H2O2 concentration-dependent kinetics of gene expression: linking the intensity of oxidative stress and mycobacterial physiological adaptation.

Defence against oxidative stress is crucial for Mycobacterium tuberculosis to survive and replicate within macrophages. Mycobacteria have evolved multilayer antioxidant systems, including scavenging enzymes, iron homeostasis, repair pathways, and metabolic adaptation, for coping with oxidative stress. How these systems are coordinated to enable the physiological adaptation to different intensities of oxidative stress, however, remains unclear. To address this, we investigated the expression kinetics of the well-characterized antioxidant genes at bacteriostatic H2O2 concentrations ranging from 1 mM to 10 mM employing Mycolicibacterium smegmatis as a model. Our results showed that most of the selected genes were expressed in a H2O2 concentration-dependent manner, whereas a subset exhibited sustained induction or repression without dose-effect, reflecting H2O2 concentration-dependent physiological adaptations. Through analyzing the dynamics of the coordinated gene expression, we demonstrated that the expressions of the H2O2 scavenging enzymes, DNA damage response, and Fe-S cluster repair function were strikingly correlated to the intensity of oxidative stress. The sustained induction of mbtB, irtA, and dnaE2 indicated that mycobacteria might deploy increased iron acquisition and error-prone lesion bypass function as fundamental strategies to counteract oxidative damages, which are distinct from the defence tactics of Escherichia coli characterized by shrinking the iron pool and delaying the DNA repair. Moreover, the distinct gene expression kinetics among the tricarboxylic acid cycle, glyoxylate shunt, and methylcitrate cycle suggested that mycobacteria could dynamically redirect its metabolic fluxes according to the intensity of oxidative stress. This work defines the H2O2 concentration-dependent gene expression kinetics and provides unique insights into mycobacterial antioxidant defence strategies.

Dexmedetomidine alleviates inflammation in neuropathic pain by suppressing NLRP3 via Nrf2 activation.

The aim of the present study was to investigate the mechanism by which dexmedetomidine (DEX) alleviates neuropathic pain in a chronic constriction injury (CCI) model in rats. A CCI rat model was established through sciatic nerve ligation. CCI rats were treated with DEX, the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385, the NLR family pyrin domain containing 3 (NLRP3) antagonist MCC950 and/or the NLRP3 activator nigericin. The mechanical withdrawal threshold (MWT) was measured to assess the pain sensitivity of CCI rats. Hematoxylin and eosin staining and TUNEL staining were used to examine spinal injury and apoptosis, respectively. ELISA was used to quantify the levels of inflammatory factors. The expression levels of Nrf2 and NLRP3 were also examined. The results indicated that a decrease in MWT and increases in spinal cord injury, apoptosis and inflammatory factors were detected in CCI rats compared with control rats. Spinal inflammation was abrogated in DEX-treated CCI rats. Compared with the model group, an increase in MWT and decreases in spinal cord injury, apoptosis and inflammatory factors were detected in rats treated with MCC950, while the opposite effects were observed in rats treated with nigericin. The opposite effects on these indicators were observed in the DEX + ML385 and MCC950 + ML385 groups compared with the DEX and MCC950 groups, respectively. MWT was increased, while spinal cord injury, apoptosis and inflammation decreased in the nigericin + DEX group compared with the nigericin group. In summary, the results of the present study indicated that DEX reduced neuropathic pain in CCI rats by suppressing NLRP3 through Nrf2 activation.

Hepatitis B e antigen-positive and high levels of alanine aminotransferase are associated with prevalence of metabolic syndrome in chronic HBV patients.

OBJECTIVE: The interactions between hepatitis B virus (HBV) infection and metabolic syndrome (MS) have not been elucidated. This study was aimed to investigate the relationship between metabolic profile and HBV infection. METHODS: A retrospective cross-sectional study including patients infected by HBV (HBV group, n=121) and healthy volunteers (control group, n=263) was conducted, serum HBV viral load and markers, serum alanine aminotransferase (ALT) levels and MS were analyzed. Factors associated with prevalence of MS were explored with multivariate adjusted logistic regression analyses. RESULTS: The prevalence of MS was 9.9% in HBV infected patients and 19.4% in controls (p=0.011). Factors associated with the prevalence of MS were (odds ratio, 95% confidence interval, p value): hepatitis B e antigen (HBeAg) positive (0.368, 0.107-0.653, 0.008) and high levels of ALT (0.183, 0.120-0.268, <0.001) in HBV patients. But clinical and virological factors (including age, HBV DNA level, male gender, BMI, and fatty liver) were not found to be associated with prevalence of MS in HBV patients who were HBeAg positive with high levels of ALT. CONCLUSION: These findings suggest that HBeAg positive and high levels of ALT are independently associated with lower prevalence of MS in HBV patients. But HBV DNA may not have impact on the lipid metabolism. HBV-related immune reactions may play a certain role in the mechanism of MS.