Current Medicinal Chemistry - Volume 32, Issue 12, 2025

Gut microbiota is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) through the metabolites, which can induce atherogenesis. One of these metabolites is trimethylamine N-oxide (TMAO). Some studies indicate that statins do not only decrease LDL-cholesterol and thus ASCVD risk, but they also affect gut microbiota. There are only a few studies on humans suggesting that statins might also decrease TMAO, but their results are not unanimous. This meta-analysis aimed to provide an answer as to whether statins do affect decreasing the plasma levels of atherogenic TMAO.

A systematic literature search in PubMed, Scopus, Embase, and Web of Science was performed from inception to January 1^st, 2023. To assess the quality of each study included in the meta-analysis, the Cochrane Quality Assessment tool 1 (ROB 1) was used. Comprehensive Meta-Analysis V3 software was used to perform the meta-analysis. The weighted mean difference was also used. A random effects meta-analysis was used to calculate the overall estimate of effect size. In the leave-one-out approach, one study was excluded from each analysis to evaluate the effect of each study on the overall effect size.

Random-effects meta-analysis of 3 studies including 244 patients demonstrated a significant decrease in plasma TMAO levels after statin treatment (WMD: -1.839, 95% CI: -2.391, -1.287, p<0.001; I²:0). The reduction in TMAO was robust in the leave-one-out sensitivity analysis.

Statins might reduce TMAO levels, but there is a need for further evidence from long-term studies taking into account different types and doses of statins.

It has been widely reported that the use of probiotics has beneficial effects on the prevention and treatment of a wide range of human diseases. Previous clinical trials have investigated the effect of probiotics on oxLDL, but the results are controversial.

This study aimed to conduct a systematic review and meta-analysis of clinical trials to assess the effect of probiotic consumption on oxLDL levels.

A comprehensive search was conducted in PubMed, ISI Web of Science, and Scopus using the appropriate search strategy. After the screening, seven studies comparing the effects of probiotic consumption with the control were included in the analysis. A random-effects analysis was used to estimate the overall effect size.

Probiotic supplementation significantly reduced oxLDL (Hedge's: -1.18; 95% CI:-1.85, -0.52) compared to the control group. Subgroup analysis showed that reduction was greater in the unhealthy group compared to healthy subjects (-2.05 vs. -0.84). The results also showed that probiotic supplementation reduced TC by -14.77 mg/dl (95% CI: -24.46, -5.08), LDL-C by -10.03 mg/dl (95% CI: -16.05, -4.001), LDL-C/HDL-C ratio by -0.37 (95% CI: -0.66, 0.07), and TG by -14.86 mg/dl (95% CI: -23.45, -6.28) but the effects on HDL-C and glucose were not significant.

In this study, probiotic supplementation was found to improve oxLDL concentrations and have favorable effects on lipid profiles, but no significant positive effect on HDL-C and glucose was reported. However, the findings should be interpreted with caution due to the low number of included studies.

Chemoresistance by stemness in HPV-induced cervical carcinogenesis has significant implications for the overall disease-specific survival of the patients. To date, there are no reports related to the implications of significant aspects of inflammation and microbiome-mediated epigenetics in cervical cancers.

The current systematic review delineates the significant aspects of the inflammation-related pathophysiology, cervical cancer diagnosis based on the HPV-indued stemness, and microbiome-mediated epigenetic markers to develop personalized therapies to target the stemness-acquired indefinitely dividing cancer stem cells.

We performed a systematic review without a meta-analysis. We searched several public databases, such as Pubmed, ReleMed, National Library of Medicine, and Scopus, related to inflammation, metabolomics, microbiome-mediated epigenetic markers, and HPV-induced stemness.

The review significantly described the correlation between microbial inflammation and stem cell stochasticity of HPV-Induced cervical cancer and the expression of epigenetics-based biomarkers through microbiome and metabolome to foster the cervical cancer progression. These are major risk factors that can cause cervical dysplasia with substantial therapy resistance in cervical cancer patients. The qualitative and quantitative examination of the spatial transcriptomic expression of these stemness markers in the dividing cervical cancer stem cells has significant implications in the clinical sector to develop early personalized medicine to prevent cervical precancerous lesions depending on the prognosis of the cervical cancer patients. Mainly, the combinatorial regimen of current therapeutic modalities, along with microbiome-related therapies with future landscape of epigenetics-modulated therapies, may enhance overall disease-specific survival by modulating the stochastic dynamics of basal epithelial cells across the cervical region.

The CLDN18 gene, encoding claudin 18.1 and claudin 18.2, is a key component of tight junction strands in epithelial cells that form a paracellular barrier that is critical in Stomach Adenocarcinoma (STAD).

Our study included 1,095 patients with proven STAD, 415 from The Cancer Genome Atlas (TCGA) cohort and 680 from the Gene Expression Omnibus database. We applied various analyses, including gene set enrichment analysis, pathway analysis, and in vitro drug screening to evaluate survival, immune cells, and genes and gene sets associated with cancer progression, based on CLDN18 expression levels. Gradient boosting machine learning (70% for training, 15% for validation, and 15% for testing) was used to evaluate the impact of CLDN18 on survival and develop a survival prediction model.

High CLDN18 expression correlated with worse survival in lymphocyte-poor STAD, accompanied by decreased helper T cells, altered metabolic genes, low necrosis-related gene expression, and increased tumor proliferation. CLDN18 expression showed associations with gene sets associated with various stomach, breast, ovarian, and esophageal cancers, while pathway analysis linked CLDN18 to immunity. Incorporating CLDN18 expression improved survival prediction in a machine learning model. Notably, nutlin-3a and niraparib effectively inhibited high CLDN18-expressing gastric cancer cells in drug screening.

Our study provides a comprehensive understanding of the biological role of CLDN18-based bioinformatics and machine learning analysis in STAD, shedding light on its prognostic significance and potential therapeutic implications. To fully elucidate the molecular intricacies of CLDN18, further investigation is warranted, particularly through in vitro and in vivo studies.

Osteoarthritis (OA) is a chronic joint disease, usually accompanied by degeneration of the articular cartilage, fibrosis, bone hyperplasia around the joint, and damage to the entire articular surface. Gossypol is a natural phenolic compound isolated from the seed of cotton plants, and gossypol acetic acid (GAA) is a medicinal form of Gossypol. Recently, various biological activities of GAA, including anti-inflammatory and anti-tumor effects, have been widely reported. However, its effect on chondrocytes in OA has yet to be determined.

In this study, we investigated the effect of GAA on ferroptosis in OA chondrocytes. The effect of GAA on the cell viability and cytotoxicity of chondrocytes in rat cells was investigated using CCK8. Western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescence staining were used to elucidate the molecular mechanisms and signaling pathways of GAA inhibition of ferroptosis in OA chondrocytes. The effect of GAA on reactive oxygen species (ROS) production and lipid peroxidation levels in chondrocytes was examined using dihydroethidium (DHE) staining and fluorescent dye BODIPY581/591 C11. In vivo, micro-CT imaging, hematoxylin and eosin staining, Safranin O-Fast staining, and immunohistochemistry were performed to evaluate the effects of GAA on OA cartilage.

The results showed that GAA treatment regulated the expression of chondrocyte extracellular matrix (ECM) related factors, including ADAMTS5, MMP13, SOX9, Aggrecan, and COL1A2 and reduced the ROS and lipid peroxidation levels. Besides, Erastin could reverse the effects of GAA on chondrocytes. Similar to GAA, 5-AZA caused the reduction of ROS and lipid peroxidation levels and reversed the effect of IL-1β on the expression of ECM-related factors in OA chondrocytes. The above results clarified that GAA alleviated the ferroptosis of chondrocytes in OA by inhibiting GPX4 methylation.

Our findings revealed that GAA might be developed as a drug for treating OA clinically.

The High Mobility Group Nucleosomal Binding Domain 1 Gene (HMGN1) is crucial for epigenetic regulation. However, the specific function of HMGN1 in cancer development is unclear.

Raw data on HMGN1 expression were procured from Genotype-Tissue Expression (GTEx), the University of Alabama- Birmingham CANcer data analysis Portal (UALCAN), and The Cancer Genome Atlas (TCGA). Thereafter, the pan-cancer analysis was implemented to understand the HMGN1 expression patterns, prognostic value, and immunological features. Furthermore, the Gene Set Enrichment Analysis (GSEA) was executed via R language. In addition, the relationship between HMGN1 and the sensitivity of antitumor drugs was also determined. Finally, real-time PCR (RT-PCR) experiments were carried out.

Pan-cancer analysis revealed that HMGN1 was upregulated in several solid tumors and was associated with pathological staging and poor prognosis. In addition, HMGN1 was found to be involved in regulating the tumor microenvironment. The GSEA enrichment analysis indicated that HMGN1 assisted in the regulation of oncogenic processes, especially metabolic and immune pathways. Furthermore, HMGN1 expression was linked to microsatellite instability (MSI) and tumor mutational burden (TMB) across diverse tumor types. RT-PCR assays indicated that HMGN1 was overexpressed in the gastric and breast cancer cell lines and tissues.

This study highlighted the potential of HMGN1 as a biomarker for pan-cancer analysis.

The bindings of several ribonucleoside triphosphate (NTP) inhibitors to the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are studied herein to identify potential drug-like candidates that can inhibit the replication of the viral genome by RdRp.

In this study, a guanosine triphosphate (GTP) bound to RdRp structure is generated to model the replication initiation state of RdRp. Subsequently, the bindings of 30 NTP inhibitors to the GTP binding site of RdRp are studied in detail by using the molecular docking method. Based on the docking scores, four NTP inhibitors, such as 2'-C-methyl-adenosine-5′-triphosphate (mATP), 7-deaza-2'-C-methyladenosine-TP (daza-mATP), 1-N6-Ethenoadenosine-5′-triphosphate (eATP), and Remdesivir-5′-triphosphate (RTP) are shortlisted for further analysis by employing molecular dynamics simulations and binding free-energy methods.

These inhibitors are found to bind to RdRp quite strongly, as evident from their relative binding free energies that lie between -31.54 ± 4.54 to -89.46 ± 4.58 kcal/mol. Among these drugs, the binding of RTP to the GTP site of RdRp would generate the most stable complex, which would be about 45 kcal/mol more stable than the binding of GTP to RdRp.

Due to the highest stability of the RTP-RdRp complex, it is likely that RTP would inhibit the RdRp activities efficiently. However, due to the strong binding of other NTPs to RdRp, they may also inhibit RdRp activities. Nevertheless, experimental evaluations of the potency of these drugs against the ZIKV RdRp are required before their clinical use.