The deacylase sirtuin 5 reduces malonylation in nonmitochondrial metabolic pathways in diabetic kidney disease.

Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. We performed a proteomics analysis of malonylated peptides and found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in nonmitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation. To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians, which revealed a tubulointerstitial-specific increase in Sirt5 expression. These data were further corroborated by immunofluorescence data of SIRT5 from nondiabetic and DKD cohorts. Furthermore, overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis. Conversely, we observed reduced glycolysis with decreased SIRT5 expression. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Taken together, our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.

[Effects of metabolites of mangrove fungus Xylaria sp. from South China Sea Coast on the activity of acetylcholinesterase in vitro].

OBJECTIVE: To investigate the effects of metabolites of mangrove fungus Xylaria sp. from South China Sea Coast, xyloketal A-D, on the activity of acetylcholinesterase (AChE) in vitro. METHODS: Activity of AChE was determined by a modified method of Ellmen. The selectivity of the compounds for AChE and butyrylcholinesterase (BuChE) was also tested and compared with that of a positive control, velnacrine. The inhibitory properties of xylokets on AChE were characterized as well. RESULTS: AChE activity was inhibited by xyloketal A-D in a dose-dependent manner, their IC50 were determined to be 29.9, 137.4, 109.3 and 425.6 micromol/L, respectively. At the same time, velnacrine and all the four compounds showed inhibitory effects on BuChE in different degree, and the inhibitory activity of xyloketals on AChE was found to be reversible and noncompetitive. CONCLUSION: Xyloketal A-D can inhibit AChE as well as BuChE activity in vitro. So xyloketal A-D were likely considered as drug candidates against Alzheimer' s disease (AD) for further development.

Effects of resveratrol on secondary spinal cord edema and activity of lactic dehydrogenase and ATPase in experimental spinal cord injury of rats / 中国药理学通报

AIM To study the effects of resveratrol on secondary spinal cord edema and the activity of lactic dehydrogenase and Na +, K + ATPase in experimental spinal cord injury (SCI)rat. METHODS The weight dropping method was used to produce the experimental spinal cord injury in adult rats. Resveratrol (Res) and methylprednisolone (MPSS) were intraperitoneally by the bolus injections of 50 mg?kg -1 , 100 mg?kg -1 and 100 mg?kg -1 , respectively, immediately after the induction of SCI. And then the effects of Res were observed at 1 h, 24 h, 48 h after SCI compared with MPSS. RESULTS Res could obvious inhibit the secondary spinal cord edema with the most remarkable suppressing rate by 11 5% at 48 h. Res was able to significantly suppress the activities of the lactic dehydrogenase with the highest suppressing rate for over 40% at 24 h. In the meantime, Res markedly improved the Na +, K + ATPase activities that promoted to the biggest extent to 60% at 48 h. The effects of Res were the same as or even stronger than those of MPSS. CONCLUSION Res may effectively protect the spinal cord from secondary spinal cord edema and improve the energy metabolism system in SCI. It suggested that Res may be having potent therapeutic effect on SCI.

Inhibition of resveratral on lipid peroxidative reaction and reactive oxygen species of early experimental rat spinal cord injury / 中国临床药理学与治疗学

AIM: To study the effects of resveratral on lipid peroxidative reaction and reactive oxygen species (ROS) in experimental spinal cord injury rats. METHODS: The weight dropping method was used to produce the experimental spinal cord injury (SCI) in adult rats. Resveratrol (Res) and methylprednisolone (MPSS) were given intraperitoneally by the bolus injections of 50, 100 mg?kg -1 and 100 mg?kg -1 , respectively, immediately after induction of SCI. And then the effects of Res were observed at 1, 24, 48 h after SCI compared with MPSS. RESULTS: Res could obvious prevented reduction of superoxide dismutase (SOD) activity and reduce malondialdehyde (MDA) production and inhibit the ROS level in the injured spinal cord tissue in comparison with the SCI model at the dose of 50 mg?kg -1 and 100 mg?kg -1 , which the most remarkable effects was at 48 h with the inhibition rate over 40%. The effects of Res were the same as or even greater than those of MPSS. CONCLUSION: Res may effectively protect the spinal cord from lipid peroxidative reaction and ROS damage in SCI.

Advances in research on pharmacological strategies for spinal cord injury / 中国药理学通报

Aim Pharmacological intervention is one of important strategies to deal with spinal cord injury.The effect of Pharmacological intervention has highly differentiated features because of complex physiopathology mechanisms in SCI.Moreover contraindications,complications having different features,it is constantly the focal point in the selection of pharmacological intervention to protect spinal cord,attenuate secondary injury and promote injuried neuron regeneration.At present only several of those have been applied in clinic and the majority are still being carried out in clinic trial stage,even preclinical animal experiment stage.This paper made a particular review of the current situation in pharmacological intervention for spinal cord injury.

The inhibitive effects of resveratrol on adhesion of neutrophils to HUVECs induced by fMLP / 中国药理学通报

Aim To study the effects of resveratrol(Res)on the release of soluble adhesion molecules from human umbilical vein endothelial cells(HUVECs)induced by N-formyl-methionyl-leucyl-phenylal-anine(fMLP)and the adhesion between neutrophils and HUVECs.Methods The effects of Res on neutrophils adhesion to human umbilical endothelial cell(HUVECs)triggered by fMLP were examined.The soluble intercellular cell adhesive molecule-1(ICAM-1),the soluble vascular cell adhesive molecule-1(VCAM-1)and E-selectin release from fMLP(10 ?mol?L-1)stimulated HUVECs were determined by ELISA kits.The neutrophils isolated from human vein blood were loaded with Fluo-3,a fluorescent indicator,to detect intracellular free calcium concentration([Ca2+]i),and CLA was used as a chemiluminescent indicator to determine superoxide production in neutrophils.Results Res(1~50 ?mol?L-1)significantly inhibited neutrophil adhesion to fMLP-stimulated HUVECs and also obviously downregulated the levels of ICAM-1,VCAM-1 and E-selectin in supernatant of HUVECs culture stimulated by fMLP in the dose-dependent pattern.Res also suppressed fMLP-activated superoxide generation and[Ca2+]i increase in neutrophils.Conclusions Res involved in neutrophil adhesion to HUVECs intermediated by cell adhesive molecules expression trigged by[Ca2+]i and superoxide production in neutrophils,which means a lot to prevent inflammatory diseases.

SARS-CoV-2 receptor networks in diabetic kidney disease, BK-Virus nephropathy and COVID-19 associated acute kidney injury

COVID-19 morbidity and mortality is increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Since ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease (DKD) and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of healthy living donor (LD) and DKD kidney biopsies revealed ACE2 expression primarily in proximal tubular epithelial cells (PTEC). This cell specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin angiotensin aldosterone system inhibitors in DKD. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing PTEC in DKD (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The DKD ACE2-positive PTEC module overlapped with expression patterns seen in SARS-CoV-2 infected cells. Similar cellular programs were seen in ACE2-positive PTEC obtained from urine samples of 13 COVID-19 patients who were hospitalized, suggesting a consistent ACE2-coregulated PTEC expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19 related kidney damage. Translational statementTo understand the overwhelming burden of kidney disease in COVID-19, we mapped the expression of the SARS-CoV-2 receptor, ACE2, in healthy kidney, early diabetic (DKD) and COVID-19 associated kidney diseases. Single cell RNA sequencing of 111035 cells identified ACE2 predominantly in proximal tubular epithelial cells. ACE2 upregulation was observed in DKD, but was not associated with RAAS inhibition, arguing against an increased risk of COVID-19 among patients taking RAAS inhibitors. Molecular network analysis linked ACE2 expression to innate immune response and viral entry machinery, thereby revealing potential therapeutic strategies against COVID-19.