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Sepsis-induced acute kidney injury (AKI) represents a major cause of mortality in intensive care units. Sivelestat, a selective inhibitor of neutrophil elastase (NE), can attenuate sepsis-related acute lung injury. However, whether sivelestat can preserve kidney function during sepsis remains unclear. In this study, we thus examined the effects of sivelestat on sepsis-related AKI. Cecal ligation and puncture (CLP) was performed to induce multiple bacterial infection in male Sprague-Dawley rats, and subsequently, 50 or 100 mg/kg sivelestat were administered by intraperitoneal injection immediately after the surgical procedure. In the untreated rats with sepsis, the mean arterial pressure (MAP) and glomerular filtration rate (GFR) were decreased, whereas serum blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels were increased. We found that sivelestat promoted the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels; specifically, the higher dose was more effective. In addition, sivelestat suppressed the CLP-induced macrophage infiltration, the overproduction of pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β, high-mobility group box 1 and inducible nitric oxide synthase) and serine/threonine kinase (Akt) pathway activation in the rats. Collectively, our data suggest that the inhibition of NE activity with the inhibitor, sivelestat, is beneficial in ameliorating sepsis-related kidney injury.

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Alpha-lipoic acid (ALA) reportedly has protective effects against sepsis, which is a leading cause of mortality worldwide and is associated with multiple organ dysfunction. The present study aimed to investigate further the possible action mechanisms of ALA. Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) in order to establish a sepsis model. The rats received an oral gavage of 200 mg/kg ALA or saline immediately after surgery. The heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and maximum rising and lowering rates of left ventricular pressure (±dp/dt) were examined for assessing the cardiac function. Blood urea nitrogen (BUN) and serum creatinine levels were assessed for evaluating renal function. Neutrophil gelatinase-associated lipocalin (NAGL) was examined for reflecting acute renal injury. Histopathological alterations of the small intestine were examined by hematoxylin-eosin staining. The ultrastructure of the small intestine and kidney was observed under electron microscopy. The levels of autophagy- and inflammation-associated proteins were determined via western blot analysis. The binding of nuclear factor-kappa B (NF-κB) to DNA was tested via an electrophoretic mobility shift assay. Cell apoptosis was examined using TUNEL staining. ALA treatment improved the survival rate, restored the loss of body weight and pro-inflammatory cytokines production in the serum of CLP-induced septic rats. ALA improved the cardiac and renal functions, downregulated the expression levels of interleukin-1β, tumor necrosis factor-α, and inducible nitric oxide synthase in the myocardium and small intestine of septic rats. ALA treatment also inactivated the NF-κB signaling pathway in the small intestine. An examination of autophagy showed that ALA increased the LC3II/I ratio, upregulated Atg5, Atg7, and beclin-1 and downregulated p62 protein levels in the myocardium, kidney, and small intestine of septic rats, and further promoted autophagosome accumulation in the kidney and small intestine. In addition, ALA could also reduce cell apoptosis in myocardium, kidney and small intestine tissues. These effects can be completely or party inhibited by 3-MA. Our findings suggest that autophagy enhancing may contribute to the organ protective effect of ALA in septic rats.

Acute kidney injury is a frequent and serious complication in patients with severe sepsis. α-Lipoic acid (ALA), a naturally occurring dithiol compound, has been shown to possess anti-inflammatory and anti-oxidative properties. In the present study we investigated whether ALA could attenuate acute kidney injury and improve survival in a rat model of sepsis. Rats were subjected to caecal ligation and puncture (CLP) to induce sepsis. α-Lipoic acid (200 mg/kg) was administered by oral gavage either immediately (early treatment) or 12 h after the surgical procedure (delayed treatment). Both early and delayed ALA treatment effectively prolonged survival, improved pathological damage in kidney tissues and reduced serum blood urea nitrogen and creatinine levels in CLP-induced septic rats. Furthermore, early treatment with ALA markedly inhibited the release of tumour necrosis factor-α, interleukin (IL)-6 and IL-1β into the serum and reduced mRNA and protein expression of inducible nitric oxide synthase and high mobility group box 1 in kidney tissues from CLP-induced rats. Finally, CLP-induced nuclear factor-κB activation in kidney tissues was significantly suppressed by early ALA treatment. Together, the results indicate that ALA is able to reduce mortality and attenuate acute kidney injury associated with sepsis, possibly by anti-inflammatory actions. α-Lipoic acid may be a promising novel agent for the treatment of conditions associated with septic shock.

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The Gravity Recovery and Climate Experiment (GRACE) data have been extensively used to evaluate the total terrestrial water storage anomalies (TWSA) from hydrological models. However, which individual water storage components (i.e., soil moisture storage anomalies (SMSA) or groundwater water storage anomalies (GWSA)) cause the discrepancies in TWSA between GRACE and hydrological models have not been thoroughly investigated or quantified. In this study, we applied GRACE mass concentration block (mascon) solutions to evaluate the spatio-temporal TWSA trends (2003–2014) from seven prevailing hydrological models (i.e., Noah-3.6, Catchment Land Surface Model (CLSM-F2.5), Variable Infiltration Capacity macroscale model (VIC-4.1.2), Water—Global Assessment and Prognosis (WaterGAP-2.2d), PCRaster Global Water Balance (PCR-GLOBWB-2), Community Land Model (CLM-4.5), and Australian Water Resources Assessment Landscape model (AWRA-L v6)) in Australia and, more importantly, identified which individual water storage components lead to the differences in TWSA trends between GRACE and hydrological models. The results showed that all of the hydrological models employed in this study, except for CLM-4.5 model, underestimated the GRACE-derived TWSA trends. These underestimations can be divided into three categories: (1) ignoring GWSA, e.g., Noah-3.6 and VIC-4.1.2 models; (2) underrating both SMSA and GWSA, e.g., CLSM-F2.5, WaterGAP-2.2d, and PCR-GLOBWB-2 models; (3) deficiently modeling GWSA, e.g., AWRA-L v6 model. In comparison, CLM-4.5 model yielded the best agreement with GRACE but overstated the GRACE-derived TWSA trends due to the overestimation of GWSA. Our results underscore that GRACE mascon solutions can be used as a valuable and efficient validation dataset to evaluate the spatio-temporal performance of hydrological models. Confirming which individual water storage components result in the discrepancies in TWSA between GRACE and hydrological models can better assist in further hydrological model development.

Background. From 2005 to 2016, the prevention and control of mumps in China have undergone three stages of transition. These include the use of MuCV as a self-supported vaccine, the introduction of one-dose MMR to the Expanded Program on Immunization (EPI), and the administration of two-dose MuCV following supplementary immunization activities (SIAs) using MM. Here, using surveillance data, we assessed the epidemiology of mumps during the three stages. Methods. Children in Quzhou of China born from 2005 to 2016 and registered in the Zhejiang Provincial Immunization Information System (ZJIIS) were included. We analyzed the epidemic data and calculated incidence and MuCV coverage via birth cohorts. Results. The average incidence of mumps in 2005-2006, 2007-2010, and 2011-2016 was 51.57, 41.02, and 12.53 per 100,000 individuals, respectively. The highest incidence was in children aged 6-14 years from 2005-2016, of which the majority were school students (67.84%). Approximately 90% of the reported outbreaks occurred in school children (primary school/middle school). The seasonal characteristics of mumps were less obvious from 2011 to 2016. The coverage of one-dose MMR in the 2005 birth cohort was 71.38%. For the 2006-2010 birth cohort, the coverage of one-dose MuCV was 96.82% and the coverage of two-dose MuCV was 17.68%. The children born from 2011 to 2016 were only free vaccinated with MMR; the coverage of one-dose MuCV was 99.10%. The mumps incidence in the three birth cohorts significantly declined (X2=805.90, P<0.001 for trend). Except the children less than two years old, the mumps incidence for the children born from 2006 to 2010 was higher than that for the children born from 2011 to 2016. Conclusion. The mumps incidence significantly declined following the introduction of one-dose MMR. The SIA using MM led to a rapid reduction of mumps cases. Therefore, we recommend a two-dose MuCV routine immunization schedule and improved vaccination coverage.