Association of mental disorders with sepsis: a bidirectional Mendelian randomization study.

Background: Substantial research evidence supports the correlation between mental disorders and sepsis. Nevertheless, the causal connection between a particular psychological disorder and sepsis remains unclear. Methods: For investigating the causal relationships between mental disorders and sepsis, genetic variants correlated with mental disorders, including anorexia nervosa (AN), attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), panic disorder (PD), posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and tourette syndrome (TS), were all extracted from the Psychiatric Genomics Consortium (PGC). The causal estimates and direction between these mental disorders and sepsis were evaluated employing a two-sample bidirectional MR strategy. The inverse variance weighted (IVW) method was the primary approach utilized. Various sensitivity analyses were performed to confirm the validity of the causal effect. Meta-analysis, multivariable MR, and mediation MR were conducted to ensure the credibility and depth of this research. Results: The presence of AN was in relation to a greater likelihood of sepsis (OR 1.08, 95% CI 1.02-1.14; p = 0.013). A meta-analysis including validation cohorts supported this observation (OR 1.06, 95% CI 1.02-1.09). None of the investigated mental disorders appeared to be impacted when sepsis was set as the exposure factor. Even after adjusting for confounding factors, AN remained statistically significant (OR 1.08, 95% CI 1.02-1.15; p = 0.013). Mediation analysis indicated N-formylmethionine levels (with a mediated proportion of 7.47%), cystatin D levels (2.97%), ketogluconate Metabolism (17.41%) and N10-formyl-tetrahydrofolate biosynthesis (20.06%) might serve as mediators in the pathogenesis of AN-sepsis. Conclusion: At the gene prediction level, two-sample bidirectional MR analysis revealed that mental disorder AN had a causal association with an increased likelihood of sepsis. In addition, N-formylmethionine levels, cystatin D levels, ketogluconate metabolism and N10-formyl-tetrahydrofolate biosynthesis may function as potential mediators in the pathophysiology of AN-sepsis. Our research may contribute to the investigation of novel therapeutic strategies for mental illness and sepsis.

ß-asarone inhibits autophagy by activating the PI3K/Akt/mTOR pathway in a rat model of depression in Parkinson's disease.

OBJECTIVE: It is unclear whether ß-asarone has a good antidepressant effect and what is the main mechanism in Depression in Parkinson's disease (DPD) model rats. METHODS: In this study, DPD model rats were screened from 6-OHDA induced rats by sucrose preference test (SPT) and forced swimming test (FST). DPD model rats were divided into eight groups: model group, pramipexole group, ß-asarone low-dose group (ß-asarone 7.5 group), ß-asarone medium-dose group (ß-asarone 15 group), ß-asarone high-dose group (ß-asarone 30 group), 3-MA group, rapamycin group, and PI3K inhibitor group. 28 days after the end of treatment, open field test (OFT), SPT and FST were conducted in rats. The level of α-synuclein (α-syn) in the striatum was determined by enzyme-linked immunosorbent assay (ELISA). The expression of Beclin-1, p62 in the striatum was determined by western blot. The expression of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR, Beclin-1, and p62 in the hippocampus was determined by western blot. The spine density of neurons in the hippocampus was detected by golgi staining. RESULTS: The results showed that 4-week oral administration of ß-asarone improve the motor and depressive symptoms of DPD model rats, and decrease the content of α-syn in the striatum. ß-asarone inhibited the expression of autophagy in the striatum of DPD model rats. Furthermore, ß-asarone decreased the levels of Beclin-1 protein, increased the expression of p62, p-PI3K, p-AKT, and p-mTOR, and improved the density of neuron dendritic spine in the hippocampus. CONCLUSIONS: We concluded that ß-asarone might improve the behavior of DPD model rats by activating the PI3K/Akt/mTOR pathway, inhibiting autophagy and protecting neuron.

Bone marrow-derived mesenchymal stem cell-derived exosomal microRNA-208a promotes osteosarcoma cell proliferation, migration, and invasion.

A recent study has discovered that mesenchymal stem cells (MSCs) are recruited into tumors and MSC-derived exosomes in a novel mechanism of cell-to-cell communication in human cancers. Here, in this study, we explore the impact of the microRNA-208a (miR-208a)-enriched exosomes derived from bone marrow-derived mesenchymal stem cells (BMSCs) on osteosarcoma cells. Human osteosarcoma cells MG-63 and Saos-2 were exposed to BMSCs-derived exosomes treated with either miR-208a mimic or inhibitor. The MTT assay, transwell migration assay, and soft agar colony formation assay were used to evaluate the viability, migration, and clonogenicity of osteosarcoma cells. Bioinformatics analysis and dual-luciferase reporter gene assays validated the targeted relationship between miR-208a and PDCD4. Western blot assay was used to detect the expression of PDCD4 and related proteins in the ERK1/2 pathway in osteosarcoma cells. BMSCs communicated with osteosarcoma cells via exosomes. Ectopic expression of miR-208a was shown to increase the viability, migration, and clonogenicity of osteosarcoma cells. Analysis of the exosomal content identified miR-208a as a mediator of the exosomal effects on osteosarcoma cells in part via downregulation of PDCD4 and activating the ERK1/2 pathway. In summary, our study illuminates that BMSC-derived exosomal miR-208a enhances the progression of osteosarcoma.

Kaempferol slows intervertebral disc degeneration by modifying LPS-induced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs.

Intervertebral disc (IVD) degeneration is a common disease that represents a significant cause of socio-economic problems. Bone marrow-derived mesenchymal stem cells (BMSCs) are a potential autologous stem cell source for the nucleus pulposus regeneration. Kaempferol has been reported to exert protective effects against both osteoporosis and obesity. This study explored the effect of kaempferol on BMSCs differentiation and inflammation. The results demonstrated that kaempferol did not show any cytotoxicity at concentrations of 20, 60 and 100µM. Kaempferol enhanced cell viability by counteracting the lipopolysaccharide (LPS)-induced cell apoptosis and increasing cell proliferation. Western blot analysis of mitosis-associated nuclear antigen (Ki67) and proliferation cell nuclear antigen (PCNA) further confirmed the increased effect of kaempferol on LPS-induced decreased viability of BMSCs. Besides, kaempferol elevated LPS-induced reduced level of chondrogenic markers (SOX-9, Collagen II and Aggrecan), decreased the level of matrix-degrading enzymes, i.e., matrix metalloprotease (MMP)-3 and MMP-13, suggesting the osteogenesis of BMSC under kaempferol treatment. On the other hand, kaempferol enhanced LPS-induced decreased expression of lipid catabolism-related genes, i.e., carnitine palmitoyl transferase-1 (CPT-1). Kaempferol also suppressed the expression of lipid anabolism-related genes, i.e., peroxisome proliferators-activated receptor-γ (PPAR-γ). The Oil red O staining further convinced the inhibition effect of kaempferol on BMSCs adipogenesis. In addition, kaempferol alleviated inflammatory by reducing the level of pro-inflammatory cytokines (i.e., interleukin (IL)-6) and increasing anti-inflammatory cytokine (IL-10) via inhibiting the nucleus translocation of nuclear transcription factor (NF)-κB p65. Taken together, our research indicated that kaempferol may serve as a novel target for treatment of IVD degeneration.