Combinatorial chemistry & high throughput screening最新文献

{"title":"Comprehensive Bioinformatics Analysis for the Identification of Hub Genes and Critical Signaling Pathways Differentiating Latent and Active Tuberculosis.","authors":"Wu Peng, Wenlai Li, Jie Qiu, Sijing Huang, Mei Li, Zhenzhen Zhao, Mengyuan Lyu, Mengjiao Li, Xingbo Song","doi":"10.2174/0113862073401054250526094910","DOIUrl":"https://doi.org/10.2174/0113862073401054250526094910","url":null,"abstract":"<p><strong>Objectives: </strong>Population with Latent tuberculosis infection (LTBI) is the principal source of active tuberculosis (ATB) cases. The identification of reliable diagnostic biomarkers is critical for the prevention and control of the progression from LTBI to ATB. The aim of this study is to screen biomarkers that can distinguish LTBI from ATB patients by using a comprehensive bioinformatics analysis strategy.</p><p><strong>Methods: </strong>The transcriptomic datasets were obtained from the GEO database. Hub genes and critical signal pathways for differentiating latent and active TB, were identified by a comprehensive bioinformatics analysis strategy comprising Weighted Gene Co-Expression Network Analysis (WGCNA), Differentially Expressed Gene (DEG), Protein-Protein Interaction (PPI), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and hub genes were verified by RT-qPCR in this study.</p><p><strong>Results: </strong>The transcriptome profiles of GSE193777, GSE157657, GSE168519, GSE107991, and GSE107992 were extracted from the GEO database, in which a total of 18,397 protein-coding genes from 206 samples were included in the bioinformatics analysis. Combined with Weighted Gene Co-Expression Network, differentially expressed gene, functional enrichment, and proteinprotein interaction analyses, six hub genes were identified. The results of RT-qPCR confirmed that the expression levels of four hub genes (HLA-DOA, ECH1, PARN and TRAPPC4) were downregulated in the LTBI group compared with the ATB group.</p><p><strong>Conclusion: </strong>Our findings may provide crucial clues to potential biomarkers that can distinguish patients with LTBI from those with ATB, aiding the understanding of the mechanism underlying the progression of LTBI to ATB.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186664","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":"ARL6IP1 Inhibits Breast Cancer Tumor Progression by Targeting OLFM4 to Regulate Glycolysis.","authors":"Lijun Zhou, Chen Chen, Lingping Zhu, Fei Gu","doi":"10.2174/0113862073358595250211053816","DOIUrl":"https://doi.org/10.2174/0113862073358595250211053816","url":null,"abstract":"<p><strong>Background: </strong>ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear.</p><p><strong>Aims: </strong>This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target.</p><p><strong>Objective: </strong>The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism.</p><p><strong>Methods: </strong>Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated.</p><p><strong>Results: </strong>ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown.</p><p><strong>Conclusion: </strong>ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186663","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":"Effect of Electroacupuncture on Intestinal Mucosal Barrier in IBS-D Rats: Analysis Based on RNA-seq.","authors":"Jingru Ruan, Jingwei Zhu, Kuiwu Li, Ziye Wang, Ting Wang, Xiaoyu Han, Xiaomin Li, Yucheng Fang, Xiaoge Song, Haoran Chu","doi":"10.2174/0113862073395229250513074835","DOIUrl":"https://doi.org/10.2174/0113862073395229250513074835","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Currently, transcriptome-level investigations into the therapeutic mechanisms of electroacupuncture (EA) on intestinal mucosal barrier dysfunction in diarrhoea-predominant irritable bowel syndrome (IBS-D) models remain scarce. This study was designed to establish a comprehensive competing endogenous RNA (ceRNA) network through integrated RNA sequencing (RNA-seq) and bioinformatics analyses while elucidating the underlying mechanisms through which EA restores intestinal barrier integrity in IBS-D rats via modulation of the long non-coding RNA (lncRNA)-microRNA (miRNA) -messenger RNA (mRNA) regulatory network.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The IBS-D model was established by neonatal maternal separation (NMS), 4% acetic acid enema, and restrain stress (RS). The rats were randomly divided into three groups: control, model and EA groups. After 2 weeks of EA, the morphological changes of the rat colon were observed by hematoxylin-eosin staining (HE) and Transmission electron microscope (TEM), and the expression of substances related to the damage of the intestinal mucosal barrier was detected by Enzyme-linked Immunosorbent Assay (ELISA) and Western blot (WB) to verify the protective effect of EA on the intestinal mucosal barrier of IBS-D rats. Then RNA-seq was used to analyse rat colon differentially expressed RNAs (DE RNAs) and construct relevant ceRNA networks. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the differentially expressed mRNAs (DE mRNAs) altered by EA to elucidate the mechanism of EA in improving the damage of the intestinal mucosal barrier. Finally, Real-Time Quantitative Reverse Transcription PCR (RT-qPCR) was used to verify the RNA-seq results, and WB and immunofluorescence (IF) were used to verify the involvement of mast cells (MCs) in the relevant signalling pathways regulated by EA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Firstly, EA had an alleviating effect on the intestinal mucosal barrier damage in IBS-D rats. Then, RNAseq results showed that 426 DE mRNAs, 342 differentially expressed lncRNAs (DE lncRNAs) and 10 differentially expressed miRNAs (DE miRNAs) were up-regulated and 429 DE mRNAs, 362 DE lncRNAs and 48 DE miRNAs were down-regulated by EA. Meanwhile, the ceRNA networks of 7 DE lncRNAs-miR-139-3p-Bid and 7 DE lncRNAs-miR-378b-Slc4a5 were successfully constructed. GO indicated that EA protected the intestinal mucosal barrier of IBS-D rats mainly by regulating a series of defense responses (e.g., against viruses and bacteria), participating in regulating the secretion and transport of hormones, and affecting the function of cytokines. KEGG indicated that there were key signal pathways such as antigen processing and presentation, neuroactive ligand-receptor interaction, PPAR signaling pathway and glutathione metabolism, which were related to the participation of MC in immune inflammation after degranulation. RT-qPCR result","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186665","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":"Evaluation of Cranberry as a Novel Therapeutic Strategy for Intracerebroventricular (ICV) Quinolinic Acid-induced Cognitive Impairment in Rats.","authors":"Li Tao, Deepika Kumari, Sai Kumar Badam, Harpreet Kaur, Vikrant Dalwal, Pallvi Kumari, Ritu Kainth","doi":"10.2174/0113862073375293250520050009","DOIUrl":"https://doi.org/10.2174/0113862073375293250520050009","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cranberry (Vaccinium macrocarpon) is a small, red fruit that has been widely recognized for its potential health benefits. The cranberry is rich in antioxidant-rich bioactive chemicals and nutritious components like essential vitamins, minerals, and antioxidants; for example, vitamin C, vitamin E, magnesium, copper, potassium, anthocyanins, flavonoids, phenolic acid, etc. Cranberries are thought to offer a variety of health advantages because they are high in Polyphenols (PPs), which have significant antioxidant activity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;The objective of the current study was to evaluate the neuroprotective effect of cranberries on behavioural and neurochemical abnormalities induced by Quinolinic Acid (QA) treatment through Intracerebroventricular (ICV) injection in Wistar rats, as well as to identify the synaptic plasticity and cognition by modulating signaling cascades, such as the ERK and PI3K/AKT pathways, which offer an adjunct treatment to slow or enhance the effects of conventional treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Material and methods: &lt;/strong&gt;A total of thirty Wistar rats were randomly assigned to several experimental groups. QA (240 nM in normal saline) was administered via ICV. Thereafter, cranberry (0.5g/kg p.o.) with QA, and high-dose cranberry group (2g/kg p.o.) with QA were administered to the animals for 21 days. The dosage of QA and cranberries was chosen based on earlier experimental research.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Result: &lt;/strong&gt;The study found that cranberries significantly decrease cognitive deficits and motor impairments caused by Quinolinic Acid (QA) in rats. QA treatment affected cognitive function, as demonstrated by the Novel object recognition and the Morris water maze tests, and caused substantial disturbances in motor activity, as demonstrated by rotarod and footprint analyses. QA-treated rats also exhibited higher oxidative and nitrosative stress, lower Glutathione (GSH) levels, higher nitrite and lipid peroxidation, cholinergic dysfunction, and abnormalities in mitochondrial complexes I, II, and IV in the striatum and hippocampus regions. Cranberry (2 g/kg p.o.) significantly enhanced memory, learning, and motor coordination. Cranberry supplementation enhanced GSH levels, decreased MDA concentration, and improved mitochondrial function and cholinergic activity. According to a histological study, cranberries can protect against neuronal degeneration and inflammation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;These findings indicate that cranberries may have neuroprotective properties, presumably through antioxidant, anti-inflammatory, and anti-excitotoxic processes that promote brain plasticity, neurogenesis, and neurotransmitter systems. This establishes the potential of cranberries as a prospective natural treatment for cognitive deficits and neurodegenerative illnesses, suggesting the need for additional research to understand the underlying mechanisms and human application better.&lt;/p","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181367","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":"Influence of Mycoplasma Resistance Genes on Pediatric Mycoplasma Pneumonia Treatment and Determinants for Second-line Antimicrobial Adjustment.","authors":"Boyin Deng, Wenhui Dong, Jie Cao, Jiwei Zhou","doi":"10.2174/0113862073364492250507095636","DOIUrl":"https://doi.org/10.2174/0113862073364492250507095636","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study is to evaluate the role of mycoplasma resistance genes in pediatric mycoplasma pneumonia and to identify the factors that necessitate antibiotic adjustments.</p><p><strong>Methods: </strong>We retrospectively analyzed clinical data from children diagnosed with mycoplasma pneumonia at Chongqing Medical University Children's Hospital (January-October 2023). We categorized patients based on antibiotic treatment adjustments: the antibiotic adjustment group and the no adjustment group. We compared demographic characteristics, clinical outcomes, and the gene resistance rate that point mutations A2063G and A2064G in the 23S rRNA between groups. Logistic regression was employed to determine the factors prompting a switch from macrolides to alternative antibiotics.</p><p><strong>Results: </strong>The study included 551 cases, with 341 in the no adjustment group and 210 in the antibiotic adjustment group (54 switched to doxycycline, 156 to levofloxacin). There was no significant difference in the prevalence of resistance genes between the groups (71.8% vs. 71.4%; P=0.916). Significant differences were observed in hospital stay duration, C-reactive protein (CRP), D-dimer, fibrinogen, procalcitonin levels, and lung consolidation (P<0.05). Logistic regression identified elevated CRP and procalcitonin levels as independent predictors of the need for alternative antibiotics.</p><p><strong>Conclusion: </strong>Resistance genes do not predict the need for second-line antibiotics in pediatric mycoplasma pneumonia; however, elevated CRP, and procalcitonin levels significantly correlate with this necessity.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141583","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":"Dengue is Still a Complicated Disease.","authors":"Rituraj Niranjan","doi":"10.2174/0113862073394882250520072757","DOIUrl":"https://doi.org/10.2174/0113862073394882250520072757","url":null,"abstract":"","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141529","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":"Inhibition of Sox4 Increases the Sensitivity of Drug-resistant Melanoma Cells to Cisplatin through the P38 Signaling Pathway.","authors":"Cheng Qiong, Zuo Fuguo","doi":"10.2174/0113862073231734231102074936","DOIUrl":"https://doi.org/10.2174/0113862073231734231102074936","url":null,"abstract":"<p><strong>Background: </strong>SRY-Box Transcription Factor 4 (Sox4) has been found to be overexpressed in a number of malignancies and is linked to medication resistance. The underlying mechanism of Sox4 in cisplatin-resistant melanomas, however, remains unknown.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC) was used to examine the expression of Sox4 in melanoma, pigmented nevi, and normal skin tissue. Induction in vitro was used to create the cisplatin- resistant cell lines SK-MEL-28R and A375R. The CCK8 test was used to determine the IC50 values of cisplatin-resistant cells. Lentivirus shut down Sox4 in SK-MEL-28R and A375R cells. The Affymetrix GeneChip array was then utilized to detect changes in signaling pathways in SK-MEL-28R interfering with Sox4. Western blot, qRT-PCR, flow cytometry, and a caspase 3 activity kit were used to confirm the biological process of Sox4 impacting cisplatin resistance in melanoma.</p><p><strong>Results: </strong>Sox4 expression in melanoma was substantially higher than in pigmented nevus and normal skin tissue (p<0.05, p<0.01).SK-MEL-28R and A375R melanoma cisplatin-resistant strains were created effectively. They were 12.6 and 10.2 times more resistant to cisplatin, respectively than the parental cells. P-gp protein expression was substantially higher in cisplatinresistant strains than in parental strains. Sox4 inhibition lowered the IC50 value of cisplatin in resistant cells. (The IC50 value of SK-MEL-28R+NC was 122.7 mg/L and 24.4 mg/L for SKMEL- 28R+sh-sox4; the IC50 value of A375R+NC was 40.55 mg/L and 5.99 mg/L for A375R+sh-sox4). Meanwhile, Sox4 knockdown causes S phase arrest and enhanced caspase-3 activity in cisplatin-resistant melanoma cells. Sox4 knockdown led to activation of the P38 signaling pathway in resistant cells, according to genome-wide expression analysis, qRT-PCR, and Western blot detection.</p><p><strong>Conclusion: </strong>Our findings imply that inhibiting Sox4 can improve the sensitivity of drugresistant melanoma cells to cisplatin via the P38 signaling pathway, thus opening up a new route for melanoma treatment.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109780","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":"Association of Increased SOAT2 Expression with Abnormal Cholesterol Esterification and Testosterone Deficiency in Late-Onset Hypogonadism Rats.","authors":"Min Pan, Ziao Liu, Jingya Li, Xiaohan Ni, Yujia Wang, Lingling Zhang, Tongsheng Wang","doi":"10.2174/0113862073402760250516120303","DOIUrl":"https://doi.org/10.2174/0113862073402760250516120303","url":null,"abstract":"<p><strong>Background: </strong>Late-Onset Hypogonadism (LOH) is a prevalent age-related condition in men, characterized by a decline in testosterone (T) and associated symptoms.</p><p><strong>Objective: </strong>This study explored the mechanism of T deficiency in LOH.</p><p><strong>Methods: </strong>Male SD rats were raised until 20 months of age in order to establish the LOH models. The hormone level and sperm quality were examined. The behavior experiments were carried out to assess whether LOH rats had anxiety and cognitive dysfunction. RNA-seq was used to explore the differential gene in the testis of LOH rats, revealing the molecular mechanism of LOH.</p><p><strong>Results: </strong>LOH rats exhibited cognitive impairment and anxiety. The sperm quality was decreased, and dysfunction of the Hypothalamic-Pituitary-Gonadal (HPG) axis was observed in LOH rats. Testosterone biosynthesis enzymes (including StAR, Cyp17A1, and HSD17β) were suppressed, reducing T levels. RNA-seq revealed that cholesterol metabolism and steroid hormone biosynthesis were abnormal. The expression of Sterol O-Acyltransferase 2 (SOAT2) was upregulated in the Leydig cells in the testes of LOH rats. Meanwhile, the testicular Cholesterol Ester (CE) increased, and Free Cholesterol (FC) decreased in the LOH rats.</p><p><strong>Conclusion: </strong>These results indicated that upregulation of SOAT2 decreased FC and increased CE, which led to testosterone deficiency and further affected spermatogenesis and the HPG axis.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109778","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":"An Integrated Computational Approach to Identify Potent HIV-1 Protease Inhibitors from Marine Sources.","authors":"Mebarka Ouassaf, Lotfi Bourougaa, Harun M Patel, Iqrar Ahmad, Bader Y Alhatlani","doi":"10.2174/0113862073344783241205075752","DOIUrl":"https://doi.org/10.2174/0113862073344783241205075752","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to identify marine-derived protease inhibitors with potential applications in immunogenicity-targeted therapies.</p><p><strong>Method: </strong>Starting with a pharmacophore model based on the GRL-09510 complex (PDB ID: 5v4y), we isolated three critical features (RAA) that facilitated the selection of 192 candidates from an initial pool of 18,547 compounds.</p><p><strong>Results: </strong>Subsequent docking analyses, validated with a strong ROC value of 0.74, revealed four high-affinity compounds: Echoside C (CMNPD22461), Anguibactin (CMNPD3610), Hansforester K (CMNPD30598), and Polyandocarpamide A (CMNPD4564), with binding scores of -7.773, -7.770, -7.690, and -7.236 kcal/mol, respectively-each exceeding the reference compound's binding efficacy. Further assessments of drug-likeness (ADME) and toxicity profiles produced favorable results and predicted biological activity from the PASS program supported their potential as potent protease inhibitors. Density Functional Theory (DFT) analysis and molecular dynamics simulations confirmed the stability of these compounds when bound to the protease's active site, with configurations similar to the GRL-09510 complex.</p><p><strong>Conclusion: </strong>These findings suggest that the identified marine-derived compounds hold significant promise as effective protease inhibitors, offering new opportunities for immunotherapy and advancements in drug development.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101506","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":"Serum Metabolomic Profiles Predict Sensitivity and Toxicity to Platinum-Fluorouracil Chemotherapy in a Gastric Cancer Xenograft Model.","authors":"Dong Yang, Yuanlin Liu, Xiangyu Meng, Chao Wang, Meng Zhang, Tao Zhang, Yefu Liu","doi":"10.2174/0113862073379369250513115909","DOIUrl":"https://doi.org/10.2174/0113862073379369250513115909","url":null,"abstract":"<p><strong>Background: </strong>The mechanisms of chemotherapy sensitivity and toxicity are complex. Metabolomics can better reflect the status of anticancer drugs, tumors, and hosts simultaneously.</p><p><strong>Aim: </strong>To identify metabolites and metabolic pathways linked to varying sensitivity and toxicity to chemotherapy in gastric cancer.</p><p><strong>Methods: </strong>Mice were implanted with human gastric cancer cells through subcutaneous xenografting, and then treated with the PF (platinum-fluorouracil) regimen, with saline serving as the control. Tumor growth was monitored by measuring tumor volume, and body weight was recorded on Days 0, 2, 4, 6, and 8. Kidney damage was assessed using H&E staining. To analyze differential responses, PF-treated mice were grouped separately according to chemotherapy sensitivity (high/medium/low via tumor response) and toxicity (high/medium/low via body weight changes). Serum metabolomics was evaluated using Mass Spectrometry.</p><p><strong>Results: </strong>Platinum-Fluorouracil (PF) chemotherapy significantly reduced tumor weight in mice (164.7 ± 73.5 mg vs. 334.0 ± 107.5 mg; 54.4% inhibition rate), although it also induced notable body weight loss and renal toxicity compared to controls. Serum metabolomic analysis revealed significant differences between PF and control groups, involving metabolites like deoxymethacin and dehydrocorticosterone, associated with AMPK and cortisol synthesis/secretion pathways. Further comparisons highlighted: (1) High- vs. low-sensitivity subgroups differed significantly in metabolites, such as palmitoyl-CoA and indoleacetic acid (linked to AGE-RAGE, insulin resistance, and AMPK pathways). (2) High- vs. low-toxicity subgroups displayed significant metabolic differences, including methylguanosine and methylcytidine (implicated in ferroptosis, ether lipid, and fatty acid metabolism pathways).</p><p><strong>Conclusion: </strong>The PF regimen effectively inhibits the growth of subcutaneous tumors in nude mice, while causing varying levels of sensitivity and toxicity in tumor chemotherapy. These observed effects of sensitivity and toxicity are linked to underlying metabolic mechanisms.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076438","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}