Combinatorial Chemistry & High Throughput Screening - Volume 28, Issue 3, 2025

To systematically evaluate the relationship between cutaneous immune-related adverse events (cirAEs) and the efficacy of PD-1/PD-L1 in the treatment of non-small cell lung cancer (NSCLC) and to provide an evidence-based reference for the clinical application of PD-1/PD-L1 and safety evaluation.

Electronic databases (PubMed, Embase, Medline, Web of Science, and the Cochrane Library) were screened systematically to collect prospective or retrospective cohort studies on the correlation between cirAEs and efficacy of PD-1/PD-L1 in the treatment of NSCLC.

A total of 3514 participants were included in 13 cohort studies (enclosing an ambidirectional cohort study). Outcomes revealed that compared with those patients with non cirAEs, patients suffering cirAEs were associated with significantly higher objective response rate (ORR) [risk ratio (RR): 1.74, 95% confidence interval (CI): 1.42–2.14, P<0.00001], longer progression-free survival (PFS) [RR: 0.52, 95% CI: 0.45–0.60, P<0.00001], and longer overall survival (OS) [RR:0.46, 95% CI: 0.38–0.56]. Sensitivity analyses through the exclusion of one study at a time did not significantly influence the outcomes, indicating that the meta-analysis results were relatively robust. Furthermore, subgroup analyses revealed consistent results in the study design (prospective or retrospective cohort studies), as well as in the endpoint results (PFS and OS) of Kaplan–Meier curves or Cox proportional hazards regression for evaluable patients.

Currently, evidence reveals that cirAEs development may be associated with a good prognosis and can be an early predictor of the efficacy of PD-1/PD-L1 in the treatment of NSCLC patients.

Phage therapy could play an important role in the bacterial pneumonia. However, the exact role of phage therapy in bacterial pneumonia is unclear to date.

The current study aims to find out the role of phage therapy in preclinical models of bacterial pneumonia.

The studies were searched in databases with proper MeSH terms along with Boolean operators and selected based on eligibility criteria as per the PRISMA guidelines. The Odd Ratio (OR) was calculated with a 95% confidence interval and the heterogeneity was also calculated. The funnel plot was used to conduct a qualitative examination of publication bias.

The OR was observed to be 0.11 (0.04, 0.27)] after 24 hrs, 0.11 [0.03, 0.34] after 7 days and 0.04 [0.01, 0.15] after 10 days that showed a significant role of phage therapy in reduction of deaths in the bacterial pneumonia models as compared to the placebo group. However, after 48hrs, a non-significant reduction was observed.

There was a significant role of phage therapy in the reduction of deaths in the bacterial pneumonia models.

As a Chinese medicinal formula, the Jianshen Lishui prescription has been clinically proven to be effective in treating intracerebral hemorrhage (ICH). Yet, the mechanisms involved are unknown.

Network pharmacology analysis: It involved the screening of active components in the Jianshen Lishui prescription, identification of potential targets for these components, and the screening of ICH-related targets. Common targets for both disease and drug were identified. Protein-protein interaction networks were constructed, followed by further screening of core targets. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on these core targets. Finally, molecular docking verification was carried out using the active components and core targets. Experimental verification: It was conducted using a rat model of intracerebral hemorrhage. This involved observing neurological deficit scores in the rats and measuring cerebral water content. The effects of Jianshen Lishui prescription on the neurological function, cerebral water content, and brain tissue core targets were observed through HE staining, Western blot and qPCR.

(1) In this study, 29 common targets were obtained by intersecting 256 potential drug targets and 642 genes associated with ICH. 9 core targets were obtained by employing the protein-protein interaction (PPI) construction system to screen more specific targets. In addition, the findings revealed that the molecular mechanism of Jianshen Lishui prescription in treating ICH was mainly related to cancer signaling pathways and signal transduction pathways, based on the results of GO and KEGG enrichment analysis. Molecular docking results showed that the active constituent of Jianshen Lishui prescription mannitol has the highest binding activity with KRAS, luteolin, and Poria sterol with AR, INS1 and KRAS, cerebrosterol with GNB1, INS 1 and ESR1, and sitosterol with AR, INS1 and KRAS. (2) Animal experiments verified that Jianshen Lishui prescription significantly alleviated encephaledema and improved nerve functions of the rat model of ICH. And INS1 expression levels were upregulated and the expression levels of AR, KRAS, PTGS2, and ESR1 were down-regulated by the prescription.

Jianshen Lishui prescription protects the nerve function of ICH patients by inhibiting inflammation and reducing cerebral edema. This study provides more supportive evidences for the clinical use of traditional Chinese prescriptions in ICH treatment.

Atherosclerosis is the most common and significant form of arterial disease, characterized primarily by lipid accumulation and inflammatory cell infiltration as its main pathological basis. This study aims to investigate the molecular mechanisms and associated pathways by which iron accumulation may be involved in lipid metabolism abnormalities in atherosclerotic mice.

Relying on ApoE-/- mouse body position observation, blood biochemical analysis, oxidative stress test and aortic tissue sectioning techniques, the effects of ferroptosis on lipid metabolism in atherosclerotic mice were analyzed. Use RT-PCR analysis and transcriptomics tests to understand the specific molecular mechanism.

Our analysis reveals a correlation between Ferroptosis and elevated levels of TC, TG, ALT, AST, IL-1β, and TNF-α in the blood of atherosclerotic model mice. At the same time, it exacerbates the pathological changes of mouse aorta tissue. Our results suggest a potential link between ferroptosis and the dysregulation of TFR1/SLC11A2/GPX4 expression, along with the presence of oxidative stress, in the progression of AS. Transcriptomics results indicate that ferroptosis-mediated deterioration of atherosclerosis in ApoE-/- mice is potentially associated with cell phagocytosis, apoptosis involving TNF-α, and the expression of atherosclerotic and other process-related genes.

Ferroptosis exacerbated the lipid metabolism disorder in atherosclerotic mice. The core mechanism of its effect is that ferroptosis activates the TFR1/SLC11A2/GPX4 signaling pathway, which leads to the up-regulation of oxidative stress in ApoE-/- mice, and ultimately aggravates the abnormal lipid metabolism in ApoE-/- mice.

Chronic bronchitis is a type of common chronic inflammatory respiratory disease, which is mainly characterized by chronic cough and expectoration. Clinical practice and experimental research have shown that the modified tonifying spleen-lung method has significant preventive and therapeutic effects on chronic lung diseases, but the mechanism of TSLR in the treatment of chronic bronchitis are not yet clear.

To explore the mechanism of tonifying spleen-lung recipe (TSLR) in the treatment of chronic bronchitis (CB) through network pharmacology combined with observational studies.

The effective components, core targets and signaling pathways of TSLR in the treatment of chronic bronchitis were obtained using network pharmacology. One hundred and thirty-seven elderly CB patients were selected as the observational group who were treated by TSLR, and 67 no-CB cases from the Physical Examination Center were selected as the control group. We compared the levels of inflammatory parameters between patients before and after TSLR treatment, and after treatment group with the control group were also compared.

The key effective components of TSLR selected by network pharmacology included quercetin, kaempferol, luteolin, and nobiletin, and the core targets involved HSP90AA1, AKT1, JUN, MAPK1, IL6, MAPK3, MAPK14, STAT1, NFKB1, and CDKN1. KEGG pathway enrichment analysis revealed that the TNF signaling pathway, PI3K-AKT and AGE-RAGE signaling pathways might play a key role in the treatment of CB. The observation study demonstrated that compared with the control group, the levels of WBC, NEU, NLR, PCT, and CRP in the research group after TSLR treatment were increased. Although the levels of WBC, NEU, NLR, and PCT in the research group after TSLR treatment were higher than those in the control group, the above indicators trend tended towards the control group, and there was no significant difference in CRP indicators between the control group and after treatment group.

TSLR had a good therapeutic effect on chronic bronchitis patients, which might be related to the fact that the natural active components in TSLR inhibit inflammation by regulating the expression of proteins related to PI3K-AKT and TNF signaling pathways.

Lung adenocarcinoma (LUAD) is a common malignant tumor with no obvious clinical symptoms in its early stages. Patients can be divided into radiotherapy-sensitive groups (RS) and radiotherapy-resistant groups (RR) due to their varying conditions. The therapeutic effect of radiotherapy is quite different between the two groups. Therefore, this paper explores the role of radiation-related lung function genes in LUAD and its immune landscape.

Firstly, we divided LUAD samples from the TCGA cohort into RS and RR groups and analyzed differential expression to obtain differentially expressed genes (DEGs). Then, DEGs and patients' grouping information were input into the weighted co-expression network, and the genes in the radiotherapy-related modules were identified. Furthermore, after the intersection of DEGs and lung function-related genes, the prognosis-related genes were obtained through univariate Cox and Lasso-Cox analyses, respectively, and the risk model was constructed. Finally, the differences in prognosis and immunity of the samples in the risk model were explored. Additionally, we also performed a qPCR experiment on lung function-related genes.

In this paper, radiation-related genes of LUAD were identified through a series of bioinformatics analyses. By conducting enrichment analysis on these genes, several pathways related to LUAD radiation were identified, and DEGs associated with significant prognosis were determined. Furthermore, a radiation-related risk model of LUAD was developed. All samples were divided into high-risk and low-risk groups based on the risk score, and the differences in immune cell infiltration abundance and immune function between these groups were evaluated. The qPCR experimental results demonstrated a significant difference in the expression of genes related to lung function.

The prognosis-related genes identified in this paper and the risk model created can serve as a reference for diagnosing and treating LUAD.

Esophageal cancer (EC) is one of the deadliest malignancies worldwide. Gynostemma pentaphyllum Thunb. Makino (GpM) has been used in traditional Chinese medicine as a treatment for tumors and hyperlipidemia. Nevertheless, the active components and underlying mechanisms of anti-EC effects of GpM remain elusive.

This study aims to determine the major active ingredients of GpM in the treatment of EC and to explore their molecular mechanisms by using network pharmacology, molecular docking, and in vitro experiments.

Firstly, active ingredients and potential targets of GpM, as well as targets of EC, were screened in relevant databases to construct a compound-target network and a protein-protein interaction (PPI) network that narrowed down the pool of ingredients and targets. This was followed by gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Next, molecular docking, ADME and toxicity risk prediction, cell viability assays, in vitro scratch assays, Transwell cell invasion assays, and Western blotting analysis were subsequently applied to validate the results of the network analysis.

The screening produced a total of 21 active ingredients and 167 ingredient-related targets for GpM, along with 2653 targets for EC. The PPI network analysis highlighted three targets of interest, namely AKT1, TP53, and VEGFA, and the compound-target network identified three possible active ingredients: quercetin, rhamnazin, and isofucosterol. GO and EKGG indicated that the mechanism of action might be related to the PI3K/AKT signaling pathway as well as the regulation of cell motility and cell migration. Molecular docking and pharmacokinetic analyses suggest that quercetin and isoprostanoid sterols may have therapeutic value and safety for EC. The in vitro experiments confirmed that GpM can inhibit EC cell proliferation, migration, and invasion and suppress PI3K and AKT phosphorylation.

Our findings indicate that GpM exerts its anti-tumor effect on EC by inhibiting EC cell migration and invasion via downregulation of the PI3K/AKT signaling pathway. Hence, we have reason to believe that GpM could be a promising candidate for the treatment of EC.

Research regarding post-operative brain protection after deep hypothermic circulatory arrest (DHCA) has gained attracted significant attention. We previously demonstrated that hydrogen can significantly reverse DHCA-induced brain damage.

In the current research, we have established the DHCA model successfully using a modified four-vessel occlusion method and injected miR-29s compounds into the hippocampal tissue of rats.

We were surprised to find hydrogen increased miR-29s expression in the hippocampal tissue of a DHCA rat model. The administration of agomiR-29s counteracted DHCA-induced hippocampal tissue injury, while the antamiR-29s had the opposite effects.

Based on the above facts, the brain protection mechanism of hydrogen in DHCA-treated rats may be related to the upregulation of miR-29s, which can exert its beneficial effects by alleviating apoptosis, inflammation, and oxidation.

Traditional Chinese medicine (TCM) can modulate the immune function of tumor patients in various ways. Zuojin Wan (ZJW, a 6:1 ratio of Huang Lian and Wu Zhu Yu) can modulate the microenvironment of ulcerative colitis, but its role in regulating the colorectal cancer (CRC) microenvironment remains unclear. Exploring the role of ZJW in CRC immunomodulation may improve the antitumor effect of existing immunotherapeutic strategies.

The active compounds of each herb in ZJW were obtained from the HIT2.0 database with literature evidence. Single-cell RNA sequencing data of CRC were obtained from published studies (PMID: 32451460, 32103181, and 32561858). Pathway enrichment was analyzed using the reactome database, and intergenic correlation analysis was performed using the corrplot R software package. ZJW-regulated gene expression was verified by RT-qPCR.

Huang Lian and Wu Zhu Yu contain 19 and 4 compounds, respectively. Huang Lian targets 146 proteins, and Wu Zhu Yu targets 28 proteins based on evidence from the literature. ZJW regulates a range of biological processes associated with immune function, including cytokine signaling and Toll-Like Receptor 4 (TLR4) cascade. ZJW regulates malignant CRC cells, immune cells (including T-cells, B-cells, mast cells, NK/NKT cells, and myeloid cells), and other non-immune cells (including endothelial cells, enteric glial cells, and pericytes). We confirmed that ZJW significantly downregulated the expression of TIMP1 and MTDHin CRC cell lines.

ZJW regulates a range of cells in the CRC microenvironment, including malignant CRC, immune cells, and stromal cells. In CRC cell lines, downregulation of TIMP1 and MTDH by ZJW may play an important role in the immunomodulation in CRC.

The aim of this study is to explore the anti-depressant mechanism of Chaihu-Shugan San based on serum medicinal chemistry and network pharmacology methods.

Depression lacks effective treatments, with current anti-depressants ineffective in 40% of patients. Chaihu-Shugan San (CHSGS) is a well-known traditional Chinese medicine compound to treat depression. However, the chemical components and the underlying mechanisms targeting the liver and brain in the anti-depressant effects of CHSGS need to be elucidated.

The chemical components of CHSGS in most current network pharmacology studies are screened from TCMSP and TCMID databases. In this study, we investigated the mechanism and material basis of soothing the liver and relieving depression in the treatment of depression by CHSGS based on serum pharmacochemistry. The anti-depressant mechanism of CHSGS was further verified by proteomics and high-throughput data.

Through serum medicinal chemistry, we obtained 9 bioactive substances of CHSGS. These ingredients have good human oral bioavailability and are non-toxic. Based on liver ChIP-seq data, CHSGS acts on 8 targets specifically localized in the liver, such as FGA, FGB, and FGG. The main contributors to CHSGS soothing the liver qi targets are hesperetin, nobiletin, ferulic acid, naringin and albiflorin. In addition, network pharmacology analysis identified 9 blood components of CHSGS that corresponded to 63 anti-depressant targets in the brain. Among them, nobiletin has the largest number of anti-depressant targets, followed by glycyrrhizic acid, ferulic acid, albiflorin and hesperetin. We also validated the anti-depressant mechanism of CHSGS based on hippocampal proteomics. CHSGS exerts anti-depressant effects on synaptic structure and neuronal function by targeting multiple synapse related proteins.

This study not only provides a theoretical basis for further expanding the clinical application of CHSGS, but also provides a series of potential lead compounds for the development of depression drugs.