Combinatorial chemistry & high throughput screening最新文献

Introduction: Icteric hepatitis remains a significant clinical challenge. The integration of Chinese Herbal Medicine (CHM) with conventional Western Medicine (WM) is becoming increasingly common; however, its overall efficacy and safety profile requires systematic evaluation. This study aims to conduct a meta-analysis to assess the safety and effectiveness of using CHM in conjunction with WM to treat icteric hepatitis.

Methods: We conducted a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and major Chinese databases (CNKI, Wanfang, VIP, CBM) from inception to December 2023 for Randomized Controlled Trials (RCTs) comparing CHM plus WM with WM alone for icteric hepatitis. Two reviewers independently performed study selection, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0 tool. Meta-analysis was performed using RevMan 5.4 software.

Results: Eight RCTs involving 645 participants were included. The combined therapy group demonstrated a significantly higher clinical efficacy rate (RR = 1.22, 95% CI [1.11, 1.34], P < 0.0001) compared to the WM alone group. The combined therapy also resulted in greater improvements in liver function, with significant reductions in ALT (WMD = -58.33 U/L, 95% CI [- 87.75, -28.91]), AST (WMD = -47.11 U/L, 95% CI [-69.83, -24.39]), TBIL (WMD = -48.27 μmol/L, 95% CI [-67.48, -29.06]), and DBIL (WMD = -31.30 μmol/L, 95% CI [-45.16, -17.44]). Furthermore, the integrated approach led to lower levels of inflammatory markers (IL-6, CRP, TNF-α) and faster symptom resolution. There was no significant difference in the incidence of adverse events between the two groups (RR = 0.83, 95% CI [0.44, 1.57], P = 0.56).

Discussion: The pooled evidence suggests that adding CHM to standard WM treatment can enhance therapeutic outcomes by improving liver function and reducing systemic inflammation. The synergistic effects may be attributed to the multi-target pharmacological properties of the herbs used. However, the findings are limited by the high risk of bias and significant heterogeneity across the included studies.

Conclusion: The adjunctive use of CHM with WM appears to be an effective and safe strategy for treating icteric hepatitis. Nonetheless, due to methodological weaknesses in the primary studies, these results should be interpreted cautiously. High-quality, rigorously designed RCTs are needed to confirm these findings.

Introduction: Allergic airway inflammation (AAI), an asthma-like condition, is characterized by Th17/Treg imbalance and PD-1/PD-L1 pathway dysregulation. Yanghe Pingchuan Granules (YP) formulation is clinically used to treat asthma, but its immunomodulatory mechanisms remain unclear.

Methods: Using an AAI rat model, the effects of YP were assessed. Flow cytometry was carried out to analyze Th17/Treg proportions. Additionally, the expression levels of Foxp3, ROR?t, IL- 10, IL-17, and TGF-1 were measured. PD-L1 siRNA knockdown and overexpression studies were performed to elucidate the role of the pathway.

Results: YP treatment restored the Th17/Treg balance by reducing Th17 and increasing Treg cells. It upregulated IL-10 and TGF-1 while downregulating IL-17. YP inhibited the PD-1/PDL1 pathway, correlating with improved immune balance and reduced inflammation. PD-L1 modulation confirmed its role in mediating the effects of YP on cellular and cytokine profiles.

Discussion: The findings indicated that the therapeutic action of YP involves modulation of the Th17/Treg imbalance, likely through inhibition of the PD-1/PD-L1 pathway, thereby shifting thecytokine milieu from a pro- to an anti-inflammatory state.

Conclusion: YP alleviates AAI by modulating the PD-1/PD-L1 pathway to restore Th17/Treg balance and suppress inflammation, thereby revealing its potential immunomodulatory mechanism.

Introduction: Despite the global burden of chronic obstructive pulmonary disease (COPD), its pathogenesis remains elusive, and current therapies fail to halt disease progression. Calycosin, a bioactive isoflavone from Traditional Chinese Medicine (TCM), exhibits antiinflammatory and antioxidant properties, yet its therapeutic potential in COPD remains unexplored.

Methods: We integrated transcriptomic data of human lung tissue from the Gene Expression Omnibus (GEO) database (GSE8581) and human serum metabolomic data from a published research paper to identify COPD-associated pathways. Network pharmacology, including target screening, analysis, and molecule docking, was employed to elucidate the mechanisms of calycosin for COPD therapy.

Results: Multi-omics analysis revealed significant activation of the pyruvate metabolism pathway and glyoxylate/dicarboxylate metabolism pathway in COPD patients, with 590 differentially expressed genes (DEGs) and 116 differentially expressed metabolites (DEMs) identified. Calycosin targets six key regulators (NME1, ALDH2, PGAM1, LDHA, PCNA, RASD1) with binding affinities (-5.1 to -10.2 kcal/mol) validated via molecular docking, implicated in these pathways.

Discussion: This study bridges TCM-derived natural products with modern omics-driven drug discovery, revealing calycosin as a promising COPD intervention by targeting metabolic hubs to mitigate inflammation and metabolic dysfunction, and pioneering an integrated multi-omics and network pharmacology framework for elucidating TCM mechanisms. However, the lack of direct experimental validation in COPD models and the use of data from different biological sources limit the extrapolation of the results. Further in vitro and in vivo experiments are needed.

Conclusions: This integrated analysis highlights distinct metabolic pathway perturbations, specifically in pyruvate and glyoxylate/dicarboxylate metabolism, as key components of COPD pathophysiology and proposes calycosin as a mechanistically grounded candidate for modulating these pathways. This work shifts focus towards metabolic dysregulation as a central therapeutic target, providing a foundation for developing novel strategies to manage COPD beyond symptom control.

Introduction: This study aimed to investigate the therapeutic effect and mechanism of Yangweishu granules (YWS) for stress gastric ulcer (SGU).

Methods: The rat SGU model was established using the water immersion restraint stress method (WIRS). The therapeutic effect of YWS was evaluated by observing the histological changes of the stomach tissue, the levels of inflammatory factors, and oxidative stress. Meanwhile, the potential core targets and signaling pathways of YWS in anti-SGU action were analyzed using network pharmacology methods, and the related pathways were experimentally verified.

Results: YWS decreased the expressions of TNF-α, IL-1β, IL-6, and MDA in serum, and increased the levels of IL-4, IL-10, SOD, and GSH-PX. Network pharmacology analysis suggested that YWS may act on the targets of TLR4, AKT1, IL-10, TNF-α, IL-1β, and TP53 through the toll-like receptor pathway to treat SGU. RT-PCR, immunohistochemical, and Western blot results showed that YWS significantly inhibited the TLR4/MyD88/IKB-α pathway. Molecular docking results showed that the main active component of YWS could bind tightly to the TLR4 protein.

Discussion: This study established an animal model of SGU and preliminarily investigated the therapeutic effects and mechanism of YWS. To more comprehensively evaluate its application value in the treatment of peptic ulcers, subsequent studies should construct various types of ulcer models, further systematically assess the efficacy of YWS, and deeply explore its potential mechanism.

Conclusion: YWS could alleviate WIRS-induced SGU in rats, and its potential mechanism was found to involve the inhibition of the TLR4/MyD88/ IKB-α signaling pathway.

Introduction: Allergic rhinitis (AR) has long been considered to be associated with chronic adenotonsillar disease (CATD). However, their causal relationship remains unclear. This study aims to investigate the causal relationship between AR and CATD and to examine the mediating role of chronic rhinosinusitis (CRS) in this association.

Methods: This study employed a two-sample Mendelian randomization (MR) design using genetic instrumental variable analysis. Data for allergic rhinitis (AR) were obtained from the MRC IEU OpenGWAS data infrastructure, data for chronic adenotonsillar disease (CATD) from the FinnGen biobank, and data for chronic rhinosinusitis (CRS) from the GWAS Catalog. Several MR methods were applied. In addition, a two-step MR approach was used to investigate the mediating role of CRS in the relationship between AR and CATD.

Results: MR analysis identified a positive correlation between AR and CATD. IVW and weighted median analyses showed significant causal effects (beta = 0.55, 95% CI: 0.26 to 0.84); p <0.001). No causal association was found between CATD and AR. AR and CRS showed a positive correlation (beta = 1.38, 95% CI: 0.78 to 1.98; p = 6.5 × 10-6). CRS had a beta value of 0.15 (95% CI: 0.06 to 0.24; p = 0.001) for CATD. CRS mediates 37.6% of the AR to CATD pathway (mediation effect = 0.20, 95% CI: 0.04 to 0.37; p = 0.013).

Discussion: These findings indicate that AR may contribute to CATD risk through CRS, highlighting the need for further research to explore underlying biological mechanisms and validate these findings.

Conclusions: This study suggests a positive causal relationship between AR and CATD, with CRS acting as a mediator.

Introduction: Metabolic Dysfunction-Associated Steatohepatitis (MASH) is a growing global health concern, with only one FDA-approved therapy currently available. Acetyl-CoA carboxylase (ACC) inhibition has emerged as a promising strategy, yet effective and clinically translatable inhibitors remain limited. This study aimed to identify potential ACC inhibitors for MASH via drug repurposing.

Methods: A small-molecule library was screened using structure-based virtual screening, and candidate compounds were validated in a free fatty acid-induced MASH cell model. Intracellular triglyceride (TG) and aspartate aminotransferase (AST) levels were measured, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate lipid metabolism- related gene expression. Molecular dynamics simulations were conducted to further evaluate binding stability.

Results: Lanatoside C was identified as the most potent candidate. In vitro studies revealed significant reductions in TG and AST levels, downregulation of lipogenesis-related genes (SREBP1, FASN, ACC), and upregulation of fatty acid oxidation genes (CPT1A, ACOX1, FABP1). Molecular dynamics simulations confirmed the stable binding of Lanatoside C to ACC.

Discussion: These findings indicate that Lanatoside C exerts dual regulatory effects on lipid metabolism by suppressing fatty acid synthesis and enhancing oxidation. As an FDA-approved cardiac glycoside, Lanatoside C's known pharmacological profile supports its potential repositioning for MASH, although further in vivo studies and mechanistic validation are warranted.

Conclusion: Lanatoside C demonstrates promise as a repurposed ACC inhibitor for MASH treatment, offering a cost-effective repurposing strategy to advance therapeutic options for MASH.

Introduction: The rising demand for sustainable, nutritionally rich food sources has sparked interest in non-traditional protein sources, including gastropods. In northeastern India, freshwater gastropod species are widely consumed, particularly by certain tribes and communities, both as a traditional delicacy and for their nutritional value. This study delves into the biochemical composition of three commonly consumed freshwater gastropod species in Assam, namely Pila globosa, Pila scutata, and Brotia costula, to evaluate their potential as alternative food sources, with a focus on nutritional value and palatability.

Methods: In the present study, proximate analysis was done by using standard methods given in the Association of Official Analytical Chemists (AOAC, 2015). Mineral analysis was carried out using the atomic absorption spectrophotometer (AAS). High Performance Liquid Chromatography (HPLC) (method QA.16.5.10/AOAC 19th edition) was employed for the determination of amino acid contents of the samples.

Results: Among the species analyzed, P. scutata and P. globosa displayed the highest protein content, whereas B. costula exhibited greater levels of ash and carbohydrates. Mineral analysis showed that P. globosa contained the highest concentrations of calcium (Ca), magnesium (Mg), iron (Fe), zinc (Zn), and copper (Cu). Amino acid profiling revealed lysine and serine as the key essential and non-essential amino acids, with P. globosa and P. scutata showing higher concentrations, respectively.

Discussion: This study highlights the nutritional richness of three freshwater gastropod species, with Pila globosa and Pila scutata showing high protein and mineral content, and Brotia costula contributing to energy and mineral intake. Their amino acid profiles further enhance their dietary value. Gastropods in local culture embody the use of snail meat as a part of traditional food source, highlighting different ethnomedicinal beliefs. Despite their benefits, these species remain underutilized, suggesting the need for broader awareness and integration into mainstream diets to support food security and nutrition in northeastern India.

Conclusion: Given the current scenario of food disparity, incorporating gastropods into human diets could provide a sustainable and reliable source of protein and micronutrients, particularly in areas where food security is a concern.

Introduction: This study aimed to examine the impact of quercetin on a mouse model of endometriosis and elucidate its underlying mechanisms.

Methods: An endometriosis model was established using C57BL/6 mice, which were divided into three groups: 1) sham group, 2) model group, and 3) model group treated with daily gavage administration of 100 mg/kg/d quercetin. Histopathological examination was performed using hematoxylin and eosin (HE) staining. The microstructure of the lesions was examined using electron microscopy. The expressions levels of related proteins, such as the peroxisome proliferator- activated receptor-γ (PPARγ), methionine adenosyl-transferase 2A (MAT2A), Ki67 and VEGF was measured using Western blotting or Immunohistochemistry.

Results: Compared to the model group, the medication group showed sparse endometrial stromal cells, irregular morphology, and numerous vacuoles, indicating apoptosis. Compared to the sham group, SAM expression was unchanged (P > 0.05), while PPARγ decreased. MAT2A, PRMT5, cyclin D1, and C-MYC increased, and vimentin, Ki67, VEGF, and caspase-1 were strongly positive (P < 0.05). Quercetin intervention reduced ectopic lesion weights, increased PPARγ, and decreased MAT2A, PRMT5, SAM, cyclin D1, and C-MYC. Vimentin, Ki67, VEGF, and caspase-1 were weakly positive (P < 0.05).

Discussion: These results indicate that quercetin effectively reduced endometriosis lesions by modulating key protein expressions and promoting apoptosis.

Conclusion: Quercetin modulated the transcription of the MAT2A/PRMT5 gene by activating PPARγ activity, thereby influencing the ectopic implantation and growth of endometrial cells.