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.

Genistein is an isoflavone primarily extracted from soybeans and the Dyer’s broom (Genista tinctora L.). It has been extensively studied using various extraction methods and characterized via NMR for structural elucidation. Its pharmacological potential, mediated through interactions with multiple receptors and signalling pathways, has been validated through numerous preclinical studies globally.

To analyze the pharmaceutical profile of genistein using PASS software, we correlated it with existing literature, and evaluated its efficacy against various diseases. The study aims to explore the broad-spectrum potential of genistein as a lead compound against the various diseases such as cancer, cardiovascular disease (CVD), neurodegenerative and viral diseases.

It is a broad-spectrum drug that is effective against – cancer, heart associated diseases, neurodegenerative diseases and viral diseases. It is a potential anticancer drug that modulates apoptosis, cell cycle, metastasis, and regulates the cancer signalling pathways. Based on the compilation of reports from the literature reviews, it is effective against breast cancer (23%), neuroblastoma (12.77%), prostate and lung cancer (10.64%). Secondly, it has cardio protectant properties and supports cardiovascular health by improving endothelial function and lowering cholesterol. It is reported to be effective against cardiac dysfunction (38.46%), atherosclerosis (26.92%), and cardiotoxicity (15.39%). Thirdly, it offers various neuroprotective benefits in neurodegenerative diseases like Alzheimer's (69.84%) and Parkinson's (19.05%). Lastly, it was also reported to be effective against HSV (23.08%), HIV (23.08%) and HPV (15.39%) viral infections.

Genistein exhibits a wide range of therapeutic properties, including anticancer, cardioprotective, neuroprotective, and antiviral effects. It has shown notable efficacy in treating cancers such as breast, prostate, and lung, as well as neurodegenerative conditions like Alzheimer's and Parkinson's. Additionally, its benefits in improving cardiovascular health and combating viral infections further support its potential as a multifunctional therapeutic agent. Although genistein has a broad pharmacological spectrum, its clinical relevance is hampered by a suboptimal pharmacokinetic profile, such as poor bioavailability, rapid systemic clearance, extensive first-pass metabolism, and low aqueous solubility, which limit its therapeutic efficacy.

This systematic review highlights genistein’s pharmacological profile, demonstrating its efficacy against various diseases and its potential as a lead candidate for drug development in oncology, cardiovascular health, and neurodegenerative therapies. Thus, underscoring its potential, Genistein can be considered a versatile therapeutic agent.

Obesity is a major risk factor for metabolic and cardiovascular disorders. Recently, emerging biomarkers, such as the Visceral Adiposity Index (VAI) and Lipid Accumulation Product (LAP), have garnered attention for their utility in assessing visceral obesity. Bilirubin, a potent endogenous antioxidant, has been associated with protective effects against various diseases. This study aims to investigate the relationship between serum total bilirubin (STB) levels and VAI/LAP in adults.

This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2003 and 2020. The calculation of VAI and LAP was performed computationally. Weighted multivariate regression models were used to explore the potential correlation between STB levels and VAI or LAP. RCS curves were used to identify the potential non-linear relationship. Moreover, subgroup analyses were conducted to examine heterogeneity across different populations.

The analysis included a cohort of 10,625 individuals aged 20 to 85 years. Both unadjusted and adjusted statistical models revealed a significant negative association between STB levels and VAI or LAP (all P< 0.001). RCS indicates that these relationships are linear. Subgroup analyses identified particularly strong associations in non-smokers aged 20-59 without hypertension/diabetes (P < 0.05).

Our study's strengths include the use of nationally representative data with appropriate weighting, comprehensive adjustment for confounding variables, and pioneering research on the link between serum bilirubin levels and visceral fat indices, which may indicate early metabolic risk markers. This finding highlights the significant role of bilirubin in body fat distribution and lipid metabolism.

This study revealed that STB was associated with VAI or LAP among the specific general American population aged 20-59 without hypertension/diabetes. Further prospective investigations are warranted to clarify the temporal relationship between STB and novel obesity indices.

Observational studies suggest the potential association between sleep traits and vertigo; however, causal evidence remains limited.

This study aimed to explore the relationship between genetically predicted sleep traits and vertigo with the Mendelian randomization (MR) method.

Instrumental variables for sleep traits (snoring, sleep duration, insomnia, daytime sleepiness, daytime napping, and chronotype) were adopted from genome-wide association studies (GWAS) data of European ancestry from UK Biobank. The summary-level datasets of vertigo were retrieved from the GWAS of FinnGen. Inverse-variance weighted (IVW) method was adopted as the main analysis.

IVW analysis revealed a significant association between genetically predicted daytime napping (OR = 1.51, 95% CI =1.08-2.12, P = 0.016) and chronotype (OR = 1.13, 95% CI =1.01-1.26, P = 0.033), both of which were associated with an increased risk of vertigo. However, we did not find evidence for a causal effect of snoring, overall sleep duration, long sleep duration, short sleep duration, insomnia, and excessive daytime sleepiness on vertigo. No reverse causality was detected.

Our findings suggest that abnormal sleep patterns may serve as risk factors for vertigo disorders and offer opportunities for the prevention and management of vertigo disorders.

Lung cancer remains the leading cause of cancer-related mortality. Determining the T790M resistance variants and epidermal growth factor receptor (EGFR) mutations is crucial for personalized treatment, especially when using targeted therapies.

This review article aims to comprehensively compare some of the various diagnostic techniques associated with liquid biopsies, such as cell-free DNA (cfDNA) for T790M and EGFR mutant identification. It also aims to evaluate their pertinence in clinical settings, as well as their sensitivity and specificity to determine how effectively they monitor treatment response and resistance.

A literature search was conducted using databases including PubMed, Scopus, and Web of Science. The keyword list included “EGFR mutations,” “T790M resistance,” “liquid biopsy,” “COLD PCR,” “NGS,” “ddPCR,” “BEAMing,” and other methods. The effect of these studies on diagnostic technologies for identifying EGFR mutations was assessed in terms of clinical practice, methodological accuracy, and significance. Sensitivity, specificity, clinical applicability, cost analysis, turnaround times, and ease of integration into clinical workflows were used as parameters for evaluation based on the literature.

There are advantages and disadvantages to cfDNA monitoring strategies for treatment response and resistance, as well as to the assessment of sensitivity, specificity, and clinical applicability for identifying EGFR mutations.

Advanced techniques such as COLD-PCR, LC-MS, qPCR, NGS sequencing, Sanger sequencing, PNA microarrays, the Allele-Specific Competitive Extension (ASCE) real-time PCR assay, and nanopore technology are necessary for personalized lung cancer management. However, depending on the objective of the work, the suitable method should be selected based on its benefits and drawbacks.

Colon cancer is a highly prevalent tumor with a high mortality rate worldwide. SLC41A2 is a member of the solute carrier family, but its role in colon cancer is still unclear.

The relationship between the expression level of SLC41A2 and clinicopathological features in colon cancer was investigated using data from the TCGA database. The differential expression genes of SLC41A2 were identified the potential role of SLC41A2 in colon cancer was analysed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. By transfecting plasmids or siRNA to overexpress or knock down SLC41A2 in colon cancer cells, the effects of SLC41A2 on colon cancer cell proliferation, migration, and apoptosis were detected through EdU, MTT, wound-healing, Transwell, and JC-1 experiments. Western blot and ubiquitination experiments validated the regulation of GSK3β stability by SLC41A2. Rescue experiments and CCK8 assays confirmed the regulatory effect of SLC41A2 on GSK3β.

Compared to normal tissues, SLC41A2 exhibited a lower expression level in colon cancer, and the expression levels of SLC41A2 were correlated with the stage and Tumor Node Metastasis (TNM) classification. GO and KEGG analyses displayed that SLC41A2 primarily affected the growth factor activity and Wnt signaling pathway. Furthermore, elevated expression of SLC41A2 notably decreased the proliferation, migration and invasion of colon cancer cells, along with increased apoptosis. The overexpression of SLC41A2 and rescue experiments confirmed that SLC41A2 enhances the protein stability of GSK3β by inhibiting its ubiquitin-proteasome degradation and causes the upregulation of GSK3β, thereby suppressing the progression of colon cancer.

SLC41A2 was lowly expressed in colon cancer tissues or cells. By inhibiting the ubiquitin-proteasome degradation of GSK3β, SLC41A2 can significantly upregulate the expression of GSK3β, which ultimately suppresses the proliferation and migration of colon cancer cells.

This study aimed to investigate the role of JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) signaling in liver injury during severe acute pancreatitis (SAP), focusing on pancreatic elastase- and lipopolysaccharide (LPS)-induced Kupffer cell (KC) activation.

A rat SAP model was established via retrograde taurocholic acid infusion into the biliopancreatic duct. Inflammatory cytokine levels and JAK2/STAT3 pathway activity were quantified in liver tissues. KCs were treated with elastase/LPS ± AG490 (JAK2 inhibitor). Proinflammatory cytokines, RNA, and protein expression were analyzed.

SAP rats exhibited elevated TNF-α, IL-6, and IL-18 levels in both serum and liver tissues, with JAK2/STAT3 pathway activation. AG490 administration suppressed JAK2/STAT3 activation, reduced inflammation, and alleviated liver injury. Similarly, KCs treated with elastase and LPS showed increased proinflammatory cytokine levels and JAK2/STAT3 upregulation, which were mitigated by AG490 treatment.

The findings highlighted the pivotal role of the JAK2/STAT3 signaling pathway in SAP-induced liver injury. Selective inhibition of this pathway by AG490 could reduce inflammation and protect against liver damage, suggesting its potential as a therapeutic target for inflammatory liver diseases.

The pathogenesis of diabetic kidney disease (DKD) is complex, and the specific biomarkers for detecting early diagnosis and monitoring kidney function deterioration are insufficient, which affects the prognosis of patients. The complement activation in glomeruli and renal interstitium contributes to the aggravation of DKD. Several key complement proteins, such as complement factor 3 (C3), CD59, and complement factor H-related protein 2 (CFHR2) were reported to be potential biomarkers for early diagnosis and prognosis for DKD.

In the current study, we focus on CFHR2, to investigate its capability and sensitivity as a DKD biomarker. As a non-invasive detection sample, urine has the characteristic of convenient sampling. In the current study, the urine samples were collected from three groups: diabetic patients without albuminuria, with micro-albuminuria, and macroalbuminuria, to analyze whether CFHR2 was associated with albuminuria concentration and declined renal function. Meanwhile, the urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and C3 were also examined by enzyme-linked immunosorbent assay (ELISA) to compare with CFHR2 to determine whether CFHR2 had an advantage in predicting the early detection and progression of DKD. The Spearman correlation analysis was performed for the correlation analysis. The receiver operating characteristic curve was used to analyze the diagnostic efficacy.

CFHR2 had superior diagnostic power to predict the early occurrence of DKD and disease progression, compared with NGAL, microalbumin, and C3 in urine.

CFHR2 has satisfactory potential to be a biomarker for early diagnosis and risk of progression of DKD.

The antiviral effects of type I interferons [IFNs] on respiratory syncytial virus [RSV]-infected airway epithelial cells have been identified. We aim to further reveal the mechanism of stat3 and kruppel-associated box-associated protein 1 [KAP1] in RSV-infected airway epithelial cells.

Using the A549 cell line, we investigated the impact of RSV infection, KAP1 overexpression, and stat3 inhibition with Stattic. Cell counting kit 8 assay was used to determine the viability, and enzyme-linked immunosorbent assay was applied to measure the levels of IL-6, IL-8, IL-1β, IFN-α, and IFN-β. Viral replication was tested via plaque assay. Meanwhile, quantitative real-time reverse transcription polymerase chain reaction or/and western blot were applied to measure the expressions of p-stat3 and KAP1 in the cells.

RSV infection repressed the viability, upregulated p-stat3 and KAP1 expressions, elevated levels of inflammation-related factors [IL-6, IL-8, IL-1β], and type I IFN immune response-associated factors [IFN-α, IFN-β], and promoted viral replication in A549 cells. Stattic attenuated the promoting effect of RSV on inflammation-related factors and viral replication, but enhanced its impact on IFN-α and IFN-β levels in the cells. More importantly, KAP1 overexpression reversed the effects of Stattic on viability, inflammation [IL-6, IL-8, IL-1β], type I IFN immune response [IFN-α, IFN-β], and viral replication in RSV-infected A549 cells.

Our findings unveil the pivotal role of stat3 inhibition in potentiating type I IFN-mediated antiviral responses against RSV in lung epithelial cells, revealing KAP1 as a potential therapeutic target for combating respiratory viral infections.

Gastric cancer (GC) remains one of the most common malignancies and the third cause of cancer-related deaths worldwide. Non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, can contribute to the pathogenesis and progression of GC and therefore could be its potent diagnostic and prognostic biomarkers. The aim of our work was to estimate the expression of PROX1-AS1 (Prospero Homeobox 1 Antisense RNA 1) and miR-647 (microRNA-647) in GC and investigate their potential interaction and clinical significance.

The study included tumor and adjacent non-tumor tissues from 110 GC patients and plasma samples from 65 GC patients; 38 sectional normal gastric tissue samples and 49 plasma samples of healthy donors were included as controls. Expression levels of both ncRNAs were quantified in all samples by using real-time polymerase chain reaction (RT-PCR) and their possible correlations with the clinical and pathological characteristics of patients were analyzed. A potential inverse correlation between PROХ1-AS1 and miR-647 expression was addressed by in vitro experiments in a panel of cancer cell lines.

The expression of PROX1-AS1 and miR-647 was not significantly different in tissues of GC patients and sectional normal gastric tissue samples. However, they have demonstrated a negative correlation both in the tumor and the adjacent non-tumor tissue of GC patients. PROX1-AS1 expression was significantly decreased in GC tissues, whereas the miR-647 expression was increased. The expression of the ncRNAs was associated with clinical and pathological characteristics of GC patients. The overexpression of miR-647 led to a significant decrease in PROX1-AS1 expression in five cancer cell lines, including the GC cell line SNU-1.

We have demonstrated a negative correlation between PROX1-AS1 and miR-647 in both GC tissues and the cancer cell lines. In addition, expression of both ncRNAs was associated with the primary tumor size. Therefore, these ncRNAs might have potential prognostic value.

The relationship between heavy metals, particularly lead (Pb), and diabetic kidney disease (DKD) remains unclear, especially regarding exposure thresholds. This study investigates the association between blood Pb levels and DKD risk using data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018.

A total of 1,343 participants were included, with 508 diagnosed with DKD. Baseline characteristics were compared between DKD and non-DKD groups. Multivariate generalized linear models (GLMs) and weighted logistic regression were used to assess correlations between blood Pb levels and DKD risk. A nomogram was developed to evaluate the predictive power of significant clinical characteristics.

Key clinical characteristics, including age, marital status, and serum Pb levels, differed significantly between DKD and non-DKD groups. Serum Pb was identified as a significant risk factor (ORs: 1.18–1.39, p < 0.01). The nomogram demonstrated good predictive accuracy (AUC = 0.717).

Elevated blood Pb levels are significantly associated with DKD, with a non-linear relationship and a defined threshold. These findings highlight the potential role of Pb exposure in DKD pathogenesis and suggest the utility of blood Pb monitoring in diabetic patients.

Chromobox 7 (CBX7) has been implicated in the progression of various malignant tumors, but its clinical relevance in lung adenocarcinoma (LUAD) remains poorly understood. This study aimed to investigate the expression, prognostic value, biological functions, and immunological role of CBX7 in LUAD.

CBX7 expression in LUAD and adjacent normal tissues was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Kaplan-Meier curves and Cox risk regression evaluated prognostic significance. Various algorithms assessed the correlation between CBX7 and immune micro-environment. The expression of CBX7 in LUAD tissues was detected by RT-qPCR, western blotting, and immunohistochemistry. The function of CBX7 in LUAD was further investigated by in vitro and in vivo experiments.

CBX7 expression significantly downregulated LUAD, which was associated with aberrant DNA methylation. Decreased CBX7 expression correlated with advanced tumor stage and poor prognosis. Notably, CBX7 is associated with immune cell infiltration and immune checkpoints, highlighting its potential role in guiding immunotherapy. Functional experiments demonstrated that CBX7 overexpression suppressed the malignant phenotype of LUAD cells, while CBX7 knockdown promoted tumor progression.

We conducted a systematic analysis of the diagnostic, prognostic, and immunological significance of CBX7 in LUAD, and found that it might serve as a diagnostic marker and therapeutic target in the future.

Alternative splicing (AS) events significantly affect melanoma progression. Therefore, understanding their effect on prognosis is important for developing new treatments.

Univariate Cox regression analysis and LASSO regression were carried out to identify key AS events, build an AS risk model, and classify sample risk levels. Pearson correlation analysis was also performed to analyze the relationship between AS events and RNA-binding protein (RBP) genes or indicators of immune infiltration. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using gene expression data from patients with varying risk levels. Univariate and multivariable Cox regression analyses were also carried out to examine the association between immune cell infiltration and prognosis.

A total of 41446 AS events were identified; among them, 446 AS events were identified as significantly associated with melanoma prognosis. An AS risk model for prognosis was established using seven key AS events. A close correlation was found between 137 AS events and 1013 RBP genes, suggesting that these genes may participate in the regulation of AS events. KEGG enrichment analysis revealed that the genes involved in AS were closely associated with immune system functions, which may explain why AS events affect the prognosis of melanoma. Finally, by combining the AS risk score and clinical indicators, we developed a nomogram model that could effectively predict melanoma prognosis.

This analysis of AS events and regulation may aid in developing novel prognostic biomarkers and therapeutic targets for melanoma.

Platinum-based drugs like cisplatin are key in treating ovarian cancer, but resistance frequently leads to treatment failure. The TGF-β1/β-catenin signaling pathway has been implicated in tumor resistance. This study investigates whether hyperthermiaenhances ovarian cancer cell sensitivity to platinum-based drugs by activating the TGF-β1/β-catenin pathway.

In vitro and in vivo models of ovarian cancer were treated with hyperthermia and cisplatin. Changes in TGF-β1 and β-catenin expression were measured using Western blotting, qPCR, immunohistochemistry, and cell viability assays to determine the impact of hyperthermia on drug sensitivity.

Hyperthermia significantly reduced TGF-β1 and β-catenin expression in ovarian cancer cells and tumor tissues, suppressing the pathway. This led to increased cisplatin sensitivity and higher apoptosis rates in vitro, while in vivo, tumor growth was significantly suppressed, and cisplatin's antitumor effects were enhanced.

Hyperthermia boosts the effectiveness of platinum-based drugs in ovarian cancer by suppressing the TGF-β1/β-catenin pathway, presenting a potential strategy to overcome chemoresistance and improve patient outcomes.

The prognosis of patients with stage III colorectal cancer (CRC) shows significant variations. The purpose of this study was to investigate the role of key regulatory proteins in glycolysis and lipid metabolism for the prognostic evaluation of stage III CRC patients.

Utilizing the Cancer Genome Atlas (TCGA) database, we analyzed the expression of various key regulatory genes in glycolysis and lipid metabolism pathways in CRC, as well as the relationship between gene expression levels and overall survival. We selected the top two key genes exhibiting differential expression patterns in glycolysis and lipid metabolism, namely, glucose transporter type 1 (GLUT1), pyruvate kinase M2 (PKM2), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), as targets for subsequent exploration. We analyzed the effects of GLUT1, PKM2, FASN, and SCD1 on the proliferation, migration, and drug sensitivity of CRC cells in vitro. These proteins were detected by immunohistochemistry (IHC) in the clinical tissues of stage III CRC patients. Based on the intensity of IHC staining for GLUT1, PKM2, FASN and SCD1, the cumulative score from these 4 target proteins for each sample was calculated (score range from 0 to 8). The relationships between high (scores of 6-8) or low (scores of 0-5) expression of glycolysis and lipid metabolism molecules and the clinicopathological characteristics, and survival of patients were analyzed.

The expression disparities of the GLUT1, PKM2, FASN, and SCD1 genes were the most prominent between tumor and normal tissues. Overexpression of GLUT1, PKM2, FASN, or SCD1 significantly promoted CRC cell growth and migration, as evidenced by CCK-8, colony formation, and Transwell assays. Exogenous introduction of GLUT1, PKM2, FASN, or SCD1 increased oxaliplatin IC50 values, enhanced cell survival, and reduced early apoptosis in CRC cells exposed to oxaliplatin. High glycolysis and lipid metabolism status were associated with poor tumor differentiation, vascular or nerve invasion, and shorter overall survival. The status of glycolysis and lipid metabolism was an independent prognostic factor for stage III CRC patients.

High glycolysis and lipid metabolism status are correlated with a poor prognosis in patients with stage III colorectal cancer.

The analysis of diabetic nephropathy (DN)-related gene dataset demonstrated that C-X-C motif chemokine ligand 3 (CXCL3) is highly expressed in DN. Exploring the impact of CXCL3 in the course of DN is the core goal of this study.

The cell model used in this study was CIHP-1 cells induced by high glucose (HG). qRT-PCR and western blot analysis were carried out to determine the expression difference of CXCL3. After down-regulating the CXCL3 level, we analyzed HG-induced CIHP-1 cell viability by MTT assay, proliferation by EdU staining, apoptosis by flow cytometry, and changes in related protein expression by western blot. In order to analyze the possible regulatory relationship between endothelial cell-specific molecule 1 (ESM-1) and CXCL3 in DN, we constructed an over-expressed ESM-1 plasmid and carried out a rescue experiment.

CXCL3 and ESM-1 were highly expressed in HG-induced podocytes (p<0.05). Silenced CXCL3 (siCXCL3) increased the viability and proliferation of CIHP-1 cells induced by HG, reduced the proportion of apoptosis, and produced corresponding protein changes (p<0.01). After the overexpression of ESM-1, the effects of siCXCL3 were partially offset (p<0.05).

In this study, ESM-1 increased HG-induced podocyte damage by promoting CXCL3 expression.

Esophageal Cancer (EC) is a commonly occurring cancer of the digestive tract. The bismuth compounds from thiosemicarbazones have been observed to be active against cancer cells. However, a synthetic nine-coordinate bismuth (III) complex (complex 1) has never been assessed so far for its anticancer in the esophageal squamous cell carcinoma cell line (EC109).

This study aimed to investigate the apoptosis effect of a complex1 in the EC109 cells.

EC109 cells were treated with complex1. The MTT assay was employed to assess the viability of EC109 cells; the changes in apoptotic and morphological characteristics, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP) were examined. The expression levels of proteins associated with apoptosis were assessed using western blotting.

Complex1 was found to inhibit the growth of EC109 cells, exhibiting an IC50 of 0.654 μM through apoptosis depends upon complexation with bismuth(III). In addition, cells exposed to complex1 exhibited a significant increase in the level of intracellular ROS through the suppression of the antioxidant system and caused a reduction in mitochondrial membrane potential(MMP). Co-treatment with N-acetyl-L-cysteine(NAC), an antioxidant agent prevented accumulation of ROS and cell death. Complex1 also led to enhanced Bax expression, and reduced Bcl-2 expression in EC109 cells, thereby enhancing caspase-3/9 activity.

Our study confirmed that complex1 induced apoptosis via enhancing the generation of ROS along with a decline in levels of antioxidant enzymes, subsequently causing MMP loss.

Cancer-associated fibroblasts (CAFs), one of the most abundant stromal cell types in the tumor microenvironment (TME), are potential targets for cancer treatments such as lung cancer. However, the underlying mechanism by which CAFs promote lung cancer progression remains elusive.

We obtained primary CAFs, normal fibroblasts (NFs), and their exosomes and constructed protease nexin-1 (PN1) stably silenced or over-expressed CAFs cells using lentivirus. Bioinformatics was used to obtain the expression of PN1 in lung cancer and normal tissues, the relationship with overall survival, and the enriched pathways. The MTT and Transwell assays were performed to detect the proliferation, migration, and invasion abilities of lung cancer cells after treatment. Western blotting, qRT-PCR, immunohistochemistry, and xenograft models were used to illustrate the role of CAFs in lung cancer progression via exosomes.

CAFs-derived exosomes, in which PN1 was more highly expressed than that in NFs-derived ones, effectively promoted the proliferation, migration, and invasion potentials of lung cancer cells A549 and H1975. Meanwhile, the PN1 expression was higher in lung cancer tissues than that in normal tissues and was negatively associated with the overall survival rate of lung cancer patients. More importantly, over-expressing or silencing of PN1 in A549 and H1975 cells promoted or inhibited cell proliferation, migration, and invasion, correspondingly. Furthermore, treated with PN1 overexpressing CAFs-derived exosomes, the lung cancer cells proliferation, migration, and invasion varied positively and were accompanied by activation of Toll-like and NF-κB signaling pathways. However, this phenomenon can be reversed by AN-3485, an antagonist of the Toll-like pathway. Finally, overexpression of PN1 leads to accelerated tumor growth by increasing the expression of the proliferation biomarker Ki67 and activation of the NF-κB signaling pathway in vivo.

CAFs promoted lung cancer progression by transferring PN1 and activating the Toll-like/NF-κB signaling pathway via exosomes.