Combinatorial chemistry & high throughput screening最新文献

{"title":"Differential Expression of miR-146a, IL-31, and IL-33 in Osteoporosis and their Associations with Disease Severity.","authors":"Morteza Sheikhi Nooshabadi, Batool Zamani, Maryam Loghman, Fatemeh Sadat Asgarian, Hossein Motedayyen, Mohammad Hosesin Pourhanifeh, Mahdi Rafiyan","doi":"10.2174/0113862073473000260911101957","DOIUrl":"https://doi.org/10.2174/0113862073473000260911101957","url":null,"abstract":"<p><strong>Introduction: </strong>Osteoporosis is a metabolic disorder characterized by reduced bone mass and microarchitectural deterioration, and it is closely associated with inflammatory processes. This study investigated the expression of microRNA-146a (miR-146a), interleukin-31 (IL-31), and interleukin-33 (IL-33) in osteoporosis and their correlations with disease severity.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells (PBMCs) were isolated from 31 patients with moderate and severe osteoporosis and 28 healthy controls. Expression levels of miR-146a, IL-31, and IL-33 were assessed using real-time PCR. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). Demographic and clinical data, including age, gender, fracture history, and femoral and spinal T-scores, were recorded.</p><p><strong>Results: </strong>MiR-146a expression was significantly lower in patients with moderate and severe osteoporosis than in healthy controls (P < 0.05). MiR-146a levels were inversely correlated with patient age (r = -0.316, P < 0.05). No significant differences in IL-31 or IL-33 expression were observed between patient and control groups. Furthermore, no significant differences in miR-146a, IL-31, or IL-33 levels were found between patients with moderate and severe osteoporosis. However, IL-31 levels were strongly correlated with IL-33 levels in patients (r = 0.76, P < 0.0001), and IL-33 levels were positively associated with C-reactive protein (CRP) values (r = 0.366, P < 0.05). ROC analysis indicated modest discriminative ability of miR-146a between patients with osteoporosis and healthy controls. Because miR-146a expression was lower in patients, the ROC direction was oriented toward the control classification, yielding an AUC of 0.655 (P < 0.05). This represents the same underlying discrimination as the complementary AUC obtained when osteoporosis is defined as the positive class and should not be interpreted as a separate metric for \"non-occurrence\" prediction. A cut-off value of 0.02 yielded a sensitivity of 82.1% and a specificity of 51.6% for the control classification direction.</p><p><strong>Discussion: </strong>The significant downregulation of miR-146a in osteoporotic patients and its positive correlation with femoral T-scores suggest a potential role for this microRNA in the pathophysiology of osteoporosis, possibly through its regulatory function in inflammatory pathways. However, the weak correlation and modest discriminative performance indicate that miR-146a alone is unlikely to serve as a reliable diagnostic biomarker. The strong correlation between IL-31 and IL-33 levels, along with the positive association between IL-33 and CRP, points to a potential interplay between these interleukins and systemic inflammation in osteoporosis. Nonetheless, the absence of significant differences in IL- 31 and IL-33 between patients and controls raises questions about their direct involvement in disease pathoge","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Anti-Prostate Cancer Mechanism of Yanghe Decoction through the PI3K/AKT/mTOR Signaling Pathway.","authors":"Jie Li, Yan Zhang, Xi Li, Xinjun Dai","doi":"10.2174/0113862073441270260211113636","DOIUrl":"https://doi.org/10.2174/0113862073441270260211113636","url":null,"abstract":"<p><strong>Introduction: </strong>Advanced prostate cancer is highly metastatic, invasive, and resistant to therapy, leading to poor patient quality of life and high mortality rates. Thus, there is an urgent need for novel and effective treatment strategies. Yanghe Decoction (YHD) is a classic anticancer herbal formula used in the treatment of various cancers. However, its therapeutic effects on prostate cancer and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>The active metabolites of YHD were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP), BATMAN-TCM, and SwissTargetPrediction databases. Prostate cancer-related targets were obtained from GeneCards and OMIM, while potential therapeutic targets of Yanghe Decoction for prostate cancer were identified through Gene Ontology (GO) and KEGG enrichment analyses. R programming was employed to elucidate the relationship between prostate cancer-related targets and potential targets of YHD. To further investigate its antiprostate cancer mechanisms, cell proliferation assays using 22RV1 cells and mouse xenograft models were conducted to validate the therapeutic effects and underlying mechanisms. The effects of PI3K/AKT/mTOR signaling on 22RV1 cell proliferation, apoptosis, and cell cycle progression were evaluated using CCK-8 assays, flow cytometry, and Western blot analysis.</p><p><strong>Results: </strong>Twenty-two active metabolites in YHD were identified through the Traditional Chinese Medicine Systems Pharmacology (TCMSP), BATMAN-TCM, and SwissTargetPrediction databases, corresponding to 1,792 potential targets. The screening criteria included Oral Bioavailability (OB) ≥30% and Drug-Likeness (DL) ≥0.18. GO and KEGG pathway analyses identified the PI3K/Akt/mTOR signaling pathway as a key pathway associated with YHD. Combined in vitro and in vivo experiments demonstrated that YHD significantly inhibits the proliferation of 22RV1 cells. YHD promoted apoptosis in both 22RV1 cells and xenograft tumors, while inhibiting cell cycle progression and invasive capacity. Mechanistically, YHD suppressed the expression of phosphorylated PI3K, AKT, and mTOR proteins.</p><p><strong>Discussion: </strong>Yanghe Decoction promoted caspase-3 activity and suppressed Bcl-2 expression. Additionally, it inhibited the phosphorylation of key proteins in the PI3K/AKT/mTOR pathway in a concentration-dependent manner. By inhibiting the PI3K/AKT/mTOR signaling pathway, Yanghe Decoction induced apoptosis in 22RV1 cells, suggesting its potential therapeutic value for prostate cancer. These findings provide novel insights and a promising strategy for the treatment of prostate cancer.</p><p><strong>Conclusion: </strong>YHD inhibited proliferation and induced apoptosis in prostate cancer 22RV1 cells, potentially through suppression of PI3K/AKT/mTOR signaling pathway activation.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Metabolomics, Network Pharmacology, and Experimental Validation Elucidate the Mechanisms Underlying Dingxiang-Guanshitong Decoction in the Treatment of Esophageal Squamous Cell Carcinoma.","authors":"Yaling Zhang, Dongdong Li, Tianqing Sang, Yajing Yang, Hao Zhang, Tao Sun, Xiaoqi Chen, Yuling Zheng, Suhui Wu","doi":"10.2174/0113862073483593260903044354","DOIUrl":"https://doi.org/10.2174/0113862073483593260903044354","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Esophageal Squamous Cell Carcinoma (ESCC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis, particularly in advanced stages. Dingxiang Guan Shitong Decoction (DGD) is a traditional Chinese medicine preparation that can alleviate symptoms in patients with advanced ESCC. However, the chemical composition, pharmacological effects, and molecular mechanisms of action of DGD remain unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study evaluated the efficacy of DGD in advanced ESCC by conducting a clinical trial. Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) was employed to identify the chemical constituents of DGD. The interaction between the bioactive compounds in DGD and potential targets of ESCC was predicted using network pharmacology analysis, and the predictions were verified by molecular docking. The effects of DGD on cell biology and the expression of predicted target genes were confirmed in vitro using the ESCC cell line.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;DGD treatment significantly improved quality of life and TCM syndrome scores in patients with advanced ESCC. The UPLC-MS analysis identified 54 bioactive components in DGD. Network pharmacological analysis indicated that these bioactive components in DGD could target 129 potential ESCC-related genes. Functional analysis demonstrated that these core target genes were enriched in tumor-related pathways, including the p53 signaling pathway, apoptosis, and the IL-17 signaling pathway. Molecular docking experiments showed that the core DGD constituents (quercetin, kaempferol, and β-sitosterol) exhibited strong binding affinities for the protein products of key target genes (such as TP53 and AKT1). Moreover, in vitro experiments demonstrated that DGD inhibited the proliferation and migration of Eca-109 cells and simultaneously induced apoptosis in a dose-dependent manner. In addition, DGD treatment upregulated the expression of Bax, cleaved caspase-3, and p53 at the protein level in Eca-109 cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;The integration of clinical observation, metabolomics, network prediction, and experimental validation provides a multi-level understanding of DGD's therapeutic mechanism. The convergence of computational predictions and in vitro experimental data strongly supports the p53/caspase-3 axis as a key mediator of DGD-induced apoptosis. These findings position DGD as a promising adjunctive therapy for advanced ESCC, particularly for patients who are ineligible for or intolerant of aggressive conventional treatments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our study provides evidence that DGD leads to significant improvements in the quality of life for individuals diagnosed with advanced ESCC. Its active ingredients may exert anti-tumor effects by inducing apoptosis through the p53/caspase-3 signaling pathway. This study provides foundational data for the clinical application of DGD and a basis ","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diosmetin Inhibits Bladder Cancer through Suppression of the PI3K-AKT Signaling Pathway and Activation of the p53 Signal Pathway Revealed by Network Pharmacology and In Vitro Experimental Verification.","authors":"Lin Chen, Xiaoming Long, Jin Yang","doi":"10.2174/0113862073484524260824112648","DOIUrl":"https://doi.org/10.2174/0113862073484524260824112648","url":null,"abstract":"<p><strong>Introduction: </strong>Diosmetin, a naturally occurring flavonoid abundant in plants such as chrysanthemums, lemons, and oranges, has been reported to exhibit diverse antitumor properties. However, its potential efficacy against bladder cancer remains unexplored. This study aims to investigate the anti-bladder cancer effects of Diosmetin and elucidate the underlying mechanisms using network pharmacology combined with in vitro experiments.</p><p><strong>Methods: </strong>Public databases were employed to identify shared targets between Diosmetin and bladder cancer. A Protein-Protein Interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to predict core targets and signaling pathways. The predicted mechanisms were subsequently validated through in vitro assays.</p><p><strong>Results: </strong>A total of 48 common targets were identified. PPI network analysis revealed 22 hub genes, including AKT1 and MDM2. GO analysis indicated enrichment in 208 biological processes, 23 cellular components, and 38 molecular functions. KEGG analysis suggested that Diosmetin exerts anti-bladder cancer effects primarily through pathways such as Pathways in cancer, PI3K-AKT signaling, and Proteoglycans in cancer. Notably, the PI3K-AKT pathway showed the highest gene enrichment, indicating its potential prominence. In vitro experiments demonstrated that Diosmetin suppresses bladder cancer cell proliferation and induces apoptosis. Additionally, Diosmetin reduced the expression of p-PI3K, p-AKT, and MDM2, while upregulating p53 expression, suggesting involvement of both the PI3K-AKT and p53 pathways.</p><p><strong>Discussion: </strong>These findings align with network pharmacology predictions and highlight the potential of Diosmetin as a multi-target agent against bladder cancer, warranting further in vivo investigation.</p><p><strong>Conclusion: </strong>Diosmetin inhibits bladder cancer cell proliferation and promotes apoptosis by suppressing the PI3K-AKT pathway and activating the p53 pathway.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZUP1 as a Novel Potential Oncogenic Driver and Prognostic Biomarker in Breast Cancer.","authors":"Weimiao Li, Changyou Shan, Shuqun Zhang, Guoxu Zheng","doi":"10.2174/0113862073486848260808184821","DOIUrl":"https://doi.org/10.2174/0113862073486848260808184821","url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer is one of the main causes of cancer death in women globally. Identifying new predictive markers and therapeutic targets is important for improving patient outcomes. Zinc finger-containing U-rich RNA-binding protein 1 (ZUP1) is an RNA-binding protein containing a zinc finger structure that has not been systematically analyzed in breast cancer research.</p><p><strong>Materials and methods: </strong>The study used data from 1,231 samples from the Cancer Genome Atlas (TCGA) database. The ZUP1 expression in tumor tissues and normal tissues was compared. Its predictive value was assessed using survival analysis and regression models. Its biological role was explored through gene functional analysis. The immune cell analysis method was used to study the tumor immune environment, and the drug susceptibility database was used to predict drug responses. Predictive models were also built and validated.</p><p><strong>Results: </strong>ZUP1 expression was significantly higher in breast cancer tissues than in normal tissues. High expression of ZUP1 is related to advanced tumor stage and is an independent indicator of poor survival prognosis in univariate and multivariate analyses. Functional enrichment revealed that ZUP1 is closely linked to cell cycle progression, DNA replication, and the Fanconi anemia (FA) pathway. Immune infiltration analysis demonstrated a significant negative link between ZUP1 levels and the abundance of resting mast cells and activated NK cells. Furthermore, high ZUP1 expression was associated with increased sensitivity to several targeted therapies, including Nutlin-3a and PD-0325901. A clinically applicable nomogram combining ZUP1 expression with key clinical factors (age, stage, T, N, M) was developed to predict 3- and 5-year OS with good calibration and discrimination.</p><p><strong>Discussion: </strong>Our study identifies ZUP1 as a potential oncogenic factor and a robust independent prognostic biomarker in breast cancer. Its involvement in critical cellular processes and modulation of the tumor immune microenvironment highlights its potential as a novel therapeutic target. Functional experiments, including immunohistochemical staining and CCK8 proliferation assays, further supported the oncogenic role of ZUP1. The established nomogram provides a valuable tool for personalized risk assessment and clinical decision-making.</p><p><strong>Conclusion: </strong>Our findings suggest that ZUP1 is a novel multifaceted biomarker with significant implications for personalized treatment strategies in breast cancer.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EDAR-Mediated Cell Fate Determination via the PGTM Network: A Potential Landscape Analysis.","authors":"Chun Li, Lu Wang, Wenjie Deng, Yide Li, Li Zu, Xiaoqi Zheng","doi":"10.2174/0113862073486745260820114658","DOIUrl":"https://doi.org/10.2174/0113862073486745260820114658","url":null,"abstract":"<p><strong>Introduction: </strong>Skin cell fate determination is a core issue in wound repair and regenerative medicine. The multistability of the PGTM gene regulatory network, comprising ΔNp63α, GRHL2, TFAP2A, and MYC, provides a structural basis for cell fate plasticity. However, the mechanism by which the key microenvironmental signal EDAR regulates the PGTM network remains unclear.</p><p><strong>Methods: </strong>We first constructed a coupled network model of the PGTM network with EDAR interference and further established a corresponding differential dynamic system model. We then inferred model parameters via a stable-state fitting method and analyzed the mechanism by combining potential landscape quantification and bifurcation analysis. For convenience, we mathematically defined three states: the M‑state, P‑state, and GT‑state. These states have expression profiles similar to those of the mesenchymal stem cell, epidermal progenitor cell, and early keratinocyte states, respectively, while satisfying the specified constraints.</p><p><strong>Results: </strong>In the absence of EDAR interference, the PGTM network exhibits three stable states corresponding to the M‑state, P‑state, and GT‑state, respectively. As a key regulatory parameter, Se modulates the system, and its variation induces a staged transition from tristability to bistability to GT-state dominance. When Se is in the range [0, 1], three stable states coexist, accompanied by the reconfiguration of the attractor basin structure. When Se > 1, the M-state completely vanishes, and the system enters the bistable regime. Specifically, when Se > 2.7, the system evolves toward a final phase characterized by GT-state dominance, mirroring the trend of cellfate transition from mesenchymal cells through skin progenitor cells to early keratinocytes.</p><p><strong>Discussion: </strong>In order to quantitatively decipher the intrinsic mechanism, we performed a bifurcation analysis with respect to Se. The increase in Se first triggers a saddle-node bifurcation in the system, which is the primary reason for the disappearance of the M-state at Se≈1.0. Thereafter, the system retains only the P-state and GT-state. As Se rises further, the stability of the P-state decreases, while the GT-state remains stable and gradually becomes dominant. This underlies the system's staged fate transition.</p><p><strong>Conclusion: </strong>This study provides a quantitative dynamical framework for investigating the regulatory effects of EDAR signaling on the PGTM network, offering model-derived theoretical insights for EDAR-targeted skin cell reprogramming and regenerative therapy.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Mechanism of Huayu Zhitong Plaster in Acute Soft Tissue Injury Rats via the PI3K/Akt/NF-κB Signaling Pathway.","authors":"Liu Xiaohui, Feng Yanting, Peng Lanchun, Zheng Qingzhu, Peng Jiangli, Wang Shi, Peng Qiuxian","doi":"10.2174/0113862073450412260807073516","DOIUrl":"https://doi.org/10.2174/0113862073450412260807073516","url":null,"abstract":"<p><strong>Introduction: </strong>To explore the therapeutic efficacy of external use of Huayu Zhitong Plaster (HZP) in treating Acute Soft Tissue Injury (ASTI) and its underlying mechanism in a rat model.</p><p><strong>Methods: </strong>UPLC-Q-TOF-MS/MS was used to analyze HZP's chemical constituents, and network pharmacology was applied to predict its therapeutic targets against ASTI. An ASTI rat model was established by blunt trauma to the gastrocnemius muscle. Inflammatory mediators and oxidative stress indicators were quantified by ELISA; ASTI severity was evaluated via H&E staining; protein localization and expression were assessed by immunofluorescence and Western blotting, respectively, to investigate the mechanism of action.</p><p><strong>Results: </strong>UPLC-Q-TOF-MS/MS identified 86 components in HZP, mainly flavonoids, alkaloids, cyclic enol ether terpenes, and phenolic acids. Network pharmacology analysis showed that ASTI- related genes were primarily associated with the PI3K-Akt and NF-κB pathways via PI3K subunit and AKT1. Animal experiments confirmed that HZP significantly inhibited p-PI3K, p- AKT, and p-NF-κB expression, blocking the PI3K/Akt/NF-κB pathway. It reduced the levels of proinflammatory mediators IL-6 and PGE2, and increased the activity of the oxidative stressrelated enzyme SOD, decreased the level of MDA and MPO, and alleviated tissue damage, edema, and inflammatory infiltration (H & E staining).</p><p><strong>Discussion: </strong>Given that effective and well-tolerated treatments for ASTI are highly desirable, our experimental data offer compelling support for the curative efficacy of HZP, paving the path for the scientific standardization of this intricate TCM preparation and affirming its potential to serve as a valuable topical treatment agent.</p><p><strong>Conclusion: </strong>By suppressing the PI3K/Akt/NF-κB pathway, HZP exerts potent antiinflammatory and antioxidant effects in ASTI, thereby mitigating tissue damage and facilitating repair.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome Analysis and Experimental Validation of Palmitoylation- Related Biomarkers in Atherosclerosis.","authors":"Zhijian Song, Yirong Ma, Yanhong Liu, Junyu Lai, Liqiang Sun, Qiming Li, Yaguo Fan, Yingying Huang, Doukun Ding, Jianguang Wu","doi":"10.2174/0113862073491675260817100248","DOIUrl":"https://doi.org/10.2174/0113862073491675260817100248","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Protein palmitoylation contributes to membrane localisation, signal transduction, and cell-fate regulation. It is closely associated with lipid metabolic dysfunction, immune inflammation, and vascular remodelling in atherosclerosis (AS). However, key palmitoylation-related transcriptomic markers and their potential causal associations with AS remain incompletely defined.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The Gene Expression Omnibus (GEO) dataset GSE100927 was used as the training cohort, and GSE43292 was used as an external validation cohort. Differentially expressed genes were identified using limma and intersected with palmitoylation-related genes to obtain palmitoylation-related differentially expressed genes (PRDEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed using clusterProfiler. Two-sample Mendelian randomisation was used to evaluate potential causal relationships between characteristic genes and AS. Feature selection was conducted using random forest and support vector machine recursive feature elimination (SVM-RFE), and the overlapping genes selected by both methods were retained. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance. A five-gene nomogram was constructed, and its clinical utility was evaluated using calibration curves and decision curve analysis (DCA). Gene set variation analysis (GSVA) was applied to compare pathway activity between high- and low-expression groups for each core gene. Single-cell analysis using Seurat and expression-based cell-cell communication analysis using CellChat were conducted with GSE159677, and upstream transcription factors were predicted using NetworkAnalyst. For in vivo validation, an AS model was established in ApoE⁸/⁸ mice fed a high-fat diet, and aortic gene and protein expression were assessed by RT-qPCR and western blotting.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In GSE100927, 51 PRDEGs were identified. GO and KEGG enrichment analyses highlighted pathways associated with regulation of monoatomic ion transport, sarcomere and myofibril organisation, and immune inflammation. Mendelian randomisation suggested a potential protective causal association between SLC7A7 and AS. By integrating MR with random forest and SVM-RFE feature selection, we prioritised five core genes: PLCB2, GMIP, NEXN, PLN, and SLC7A7. These genes showed good diagnostic performance in GSE43292. The resulting nomogram was well calibrated and demonstrated stable net benefit in decision curve and clinical impact curve analyses. Single-gene GSVA identified consistently activated pathways across multiple genes, including innate and adaptive immune recognition, calcium signalling and myocardial contraction/cardiomyopathy, extracellular matrix-receptor interaction, cell junction pathways, autophagy-lysosome pathways, and several metabolic programmes. At the single-cell level, PLCB2 and GMIP were predo","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Metagenomics and Network Pharmacology Reveals That Hypericum perforatum L. Alleviates Depressive-Like Behaviors via Gut Microbiota-Associated Inflammatory and PI3K-Akt Signaling.","authors":"Sumin Dong, Tong Li, Chengchong Li, Libo Li, Tong Wu, Yandong Ren, Yu Jiao, Luan Wang, Tianci Zhu, Ping Li","doi":"10.2174/0113862073500203260805052728","DOIUrl":"https://doi.org/10.2174/0113862073500203260805052728","url":null,"abstract":"<p><strong>Introduction: </strong>Hypericum perforatum L. (HP) is a well-known herbal antidepressant with reliable antidepressant effects. However, its underlying mechanism, particularly the interplay with the gut-brain axis, remains poorly elucidated. In this study, aimed to explore the potential mechanism by which HP relieves depressive-like behaviors by integrating metagenomic sequencing and network pharmacology, with a focus on gut microbiota and host signaling pathways.</p><p><strong>Methods: </strong>A rat model of depressive-like behaviors was established using Chronic Restraint Stress (CRS). Sucrose Preference Test (SPT), Open Field Test (OFT), and Forced Swimming Test (FST) were applied to evaluate behavioral performance. Histopathological changes in the hippocampus and colon were assessed by Hematoxylin and Eosin (HE) staining. Serum levels of inflammatory cytokines were measured by ELISA. Gut microbiota composition was profiled by metagenomic sequencing; intestinal barrier integrity was evaluated by assessing the expression of tight junction proteins Zona Occludens 1 (ZO-1) and occludin. Network pharmacology was used to predict active components, targets, and pathways of HP. Key hippocampal pathway proteins were validated by western blot analysis.</p><p><strong>Results: </strong>HP intervention ameliorated CRS-induced depressive-like behaviors, alleviated hippocampal neuronal damage, and restored intestinal barrier integrity. Serum levels of proinflammatory cytokines were also reduced. Metagenomic analysis revealed that HP reversed CRS-induced gut dysbiosis, notably by increasing the relative abundance of beneficial bacteria (e.g., Prevotella) and decreasing pro-inflammatory taxa. Redundancy Analysis (RDA) revealed close correlations between microbial alteration and inflammatory cytokine levels. Network pharmacology identified six active components and 42 potential therapeutic targets; the phosphoinositide 3- Kinase-Protein Kinase B (PI3K-Akt) signaling pathway was determined as the core pathway. Experimental verification confirmed that HP could regulate the PI3K-Akt signaling pathway and modulate the expression of its downstream protein Nuclear Factor Kappa B (NF-κB) in the hippocampus.</p><p><strong>Discussion: </strong>Our work provides integrative insight into the pharmacological characteristics of HP and supports that gut microbiota may be potentially involved in its antidepressant-like effects.</p><p><strong>Conclusion: </strong>This study provides evidence that HP ameliorates CRS-induced depressive-like behaviors, which is closely associated with the restoration of gut microbial homeostasis, suppression of systemic inflammation, and regulation of the brain PI3K-Akt signaling pathway.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Therapeutic Potential of Compound Fufangteng Oral Liquid in Chronic Heart Failure: Efficacy in a Multifactorial Model.","authors":"Yin Lu, Hongtao Chen, Liangxing Ding, Jieyuan Deng, Xiaoyun Pang, Anqiang Tan, Xiaoyi Chen, Fangchan Li, Yudong Luo","doi":"10.2174/0113862073473456260804042252","DOIUrl":"https://doi.org/10.2174/0113862073473456260804042252","url":null,"abstract":"<p><strong>Introduction: </strong>CHF is a complex syndrome involving neurohormonal overactivation, inflammation, and myocardial injury. Current therapies remain limited. Compound Fufangteng Oral Liquid (CFFOL) shows multi-target potential, but its effects across different CHF models remain unclear. The study aims to investigate CFFOL's therapeutic effects in three CHF models (qi deficiency, cardiac overload, myocardial injury) and clarify its dose-response relationship.</p><p><strong>Methods: </strong>Three CHF models were established in rats/mice. Animals were randomized into blank control, model, captopril, and CFFOL groups. Cardiac function (EF, FS) was assessed by echocardiography. Serum NT-proBNP, TNF-α, and myocardial enzymes (CK, LDH, α-HBDH) were measured by ELISA. Heart tissues were collected for H&E staining.</p><p><strong>Results: </strong>CFFOL significantly improved cardiac function (EF, FS), reduced serum NT-proBNP, CK, LDH, α-HBDH, and TNF-α levels, and alleviated myocardial pathological changes (vacuolization, fiber disorganization, nuclear condensation, fibrosis).</p><p><strong>Discussion: </strong>Our findings demonstrate that CFFOL exerts cardioprotective effects across multiple CHF models by reducing myocardial damage and attenuating inflammation, consistent with known activities of ginsenosides and astragaloside IV. However, mechanistic claims (JAK/STAT, TGF-β/Smad, IL-17) remain speculative, as molecular assays were not performed. Limitations include lack of blinding, male-only animals, and no pharmacokinetic data. Future studies should incorporate blinded designs, both sexes, and pathway-specific molecular validation.</p><p><strong>Conclusion: </strong>CFFOL shows potential for heart failure treatment, particularly in qi deficiency syndrome. Further clinical studies are needed.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}