Current Molecular Medicine - Online First

Stem cells play a pivotal role in immunomodulation and tissue repair, and their functions can be influenced by TLR signaling. The Toll/interleukin-1 receptor domain-containing protein C (TcpC), secreted by Uropathogenic Escherichia coli, can inhibit host immunity by interfering with TLR pathways. As mitochondria are crucial for stem cell function, there may be links between TcpC and mitochondrial homeostasis.

We isolated MSC mitochondria using magnetic beads coated with a monoclonal antibody against the outer mitochondrial membrane protein OMP25 and conducted a proteomic study to examine the MSC mitochondrial proteome with or without TcpC. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analysis, were employed.

A total of 33 proteins with significant changes in abundance were identified: 4 increased in abundance, including glycolytic enzymes (Pkm [FC=1.6599, p=0.0217]) and stress response proteins (Ywhaq [FC=1.4666, p=0.04502]); and 29 decreased, mainly related to mitochondrial oxidative phosphorylation (e.g., Atp5f1e [FC=0.001, p=0.00120], Ndufa11 [FC=0.001, p=0.00674]) and protein quality control (e.g., Grpel1 [FC=0.46663, p=0.02083], Hspa9 [FC=0.48089, p=0.0435], Pitrm1 [FC=0.12764, p=0.01388]).

The possible effects of TcpC on the MSC mitochondrial proteome are reported here for the first time. This information provides a clearer understanding of MSCs in the context of infectious disease and offers a scientific basis for future stem cell therapy research.

TCP-C intervention leads to a series of differentially expressed proteins in MSC mitochondria, which are involved in several functional clusters, including oxidative phosphorylation, respiratory electron transport, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, branched-chain amino acid catabolism, and cristae formation.

Menstrual hygiene practices are a critical health concern, and if neglected, they may lead to reproductive tract infections (RTIs), toxic shock syndrome, and other vaginal diseases. To prevent these conditions, antiseptic and antibacterial properties must be incorporated into sanitary napkins.

In this study, nanolayered topsheets were synthesized by embedding silver nanoparticles (AgNPs) into PVA in Aloe vera extract, which was then coated onto a non-woven fabric. The polymer-entrapped AgNPs in Aloe vera (AgNPs + PVA + Aloe vera) were characterized using UV-visible spectrometry, dynamic light scattering (DLS), zeta potential, FTIR, and SEM analyses.

The release kinetics of AgNPs from the coated fabric were studied in simulated vaginal fluid (SVF), showing an initial burst release followed by sustained release. The toxicity of the released nanosilver was evaluated both in vitro using A375 cells and in vivo using zebrafish embryos, establishing a safe dose of 3 μM. The antimicrobial effect of the coated fabric was tested against S. aureus and E. coli, showing clear zones of inhibition.

The AgNPs and the coated fabric demonstrated comparable antimicrobial activity.

This product has potential for use in coating sanitary napkins to provide skin-soothing and antimicrobial effects.

Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Understanding the regulatory mechanisms of sorafenib resistance is critical to inhibit sorafenib resistance and develop novel therapeutic strategies. Here, we aimed to study the role of SSR2 (signal sequence receptor subunit 2) in sorafenib resistance of HCC.

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and cell viability assay were used to determine the role of SSR2 in sorafenib resistance of HCC. Co-immunoprecipitation (CoIP) was used to determine the interacting protein of SSR2.

We found SSR2 was upregulated in sorafenib-resistant HCC tissues. In addition, in HCC patients, SSR2 was associated with both poor response to sorafenib and poor clinical outcomes. Functional assay showed that SSR2 promoted sorafenib resistance in HCC cells. Mechanistically, SSR2 suppressed ferroptosis. Further analysis showed that SSR2 interacted with ferroptosis master regulator glutathione peroxidase 4 (GPX4) and increased the catalytic activity of GPX4, leading to inhibition of ferroptosis. Induction of ferroptosis could reverse the promotion effect of SSR2 overexpression on sorafenib resistance.

SRR2 plays a critical role in sorafenib resistance generation. However, the detailed mechanism of SRR2 increasing the catalytic activity of GPX4 will be further studied.

In summary, we reveal that SSR2 enhances sorafenib resistance of HCC via interacting with GPX4 and inhibiting ferroptosis, providing a potential target for HCC treatment. The molecular mechanism of GPX4-SSR2 interaction in ferroptosis will be further studied.

Intrauterine Adhesions (IUA), a common gynecological condition often caused by infection or endometrial injury, significantly impact women's reproductive and mental health. Its unclear pathogenesis hinders the development of effective treatments. Adiponectin, a bioactive protein with anti-inflammatory and anti-fibrotic properties, may offer therapeutic potential. This study investigates adiponectin's effects and mechanisms in IUA to inform new clinical strategies..

Endometrial tissues from IUA patients and controls were analyzed via immunohistochemistry to assess NLRP3, IL-1β, TGF-β1, and adiponectin expression. A human IUA cell model was established by stimulating human endometrial stromal cells (HESCs) with TGF-β1 (10 ng/ml, 48 hours). Interventions using the NLRP3 inhibitor MCC950, activator nigericin sodium salt, and adiponectin were applied. Protein and mRNA expression levels of NLRP3, IL-1β, TGF-β1, α-SMA, and COL1A1 were evaluated via Western blot and RT-qPCR. In vivo, IUA model rats were treated with adiponectin, and uterine morphology, gland count, collagen deposition, and inflammatory/fibrotic markers were analyzed.

NLRP3, IL-1β, and TGF-β1 expression were significantly upregulated in IUA patient tissues, while adiponectin was downregulated (P<0.05). In the TGF-β1-induced IUA cell model, NLRP3 inhibition with MCC950 reduced IL-1β and TGF-β1 levels, whereas NLRP3 activation with nigericin increased them. Adiponectin intervention significantly decreased NLRP3, IL-1β, TGF-β1, α-SMA, and COL1A1 expression in vitro (P<0.05). In IUA rats, adiponectin improved uterine morphology, increased endometrial glands, reduced collagen fiber deposition, and downregulated NLRP3, IL-1β, and TGF-β1 expression (P<0.05).

Adiponectin alleviates endometrial inflammation and fibrosis in IUA, potentially by modulating the NLRP3/IL-1β/TGF-β1 signaling pathway. These findings highlight adiponectin’s role in mitigating IUA progression and provide a theoretical basis for its clinical applications.

Adiponectin reduces inflammation and fibrosis in IUA by suppressing the NLRP3/IL-1β/TGF-β1 axis, offering new insights for IUA treatment strategies.

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.

The causal relevance of circulating plasma protein-to-protein ratios (PPRs) in Rheumatoid Arthritis (RA) remains unclear. We employed Mendelian Randomization (MR) to investigate this relationship.

This study utilized summary data of ratio quantitative trait loci (rQTLs) for 2,821 circulating PPRs from the GWAS Catalog and two RA-related GWAS datasets (FinnGen and GWAS Catalog). Causal estimates were obtained using various Mendelian randomization (MR) methods, including IVW and MR-Egger regression. Significant PPRs were further analyzed via protein–protein interaction (PPI), functional enrichment, and druggability assessments. Key genes were validated using qPCR.

Fifteen candidate PPRs with consistent directional effects, and nine core PPRs, achieved statistical significance in both datasets. Protein–protein interaction (PPI) network analysis revealed involvement of these proteins in various biological processes. Gene Ontology (GO) analysis indicated roles in immune response and protein binding, while KEGG pathway analysis showed enrichment in Toll-like receptor signaling pathways. Friends analysis identified UBAC1 as a key gene, and seven PPR-associated proteins were found to be druggable. qPCR validation confirmed differential expression of UBAC1, CD40, ITGB5, and GLOD4.

Our findings establish a robust genetic causal link between specific PPRs and RA, moving beyond association to suggest potential etiology. Integrated analyses prioritize UBAC1, CD40, ITGB5, and GLOD4 as key contributors to RA pathogenesis, with functional enrichment indicating their involvement in immune and inflammatory pathways. The druggability of several implicated proteins underscores the translational potential of these results.

This study used MR to establish a causal relationship between plasma PPRs and RA risk. UBAC1, CD40, ITGB5, and GLOD4 may play key roles in the pathogenesis of RA.

Anaerobic and aerobic exercise are known to increase reactive oxygen species (ROS) and cytokines, which may lead to oxidative stress when ROS accumulate. However, the findings are still inconsistent, with most studies focusing on short exercise durations. This study aimed to compare the effects of anaerobic and aerobic exercise on oxidative stress and cellular fitness in healthy trained young men.

A randomized trial was conducted involving 18 young male subjects, divided into two groups: anaerobic (short-distance running) and aerobic (long-distance running), with each group exercising three times per week for one month. Blood samples were collected before and after the intervention. Malondialdehyde (MDA) reflected oxidative stress, ROS (H2O2), and antioxidant levels (total antioxidant capacity, superoxide dismutase/SOD, glutathione peroxidase/GPX) were detected using spectrophotometry, while Interleukin-6 (IL-6) and ATPase Inhibitory Factor 1 (ATPIF1) reflected cellular fitness, were measured using ELISA.

Both anaerobic and aerobic exercise significantly reduced MDA levels. Aerobic exercise significantly increased SOD and total antioxidant capacity, while anaerobic exercise resulted in decreased GPX levels. No significant changes were observed in H2O2, IL-6, or ATPIF1 levels in either group.

The findings suggest that aerobic exercise enhances the body’s antioxidant defense system more effectively than anaerobic exercise, contributing to reduced oxidative stress. The participants’ trained status may have influenced the SOD response. Limitations include a lack of control over lifestyle variables and limited generalizability due to the homogenous sample.

One month of exercise reduces oxidative stress in trained young men, with aerobic exercise showing greater benefits in boosting endogenous antioxidants.