BackgroundErythropoietin is an important drug for the treatment of anemia in hemodialysis patients. However, many patients show erythropoietin-hyporesponsiveness. Roxadustat has been shown to be effective in treating patients with anemia due to chronic kidney disease. However, its efficacy and safety in hemodialysis patients with erythropoietin-hyporesponsive anemia remain unclear.MethodsErythropoietin-hyporesponsiveness was defined as erythropoietin dose of more than 450U/kg intravenously or 300U/kg subcutaneously for 16 weeks, with hemoglobin rising rate below 1 g/dL/month or 11.0 g/dL. A cohort of hemodialysis patients with anemia and a low response to erythropoietin from January 2020 to December 2020 were treated with roxadustat for 12 weeks to observe changes in hemoglobin, iron metabolism, blood lipid, and inflammatory indicators and to evaluate the safety and efficacy of roxadustat.ResultsThere were 56 patients with erythropoietin-hyporesponsiveness, and a total of 44 patients (78.6%) completed the 12-week follow-up, including 16 males (36.4%); patient ages were 54.6±14.2 years. The mean initial treatment dose of roxadustat was 104.4±12.4 mg thrice a week. At week 12, 30 subjects (68.2%) met the protocol-defined primary efficacy endpoint. After 12 weeks of treatment, hemoglobin was significantly increased from 7.81±1.36 g/dL to 9.80±1.94 g/dL (P<0.001), serum ferritin, serum total cholesterol and triglyceride were significantly decreased. While white blood cells and neutrophils significantly increased than baseline.ConclusionThis study indicated that roxadustat significantly increases hemoglobin levels, improving iron absorption and utilization, reducing cholesterol and triglyceride levels, with good short-term safety profile in hemodialysis patients with erythropoietin-hyporesponsive anemia.
BackgroundDachengqi decoction (DCQD), one of classic prescription of Chinese herbal medicine has been widely used in clinic to treat severe acute pancreatitis (SAP). The damage of pancreatic microcirculation plays key pathogenesis of SAP. However, little is known about the molecular pharmacological activity of DCQD on pancreatic microcirculation in SAP. Therefore, the purpose of the study attempted to confirm the improvement of DCQD on pancreatic microcirculation is associated with suppressing neutrophil mediated immune-inflammatory response through promoting the inactivation of HMGB1-TLR-4-IL-23-IL-17A axis via targeting the SIRT1 signal pathway in SAP.Material and MethodsSodium taurodeoxycholate and cerulein were used to establish model of SAP in vitro and vivo, respectively. The pancreatic pathological morphology, wet weight ratio, myeloperoxidase (MPO) activity, cell viability and microcirculatory function of the pancreas, as well as serum lipase and amylase expressions were evaluated. The expression levels of SIRT1, acety-HMGB1, TLR-4, HMGB1, IL-23, IL-17A, neutrophil chemokines (KC, LIX, and MIP-2), and inflammation-related factors (IL-6, IL-1β, and TNF-α), the translocation of HMGB1 and the interaction of SIRT-HMGB1 in the pancreas and serum were determined by ELISA real-time PCR, western blotting and immunoprecipitation.ResultsIn-vivo studies showed DCQD or neutralizing antibody (anti-23p19 or anti-IL-17A) could significantly decrease the activity of lipase, amylase, down-regulate the expression of CD68, MPO, wet/weight, IL-1β, IL-6, TNF-α,neutrophil chemokines (KC, LIX, MIP-2 ), alleviate pathological injury, and improve the microcirculatory function of the pancreas in rats with SAP. Moreover, DCQD remarkably augmented SIRT1 expression, promoted SIRT1 and HMGB1 combination, reduced HMGB1 translocation from nuclear to cytoplasm, and alleviated the expression of acetyl-HMGB1, HMGB1, IL-17A, TLR-4 and IL-23 in vitro and vivo with SAP. However, the intervention with EX527 (SIRT1 inhibitor) or r-HMGB1 (recombinant HMGB1) could obliviously reverse the above-mentioned influence of DCQD in SAP. In vitro, we confirmed that DCQD could decrease the acetylation, migration and release of HMGB1, and improve the decline of cell viability, SIRT1, SIRI-HMGB1 combination induced by cerulein with promoting macrophage to release IL-23 through HMGB1/TLR-4. ConclusionDCQD treatment improves SAP-induced pancreatic microcirculatory dysfunction by inhibiting neutrophil-mediated inflammation through the inactivation of HMGB1-TLR-4-IL-23-IL-17A signaling via Targeting SIRT1.Trial registration: No. 365, 2020.
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