Ginsenoside Rg1 Alleviates Rat Liver Ischemia-Reperfusion Ischemia Through Mitochondrial Autophagy Pathway.

Aim: The aim of this study was to elucidate the potential mechanism of Rg1 in alleviating hepatic ischemia-reperfusion (HIRI) through the mitophagy pathway. Methods: The HIRI rat models were established and divided into 4 groups: the sham group, sham+Rg1 group, ischemia/perfusion (I/R) group and I/R+Rg1 group. Then the activities of aspartate transaminase (AST) and alanine aminotransferase (ALT) were detected by automatic serum analyzer. Meanwhile, cell apoptosis and changes in liver tissues were checked by TUNEL assay and histopathological analysis, respectively. The relative protein levels were detected by western blotting. Subsequently, cell counting Kit-8 assay and cytometric analysis were used to investigate cell viability and apoptosis of liver cells. Finally, the time points of the strongest mitochondrial autophagy were explored and the mitochondrial morphology was observed by the mitochondrial transmembrane potential (MMP) in vivo and in vitro. Results: The mitophagy aggravated hepatocyte damage during liver I/R in vivo. In addition, Rg1 alleviated liver damage after liver I/R, maintained the stability of MMP and inhibited mitochondrial autophagy and signaling pathways during liver I/R in vivo. Furthermore, Rg1 could effectively increase cell viability, inhibit cell apoptosis and stabilize MMP after OGD/R injury in vitro Moreover, Rg1 exerted its protective effect on HIRI by regulating the PINK1/Parkin signaling pathway and the mitochondrial autophagy. Conclusion: Rg1 could further improve its mechanism of alleviating HIRI in apoptosis and autophagy, 2 types of regulated programmed cell death via the mitochondrial pathway.

Gastrodin Pretreatment Protects Liver Against Ischemia-Reperfusion Injury via Activation of the Nrf2/HO-1 Pathway.

Hepatic ischemia-reperfusion (IR) injury remains the major cause of liver damage post-liver surgery or transplantation. Diminishing oxidative stress and inflammatory responses is a powerful channel to reduce the rate of morbidity and mortality. Gastrodin (GSTD), a bioactive compound extracted from the traditional Chinese herbal agent with a long history of clinical application in nervous system diseases, is suggested to possess anti-oxidative effects on liver diseases, such as nonalcoholic fatty liver disease. However, the therapeutic potential of GSTD in liver IR injury remains unclear. In this paper, we performed surgery to set up the 70% hepatic IR injury models in mice after a three-day pretreatment of GSTD. We found the administration of GSTD reduced liver damage, which correlated with lower histological Suzuki's score, lower serum alanine transaminase (AST) and alanine transaminase (ALT) levels, less oxidative stress, and cell apoptosis in a dose-responsive manner, as compared to the parallel control. Meanwhile, we observed a great induction of heme oxygenase-1 (HO-1) and an activation of the p38 mitogen-activated protein kinases/nuclear factor erythroid 2-related factor 2 (p38MAPK/Nrf2) pathway in response to the GSTD pretreatment, while the protective effects upon GSTD diminished in mice with HO-1 heterozygous mutation. In addition, GSTD inhibited IR induced toll-like receptor (TLR) 4, but not TLR2 in a HO-1 dependent manner, leading to a down-regulation of cytokines, such as interleukin (IL)-6 and TNF-[Formula: see text]. Collectively, our findings revealed GSTD attenuated liver IR injury via activation of the HO-1 pathway, providing a novel therapeutic strategy to minimize the IR induced oxidative stress in the process of liver transplantation.

Effects of Vitamin D Supplementation on Renal Function, Inflammation and Glycemic Control in Patients with Diabetic Nephropathy: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Vitamin D (VD) is widely recognized as renal protective. However, whether VD supplementation provides benefit to patients with diabetic nephropathy (DN) remains controversial. Here, we performed a meta-analysis to systematically evaluate the impact of VD supplementation on indexes of renal function, inflammation and glycemic control in DN patients, and to explore the potential renal protective mechanism of VD. METHODS: We searched Pubmed, Embase, Cochrane Library, and three major Chinese biomedical databases (CNKI, WANGFANG and VIP) for randomized controlled trials (RCTs) examining the effects of VD or its analogs in DN patients, published between September 2007 and July 2018. Quality assessment and data extraction were performed independently by two authors, according to the Cochrane systematic review methods. Meta-analysis based on the extracted results were performed via Revman 5.2 software. RESULTS: We included 20 RCTs representing 1,464 patients with DN in this meta-analysis. VD supplementation significantly reduced 24-hour urine protein [MD = -0.26; 95% CI (-0.34, -0.17); P < 0.00001; I2 = 95%], UAER [MD = -67.36; 95% CI (-91.96, -42.76); P < 0.00001; I2 = 97%], hs-CRP [MD = -0.69; 95% CI (-0.86,-0.53); P < 0.00001; I2 = 0%], TNF-α [MD = -56.79; 95% CI (-77.05, -36.52); P < 0.00001; I2 = 89%] and IL-6 [MD = -0.73; 95% CI(-1.03, -0.44); P < 0.00001; I2 = 0%]. However, VD supplementation failed to decrease SCr [MD = -0.83; 95% CI (-3.67,2.02); P = 0.57; I2 = 0%] or increase eGFR [MD = 2.13; 95% CI (-2.06, 6.32); P = 0.32; I2 = 0%]. In addition, VD supplementation showed no impact on indexes of glycemic control, such as HbA1c [MD = 0.01; 95% CI (-0.09, 0.11); P = 0.84; I2 = 0%] and FBG [MD = -0.05; 95% CI (-0.29, 0.20); P = 0.70; I2 = 0%]. Analysis of 24-hour urine protein, SCr, eGFR, hs-CRP or HbA1c revealed no difference between subgroups based on the type of VD supplementation, including calcitriol, alfacalcidol and vitamin D3, and the dose or duration of calcitriol usage. CONCLUSION: In patients with DN, VD supplementation provides beneficial effects on 24-hour urine protein and inflammation indexes, but not on SCr, eGFR or glycemic control indexes. More RCTs that comprehensively evaluate the impact of VD supplementation on indexes of renal function, inflammation and glycemic control in DN atients are required in order to reach conclusive results.

Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation.

Nuclear factor erythroid-related factor 2 (Nrf2) has been implicated in several detoxifying and antioxidant defense processes. Nrf2-mediated heme oxygenase-1 (HO-1) expression was demonstrated to play a key role against oxidative stress. Gastrodin (GSTD) is a well-known active compound isolated from the roots of Rhizoma gastrodiae, a plant used in ancient Chinese traditional medicine. The aim of this work was to investigate whether GSTD could alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells (LSECs). In LSECs exposed to 1 mM H2O2, treatment with GSTD (1, 10, or 50 µM) resulted in higher cell viability than the untreated control. Treated cells maintained a higher Bcl2/Bax ratio and suppressed caspase-9 expression compared with untreated cells, reducing cell apoptosis. GSTD was protective for H2O2-induced oxidative injury by reducing the generation of intracellular reactive oxygen species and malondialdehyde. HO-1 and Nrf2 expressions were synergistically upregulated by GSTD. Inhibition of HO-1 by 10 µM zinc protoporphyrin resulted in less protective effects on cell viability and malondialdehyde reduction by GSTD treatment in H2O2-exposed LSECs. Additionally, phosphorylated p38 in LSECs exposed to H2O2 was elevated by GSTD. Inhibition of p38 phosphorylation by SB203580 did not induce Nrf2 and HO-1 expression after 1 or 10 µM GSTD treatment and the protective effect on cell viability and malondialdehyde reduction in H2O2-exposed LSECs was reduced. The data conclusively demonstrated that GSTD-induced HO-1 and Nrf2 expression is involved in protection of LSECs from H2O2-induced oxidative injury, which may be regulated by p38 phosphorylation.

Effects of Omega-3 Fatty Acids on Markers of Inflammation in Patients With Chronic Kidney Disease: A Controversial Issue.

Chronic kidney disease (CKD) is a global problem which contributes to a significant morbidity and mortality in China. Concomitant inflammatory state further boosts the mortality due to cardiovascular events in patients with CKD undergoing dialysis. There is a general notion that Omega-3 fatty acids including docosahexaenoic acids (DHA) and eicosapentaenoic (EPA) have certain health benefits perhaps via the regulation of inflammation. However, the anti-inflammatory effect of omega-3 fatty acids in patients with CKD is controversial. We analyzed the data of oral supplementation of omega-3 fatty acids in CKD patients by searching literature on database from inception to August 2016. The analysis included randomized controlled trials (RCTs) derived from multiple databases, and the effect of omega-3 fatty acids supplementation versus the control cohorts were compared. All of the data analysis was calculated by RevMan 5.2. A total of 12 RCTs involving 487 patients were included in the meta-analysis. Among them 254 patients received omega-3 fatty acids and 233 patients served as controls who received placebo. The meta-analysis revealed no statistical significance in serum levels of C-reactive protein (CRP) (SMD, -0.20; 95% CI, -0.44 to 0.05; P = 0.11), IL-6 (SMD, 0.00; 95% CI, -0.33 to 0.33; P = 0.99) and TNF-α (SMD, 0.14; 95% CI, -0.17 to 0.44; P = 0.38) between the omega-3 fatty acids supplementation group and control. This suggested that there is insufficient evidence to conclude the benefit of omega-3 fatty acids oral supplementation in reducing serum levels of CRP, IL-6 and TNF-α in patients with CKD.

Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation

Nuclear factor erythroid-related factor 2 (Nrf2) has been implicated in several detoxifying and antioxidant defense processes. Nrf2-mediated heme oxygenase-1 (HO-1) expression was demonstrated to play a key role against oxidative stress. Gastrodin (GSTD) is a well-known active compound isolated from the roots of Rhizoma gastrodiae, a plant used in ancient Chinese traditional medicine. The aim of this work was to investigate whether GSTD could alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells (LSECs). In LSECs exposed to 1 mM H2O2, treatment with GSTD (1, 10, or 50 µM) resulted in higher cell viability than the untreated control. Treated cells maintained a higher Bcl2/Bax ratio and suppressed caspase-9 expression compared with untreated cells, reducing cell apoptosis. GSTD was protective for H2O2-induced oxidative injury by reducing the generation of intracellular reactive oxygen species and malondialdehyde. HO-1 and Nrf2 expressions were synergistically upregulated by GSTD. Inhibition of HO-1 by 10 µM zinc protoporphyrin resulted in less protective effects on cell viability and malondialdehyde reduction by GSTD treatment in H2O2-exposed LSECs. Additionally, phosphorylated p38 in LSECs exposed to H2O2 was elevated by GSTD. Inhibition of p38 phosphorylation by SB203580 did not induce Nrf2 and HO-1 expression after 1 or 10 µM GSTD treatment and the protective effect on cell viability and malondialdehyde reduction in H2O2-exposed LSECs was reduced. The data conclusively demonstrated that GSTD-induced HO-1 and Nrf2 expression is involved in protection of LSECs from H2O2-induced oxidative injury, which may be regulated by p38 phosphorylation.

Effects of far infrared therapy on arteriovenous fistulas in hemodialysis patients: a meta-analysis.

BACKGROUND: Far infrared (FIR) therapy may have a beneficial effect on maturity and function of arteriovenous fistulas (AVFs) in hemodialysis (HD) patients. Therefore, we performed this pooled analysis to assess the protective effects of FIR therapy in HD patients. METHODS: The randomized controlled trials (RCTs) and quasi-RCTs of FIR therapy for HD patients were searched from multiple databases. Relevant studies were screened according to the predefined inclusion criteria. The meta-analyses were performed using RevMan 5.2 software (The Cochrane Collaboration, Oxford, UK). RESULTS: Meta-analysis showed that FIR therapy could significantly increase the vascular access blood flow level (MD, 81.69 ml/min; 95% CI, 46.17-117.21; p < .001), AVFs diameter level (MD, 0.36 mm; 95% CI, 0.22-0.51; p < .001), and the primary AVFs patency (pooled risk ratio = 1.24; 95% CI, 1.12-1.37, p < .001). In addition, therapy with FIR ray radiation could decrease AVFs occlusion rates (pooled risk ratio = 0.20; 95% CI, 0.08-0.46; p < .001) and the level of needling pain (pooled risk ratio = 0.08; 95% CI, 0.06-0.10, p < .001). CONCLUSIONS: FIR therapy can reduce AVFs occlusion rates and needling pain level, while significantly improve the level of vascular access blood flow, AVFs diameter and the primary AVFs patency.

Use of Ophiocordyceps sinensis (syn. Cordyceps sinensis) combined with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) versus ACEI/ARB alone in the treatment of diabetic kidney disease: a meta-analysis.

Ophiocordyceps sinensis (O. sinensis; syn. Cordyceps sinensis) has been used in clinical therapy for diabetic kidney disease (DKD) for more than 15 years. O. sinensis is a household name in china and it is available even in supermarket. However, the precise role of O. sinensis has not been fully elucidated with meta-analysis. The aim of this study was to review existing evidence on the effectiveness of O. sinensis for the treatment of DKD. We identified 60 trials involving 4288 participants. Overall, O. sinensis combined with ACEI/ARB had a better effect when compared to ACEI/ARB alone on 24 h UP (MD = -0.23 g/d, 95% CI: - 0.28 to -0.19, p < 0.00001), UAER (MD = -19.71 µg/min, 95% CI: -22.76 to -16.66, p < 0.00001), MAU (MD = -45.09 mg/d, 95% CI: -55.68 to -34.50, p < 0.00001), BUN (MD = -0.70 mmol/L, 95% CI: -1.02 to -0.39, p < 0.0001), SCr (MD = -8.37 µmol/L, 95% CI: -12.41 to -4.32, p < 0.0001), CRP (MD = -1.32 mg/L; 95% CI: -1.78 to -0.86; p < 0.00001), TG (MD = -0.51 mmol/L; 95% CI: -0.69 to -0.34, p < 0.00001), TC (MD = -0.64 mmol/L; 95% CI: -0.91 to -0.37, p < 0.00001), and SBP (MD = -2.01 mmHg; 95% CI: -3.45 to -0.58, p = 0.006). However, no effects were found for DBP, FBG, and HbA1C. This meta-analysis suggested that use of O. sinensis combined with ACEI/ARB may have a more beneficial effect on the proteinuria, inflammatory, dyslipidemia status as compared to ACEI/ARB alone in DKD III-IV stage patients, while there is no evidence that O. sinensis could improve the hyperglycemia status. However, with regard to low-quality and significant heterogeneity of included trials, to further verify the current results from this meta-analysis, long-term and well-designed RCTs with high-quality study are warranted to ascertain the long-term efficacy of O. sinensis.

Preventive effect of pentoxifylline on contrast-induced acute kidney injury in hypercholesterolemic rats.

Oxidative stress is an important mechanism of contrast-induced acute kidney injury (CIAKI). The optimal strategy to prevent CIAKI remains unclear. The aim of the present study was to assess the effect of pentoxifylline, a nonspecific phosphodiesterase inhibitor, on the prevention of CIAKI. A total of 32 healthy male Sprague-Dawley rats were randomly divided into normal dietary group (NN; n=8) and a high cholesterol-supplemented dietary group (HN; 4% cholesterol and 1% cholic acid; n=24). At the end of eight weeks, the rats in the high cholesterol diet group were randomly divided into three subgroups (n=8 in each group). CIAKI was induced in two of the subgroups via intravenous injection of the radiocontrast media iohexol (10 ml/kg). Pentoxifylline (50 mg/kg) was administered to one of the iohexol-treated groups via intraperitoneal injection 12 h prior to and following contrast media (CM) injection. Kidney function parameters and oxidative stress markers were then measured. The renal pathological changes were evaluated using hematoxylin and eosin staining and scored semi-quantitatively. In iohexol-injected rats, serum creatinine (Scr), renal pathological scores, renal malondialdehyde (MDA) content, renal NADPH oxidase activity, fractional excretion of sodium (FENa%) and fractional excretion of potassium (FEK%) were significantly increased (P<0.01). The Scr, histologic scores, renal MDA content, NADPH oxidase activity, FENa% and FEK% in the rats treated with pentoxifylline prior to iohexol were observed to be reduced compared with those in rats treated with iohexol alone (P<0.01). This suggests that pentoxifylline significantly attenuates renal injuries, including tubular necrosis and proteinaceous casts induced by CM. It may be concluded that pentoxifylline protected the renal tissue from the nephrotoxicity induced by low-osmolar CM via an antioxidant effect.

Effect of L-carnitine therapy on patients in maintenance hemodialysis: a systematic review and meta-analysis.

BACKGROUND: L-Carnitine has been used as adjuvant therapy in hemodialysis (HD) patients for many years. However, there is controversy whether L-carnitine supplementation is beneficial. Therefore we performed a meta-analysis of randomized controlled trials (RCTs) to assess the effect of L-carnitine on HD patients. METHODS: RCTs of L-carnitine versus placebo for HD patients were searched from Medline, EMBASE and the Cochrane Central Register of Controlled Trials. We screened relevant studies according to predefined inclusion and exclusion criteria, and performed meta-analyses using Revman 5.1 software. RESULTS: Meta-analysis showed L-carnitine could not increase the total score of 36-item Short-Form Health Survey Questionnaire (SF-36) (SMD 0.76, 95 % CI -0.13 to 1.65, P = 0.09), and L-carnitine therapy did not improve serum C-reactive protein (SMD -0.37, 95 % CI -0.88 to 0.14, P = 0.16), oxidized low-density lipoprotein (SMD 0.04, 95 % CI -0.43 to 0.50, P = 0.87), albumin (SMD 0.25, 95 % CI -0.31 to 0.81, P = 0.38;), hemoglobin (SMD 0.23, 95 % CI -0.23 to 0.68, P = 0.33), cholesterol (SMD -0.24, 95 % CI -0.71 to 0.24, P = 0.33), triglycerides (SMD 0.02, 95 % CI -0.4 to 0.44, P = 0.91) or parathyroid hormone (SMD 0.21, 95 % CI -0.35 to 0.76, P = 0.46) levels. CONCLUSIONS: There is no evidence that L-carnitine can improve the inflammation, oxidative stress, nutrition, anemia, dyslipidemia, hyperparathyroidism status or quality of life in HD patients. However, given methodological limitations and lack of hard endpoints, high-quality, long-term randomized trials are required to fully elucidate the clinical value of L-carnitine administration in hemodialysis patients.

Is lead chelation therapy effective for chronic kidney disease? A meta-analysis.

The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure and the presence of chronic kidney injury. Some studies have suggested that chelation therapy with calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) might help decrease the progression of chronic kidney disease among patients with measurable body lead burdens. However, calcium disodium EDTA chelation in lead exposure is controversial due to the potential for adverse effects such as acute tubular necrosis. Therefore, we investigated the available randomized controlled trials assessing the renoprotective effects of calcium disodium EDTA chelation therapy. Our meta-analysis shows that calcium disodium EDTA chelation therapy can effectively delay the progression of chronic kidney disease in patients with measurable body lead burdens reflected by increasing the levels of estimated glomerular filtration rate (eGFR) and creatinine clearance rate (Ccr). There appears to be no conclusive evidence that calcium disodium EDTA can decrease proteinuria.

Mitochondria-targeted peptides prevent on contrast-induced acute kidney injury in the rats with hypercholesterolemia.

OBJECTIVE: The objective of this study is to evaluate the effect and mechanism of mitochondria-targeted peptides (MTP131 and SPI20) on contrast-induced acute kidney injury (CI-AKI) in rats with hypercholesterolemia. METHOD: Forty SD rats were randomly divided into normal diet group (NN, n = 8) and high cholesterol supplemented dietary group (HN, n = 32). At the end of 8 weeks, the group HN was divided into four subgroups. All Rats were given injection of either diatrizoate (10 mL/kg) or equal volume of normal saline, the rats pretreated with MTP131 or SPI20 were given injection with MTP131 or SPI 20 (3 mg/kg) by peritoneal cavity for 3 times. Blood, urine and renal tissue samples were prepared to determine biochemical parameters. The renal pathological changes were evaluated by hematoxylin and eosin staining and scored semiquantitatively, The protein expression of renal NOX4 was also measured by Western blotting. RESULTS: In diatrizoate-injected rats, Serum creatinine (Scr), fractional excretion of sodium (FeNa%), fractional excretion of potassium (FeK%), pathological scores, renal malondialdehyde (MDA) content, the NADPH oxidase activity and the expression of NOX4 in kidney tissue were significantly increased (p < 0.01). In the groups pretreated with MTP131 or SPI20, the levels of Scr, FeNa%, FeK%, MDA content and NADPH oxidase activity in renal tissue decreased (p < 0.01), the levels of renal super oxygen dehydrogenises and ATPase activity increased (p < 0.01). The renal injuries induced by contrast media (CM) were alleviated. CONCLUSION: MTP131 and SPI20 might protect acute kidney injury induced by CM in rats with hypercholesterolemia.