Neuropathic pain is a worldwide health concern with poor treatment outcomes. Accumulating evidence suggests that histone hypoacetylation is involved in development and maintenance of neuropathic pain. Thus, many natural and synthetic histone deacetylase (HDACs) inhibitors were tested and exhibited a remarkable analgesic effect against neuropathic pain in animals. However, studies evaluating specific subtypes of HDACs contributing to neuropathic pain are limited. In this study, using the chronic constriction injury (CCI) rat model, we found that mRNA and protein levels of HDAC2 were increased in the lumbar spinal cord of rats after sciatic nerve injury. Intrathecal injection of TSA, a pan-HDAC inhibitor, suppressed the increase in HDAC2 protein but not mRNA, and showed a dose-dependent pain-relieving effect. By introducing HDAC2-specific shRNA into the spinal cord via a lentivirus vector, we confirmed that HDAC2 mediates mechanical and thermal hyperalgesia after nerve injury. Further examination found two essential participants in neuropathic pain in the inhibitory circuit of the central nervous system: GAD65 and KCC2 were increased in the spinal cord of CCI rats after HDAC2 knockdown. Thus, our research confirmed that HDAC2 was involved in mechanical and thermal hyperalgesia induced by peripheral nerve injury. Furthermore, GAD65 and KCC2 were the possible downstream targets of HDAC2 in pain modulation pathways.

Background: Chloride is the most abundant anion in the human extracellular fluid and plays a crucial role in maintaining homeostasis. Previous studies have demonstrated that hypochloremia can act as an independent risk factor for adverse outcomes in various clinical settings. However, the association of variances of serum chloride with long-term mortality risk in general populations has been rarely investigated. Objective: This study aims to assess the association of serum chloride with all-cause and cause-specific mortality in the general American adult population. Methods: Data were collected from 10 survey cycles (1999-2018) of the National Health and Nutrition Examination Survey. All-cause mortality, cardiovascular disease (CVD) mortality, cancer mortality, and respiratory disease mortality data were obtained by linkage to the National Death Index through December 31, 2019. After adjusting for demographic factors and relevant lifestyle, laboratory items, and comorbid factors, weighted Cox proportional risk models were constructed to estimate hazard ratios and 95% CIs for all-cause and cause-specific mortality. Results: A total of 51,060 adult participants were included, and during a median follow-up of 111 months, 7582 deaths were documented, 2388 of CVD, 1639 of cancer, and 567 of respiratory disease. The weighted Kaplan-Meier survival analyses showed consistent highest mortality risk in individuals with the lowest quartiles of serum chloride. The multivariate-adjusted hazard ratios from lowest to highest quartiles of serum chloride (≤101.2, 101.3-103.2, 103.2-105.0, and ≥105.1 mmol/L) were 1.00 (95% CI reference), 0.77 (95% CI 0.67-0.89), 0.72 (95% CI 0.63-0.82), and 0.77 (95% CI 0.65-0.90), respectively, for all-cause mortality (P for linear trend<.001); 1.00 (95% CI reference), 0.63 (95% CI 0.51-0.79), 0.56 (95% CI 0.43-0.73), and 0.67 (95% CI 0.50-0.89) for CVD mortality (P for linear trend=.004); 1.00 (95% CI reference), 0.67 (95% CI 0.54-0.84), 0.65 (95% CI 0.50-0.85), and 0.65 (95% CI 0.48-0.87) for cancer mortality (P for linear trend=.004); and 1.00 (95% CI reference), 0.68 (95% CI 0.41-1.13), 0.59 (95% CI 0.40-0.88), and 0.51 (95% CI 0.31-0.84) for respiratory disease mortality (P for linear trend=.004). The restricted cubic spline analyses revealed the nonlinear and L-shaped associations of serum chloride with all-cause and cause-specific mortality (all P for nonlinearity<.05), in which lower serum chloride was prominently associated with higher mortality risk. The associations of serum chloride with mortality risk were robust, and no significant additional interaction effect was detected for all-cause mortality and CVD mortality (P for interaction>.05). Conclusions: In American adults, decreased serum chloride concentrations were independently associated with increased all-cause mortality, CVD mortality, cancer mortality, and respiratory disease mortality. Our findings suggested that serum chloride may serve as a promising cost-effective health indicator in the general adult population. Further studies are warranted to explore the potential pathophysiological mechanisms underlying the association between serum chloride and mortality.

Anaemia, a disorder characterised by a reduction in haemoglobin or red blood cells [1], is attributed to various aetiologies, including nutritional deficiencies, inflammation, genetic haemoglobin disorders, blood loss, and haemolysis [2]. It has long been a major health concern worldwide due to its associations with unfavourable outcomes, such as increased morbidity and mortality in various […]

Bone cancer pain (BCP) seriously deteriorates the life quality of patients, but its underlying mechanism is still unclear. Spinal microRNAs might contribute to the development of BCP and the role of microglial activation is controversial. In this study, we established a BCP model by injecting Walker 256 breast carcinoma cells into the tibial intramedullary cavity of rats and significant hyperalgesia was observed in the BCP rats. The lumbar spinal cords were harvested to perform RNA sequencing (RNA-seq), and 31 differentially expressed miRNAs (26 upregulated and 5 downregulated) were identified in the BCP rats. Among them, miR-155-5p was significantly upregulated in the BCP rats. Spinal microglial activation was observed during BCP development. miR-155-5p could be expressed in spinal microglia and was significantly upregulated in microglia treated with lipopolysaccharide (LPS) in vitro. Serum/glucocorticoid regulated kinase family member 3 (Sgk3) was predicted to be the possible downstream target of miR-155-5p and this was confirmed using a dual-luciferase reporter assay in vitro. The inhibition of miR-155-5p restored Sgk3-expression-attenuated microglial activation and alleviated hyperalgesia in the BCP rats. In conclusion, spinal miR-155-5p/Sgk3/microglial activation might play an important role in BCP pathogenesis.

Background: Bone cancer pain is a global medical concern with limited treat-ment options that significantly reduce the quality of life for cancer patients. Therefore, identifying a promising therapeutic target for bone cancer pain is urgently needed. Objective: Our previous research indicated that KCC2 may be associated with the modula-tion of HDAC2 in a rat model of bone cancer pain. The current study aimed to investigate whether KCC2 in the lumbar spinal cord is a key downstream molecule in the modulation of HDAC2 related to bone cancer pain. Methods: In this study, we assessed the expression levels of KCC2 and HDAC2 in the lumbar spinal cord of rats with bone cancer pain using Western blotting and RT-PCR. Mechanical hyperalgesia was evaluated using Von Frey hairs, and immunofluores-cence was employed to localize KCC2 in central nervous system cells. Results: The expression of KCC2 was down-regulated in a time-dependent manner in the lumbar spinal cord of rats with bone cancer pain. Furthermore, the use of an RNA-interfering lentivirus targeting HDAC2 restored KCC2 expression and alleviated mechani-cal hyperalgesia in these rats. Notably, the analgesic effect of the HDAC2-targeting lenti-virus was completely reversed by the KCC2 inhibitor VU0240551. Conclusion: KCC2 in the lumbar spinal cord mediated the modulation of HDAC2 in rat models of bone cancer pain, suggesting that KCC2 could be a promising therapeutic target for treating bone cancer pain.

BACKGROUND The progression of hypertension is highly heterogeneous among populations and cost-effective biomarkers assessing the prognosis of hypertension have been rarely investigated. Recent studies have highlighted the diagnostic and prognostic potential of red cell distribution width (RDW) beyond hematologic disorders. The relationship between RDW and the prognosis of hypertension has been rarely investigated. OBJECTIVE This study aimed to clarify the association of RDW with all-cause and cardiovascular disease (CVD) mortality in hypertensive adults. METHODS This prospective cohort study included 20968 adults with hypertension from the National Health and Nutritional Examination Surveys (NHANES) 1999-2018 with mortality follow-up through December 31, 2019. The participants were grouped based on the RDW quartiles as follows: Q1(≤12.5%), Q2(12.6%–13.1%), Q3(13.2%–13.9%), and Q4(≥14.0%). Kaplan-Meier curves and Cox regressions were performed to assess the relationship between RDW and mortality risk due to all-cause and CVD. The restricted cubic spline regressions were used to profile the dose-response relationship between RDW and mortality risk. The receiver operating characteristic curves were used to examine the predictive performance of RDW for mortality risk. RESULTS During a median follow-up of 96 months, 5475 deaths were documented including 1890 due to CVD. Multivariate analysis revealed that mortality risk increased step-wise by RDW quartiles, in which the HRs (95% CIs) from Q1 to Q4 were 1.00 (reference), 1.18 (1.06-1.31), 1.41 (1.27-1.56), and 2.19 (1.94-2.48) for all-cause mortality (P for trend <.001), and those were 1.00 (reference), 1.12 (0.94-1.33), 1.35 (1.12-1.63), and 2.20 (1.75-2.75) for CVD mortality (P for trend <.001). The RCS analysis revealed S-shaped associations between RDW and all-cause and CVD mortality risk. The ROC curves demonstrated acceptable predictive performance of RDW for all-cause and CVD mortality in hypertensive adults. CONCLUSIONS In American adults with hypertension, higher RDW was significantly associated with higher risks of all-cause and CVD mortality. RDW might be a promising cost-effective prognostic biomarker in the management of hypertension. Further studies are warranted to explore the potential pathophysiological mechanisms underlying the association between RDW and mortality.