Modulations of Keap1-Nrf2 signaling axis by TIIA ameliorated the oxidative stress-induced myocardial apoptosis.

Mounting evidence has strongly implicated oxidative stress in the development of cardiac dysfunction, and myocardial apoptosis contributes to the pathogenesis of heart failure. Quantitative cardiac proteomics data revealed that pressure load by TAC resulted in a significant decline in mitochondrial metabolic activity, where TIIA (Tanshinone IIA sulfonate) treatment reversed it in vivo, which might be mediated by Nrf2. In NRVMs, TIIA treatment ameliorated H2O2-induced caspase-3/9 activations through the suppression of p38 and mTOR signaling pathways, where caspase-mediated cleavage of YY1 and PARP resulted in the defects in mitochondrial biogenesis and DNA repair, and this event finally led to cardiomyocyte apoptosis. Mass spectrometry analysis showed that TIIA hydrophobically interacted with Keap1 (the cytoplasmic repressor of Nrf2) and induced its degradation in vitro. Site-directed mutagenesis of Keap1 identified V122/V123/I125 to be the critical residues for the TIIA-induced de-dimerization and degradation of Keap1. Besides, TIIA treatment also epigenetically up-regulated Nrf2 gene transcription, where it hypomethylated the first 5 CpGs of Nrf2 promoter. Furthermore, cardiac-specific Nrf2 knockout mice exhibited the significantly dampened anti-apoptotic effects of TIIA.

Risk factors affecting the mortality of HIV-infected patients with pulmonary tuberculosis in the cART era: a retrospective cohort study in China.

BACKGROUND: Tuberculosis infection still places a great burden on HIV-infected individuals in China and other developing countries. Knowledge of the survival of HIV-infected patients with pulmonary tuberculosis (PTB) would provide important insights for the clinical management of this population, which remains to be well described in current China. METHODS: HIV-infected patients with PTB admitted to Shanghai Public Health Clinical Center from January 2011 to December 2015 were retrospectively enrolled. In this cohort, the survival prognosis was estimated by the Kaplan-Meier method, while univariate and multivariate Cox proportional hazards models were used to determine the risk factors affecting mortality. RESULTS: After reviewing 4914 admitted patients with HIV infection, 359 PTB cases were identified. At the time of PTB diagnosis, the patients' median CD4+ T cell count was 51 /mm3 (IQR: 23-116), and 27.30% of patients (98/359) were on combination antiretroviral therapy (cART). For the 333 cases included in the survival analysis, the overall mortality was 15.92% (53/333) during a median 27-month follow-up. The risk factors, including age older than 60 years (HR: 3.18; 95% CI: 1.66-6.10), complication with bacterial pneumonia (HR: 2.64; 95% CI: 1.30-5.35), diagnosis delay (HR: 2.60; 95% CI: 1.42-4.78), CD4+ T cell count less than 50/mm3 (HR: 2.38; 95% CI: 1.27-4.43) and pulmonary atelectasis (HR: 2.20; 95% CI: 1.05-4.60), might independently contribute to poor survival. Among patients without cART before anti-TB treatment, the later initiation of cART (more than 8 weeks after starting anti-TB treatment) was found to increase the mortality rate (OR: 4.33; 95% CI: 1.22-15.36), while the initiation of cART within 4-8 weeks after starting anti-TB treatment was associated with the fewest deaths (0/14). CONCLUSIONS: The subjects in this study conducted in the cART era were still characterized by depressed immunological competence and low rates of cART administration, revealing possible intervention targets for preventing TB reactivation in HIV-infected individuals under current circumstances. Furthermore, our study indicated that the timely diagnosis of PTB, prevention of secondary bacterial pneumonia by prophylactic management and optimization of the timing of cART initiation could have significant impacts on decreasing mortality among HIV/PTB co-infected populations. These findings deserve further prospective investigations to optimize the management of HIV/PTB-co-infected patients. TRIAL REGISTRATION: NCT01344148 , Registered September 14, 2010.

Serum TRSUT Titer ≥1: 16 Is a Predictor for Neurosyphilis Among HIV-Infected Patients With Concurrent Syphilis and No Neurological Symptoms.

Investigating the predictors for lumbar puncture to diagnose the asymptomatic neurosyphilis among HIV and syphilis co-infected patients in Shanghai, China. Respectively, screening the medical records from August 1, 2009 to June 30, 2015. Those HIV-infected patients with concurrent syphilis who had received lumbar puncture were selected and their clinical and demographic data were recorded. Participants comprised symptomatic and asymptomatic patients. The latter ones could be further divided into 3 groups: late syphilis, early syphilis with anti-syphilis treatment failure, and early syphilis with serum toludine red unheated serum test (TRUST) ≥1:32. Both syphilis stage and anti-syphilis treatment effect were defined by common criteria, and syphilis of unknown duration was considered as late syphilis. Asymptomatic neurosyphilis was defined as neurosyphilis without neurological symptoms such as headache, cognitive dysfunction, motor deficits, auditory or ophthalmic abnormalities, and stroke. Neurosyphilis was defined as reactive cerebrospinal fluid (CSF) TRUST and/or CSF white blood cell >20 cells/µL without other reasons. Mann-Whitney test and Fisher's exact test were used for analyzing the difference between neurosyphilis and non-neurosyphilis group. Logistic regression test was performed to analyze the risk factors for neurosyphilis. In total, 170 participants were collected, and the rate of neurosyphilis was 32.35%. Among all the 105 participants without neurological symptoms, 80 patients were with late syphilis and 25 were with early syphilis. Among the early syphilis patients, 23 had a TRUST ≥1:32 and the other 2 experienced an anti-syphilis treatment failure. The differences of clinical and demographic variables between neurosyphilis and non-neurosyphilis group were not statistically significant except the serum TRUST titer (P < 0.01). From HIV/syphilis co-infected patients with or without neurological symptom, those who had neurological symptoms, CD4 <350 per µL and serological TRUST titer ≥1:16 were 4.9-fold (95% confidence interval [CI]: 2.37-10.31), 4.3-fold (95% CI: 1.17-15.78), and 4.1-fold (95% CI: 1.58-10.76), respectively, more likely to be diagnosed with neurosyphilis. Asymptomatic patients whose serum TRUST titer ≥1:16 were 8.48-fold (95% CI: 1.08-66.63) more likely to have asymptomatic neurosyphilis. Among asymptomatic HIV-infected patients with late syphilis or early syphilis experienced an anti-syphilis treatment failure, those who have a serum TRUST titer ≥1:16 are suggested to perform lumbar puncture in order to avoid delayed diagnosis and the occurrence of severe sequelae of syphilis.