Drug Development Research最新文献

This study aimed to explore the function and regulatory mechanism of ALKBH5 in the progression of coronary artery calcification. Human aortic vascular smooth muscle cells (HA-VSMCs) were treated with inorganic phosphate (Pi) and exosomes derived from bone marrow mesenchymal stem cell (BMSC) carrying ALKBH5, a GSDME overexpression vector or si-GSDME. The morphology and size of the exosomes were assessed using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Calcium deposition was measured using Alizarin red staining and cell pyroptosis was evaluated using Hoechst 33342/PI staining. The association between ALKBH5 and m6A modifications was confirmed by methylated-RNA immunoprecipitation assay (MeRIP) and dot blot assays. The expression levels of ALKBH5 and GSDME were quantified by quantitative real-time polymerase chain reaction (qRT-PCR), and protein levels were quantified by western blot. BMSCs-derived exosomes reduced calcium deposition and cell pyroptosis in Pi-treated HA-VSMCs. Exosomes containing ALKBH5 overexpression inhibited high mobility group box 1 (HMGB1) and cell apoptosis, thereby promoting vascular calcification, whereas ALKBH5 knockdown in exosomes exerted the opposite effect on calcification development. Additionally, ALKBH5 was found to regulate the m6A modification of GSDME. Overexpression of GSDME reversed the effects of ALKBH5 in exosomes on HMGB1 expression and cell apoptosis. Exosomal ALKBH5 mitigated HMGB1 expression and cell pyroptosis by modulating the m6A modification of GSDME, thus influencing the progression of coronary artery calcification.

Leishmaniasis, caused by protozoan parasites of the genus Leishmania, affects nearly 12 million people annually worldwide, and has limited, highly toxic therapeutic options. This study reports the synthesis, in vitro and in silico evaluations of four novel antimony complexes (3a-3d) as potent and safe antileishmanial agents. The complexes were synthesized using Sb-salts with different phenolic ligands and characterized by elemental analysis, FT-IR and NMR spectroscopic techniques. Structural parameters were further evaluated via DFT studies. The antileishmanial activity of these complexes (3a-3d) was assessed in vitro against promastigote and axenic amastigote forms of Leishmania tropica, showing promising potential as antileishmanial agents. Complex 3a and 3c were particularly active, with IC₅₀ values of 10.8 ± 2.1 and 11.0 ± 2.0 μmol/L against promastigotes, and 20.14 ± 6.11 and 27.72 ± 0.13 μmol/L against amastigotes, respectively. Molecular docking analysis against receptor protein (PDB ID: 8FI6) from genus Leishmania revealed high binding conformations of synthesized molecules within the active cavity of the target protein. With the lowest Ki value of 1.25 and a pattern of hydrophobic π-interactions and strong conventional hydrogen bonds, complex 3d demonstrated excellent binding affinities within the active pocket. Notably, these complexes exhibited low cytotoxicity, compared to the standard antileishmanial drugs, TA (potassium antimonyl tartrate) and AmB (Amphotericin B), with hemolysis rates of < 12% for all complexes. Our findings suggest that these complexes (3a-3d) are promising candidates for the development of new, safer antileishmanial therapies, combining potent activity against L. tropica with significantly lower cytotoxicity compared to existing treatments.

Curcumin, a polyphenol compound derived from turmeric, has garnered attention for its anti-inflammatory and antioxidant properties, making it a promising candidate for treating skin inflammation. Despite its potential, the underlying pharmacological effects to skin inflammation remain unclear. Therefore, this study aimed to reveal the curcumin's molecular targets and its potential in suppressing skin inflammation using network pharmacology and in vitro experiments. A total of 7,393 and 239 targets related to curcumin and skin inflammation, respectively, were obtained from public databases. By drawing a Venn diagram, 216 common targets were identified as candidate targets. These targets were subjected to gene function and pathway enrichment analyses, and a protein-protein interaction network was established to investigate curcumin's impact on inflammation. The gene functions were mainly associated with inflammatory response, membrane raft, and serine-type endopeptidase activity. The NF-κB and MAPK pathways could be the major pathways through which curcumin acts on skin inflammation. Ten major targets of curcumin in the treatment of skin inflammation were identified: AKT1, TNF, EGFR, APP, MMP9, STAT3, HIF1A, PTGS2, EP300, and GSK3B. Molecular docking analysis results showed high binding affinity of curcumin to PTGS2, GSK3B, HIF1A, and STAT3, which may contribute to its inhibitory effect on skin inflammation. In vitro experiments confirmed curcumin's anti-inflammatory effect on inflammation by reducing the expression levels of NO, IL-1β, and IL-6 in LPS-induced HaCaT cells. Taken together, this study reveals major targets and pathways of curcumin in the treatment of skin inflammation, paving the way for invivo and clinical investigations.

The emergence of drug-resistant bacteria, often referred to as “superbugs,” poses a profound and escalating challenge to global health systems, surpassing the capabilities of traditional antibiotic discovery methods. As resistance mechanisms evolve rapidly, the need for innovative solutions has never been more critical. This review delves into the transformative role of AI-driven methodologies in antibiotic development, particularly in targeting drug-resistant bacterial strains (DRSBs), with an emphasis on understanding their mechanisms of action. AI algorithms have revolutionized the antibiotic discovery process by efficiently collecting, analyzing, and modeling complex datasets to predict both the effectiveness of potential antibiotics and the mechanisms of bacterial resistance. These computational advancements enable researchers to identify promising antibiotic candidates with unique mechanisms that effectively bypass conventional resistance pathways. By specifically targeting critical bacterial processes or disrupting essential cellular components, these AI-designed antibiotics offer robust solutions for combating even the most resilient bacterial strains. The application of AI in antibiotic design represents a paradigm shift, enabling the rapid and precise identification of novel compounds with tailored mechanisms of action. This approach not only accelerates the drug development timeline but also enhances the precision of targeting superbugs, significantly improving therapeutic outcomes. Furthermore, understanding the underlying mechanisms of these AI-designed antibiotics is crucial for optimizing their clinical efficacy and devising proactive strategies to prevent the emergence of further resistance. AI-driven antibiotic discovery is poised to play a pivotal role in the global fight against antimicrobial resistance. By leveraging the power of artificial intelligence, researchers are opening new frontiers in the development of effective treatments, ensuring a proactive and sustainable response to the growing threat of drug-resistant bacteria.

Acne is a skin disease that impacts 9.4% of the world's population. Available treatments for managing acne include retinoid-like drugs, antibiotics, corticosteroids, photo, and radiotherapy. Howevere, the aforementioned treatments have certain limitations such as possibility of developing skin cancer from tetracycline, doxycycline, and corticosteroids, microbial resistance to antibiotics, and deadly side effects, and so forth. Repurposing of existing therapeutics having excellent safety profile can be promising way to treat acne efficiently. The repurposed drugs and phytoceuticals from diverse classes have demonstrated promising effects in treating acne. These repurposed drugs have displayed antiacne effectiveness by targeting single or multiple signaling pathways. Various repurposed therapeutics undergoing clinical trials at different phases demonstrated their safety and efficacy in treating acne. Despite being a very good, safe, and less time-consuming strategy, drug repurposing (DR) faces multiple challenges such as lack of regulatory guidelines, preservation of intellectual property, and clinical validation of claimed therapeutic indication. DR appears to be a viable approach and is likely to offer effective treatment at a reasonable cost in alleviating acne.

Oleuropein (OLP), a compound predominantly found in olive leaves, has been known for its numerous biological activities, including antioxidant, anti-inflammatory, and antimicrobial properties. Despite its established therapeutic potential, its role in treating diarrhea has not been extensively explored. This study aimed to evaluate the antidiarrheal effects of OLP in an in vivo model and to investigate its molecular interactions using in silico docking studies, pharmacokinetic predictions, and toxicity analysis. In the in vivo study, castor oil was used to induce diarrhea in 3-day-old chicks, and the antidiarrheal effect of OLP was tested at doses of 10 and 20 mg/kg. The standard drug, loperamide (LOP) at 3 mg/kg, was used for comparison. The results showed that OLP at both doses significantly (p < 0.05) reduced diarrheal secretions and increased latency, with the 20 mg/kg dose demonstrating the most effective results. The combination of OLP (20 mg/kg) with LOP (3 mg/kg) further enhanced the antidiarrheal effect. In the in silico study, molecular docking revealed that both OLP and LOP exhibited strong binding affinities (BAs) to the key receptor, μ-opioid receptor associated with diarrhea, while OLP showed higher BA (‒8.9 kcal/mol) compared to LOP (‒8.7 kcal/mol). Pharmacokinetic analysis of OLP revealed favorable properties and toxicity studies revealed no acute toxicity, with an LD₅₀ of 2000 mg/kg. In conclusion, the findings suggest that OLP possesses significant antidiarrheal potential both in vivo and through receptor interaction, positioning it as a promising natural therapeutic agent for managing diarrhea. Further studies are warranted to fully elucidate its mechanisms of action and clinical applicability.

Novel thienopyrimidinone hybrids 5–25 were developed and synthesized as potential inhibitors of human EGFR and FGFR. The in vitro antiproliferative action of all compounds, towards the human breast tumor cells MDA-MB-231 and MCF-7, was evaluated with doxorubicin serving as a reference (IC₅₀ = 6.72 µM). Compound 23 demonstrated the highest anti-breast cancer efficacy against both cellular lines having IC₅₀ ranging from 2.95 to 3.80 µM. The enzyme inhibition of human EGFR and FGFR by the most active candidates 18, 21and 23–25 was further evaluated. Compounds 21 and 25 were the best EGFR inhibitors having IC₅₀ values of 0.077 and 0.059 µM, respectively, in comparison to Erlotinib (IC₅₀ = 0.04 µM). In comparison with Staurosporine (IC₅₀ = 0.024 µM), compounds 24 and 25 were the most active FGFR inhibitors having IC₅₀ values of 0.055 and 0.029 µM, respectively. The study of molecular docking was carried out among the most active EGFR inhibitors 21 and 25 and the most active FGFR inhibitors 24 and 25 to examine the relation between the binding pattern of these compounds with EGFR and FGFR catalytic active sites and their biological activity, whereas the computational results were aligned with the biological results. Finally, compound 25, which was found to be the best dual inhibitor against EGFR and FGFR, was tested for inducing apoptosis and affecting cellular arrest within G2/M phase as well as it was screened to measure its safety towards normal breast cells MCF10a with IC₅₀ value of 47.16 µM in contrast to the reference Staurosporine (IC₅₀ = 18.86 µM). Accordingly, compound 25 could be considered as a potential breast cancer therapy.

The anticancer potential of certain newly synthesized pyrazole and pyrazolopyridine derivatives has been estimated. NCI 60 cancer cells cytotoxic screening pointed out compounds 3e and 3f as the highest cytotoxic agents with % mean growth inhibition of 67.69% and 87.34%, respectively. The five dose outcomes outlined 3f as the most potent cytotoxic agent with promising MG-MID GI₅₀ = 3.3 µM when compared to erlotinib (MG-MID GI₅₀ = 7.68 µM). In the in vitro assays, compounds 3d, 3e, 3f, and 4a demonstrated dual inhibitory potential on EGFR^WT and VEGFR-2 with IC₅₀ range of 0.066−0.184 µM and 0.102−0.418 µM, respectively. The best dual EGFR/VEGRF-2 inhibitory effect was shown by the compound 3f. Moreover, the latter compound stopped the cell cycle at the G1/S phase. Also, it greatly boosted total apoptosis, including early and late apoptosis, by 54.5- and 84.7-fold, respectively, which supposes HCT-116 cell death via inducing apoptosis. This was confirmed by the elevation of the BAX and caspase-3 levels, and the decreased BCL-2 level. Moreover, the safety of the most active compound 3f was assessed and the results showed promising selectivity of compound 3f toward HCT-116 over FHC (selectivity index [SI]: 20.84) when compared to erlotinib (SI: 3.42). Finally, compound 3f demonstrated efficient binding to both EGFR and VEGFR-2 enzymes, which could explain the sufficient inhibition level of each enzyme.

Multiple sclerosis (MS) is a demyelinating disease in which the insulating cover (myelin sheath) of the brain and spinal cord is damaged. Demyelination results in a decreased signal transmission in the nervous system. Symptoms include double vision, muscle weakness, and difficulty with coordination. Genetic and viral infections have been proposed as plausible factors responsible for MS. Although there is no cure for MS, treatment prevents future attacks. At present, chemotherapy and monoclonal antibodies are the available treatments for MS. Heterocyclic compounds are currently being tested clinically for their efficacy. Some heterocyclic scaffolds have been found to be promising for the treatment of MS. In view of this, research has been conducted towards the design and discovery of chemical agents for MS. Hence, the literature relevant to drug design for MS in the last decade has been collated and described comprehensively so that it would be helpful for efficient drug design for MS in the future. Additionally, through the structure–activity relationship, the importance of crucial structural features was emphasized. The classification was primarily based on the type of heterocycle.