BackgroundTraumatic brain injury (TBI) induces a complex sequence of apopototic cascades that contribute to secondary tissue damage. The aim of this study was to investigate the effects of salidroside, a phenolic glycoside with potent anti-apoptotic properties, on behavioral and histological outcomes, brain edema, and apoptosis following experimental TBI and the possible involvement of the phosphoinositide 3-kinase/protein kinase B (PI3K)/Akt signaling pathway.Methodology/Principal FindingsMice subjected to controlled cortical impact injury received intraperitoneal salidroside (20, or 50 mg/kg) or vehicle injection 10 min after injury. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of PI3K/Akt signaling-related molecules, apoptosis-related proteins, cytochrome C (CytoC), and Smac/DIABLO were also analyzed. LY294002, a PI3K inhibitor, was administered to examine the mechanism of protection. The protective effect of salidroside was also investigated in primary cultured neurons subjected to stretch injury. Treatment with 20 mg/kg salidroside_significantly improved functional recovery and reduced brain tissue damage up to post-injury day 28. Salidroside_also significantly reduced neuronal death, apoptosis, and brain edema at day 1. These changes were associated with significant decreases in cleaved caspase-3, CytoC, and Smac/DIABLO at days 1 and 3. Salidroside increased phosphorylation of Akt on Ser473 and the mitochondrial Bcl-2/Bax ratio at day 1, and enhanced phosphorylation of Akt on Thr308 at day 3. This beneficial effect was abolished by pre-injection of LY294002. Moreover, delayed administration of salidroside at 3 or 6 h post-injury reduced neuronal damage at day 1. Salidroside treatment also decreased neuronal vulnerability to stretch-induced injury in vitro.Conclusions/SignificancePost-injury salidroside improved long-term behavioral and histological outcomes and reduced brain edema and apoptosis following TBI, at least partially via the PI3K/Akt signaling pathway.

By following the KDIGO guidelines, we confirmed that TDF was associated with a higher risk of renal dysfunction as compared to ETV.

Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. Methods: In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). Results: The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95%CI: 27.84–57.73% vs. 25.42%, 95%CI: 16.26–34.58%; p = 0.045) and SAE recurrence (25.91%, 95%CI: 10.91–40.91% vs. 1.04%, 95%CI: 0–3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95%CI: 1.04–3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95%CI: 2.34–31.30% vs. 6.02%, 95%CI: 0–13.23%; p = 0.049). Conclusions: Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.

The nephrotoxicity of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients without chronic kidney disease (CKD) remains controversial. We aimed to evaluate nephrotoxicity of TDF in this population. In this hospital‐based cohort study, CHB patients who received either TDF or entecavir (ETV) therapy, and did not have underlying CKD, were retrospectively recruited from January, 2008 to January, 2019. After excluding those with confounding conditions, 257 TDF‐treated patients were matched through propensity scores with 514 ETV‐treated patients. Cumulative incidences of, and hazard ratios (HRs) for the CKD guideline‐defined renal dysfunction, were analysed. The mean decline in glomerular filtration rate was similar over 60 months (TDF vs. ETV: 10.1 ml/min/1.73 m2, 95% confidence interval [CI]: 7.4–12.7 vs. 8.0 ml/min/1.73 m2, 95% CI: 6.4–9.6; p = .34). The 5‐year cumulative incidence of renal dysfunction was not significantly different (TDF vs. ETV: 10.4%, 95% CI: 5.6–18.0 vs. 5.8%, 95% CI: 3.6–9.0; p = .18). However, in multivariable stratified analysis, TDF was associated with an increased risk of renal dysfunction in the elderly (age ≥60 years), when compared to ETV (HR 2.86, 95% CI: 1.02–8.01; p < .05). For confirming the effect of TDF amongst the elderly, 61 TDF‐treated patients were further matched with 183 ETV‐treated patients, with 5‐year cumulative incidence of renal dysfunction being significantly higher in TDF users (TDF vs. ETV: 34.4%, 95% CI: 17.7–59.8 vs. 15.5%, 95% CI: 9.4–25.1; p < .05). TDF use was independently related to renal dysfunction (HR 2.71, 95% CI: 1.19–6.14; p < .05). Although TDF is generally safe for CHB patients without CKD, it is best to be avoided in the elderly.