNA), survival analysis, and Mendelian Randomization (MR), we pinpointed genes with prognostic relevance to LUSC. These genes were further scrutinized for their therapeutic potential through LASSO regression, Protein-Protein Interaction (PPI) network analysis, and immune infiltration assessments. To delve into the roles and cell-specific expressions of these genes within the LUSC microenvironment, pathway enrichment analysis, single-cell RNA sequencing (scRNA-seq), and pseudotime analysis were conducted.

Results: Our integrative approach identified 23 prognostically significant therapeutic targets, categorized into tier-one, tier-two, and tier-three genes based on their potential therapeutic relevance. Functional enrichment analyses highlighted the significant role of these genes in immune response regulation, particularly in T-cell receptor signaling and the complement system. scRNA-seq analysis revealed cell-type-specific expression patterns and pseudotime analysis provided insights into cellular heterogeneity and developmental trajectories in LUSC.

Conclusions: In this study, we identified 3 tier-one genes (MCM6, C4B, CTC-463A16.1), 7 tier-two genes (C4A, HLA-DRB9, LIMS2, LINC00654, MYO7B, SIGLEC5, TIE1), and 13 tier-three genes (AC007743.1, AC147651.4, ALDH2, BTN3A2, BTNL9, CCR1, GIPC3, HLA-DQB1, ICAM5, LIMD1, PM20D1, RP11-302L19.3, RP11-768F21.1).

Introduction: Fat grafting procedures for body contouring and cosmetic reconstruction have received widespread attention.

Method: In recent years, there has been an increase in post-fat grafting infections caused by Mycobacterium abscessus (MA), and there is a lack of representative and standardized murine models of infection; therefore, there has been limited research on the treatment of post-fat grafting MA infections. To overcome this challenge, we constructed an MA infection model after fat grafting.

Result: By evaluating skin charge, dermatopathology, and inflammatory markers, we found that the fat graft + 1 × 109 CFU/mL bacterial suspension infection group had significant inflammatory symptoms and elevated inflammatory factors on postoperative day 10.

Conclusion: The model construction process was simple and reproducible, which paves the way for further studies on the impact of MA pathogenesis and the efficacy of new treatments.

Introduction/objectives: Escherichia coli strains are known to cause various gastrointestinal disorders, with Shiga toxin 2, a potent cytotoxin, being a key virulence factor contributing to disease severity. Targeting Shiga toxin 2 presents a promising approach for therapeutic intervention in controlling E. coli O157 infections. This study aims to explore natural and synthetic inhibitors as potential therapeutic agents against Shiga toxin 2 through in-silico molecular docking and drug-likeness predictions.

Methods: An in-silico molecular docking study was conducted using AutoDock Vina and Chimera to assess the binding affinity of various natural and synthetic inhibitors against Shiga toxin 2. The selected inhibitors were evaluated for their drug-likeness based on adsorption, distribution, metabolism, and excretion (ADME) properties, applying Lipinski's rule of five and the Boiled-Egg technique to predict their suitability as potential drugs in biological systems.

Results: During the screening process, luteolin, a natural flavonoid, exhibited the highest binding affinity to Shiga toxin 2, with a notable negative binding energy of -8.7 kcal/- mol, indicating strong interaction potential.

Conclusion: The findings suggest that luteolin holds promise as a lead molecule for further development as a therapeutic agent against E. coli infections, warranting additional studies to validate its efficacy and safety.

Background: Calix[n]arenes have attracted great attention due to their biocompatibility and superior stability. When the necessary functional groups are attached to these compounds, they may have the potential to target tumor tissues. Benzimidazoles were among the anticancer drugs discovered in recent years.

Aim: The aim of this study was to design and synthesise a series of calix[4]arenes-benzimidazole. For comparison purposes, a benzimidazole derivative was synthesized by attaching it to the diester. Present the anticancer effects of these compounds by performing cell proliferation, apoptosis and cell imaging studies in cancer cell lines.

Methods: Some of the obtained compounds were synthesized by methods in literature studies, and the rest were synthesized by modifying previous methods. As a result, a total of 3 new fluorescent calix[4]arene-benzimidazole derivatives were synthesized. MTT was used for cell proliferation, and Annexin V was used for apoptosis studies. For Confocal imaging studies, cells were treated with DAPI and MitoTracker dyes.

Results: Four designed calix[4]arene-benzimidazole were successfully synthesized and structurally confirmed by NMR, and IR spectroscopy. Anticancer study of four synthesized substances was performed. Bio-imaging studies were performed using Confocal Microscopy for these three successfully synthesized fluorescent compounds.

Conclusion: CB5-a and CB5-b were found to be the most effective against HT-29 cells and CB5-c against HELA cells in the MTT test. Apoptosis analyses also proved that these compounds inhibited the proliferation of cancer cells. As a comparison substance, the synthesized CB5-R proven to be less cytotoxic than the fluorescent compounds by the MTT method, and we can say that the cationic compound bound to the calix[4]arene is more effective than the molecule bound to the diester.

Lipids play a variety of roles in living systems. They are a source of extremely high energy and a part of almost all signaling and biological processes. Despite the liver being the hub of lipid metabolism, lipid metabolism occurs across the human body. Any perturbation in the lipid metabolism or lipid storage systems can lead to diseases or disorders that can hamper the normal functioning of the human body. Lipids have been explored for their role in cancers. The intake of saturated fatty acids has been found to increase the metastasis and growth of cancerous cells. The role of lipids has also been studied in brain diseases. In Tay-Sachs disease, the inability to metabolize GM2 ganglioside alters normal nerve cell functioning. Similarly, lipids also play critical roles in Parkinson's and Alzheimer's disease. Moreover, atherosclerosis is a leading cause of cardiovascular diseases and brain stroke. Dyslipidemia or excess fatty acids is a leading cause of non-alcoholic fatty liver disease, insulin resistance, and diabetes mellitus. Dyslipidemia also leads to jaundice, which, in turn, can seriously damage the kidneys. This review focuses on the various human diseases occurring because of lipid metabolism.

The present review was undertaken to clarify the potential role of the lysyl oxidase (Lox) family of enzymes in delaying graft dysfunction. Delayed graft failure is a well-known event that occurs post-transplantation period. Ischemia and trauma to the graft tissue before or during the operation procedures are likely to be the most important etiological causes of this complication. The lox proteins family including Lox and Lox-- like proteins (LoxL1-4) are copper-dependent enzymes that catalyze the cross-linking of collagens to stabilize extracellular matrix (ECM). Hypoxia-induced factor 1-α (HIF-1α) and transforming growth factor β (TGF-β) are two upstream regulators of the Lox proteins family whose expression increased following hypoxia and tissue injury. Lox proteins' overactivation upregulates several intracellular transduction pathways to promote oxidative stress (OS), ECM proteins accumulation, and epithelial to mesenchymal transition (EMT) contribute to vascular stiffness and tissue fibrogenesis, which increase the risk of graft failure post solid organ transplantation (SOT). Preclinical studies have shown that Lox protein inhibitors have the potential to prevent organ fibrosis. Regarding the molecular effects of Lox proteins in causing tissue fibrosis, these molecules can be further investigated as a drug target in reducing the possibility of organ fibrosis after allograft transplantation.

Background: Infertility was often considered a female issue, but male infertility emerged significantly after the Covid-19 pandemic. Hence, assessments are crucial for planning policies on health care and family planning and reasons thereof post vaccinations.

Material and methods: The present study was a case-control, dual-centers, prospective study with normal sperm parameters. Semen samples collected by masturbation for idiopathic reasons were conducted at King Abdulaziz University with 133 samples, followed by molecular modeling via interaction between IZUMO1, Alpha2A adrenergic receptor, and Fibroblast growth factor receptor 2 protein with IgA antibody produced post vaccination/infection.

Results & discussion: The infertile males under 30 (21%), 31-40 (50%), 41-50 (24%) and over 50 (5%), with altered sperm motility grades are A (8.45%), B (11.1%), C (15.8%), and D (59.8%) were reported. Liquefaction times range from 36 to 30 minutes by age, with abnormal sperm percentages between 43.85% and 46.33%. Protein molecular interaction between IZUMO1, Alpha2A adrenergic receptor, and Fibroblast growth factor receptor 2 protein with IgA antibody shows cumulative length of 25.354 Å, 39.049 Å, and 41.999 Å, respectively, with significant interaction between atoms chain, amino acid, marked variation in bond length.

Conclusion: Male infertility peaks at 31-40 years, with lowering in men aged 41-50 years, IgA antibody reduced sperm motility, causing immunogenic infertility exacerbated post-Covid-19 vaccination or infection. Interaction of IgA and various receptors produced stable interactive molecules of IgA and proteins on sperm, affecting motility, aliquefication, and abnormal sperm percentage disturbing the normal dynamics of sperm cells opening a new dimension of infertility among males.

Mercury is a pervasive global pollutant, with primary anthropogenic sources including mining, industrial processes, and mercury-containing products such as dental amalgams. These sources release mercury into the environment, where it accumulates in ecosystems and enters the food chain, notably through bioamplification in marine life, posing a risk to human health. Dental amalgams, widely used for over a century, serve as a significant endogenous source of inorganic mercury. Studies have demonstrated that mercury vapor can be released from amalgams at room temperature due to material corrosion, potentially leading to chronic exposure. Pregnant women and children are particularly susceptible to mercury's toxic effects, with research linking prenatal mercury exposure to developmental delays, neurocognitive deficits, and conditions such as autism spectrum disorder. Moreover, the long-term accumulation of mercury in the body raises concerns about delayed health impacts in individuals exposed during childhood. Recent findings suggest even low levels of mercury exposure may contribute to kidney damage mediated by oxidative stress, highlighting the importance of monitoring mercury levels in vulnerable populations. Prenatal mercury transfer and postnatal exposure through breastfeeding further amplify the risks. This review critically assesses the health implications of mercury exposure from dental amalgams, focusing on its impact on pregnancy and childhood development. It underscores the need for updated regulatory measures to mitigate mercury-related risks and calls for further research to clarify the extent of mercury's long-term effects on human health.