Current Medicinal Chemistry - Volume 32, Issue 40, 2025

To treat diseases like cancer, conventional Paclitaxel (PTX)-based monotherapy treatment regimens are becoming less effective due to the development of resistance. In this aspect, the phytomolecule curcumin (Cur), having ethnopharmacological importance in traditional South Asian remedies, like Ayurveda and Chinese traditional medicine, has been studied as a promising chemo-sensitizing and synergistic partner of PTX.

This study aimed to evaluate the combined effect of PTX and Cur compared to PTX therapy alone in the in vitro and in vivo environments.

An extensive PubMed search was performed wherein 169 papers were shortlisted and screened to identify 30 studies that have reported the effect of PTX and Cur either in vitro, in vivo, or both. The pooled Odds Ratio (OR) was calculated at a 95% Confidence Interval (CI) for determining the effect of combination therapy.

The meta-analysis has indicated PTX and Cur combination therapy to be associated with a significant decrease in cell viability (OR: 0.37, 95% CI: 0.27-0.51; p < 0.01) and tumor volume (OR: 0.32, 95% CI: 0.15-0.71; p = 0.01). Additionally, the effect of this combination on drug-resistant cell lines has exhibited a significant decrease in the odds of cell viability (OR: 0.45, 95% CI: 0.35-0.57; p < 0.01).

Overall, the current meta-analysis has shown PTX and Cur combination to effectively inhibit the viability of cancer cells, reduce tumor volume, and diminish the growth of drug-resistant cancer cells.

Ovarian cancer, a significant contributor to global female mortality and the third most prevalent gynecological cancer in India, poses challenges for conventional treatments like chemotherapy and radiotherapy.

This study explores the effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on the efficacy of chemotherapy, particularly doxorubicin (DOXO), in ovarian teratocarcinoma (PA-1) cells. Rigorous cell viability assays demonstrated that n-3 PUFAs in combination significantly enhanced DOXO-induced cytotoxicity, reducing cell survival and migration potential. N-3 PUFAs and DOXO synergistically reduced colony formation in the group receiving the combination treatment as seen in the clonogenic assays, as further validated by hanging drop and apoptosis assays results.

Network pharmacological investigations pinpointed the gene topoisomerase II A (TOP2A) as a pivotal target, while molecular docking simulations revealed structural similarities between n-3 PUFAs (DHA or EPA) and DOXO, implying probable common mechanisms such as DNA intercalation and topoisomerase II inhibition. Molecular dynamics simulations delineated distinct interaction profiles for Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) with TOP2A, offering mechanistic insights. Combining computational and experimental methodologies reveals the synergistic benefits of n-3 PUFAs and DOXO in treating ovarian cancer, leading to improved therapeutic outcomes.

These results provide a comprehensive view of the potential of combining n-3 PUFAs with DOXO for more potent ovarian cancer treatments.

Considering infants and young children, it is well established that their physiological and developmental peculiarities should not be confused with those of other patient categories, such as adults or vulnerable patients. Indeed, their anatomic-functional characteristics specifically influence the drug pharmacokinetic/pharmacodynamic profile. Therefore, the availability of specialists devoted to pediatric pharmacology within multidisciplinary teams is highly desirable to improve the care of these patients.

This work aims to describe the role of pediatric clinical pharmacologists in the context of pediatric clinical care in Italy, using a qualitative method based on the type of articles published.

A literature review was conducted according to the PRISMA guidelines, considering articles published on the PubMed database between January 2017 and March 2022 and using specific MeSH terms. The papers were attributed to two blind assessors and then processed for discussion. To support article screening, focusing on the words contained in article titles, the R package evidence synthesis tool revtools was used.

The search identified a total of 1544 articles, of which 93 were selected. The articles analyzed mainly concern therapeutic drug monitoring and pharmacovigilance with adverse drug reactions.

An insight into multidisciplinary work to prevent, diagnose, and treat pediatric diseases and to monitor treatments is provided in this study. However, this concept needs to be strengthened in the long term.

Explore the role of mitochondrial membrane permeability transition (MPT) in colon adenocarcinoma (COAD).

Further exploration of risk stratification for COAD prognostic assessment has important clinical value. MPT-related pathways play a key role in the pathogenesis of many human diseases, including tumorigenesis. Its impact on COAD is still unknown.

Bioinformatics analysis was conducted by analyzing the GEO database and TCGA database, and the bioinformatics results were verified by in vitro experiments.

Through the analysis of the transcriptome data of 1008 COAD samples in the GEO database and TCGA database, the differential expressions of MPT-related genes in COAD were explored, followed by molecular subtype analysis based on MPT characteristics by univariate Cox algorithm analysis and the consensus clustering algorithm. The gene signature associated with MPT molecular subtypes was further identified and the MPT scoring system was established by the LASSO-univariate Cox analysis algorithm. After evaluating the prognostic value of the MPT scoring system in COAD patients via nomogram establishment, the clinical value of the MPT scoring system was comprehensively analyzed through somatic mutation characteristics analysis, immunotherapy response analysis, immunoinfiltration analysis, and drug sensitivity analysis. CCK-8, WB, PCR, colony formation method, and Transwell method were used to verify the effect of the screened target on the proliferation and invasion of COAD cells.

We successfully established a scoring system related to MPT and validated the prognostic value of COAD patients. The potential clinical value of the MPT scoring system was also analyzed. VSIG4 was selected for further in vitro experiments to verify the effect of the screened targets on the proliferation and invasion ability of COAD cells.

We established an MPT scoring system for effective risk stratification of COAD patients, demonstrating the impact of MPT on the development of COAD and its potential value as an intervention factor.

Mitochondrial fission and fusion play important roles in tumorigenesis, progression and therapy. Dysregulation of these processes may lead to tumor progression, and regulation of these processes may provide novel strategies for cancer therapy. The involvement of genes related to mitochondrial fission and fusion (MD) in gastric cancer (GC) remains poorly understood.

The aim of this study was to establish an MD gene signature for GC patients and to investigate its association with prognosis, tumor microenvironment and treatment response in GC.

We use the TCGA-GC database as the cohort, focusing specifically on genes associated with MD. We conducted identification and consistency clustering analysis of differentially expressed genes in MD, conducted MD gene mutation and copy number variation analysis, as well as correlation and functional enrichment analysis between MD gene cluster classification and immune infiltration. TCGA-GC and GSE15459 were used to construct training and validation cohorts for the model. We used various statistical methods, including Cox and Lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE13861, GSE26901, GSE66229, and GSE13450). We used GSEA enrichment, CIBERSORT algorithm, ESTIMATE, and TIDE to gain insight into the annotation of MD signature and the characterization of the tumor microenvironment. OncoPredict was used to analyze the relationship between the PRG signature and the drug sensitivity. We validated the expression of several key genes in MD signature on GC cell lines using quantitative real-time PCR (qRT-PCR).

These MDs-related subtypes exhibited different prognosis and immune filtration patterns. A five-gene signature, comprising AGT, HCFC1, KIFC3, NOX4, and RIN1, was developed. There was a clear distinction in overall survival between low- and high-risk patients. The analyses showed further confirmation of the independent prognostic value of the gene signature. There was a notable correlation between the MD signature, immune infiltration and drug susceptibility. The expression levels of AGT, HCFC1, KIFC3, NOX4 and RIN1 mRNA were all increased in these GC cells.

The MD signature has the capacity to significantly contribute to the prediction of personalized outcomes and the advancement of novel therapeutic strategies tailored for GC patients.

Copine-3 (CPNE3) is a conservative calcium-dependent phospholipid-binding protein belonging to the copines protein family. CPNE3 has been implicated in the development and progression of several diseases, including cancer.

Herein, we investigated the molecular mechanisms through which CPNE3 regulates the migration of lung adenocarcinoma (LUAD) cells in vitro. Western blotting and immunohistochemical assays showed that CPNE3 is widely distributed in LUAD tissues and cell lines and that CPNE3 downregulation promotes the migration of human LUAD A549 cells.

Stable isotope labelling with amino acids in cell culture, which is a quantitative proteomics approach coupled with bioinformatic analyses, revealed that CPNE3 regulates SQSTM1/p62 and vimentin expression, indicating that CPNE3 may mediate epithelial-mesenchymal transition (EMT). CPNE3 silencing by siRNA upregulated vimentin levels but downregulated E-cadherin levels in the A549 cells.

Furthermore, SQSTM1/p62 knockdown enhanced migratory ability and EMT progression in CPNE3-silenced A549 cells. Overall, CPNE3 knockdown was found to promote EMT by inhibiting SQSTM1/p62 signalling and facilitating cell migration. Our findings highlight the role of CPNE3 as a tumour suppressor, providing deeper insights into its tumour-suppressive roles in LUAD.

We aimed to develop a reliable prognostic tool related to glucagon-like peptide-1 (GLP-1) for guiding treatment of pancreatic cancer (PC).

The treatment strategies for PC being greatly advanced the prognosis of cancer still remains unfavorable.

To develop a RiskScore model for evaluating PC prognosis.

The bulk RNA-seq data of PC patients were obtained from the UCSCXena and GEO database, and the GSE156405 cohort was used for single-cell RNA-seq (scRNA-seq) analysis in the “Seurat” package. Firstly, the gene expression and mutation in the PC samples were analyzed to perform differentially expressed genes (DEGs) analysis using the “limma” package. The “survival” package was employed to conduct un/multivariate Cox regression and Kaplan-Meier (KM) survival analysis. Secondly, a RiskScore model was developed and assessed using the “glmnet” and “timeROC” packages. Next, the CIBERSORT algorithm and the ssGSEA method were applied for immune infiltration analysis and calculation of the immune cell scores, respectively. Finally, pathway enrichment analysis was conducted using gene set enrichment analysis (GSEA).

Most GLP-1 signaling genes were overexpressed in the PC samples with multiple mutation types. LASSO analysis selected 3 GLP-1 genes for the development of a RiskScore model with a high classification accuracy (AUC >0.6). Notably, high-risk patients showed a significantly shorter survival time in both training and validation sets. In addition, as an independent factor, the RiskScore was further used to establish a nomogram model for the survival prediction of PC in clinical practice. The tumor microenvironment (TME) analysis revealed that low-risk patients with more abundant immune and stroma components had higher levels of anti-tumor immune cell infiltration (such as activated B and T cells), while the proliferation pathways (E2F targets, G2M checkpoint) were significantly activated in the high-risk groups. The genes in the RiskScore model may affect the survival of PC patients through modulating the activities of NK cells and macrophages.

We demonstrated that the GLP-1 signaling affected PC development and developed a reliable RiskSocre model for the prognosis assessment in PC. Our findings are expected to improve PC diagnosis and treatment in clinical practice.

Acute kidney injury (AKI) is a common renal condition associated with various factors, including pre-renal, post-renal, and renal causes, with ischemia-reperfusion being a frequent contributor leading to tubular injury. Early identification of AKI is crucial but remains challenging.

This study explored the molecular signature of AKI using gene microarray data from the GEO dataset, focusing on identifying ferroptosis-related features through three machine-learning algorithms. We also validated potential biomarkers through a hypoxia/reoxygenation model.

ROC curves, expression differences, and associations with immune cells were analyzed for the three markers to confirm their potential as AKI biomarkers, each demonstrating strong diagnostic ability. Combining these markers proved more effective.

The combination of AEBP2, MDM2, and NR4A1 as diagnostic biomarkers for AKI not only enhances detection capability but also holds promise as a significant tool in clinical practice, providing patients with diagnostic and therapeutic guidance.

The interplay between dietary habits and the development of Diverticular Disease (DD) has long been a subject of vibrant debate.

Utilizing Mendelian Randomization (MR), this study aims to meticulously examine the causal dynamics at play.

The foundation for the Genome-Wide Association Studies (GWAS) on DD was established using a dataset from the FinnGen consortium, encompassing 33,619 patients and 329,381 control participants. Data on 18 dietary habits and DD for the validation cohort were procured from the UK Biobank. An MR analysis was executed to delve into the causal relationship between dietary habits and DD, adhering to a rigorous Bonferroni correction threshold of 3.00E-03. Our main analysis method was the Inverse Variance Weighted (IVW) approach. To improve the accuracy and reliability of our study, we also conducted heterogeneity analysis, tests for horizontal pleiotropy, outlier identification, and “leave-one-out” sensitivity analysis.

Our analysis unearthed a potential causal association between the consumption of dried fruits and a lower risk of developing DD (IVW: odds ratio (OR) 0.372, 95% confidence interval (CI) 0.272 - 0.509, p = 5.79E-10), a finding that was corroborated in the validation cohort (IVW: OR 0.975, 95% CI 0.961 - 0.990, p = 1.04E-03). Conversely, our results do not substantiate a causal link between the consumption of alcohol, dietary fiber, and red meat and the risk of DD.

Our detailed MR analyses show that eating dried fruit lowers the risk of DD, providing strong support for prevention and treatment approaches for DD.