Current Molecular Medicine - Online First

The present study aimed to examine the functions of heat shock protein 90 (HSP90), NF-κB, C3, and C5a in cardioprotective effects induced by vericiguat in mice.

Male mice were randomly assigned to six groups: sham, ischemia/ reperfusion (I/R), vericiguat preconditioning (VPre), VPre + HSP90 inhibitor geldanamycin (GA), vericiguat postconditioning (VPost), and VPost + GA. An experimental mouse model of I/R was established in mice through surgery and treatments with vericiguat and GA. The following parameters were assessed: myocardial infarct size; cardiomyocyte apoptosis; cTnI, CK-MB, and LDH serum levels, protein expression levels of Bcl-2, Bax, HSP90, NF-κB, and complement components C3 and C5a, and mRNA expression levels of IL-1β, TNF-α, and ICAM-1.

Vericiguat significantly attenuated the myocardial infarct size induced by I/R injury; suppressed cardiomyocyte apoptosis; reduced serum levels of myocardial markers (CK-MB, LDH, and cTnI); decreased C5a, and C3 levels, NF-κB signaling, and expression of inflammatory cytokine (ICAM-1,TNF-α, and IL-1β); and enhanced HSP90 and Bcl-2 expression levels. However, GA reversed these effects.

The study contributes to the investigation of the crosstalk between HSP90 and complement in the protective effects of vericiguat on myocardial I/R injury. However, further in-depth research is needed to explore the underlying mechanisms of vericiguat's cardioprotective effects against myocardial I/R injury.

HSP90 plays a crucial role in the cardioprotective effects of vericiguat, providing new insights into its mechanisms of action.

Mutations in Chromodomain Helicase DNA Binding Protein 7 (CHD7) and Paired Box Gene 4 (PAX4) are critical for normal cartilage development and are implicated through their impact on chondrocyte functions. This study examines how these genetic alterations specifically modulate Tumor protein p53 (p53) expression to affect cellular proliferation and apoptosis, shedding light on potential therapeutic targets for mitigating developmental anomalies in cartilage.

Using Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein 9 (Cas9), specific mutations were introduced into CHD7 and PAX4 in chondrocytes. Subsequent analyses included 5-ethynyl-2'-deoxyuridine (EdU) assay for proliferation, Terminal deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining for apoptosis, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot alongside co-immunoprecipitation (Co-IP) to evaluate expression levels and protein interactions.

Mutations in CHD7 and PAX4 resulted in decreased proliferation and increased apoptosis in chondrocytes. Notably, these mutations disrupted the interaction between the mutant proteins and p53, leading to altered expression of apoptotic regulators such as Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), indicating activation of p53-dependent apoptotic pathways.

This study elucidates the core molecular mechanism by which mutations in the CHD7 and PAX4 genes disrupt their interaction with p53, leading to aberrant activation of the p53-dependent apoptotic pathway. These findings provide a new theoretical basis and potential intervention strategies for developing p53 pathway-targeted therapies to treat related cartilage developmental disorders. Future research should focus on in vivo validation and mechanistic refinement.

The study reveals that CHD7 and PAX4 mutations exacerbate the apoptotic pathways in chondrocytes by enhancing the activity of p53, leading to decreased cell proliferation and increased apoptosis. These findings underscore the mutations’ profound impact on cartilage cell dynamics and highlight the therapeutic potential of targeting p53 to correct the cellular imbalances caused by these genetic changes in cartilage-related developmental disorders.

Gastric cancer (GC) remains a major health burden with poor prognosis, highlighting the need for reliable prognostic biomarkers and therapeutic targets. ELOVL4 (Elongation of Very Long Chain Fatty Acids Protein 4) is an enzyme involved in lipid metabolism, which has been implicated in various cancers, but its role in GC remains largely unexplored.

We evaluated the prognostic value of ELOVL4 expression in GC based on samples from The Cancer Genome Atlas (TCGA) database. Subsequently, we investigated the associations between ELOVL4 expression and tumor immune microenvironment features, including tumor microenvironment (TME) scores, immune cell infiltration, and immune checkpoint gene expression. Moreover, we assessed the correlation between ELOVL4 expression and tumor mutational burden (TMB) as well as drug sensitivity profiles. Functional and pathway enrichment analyses were performed to gain mechanistic insights.

High ELOVL4 expression was significantly associated with adverse clinical outcomes. A nomogram incorporating ELOVL4 expression was developed for individualized prognosis evaluation. Patients with high ELOVL4 expression exhibited an activated TME, with distinct immune cell infiltration patterns and correlations with immune checkpoint gene expression. Additionally, ELOVL4 expression was negatively correlated with TMB. Differential drug sensitivity profiles were identified between the high and low ELOVL4 expression groups. Enrichment analyses revealed the involvement of ELOVL4 in various biological processes and signaling pathways.

Our findings establish ELOVL4 as a biomarker for poor prognosis and therapeutic target in GC, with implications for prognosis evaluation, immune microenvironment modulation, and chemotherapeutic response.

This systematic review assesses the role of the tumor microenvironment (TME) in cancer progression and therapy resistance by defining drug-microenvironment interactions and determining the molecular determinants in the TME that could help improve the efficacy of administered treatments and alleviate existing adverse effects.

This systematic review follows the PRISMA protocol and the PICOS selection framework to retrieve studies from PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library. Only original human-related research published in English between 2008 and 2023 was used to explore the reciprocal relation between tumor cells and TME components. The ROBINS-I tool assessed the risk of bias.

Out of 258 articles initially identified, 15 met the inclusion criteria for this review. The results showed that TMEs significantly influence treatment outcomes in cancer progression, metastasis, and drug resistance. Focusing on TMEs like CAFs, immune cells, and ECM enhances drug efficacy. The study highlighted potential strategies to improve drug delivery, suppress metastatic processes, and restore immune function, ultimately leading to better outcomes for cancer patients.

Original evidence suggests that Cancer-Associated Fibroblasts (CAFs), immune cells, and Extracellular Matrix (ECM) contribute to therapeutic resistance and metastasis within the TME. They also promote metastasis by inducing Epithelial-Mesenchymal Transition (EMT) and affecting Cancer Stem Cell (CSC) populations. Moreover, the immunosuppressive TME consists of regulatory T cells and myeloid-derived suppressor cells that allow tumors to evade the immune system, a concern for immunotherapy.

The TME plays a vital role in cancer development, metastasis formation, and therapy failure. The perspectives for innovative ECM-modulating treatments and interventions targeting the direct interactions between TME and cancer cells can be revolutionary and suggest better outcomes for treatment-naïve and refractory cancers. Future research should use these results as inputs to apply clinical and therapy studies to enhance cancer management outcomes.

This study aimed to explore the mechanism of semaphorin 3F- (Sema3F) induced hippocampal axonal growth cone collapse by studying the effect of Sema3F on vascular endothelial growth factor (VEGF) in vitro primary rat hippocampal neuron culture system.

Hippocampal neurons were taken from Wistar rats within 24 hours after birth for primary culture in vitro. On the third day, Sema3F was added to the experimental group, and fetal bovine serum at the same concentration was added to the control group. The cells were collected at 0, 5, 15, and 30 min. The expression of VEGF messenger ribonucleic acid (mRNA) in the hippocampal neurons was detected by real-time polymerase chain reaction (PCR), while VEGF expression was detected by Western blot. The level of VEGF expression in the hippocampal neuron culture medium was detected by enzyme-linked immunosorbent assay.

The expression of both VEGF mRNA and VEGF protein in the rats’ hippocampal neurons decreased at different times. The VEGF concentration in the culture medium initially increased before decreasing over time.

Sema3F is known to induce growth cone collapse in hippocampal neurons, and this study provides evidence that this effect may be mediated by downregulating VEGF expression and secretion. The initial increase in VEGF concentration in the culture medium could be a compensatory response to the collapse of growth cones, while the subsequent decrease suggests a sustained effect of Sema3F on VEGF regulation. The findings highlight the complex interplay between Sema3F and VEGF in neuronal development and repair. Future research should explore the underlying signaling pathways and potential therapeutic applications of these interactions.

Sema3F inhibited the synthesis of VEGF in hippocampal neurons at transcription and translation levels in a time-dependent manner. Sema3F may also affect the secretion level of VEGF, initially increasing its extracellular expression before decreasing it over time.

Endometriosis is a chronic disorder characterized by abnormal endometrial tissue growth. This study evaluates a novel combination immunomodulatory treatment involving etanercept (ETN) and exosomes derived from human Wharton's jelly mesenchymal stem cells (hWJMSC-Exo) as a promising alternative to conventional therapies for modulating inflammation in endometriosis.

Endometrial stromal cells were isolated by enzymatic digestion of eutopic (EuESCs, N = 6) and ectopic (EESCs, N = 6) tissues of endometriosis patients and non-endometriotic controls (CESCs, N = 6). hWJMSC-Exo were confirmed by flow cytometry, SEM, and DLS tests. Cells were treated with varying concentrations of ETN (0-40 µg/ml), hWJMSC-Exo (0-15 μg/ml), and their combination (E+E). IC50 values were determined using the MTT assay at 24, 48, and 72 hours. Protein levels of TNF-α, VEGF-A, and IL-10, and gene expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 were measured using ELISA and RT-PCR, respectively.

The combination of ETN (10 µg/ml) and hWJMSC-Exo (10 μg/ml) at 24 and 48 hours, respectively, reduced protein expression of TNF-α, VEGF-A, and IL-10 in EESCs, EuESCs, and CESCs compared with untreated groups (P < 0.001). Additionally, E+E treatment significantly reduced mRNA expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 in all three groups compared to untreated groups.

This combination therapy improves inflammation, angiogenesis, tissue remodeling, and immune regulation in endometriosis. However, clinical validation and long-term safety require further in vivo studies with larger sample sizes.

Studies have stated that there has been a close association between the telomere length (TL) and the incidence of non-alcoholic fatty liver disease (NAFLD). The goal of this report is to explore the possible association between TL and NAFLD.

This study adhered to the PRISMA guidelines for systematic reviews. An extensive literature search was conducted in the Cochrane Library, CINAHL, Scopus, PubMed, and Web of Science. The “meta” package in the R programming language, version 4.3.1, was used for statistical analysis.

The meta-analysis of the included studies showed a pooled standard mean difference (SMD) of -0.25 (95% CI: -0.39 to -0.10), indicating shorter TL in NAFLD patients. Subgroup analyses revealed significant TL shortening in NAFLD patients with body mass index (BMI) <28 (SMD = -0.68, 95% CI: -0.96 to -0.39) and in case-control (-0.35, 95% CI: -0.51 to -0.20) and cohort studies (-0.68, 95% CI: -1.19 to -0.17). An odds ratio (OR) meta-analysis of six studies found that individuals with short TL had 1.72 times higher odds of NAFLD, which was statistically significant (95% CI: 1.23-2.42, I² = 85%). Excluding one study reduced heterogeneity (I² = 37%) and increased the OR to 1.93 (95% CI: 1.45-2.56), confirming a strong association between short TL and NAFLD risk.

The findings suggest a potential link between shorter TL and NAFLD. The odds ratio analyses further emphasized the increased risk of NAFLD in individuals with short TL. Nevertheless, the residual heterogeneity highlights the need for further high-quality, standardized research.

Our findings supported the connection between reduced TL and NAFLD. Regardless of significant between-study diversity, the results remained consistent even after repeated sensitivity evaluations. Despite these findings, the high heterogeneity highlights the need for further well-designed studies to confirm TL as a reliable biomarker for NAFLD risk and progression.