METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.

Activation of G-protein-coupled receptor 183 initiates inflammatory pain via macrophage CCL22 secretion.

Chronic pain is a major public health problem with limited effective therapeutic options. G-protein-coupled receptors play a significant role in pain modulation; however, whether and how G-protein-coupled receptor 183 participates in pain regulation remain unclear. In the present study, we found that G-protein-coupled receptor 183 expression was specifically upregulated in the hind paws of mice in various inflammatory pain models. Activation of G-protein-coupled receptor 183 induced acute pain, whereas inhibition or silencing of this receptor alleviated mechanical allodynia and thermal hyperalgesia in complete Freund's adjuvant (CFA) model. Mechanistically, activating G-protein-coupled receptor 183 triggers pain responses via the upregulation of C-C motif chemokine 22(CCL22) in macrophages while blocking the CCL22 receptor C-C motif chemokine receptor 4 (CCR4) attenuates pain hypersensitivity. Taken together, our findings indicate that the G-protein-coupled receptor 183-CCL22 axis has a critical role in the development and maintenance of inflammatory pain.

Associations between seminal plasma triclosan and low sperm quality: A case-control study.

OBJECTIVE: Triclosan (TCS), a novel endocrine disrupter, has induced widespread human exposure due to its widespread use in personal care products. Environmental TCS exposure was suggested to be associated with human semen quality. However, little is known about seminal plasma TCS concentration and the risk of low sperm quality. This case-control study is established to examine the relationship between seminal plasma TCS and the risk of low sperm quality. STUDY DESIGN: One hundred men with low sperm quality as cases and one hundred normal men as controls were recruited a fertility clinic in Shijiazhuang, China, during 2018-2019. Seminal plasma TCS concentration was determined using an ultrahigh-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). Sperm concentration, sperm count, sperm motility and sperm progressive motility were evaluated according to World Health Organization (WHO) guidelines to assess the sperm quality. We used the Mann-Whitney rank-sum test and Kruskal-Wallis test to assess the differences of seminal plasma TCS concentration between the cases and the controls. In addition, logistic regression analysis was used to estimate the associations between seminal plasma TCS concentrations and low sperm quality risk adjusting for age, body mass index (BMI), abstinence time, smoking, and drinking RESULTS AND CONCLUSIONS: The level of seminal plasma TCS was observed slightly but not significantly higher in the case group than the control group. We also observed significant association between seminal plasma TCS concentrations and semen parameters in both control and case groups. Moreover, the seminal plasma TCS levels at the fourth quartile were found to be more likely to exhibit low sperm quality risk with increased adjusted odds ratios of 2.36 (95% confidence interval 1.03-5.39) compared to the first quartile. Our results reveal that seminal plasma TCS concentration was positively associated with low sperm quality risk.

Identification of CD8+ T Cell Related Biomarkers in Ovarian Cancer.

Background: Immunotherapy is a promising strategy for ovarian cancer (OC), and this study aims to identify biomarkers related to CD8+ T cell infiltration to further discover the potential therapeutic target. Methods: Three datasets with OC transcriptomic data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Two immunotherapy treated cohorts were obtained from the Single Cell Portal and Mariathasan's study. The infiltration fraction of immune cells was quantified using three different algorithms, Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), and microenvironment cell populations counter (MCPcounter), and single-sample GSEA (ssGSEA). Weighted gene co-expression network analysis (WGCNA) was applied to identify the co-expression modules and related genes. The nonnegative matrix factorization (NMF) method was proposed for sample classification. The mutation analysis was conducted using the "maftools" R package. Key molecular markers with implications for prognosis were screened by univariate COX regression analysis and K-M survival analysis, which were further determined by the receiver operating characteristic (ROC) curve. Results: A total of 313 candidate CD8+ T cell-related genes were identified by taking the intersection from the TCGA-OV and GSE140082 cohorts. The NMF clustering analysis suggested that patients in the TCGA-OV cohort were divided into two clusters and the Cluster 1 group showed a worse prognosis. In contrast, Cluster 2 had higher amounts of immune cell infiltration, elevated ssGSEA scores in immunotherapy, and a higher mutation burden. CSMD3, MACF1, PDE4DIP, and OBSCN were more frequently mutated in Cluster 1, while SYNE2 was more frequently mutated in Cluster 2. CD38 and CXCL13 were identified by univariate COX regression analysis and K-M survival analysis in the TCGA-OV cohort, which were further externally validated in GSE140082 and GSE32062. Of note, patients with lower CXCL13 expression showed a worse prognosis and the CR/PR group had a higher expression of CXCL13 in two immunotherapy treated cohorts. Conclusion: OC patients with different CD8+ T cell infiltration had distinct clinical prognoses. CXCL13 might be a potential therapeutic target for the treatment of OC.

A novel prognostic time window based on conditional survival and outcomes analyses of primary liver cancer patients.

BACKGROUND: Liver cancer is one of the most deadly and prevalent cancers. A routine follow-up plan for liver cancer is crucial but limited. In the present study, we aimed to disclose possible risk factors and critical survival time windows for primary liver cancer. METHODS: We enrolled 692 liver cancer patients from Sun Yat-sen University Cancer Center (SYSUCC). Univariate and multivariate logistic regression analyses of cirrhosis and recurrence were conducted. A meta-analysis was utilized to validate an indication of creatinine (CRE) in recurrence. Conditional survival analysis was performed using the Kaplan-Meier method. The results were further verified by the SYSUCC validation cohort and Surveillance, Epidemiology, and End Results (SEER) validation cohort. RESULTS: Our results indicated that A/G, history of hepatitis, history of alcohol consumption and platelet (PLT) might be potential prognostic factors for cirrhosis in liver cancer patients. CRE was significantly correlated with recurrence due to various therapies, especially after transarterial embolization. Moreover, 1.5 years to 2 years may be a critical time window for deterioration in survival rate based on the conditional survival analysis. CONCLUSION: A/G, history of hepatitis, alcohol consumption and PLT may be potential prognostic factors for cirrhosis in liver cancer patients. More attention should be focused on the renal function when treating the patients due to the significant role of CRE. 1.5 years to 2 years is a critical time window for deterioration in survival rate for liver cancer patients that contributes to determining the optimal follow-up plan in the future.

[Clinical effect of treatment with lipo-prostaglandin E1 on the patients with chronic glomerulonephritis].

OBJECTIVE: To investigate potential mechanism underlying lipo-prostaglandin E1 (PGE1) in treatment of patients with chronic glomerulonephritis. METHODS: The recommended dose of 20 microg lipo-PGE1 for treatment of chronic glomerulonephritis was as a daily dose by continuous intravenous infusion or intravenous injection for 4 weeks. The levels of interleukin-1 (IL- 1), tumor necrosis factor-alpha (TNF-alpha), blood urea nitrogen (BUN), serum creatinine (SCr) and clearance of creatinine (CCr) were measured before and after treatment. RESULTS: After treatment with lipo-PGE1, levels of IL-1, TNF-alpha, BUN and SCr were lower than those before treatment (all P<0.01), but CCr values were higher than those before treatment (P<0.05). CONCLUSION: Lipo-PGE1 can reduce the renal inflammatory response and improve the renal function in the patients with chronic glomerulonephritis.

[Clinical application of fistulation of artery and vein with self-blood vessel transplantation].

OBJECTIVE: To investigate the clinical application of fistulation of artery and vein with self-blood vessel transplantation. METHODS: Seven patients with renal failure were given antebrachial fistulation of artery and vein with great saphenous veins of themselves. The ortho- and pachy-great saphenous vein was chosed after it was cut. The great saphenous vein was passed bridge inside forearm in straight line or morpha-U. The method was anastomosis of the radial artery or brachial artery and cephalic vein, basilic vein or median cubital vein. RESULTS: The fistulations of artery and vein were successful and all patients were in hemodialysis regularly. CONCLUSION: The fistulation of artery and vein with self-blood vessel transplantation is a convenient, easy, cheap operation. It can coincide with the clinical demand and be used to make up the failure of fistulation or the fistulation that there is no blood vessel in the forearm.