Acta Pharmaceutica最新文献

The voltage-gated potassium channel Kv1.3 is a key regulator of T-cell activation and a validated therapeutic target for autoimmune and inflammatory diseases. In this study, a ligand-based design strategy was employed to expand a library of benzamide-derived K_v1.3 inhibitors. Starting from a previously optimised thiophene-based inhibitor, structu ral modifications were introduced to the 2-methoxybenzamide moiety and the central tetrahydropyran or cyclohexane scaffold. A series of ketone, hydroxy, and carbamate derivatives was synthesised and evaluated for K_v1.3 inhibition using whole-cell patch-clamp electrophysiology. Structure-activity relationship analysis revealed that cis-isomers in the hydroxy series exhibited stronger activity than their trans counterparts, with some analogues displaying submicro-molar IC ₅₀ values. In the carbamate series, trans-isomers were generally more potent, with trans-18 and trans-16 achieving IC ₅₀ values of 122 and 166 nmol L-1, respectively. These results provide valuable insights into the design of K_v1.3 inhibitors and support further development of these compounds for immunomodulatory applications.

In the present work, we describe the design, synthesis, and evaluation of a galectin-8-binding fluorescent probe designed for a competitive fluorescence polarization (FP) assay for screening new galectin-8N inhibitors. The probe was characterized for its photophysical properties and its binding affinity for galectin-8N was determined by using FP. We evaluated the probe in a competitive FP assay with three known galectin-8N inhibitors and demonstrated its suitability for high-throughput screening.

Toll-like receptors (TLRs) are essential for the innate immune system as they recognize pathogen-associated molecular patterns and trigger immune responses. Overactivation of TLR8 by endogenous nucleic acids is associated with the development of autoimmune diseases and promotes inflammatory responses. This study presents the design, synthesis, and evaluation of a series of TLR8 antagonists based on the optimization of previously reported 6-(trifluoromethyl)pyrimidin-2-amines, with targeted modifications to further explore structure-activity relationships (SAR) and increase potency. A two-step synthesis involving nucleophilic aromatic substitution and Suzuki coupling was used to prepare two series of new compounds. The biological evaluation revealed that compounds 14 and 26 exhibited promising TLR8 antagonistic activity with IC ₅₀ values of 6.5 and 8.7 μmol L^{- 1}, respectively. Compound 14 showed reduced cell viability at higher concentrations, while compound 26 showed no cytotoxic effects, making it a promising candidate for further investigation.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading global health challenge, exacerbated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. One promising therapeutic target is the enzyme enoyl-acyl carrier protein reductase (InhA), which plays a vital role in the biosynthesis of mycolic acids, essential components of the bacterial cell wall. Direct inhibition of InhA offers a potential strategy for overcoming resistance mechanisms, particularly in cases where the activation of conventional drugs like isoniazid is compromised. This study investigates two novel series of InhA inhibitors based on thiadiazole and tetrahydropyran lead compounds, originally identified through high-throughput screening by GSK. Analogues were synthesised using the copper-catalysed azide-alkyne cycloaddition (CuAAC) click reaction, and their inhibitory activity was tested against InhA. Among the tested compounds, only one exhibited modest inhibitory activity, with an IC ₅₀ of 11 µmol L-1, while others were inactive. Interestingly, during the synthetic efforts, a novel reaction was discovered between aryl methyl ketones and ethynylmagnesium bromide, yielding 1,3-diols, as confirmed by X-ray diffraction analysis. These findings underscore the challenges of optimising InhA inhibitors and highlight the potential of synthetic innovations in exploring new synthetic pathways.

Famotidine, a widely used H₂-receptor antagonist, exhibits sensitivity to oxidative degradation, particularly in the presence of excipients containing peroxide impurities. This study explores the oxidative stability of famotidine under various storage conditions, with a specific focus on excipients with varying peroxide contents. A stability-indicating liquid chromatography-mass spectrometry (LC-MS) method was developed to identify and quantify famotidine degradation products, providing detailed insights into oxidative pathways. In addition, Zeneth software was employed to predict potential degradation products, and its predictive accuracy was evaluated against experimental findings. Antioxidants, including ascorbic acid, propyl gallate, and ethylenediaminetetraacetic acid (EDTA), were incorporated into compressed compatibility mixtures to assess their effects on peroxide-mediated degradation. While propyl gallate and EDTA consistently reduced peroxide levels and enhanced stability, ascorbic acid unexpectedly acted as a pro-oxidant under stress conditions, accelerating peroxide formation in povidone. These findings provide critical insights into mitigating oxidative degradation in famotidine and other solid dosage forms, emphasizing the importance of selecting appropriate excipients, antioxidants, and predictive tools to ensure product stability.

This study aims to investigate the regulatory mechanisms of METTL3, YTHDF1, and the long non-coding RNA FOXD2-AS1 in the proliferation and apoptosis of esophageal cancer, with the goal of providing a basis for molecular diagnosis and targeted therapies. Gene expression was evaluated using qRT-PCR (METTL3/14) and Western blot analysis. The Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and Transwell assay were employed to assess cell proliferation and apoptosis. The EpiQuik m6A RNA Methylation Quantification Kit was utilized to quantify total m6A levels. The interaction between YTHDF1, FOXD2-AS1, and METTL3 was confirmed using RNA Binding Protein Immunoprecipitation (RIP), Co-Immunoprecipitation (CO-IP), and RNA pull-down assays. Methylated RNA Immuno preci pitation (MeRIP) was employed to assess the m6A modification levels of FOXD2-AS1. Tissue samples from animal models were analyzed via Hematoxylin-eosin staining (HE) staining and immunohisto-chemistry to assess METTL3 expression. The expression of METTL3 was up-regulated in esophageal cancer tissues and cells. Flow cytometry and CCK-8 detection showed that silencing METTL3 could inhibit the proliferation of esophageal cancer cells but accelerate their apoptosis. MeRIP-qPCR and Prediction of m6A-modified sites indicated that METTL3 regulated the m6A modification of FOXD2-AS1. In vitro and in vivo experiments showed that YTHDF1 binds to METTL3 and regulates the m6A modification of FOXD2-AS1 to affect esophageal cancer. Our results indicate that METTL3 regulates FOXD2-AS1 in an m6A-dependent manner through its interaction with YTHDF1, thereby influencing EC proliferation and apoptosis. This suggests a potential therapeutic target for the treatment of esophageal cancer.

The aim of this study is to explore the impact of blood lipids and statins on renal function and all-cause mortality in patients with diabetic nephropathy (DN). PubMed, Embase, Web of Science, and Cochrane Library were systematically searched until April 9, 2024, for relevant studies of blood lipids and statins on renal function and all-cause mortality in patients with DN. After the selection, total cholesterol levels (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), serum creati-nine (SCR), end-stage renal disease (ESRD), and all-cause mortality indexes were extracted for finally meta-analysis. In total, 25 papers containing 21,411 patients with DN were finally included in this study. Levels of TC and LDL-C, which are continuous variables, were higher in DN patients who developed ESRD [TC/weighted mean difference (WMD) = 0.517, 95 % confidence interval (CI): (0.223, 0.812), p = 0.001; LDL-C/WMD = 0.449, 95%CI: (0.200, 0.698), p < 0.001]. In addition, this study also observed that statins may reduce UAE levels [WMD = -46.814, 95% CI: (-71.767, -21.861), p < 0.001]. Finally, the survey indicated that statins may be associated with an ESRD reduction [HR = 0.884, 95% CI: (0.784, 0.998), p = 0.045]. Blood lipids, particularly TC and LDL-C, may slow the progression of DN to ESRD. Besides, statins may protect the kidneys by lowering the excretion of UAE levels and reducing the risk of ESRD. Based on the above outcomes, the findings of this study provided robust evidence-based medical support for the future prevention, surveillance, and management of DN.

This meta-analysis directly compares the efficacy and safety of vedolizumab and tumor necrosis factor-α (TNF-α) inhibitors for patients with inflammatory bowel disease (IBD), contrary to the previous one which provided an indirect comparison. In this meta-analysis, only the studies that directly compared two treatments (vedolizumab and TNF-α inhibitors) to each other (head-to-head approach) were considered. A comprehensive literature search was conducted using the following databases: PubMed, Embase, the Cochrane Library, and Web of Science. The pooled estimates of efficacies and safety were calculated as relative risk (RR) and 95 % confidence interval (CI). The presence of bias in the published material was evaluated using Begg's test. Sensitivity analysis was used to evaluate the pooled results' robustness. In total, 32 eligible studies were finally included. Results showed that the efficacy of vedolizumab was superior to TNF-α inhibitors in clinical remission [1.26, 95 % CI: 1.15-1.39]. Moreover, the vedolizumab group showed a reduced incidence of severe adverse events (RR = 0.63, 95 % CI: 0.42-0.94) compared to TNF-α inhibitors. Our results revealed superior efficacy and safety of vedolizumab compared to TNF-α inhibitors, which provided direct evidence for the use of vedolizumab in IBD treatment. Future studies are needed to confirm our findings.

Oleanolic acid (OA) has demonstrated anticancer effects across various cancers, with some derivatives advancing to clinical trials. Howe ver, its precise mechanisms of action remain unclear, especially in oral squamous cell carcinoma (OSCC). This study employed network pharmacology, bioinformatics, molecular docking, dynamics simulations, and experimental validation to explore OA's anticancer effects in OSCC and elucidate its mechanism of action. OA's pharmacokinetic and physicochemical properties were assessed using SwissADME and Molsoft, revealing high oral bioavailability and GI absorption. SwissTargetPrediction and SuperPred identified protein targets, whereas GeneCards provided OSCC-related targets. A Venn diagram showed 34 overlapping targets between OA and OSCC. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network with 32 nodes and 164 edges, identifying HSP90AA1, STAT3, HSP90AB1, PI3KR1, and NFKB1 as key hub genes. Gene ontology and KEGG enrichment analyses highlighted relevant biological processes, molecular functions, and pathways. Molecular docking and dynamics simulations confirmed the strong binding of OA to hub targets. Experimental validation showed that OA inhibited cell viability and colony formation in a dose-dependent manner, induced apoptosis, and downregulated HSP90AA1, STAT3, and PI3KR1 proteins. In conclusion, this comprehensive study combining network pharmacology, bioinformatics, molecular simulations, and experimental assays provides valuable insights into OA's anticancer potential and detailed mechanism of action in OSCC.

Arum maculatum is a medicinal plant that has been employed in traditional medicine for treating liver diseases. The objective of the current study was to evaluate the hepatoprotective impacts of ethanolic extract of the A. maculatum leaves on cirrhosis induced by thioacetamide (TAA) in Sprague--Dawley rats. The rats were treated for two months with thioacetamide (TAA) administered intraperitoneally thrice weekly. Histopathological examination revealed severe liver damage in the thioacetamide control group, while the silymarin treatments (p < 0.05). Furthermore, A. maculatum treatment led to the normalization of pro-inflammatory cytokines TNF-α and IL-6, and increased expression of the anti-inflammatory cytokine IL-10 (p < 0.05). Thus, A. maculatum leaves might have a hepatoprotective role in rat liver cirrhosis induced by TAA, along with antioxidant and anti-inflammatory effects.