Current Molecular Medicine - Volume 25, Issue 11, 2025

Growth Differentiation Factor 15 (GDF15) has been described as influencing skeletal physiology. Nevertheless, no systematic appraisal of the effect of GDF15 on skeletal muscle tissues has been developed to the present day.

The aim of the present work was to review the evidence on the topic.

In this preregistered systematic review (https://osf.io/wa8xr), articles were retrieved from MEDLINE/PubMed, EMBASE, and WebOfScience. Inclusion criteria comprised studies on humans or animal models, assessment of peripheral or local tissue GDF15 concentrations, as well as the direct expression of GDF15 in skeletal muscle, and direct or indirect correlates of GDF15 with physical activity/ sarcopenia/trophism/ function.

A total of 646 studies were retrieved, and 144 finally included. Molecular inducers or inhibitors of GDF15 in skeletal muscle tissues were described. GDF15 was reported to promote skeletal muscle health, metabolic homeostasis, and overall physical conditioning. In pathology, GDF15 seems to be correlated to the degree of muscle impairment and mitochondrial stress. GDF15 has also been described as having the potential to stratify patients based on clinical prognosis and functional outcome.

A hormetic hypothesis for GDF15 on skeletal muscle was proposed. In fact, GDF15 exhibited beneficial effects when expressed at high levels facing acute stressors (i.e., “myoprotection”). Conversely, GDF15 exhibited maladaptive effects, such as chronic low-grade inflammation, when chronically expressed in pathological processes (e.g., obesity, aging). GDF15 may be a potential molecular target for disease-modifying interventions. The current review underscores the need for further research on GDF15 to elucidate its therapeutic potential across different pathological states.

The study protocol, registered before data collection and analysis, can be retrieved at https://osf.io/wa8xr. It should be noted that the study deviated from the protocol after peer review, including other electronic databases beyond MEDLINE/PubMed alone.

Ovarian cancer is one of the deadliest gynecologic cancers, with chemotherapy resistance as the greatest clinical challenge. Autophagy occurrence is associated with cisplatin (DDP)-resistant ovarian cancer cells. Herein, the role and mechanism of alpha-synuclein (SNCA), the autophagy-related gene, in DDP resistance of ovarian cancer cells are explored.

Differentially expressed genes in DDP resistance of ovarian cancer cells were analyzed by GEO2R tools. DDP-resistant ovarian cancer cells (A2780/DDP) were transfected and treated with 2.5 µg/mL DDP for 72 h, followed by the determination of cell viability, proliferation, apoptosis, and expressions of SNCA, lysine demethylase 4A (KDM4A), histone H3 lysine 9 trimethylation (H3K9me3), and mitophagy-related proteins. The H3K9me3 demethylation of SNCA by KDM4A was confirmed by chromatin immunoprecipitation.

SNCA and KDM4A were highly expressed in DDP-resistant ovarian cancer cells and their parental cells. KDM4A knockdown diminished expressions of KDM4A and SNCA and elevated H3K9me3 expression and H3K9me3 enrichment on SNCA promoter in A2780/DDP cells. SNCA or KDM4A knockdown inhibited cell viability, proliferation, and levels of LC3-II/LC3-I and Parkin while inducing cell apoptosis and upregulating Cyt-C expression of A2780/DDP cells with/without DDP treatment; however, SNCA overexpression not only did conversely but also reversed the effects of KDM4A knockdown on DDP-treated A2780/DDP cells and vice versa.

Silencing of KDM4A-mediated transcription inactivation of SNCA reduces mitophagy, thus inhibiting the resistance of ovarian cancer cells to cisplatin. KDM4A may be a promising drug target for DDP-resistant ovarian cancer cells.

The activation of the complement system is accompanied by the occurrence and development of preeclampsia, as well as kidney diseases. Here, the role of complement C3 [C3] in renal injury in preeclampsia was explored, and its potential application as an early diagnostic biomarker or drug target to ameliorate kidney injury induced by preeclampsia was preliminarily evaluated.

A total of 48 subjects were included in the present study, and the complement C3 levels and renal function were analyzed.

Patients with preeclampsia with severe features [sPe] had poorer renal function compared with the patients with preeclampsia. Urinary C3 levels could be used to distinguish between healthy controls, patients with preeclampsia, and patients with sPe. Increased renal inflammation and oxidative stress were notably increased in the preeclampsia mice with impaired renal function and attenuation of C3 activity using a C3 receptor antagonist, which reduced Pe-like symptoms and renal impairment, decreased serum blood urea nitrogen, creatinine, and urinary albumin levels, and decreased expression of the oxidative stress marker malondialdehyde, whilst increasing superoxide dismutase activity. In addition, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 ([HO-1) pathway was involved in the inhibition of complement C3 in the kidney.

Higher urinary C3 levels could be used to predict kidney damage in preeclampsia, and inhibition of C3 activity might ameliorate the renal impairment in preeclampsia through activation of Nrf2/HO-1 pathway.

The anticancer activity and radiosensitizing effect of Auranofin, an an-tirheumatic and an approved gold metallic drug, have been investigated from multiple perspectives. In this study, the action of the new gold complex compound TPN-Au(I)-MM4 was compared with that of auranofin.

The inhibitory effect of 10 µM and 50 µM concentrations on cell proliferation was investigated using the human colon cancer cell lines HCT116 and SW480. The radiosensitizing effect of HCT116 cells was evaluated by measuring the ability to induce apoptotic cell death. The mechanism of action was qualitatively determined via western blotting analysis of the level of cleaved caspase-3 protein.

Auranofin completely inhibited cell proliferation in both cell lines at both concentrations. In contrast, only 50 µM of TPN-Au(I)-MM4 significantly inhibited the proliferation of SW480 cells, but did not affect the proliferation of HCT116 cells. On the other hand, both compounds effectively increased the apoptotic cell death rate when combined with 4 Gy of X-ray irradiation. This mechanism was caused by a significant increase in the level of caspase-3, which is an apoptosis execution factor, by the combination of these two treatments.

Both compounds promoted the significant expression of caspase-3, an apoptosis execution factor, and exhibited radio-sensitizing effects. In particular, TPN-Au(I)-MM4 showed no inhibitory effect on cell proliferation alone, but had a significant radiosensitising effect on HCT116 cells. Therefore, TPN-Au(I)-MM4 has the potential for use as a new radiosensitizer.

This study aimed to investigate the roles of Mucin 1 (MUC1), the PI3K/AKT pathway, and enterocyte apoptosis in Necrotizing Enterocolitis (NEC).

Using an NEC Caco-2 cell model, retinoic acid treatment and MUC1 gene silencing were employed. Flow cytometry was used to assess apoptosis, while quantitative PCR and western blot analyses were conducted to evaluate the gene and protein expressions of MUC1, PI3K, Akt, and factors related to apoptotic modulation.

In comparison to the control group, NEC induction resulted in a significant reduction in MUC1 expression, accompanied by an elevation in enterocyte apoptosis. In NEC and Si-MUC1 Caco-2 cells, downregulation of PI3K/AKT signals and Bcl-2 was observed, while upregulation of Bax, CytoC, and Caspase 3 at both mRNA and protein levels was prominent. Retinoic acid supplementation exhibited a noteworthy increase in MUC1, AKT, and Bcl-2 mRNA and protein expressions, coupled with a decrease in Bax, CytoC, and Caspase 3, thereby mitigating apoptosis in NEC.

Our findings suggested that reduced MUC1 expression in NEC contributes to the upregulation of enterocyte mitochondrial apoptosis through the PI3K/AKT signaling pathway. Retinoic acid supplementation emerges as a potential therapeutic strategy for NEC, demonstrating its ability to upregulate MUC1 expression and attenuate apoptosis via the PI3K/AKT signaling pathway.

Paired box 9 (PAX9) has been linked to several human disorders; however, its relevance in Head And Neck Squamous Cell Carcinoma (HNSCC) remains unknown.

The difference in PAX9 mRNA expression in pan-cancer was analyzed utilizing The Cancer Genome Atlas (TCGA), and the level of PAX9 protein expression across various types of cancer was assessed utilizing the Human Protein Atlas (HPA) and UALCAN databases, as well as the cellular localization of PAX9. UALCAN studied the methylation levels of PAX9 in pan-cancer. The predictive significance of PAX9 in pan-cancer was assessed utilizing the Kaplan-Meier Plotter website. Functional enrichment analysis was carried out with the “cluster Profiler” program. By employing CCK8 and colony formation methods, the influence of PAX9 on the growth of HNSCC cells was evaluated. By conducting a transwell experiment, we assessed the influence of PAX9 on the migration of HNSCC cells. Western blotting was used to determine the levels of Bax and Bcl-2, two proteins involved in the regulation of apoptosis. A nude mouse model was established to study the impact of PAX9 overexpression on the growth of subcutaneous HNSCC tumors.

In HNSCC, the expression of PAX9 was found to be low, while levels of promoter methylation rose considerably. Low PAX9 expression has been linked to a decrease in overall survival (OS) rates among individuals with HNSCC. Furthermore, overexpressing the PAX9 gene decreased HNSCC cell proliferation, migration, and invasion while boosting apoptosis rates.

The abnormal expression of PAX9 is linked to various cancers. In HNSCC, PAX9 is a potential tumor suppressor, inhibiting tumor invasion and migration. The results reveal a potentially significant new therapeutic target for HNSCC.

Gastric cancer is a major global cause of cancer-related deaths, necessitating investigation into Matrix Metalloproteinases’ (MMPs) diagnostic and prognostic value. Our study aimed to analyze their significance in gastric cancer.

We evaluated MMP family genes' mRNA and protein expression using the University of Alabama at Birmingham (UALCAN) and Human Protein Atlas (HPA) databases. Then, we analyzed the relationship between their mRNA expression and gastric cancer staging and survival using Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter. Furthermore, we assessed this family’s gene mutation rates in gastric cancer patients using Search Tool for the Retrieval of Interaction Genes/Proteins (STRING) and explored potential pathways and mechanisms via Database for Annotation, Visualization, and Integrated Discovery (DAVID), cBioPortal, and R. Finally, we established a predictive model for gastric cancer based on these analyses to understand these genes’ roles in cancer.

Our findings revealed significantly upregulated mRNA expression of MMP1/2/3/7/9/10/11/12/13/14 in gastric cancer tissues (p<0.05). Higher levels of MMP2/7/10-encoded proteins (middle or high) were observed in tumor tissues, with MMP2/11/14 closely associated with different cancer stages (p<0.05). Additionally, MMP2/7/11/14/20 mRNA levels correlated with short-term overall survival (about 20 months), while MMP1/3/9/12/13 expression was associated with favorable overall survival (about 30 months). Gastric cancer patients exhibited a 21% mutation rate of MMP family genes, which correlated with favorable overall survival. Enrichment analysis and protein-protein interaction results underscored the close association of MMPs with gastric cancer development. The MMP2 model demonstrated a significant decline in survival rates for the high expression group, with a Hazard Ratio (HR) of 1.78 (95% CI 1.47-2.16) and a log-rank P value of 2.9e-09. Statistical significance was set at p < 0.05. Univariate Cox regression identified MMP2 as a risk factor for gastric cancer patients.

Our findings highlighted MMPs' essential role in gastric cancer progression, impacting patient survival. MMP2 emerged as a promising target for gastric carcinoma detection and treatment.