Meta-Analysis of Clinical Efficacy and Safety of Tripterygium wilfordii Polyglycosides Tablets in the Treatment of Chronic Kidney Disease.

OBJECTIVE: Tripterygium wilfordii polyglycosides tablet (TGt) is an oral preparation extracted from plant Tripterygium wilfordii. It has the effects of anti-inflammation and inhibition of cellular and humoral immunity. However, many reports of adverse reactions caused by TGt have limited its application. In this paper, the clinical efficacy and safety of TGt in the treatment of chronic kidney disease (CKD) were verified by data mining and analysis, so as to provide theoretical data support for the application and development of TGt. METHODS: A computer search of the following databases was conducted: PubMed, Web of Science, CBM, VIP, Wanfang Data, and CNKI. The search time limit is from the establishment of the database to September 2020. We searched for clinical randomized controlled trials of TGt in the treatment of CKD. The main types of CKD involved are nephrotic syndrome (NS), primary nephrotic syndrome (PNS), refractory nephrotic syndrome (RNS), and IgA nephropathy (IgAN). RevMan 5.2 and Stata 12.0 software were used to evaluate the literature quality and analyze the data. Finally, GRADEpro software was used to evaluate the quality of evidence. RESULTS: According to the inclusion and exclusion criteria, 75 articles with a total of 6418 subjects were included. The results of the meta-analysis showed that TGt could reduce 24-hour urinary protein, increase serum albumin, improve clinical efficacy, and reduce disease recurrence rate in patients (P < 0.05) with CKD compared with adrenocortical hormones or immunosuppressants. TGt could significantly reduce the level of serum creatinine (Scr) in patients with CKD (P < 0.05), but it was not significant in reducing the level of blood urea nitrogen (P > 0.05). In terms of safety evaluation, in patients with CKD, it could significantly reduce the incidence of gastrointestinal adverse reactions and neurogenic dizziness and headache (P < 0.05). However, in terms of adverse reactions such as liver injury, respiratory infection, and leukopenia, TGt was as harmful as corticosteroids or immunosuppressants (P < 0.05). The quality of the evidence was evaluated with GRADEpro software, and the results showed that TGt was strongly recommended for the treatment of CKD. CONCLUSION: TGt has certain efficacy in the treatment of CKD and has fewer side effects in certain types of diseases. The effect of TGt combined with other drugs is better than that of single use. This paper also has some limitations. Due to the limited number of the included studies, with all being from China, there may be methodological differences. Therefore, more high-quality literature data from different countries are needed.

Meta-Analysis of Randomized Controlled Trials of Xueshuantong Injection in Prevention of Deep Venous Thrombosis of Lower Extremity after Orthopedic Surgery.

OBJECTIVE: To systematically evaluate the clinical efficacy of Xueshuantong injection (Panax notoginseng saponins) in preventing deep venous thrombosis (DVT) of lower extremity after orthopedic surgery. METHODS: The randomized controlled trials (RCTs) of Xueshuantong injection in prevention of lower extremity DVT after orthopedic surgery were retrieved from CNKI, Wanfang database, VIP, PubMed, and Cochrane Library by August 2020. Revman5.2 was used to analyze the results. RESULTS: A total of 20 articles including 2336 patients were included. The results of meta-analysis showed that the incidence of DVT in the experimental group was lower than that in the control group; after operation, the D-dimer (Ddimer), thrombin time (APTT), and prothrombin time (PT) in the experimental group were significantly improved compared with those in the control group, and the difference between the two groups was statistically significant. CONCLUSION: Xueshuantong injection can effectively prevent the formation of lower extremity DVT after orthopedic surgery and antagonize the postoperative hypercoagulable state of blood, which has high clinical value.

Meta-Analysis of the Therapeutic Effect of Shenqi Jiangtang Granule on Type 2 Diabetes Mellitus.

OBJECTIVE: To systematically evaluate the effectiveness of Shenqi Jiangtang granule (SQJT) in the treatment of type 2 diabetes. METHODS: We searched CNKI, Wanfang Data, VIP, and PubMed databases to collect randomized controlled trials (RCT) of Shenqi Jiangtang granules in the treatment of type 2 diabetes. The search time was from January 2014 to the present. Data were extracted, and quality was evaluated. Metadata analysis of the extracted data was carried out using RevMa5.2 software. The final results are expressed in relative risk (RR), mean difference (MD), and 95% CI. RESULTS: This study included a total of 13 studies, 1160 subjects. Meta-analysis results showed that the test group was better than the control group (RR = 1.26, 95% CI 1.18-1.34, P < 0.00001). The fasting blood glucose, postprandial blood glucose, and glycated hemoglobin of the test group were also significantly better than those of the control group. CONCLUSION: Shenqi Jiangtang granules have a certain clinical effect and low adverse reaction rate for the treatment or adjuvant treatment of type 2 diabetes. At present, the drug has been widely used in clinical practice, but a large number of large-sample clinical trials are needed to further verify its specific efficacy and safety.

Effects and Mechanism of Combination of Rhein and Danshensu in the Treatment of Chronic Kidney Disease.

Traditional Chinese medicine (TCM) plays a systemic role in disease treatment, targeting multiple etiological factors simultaneously. Based on clinical experience, rhubarb and Salvia miltiorrhiza are commonly prescribed together for the treatment of chronic kidney disease (CKD) and have been proven to be very effective. However, the rationale of the combination remains unclear. The major active ingredients of these two herbs are rhein (RH) and danshensu (DSS), respectively. The aim of this paper is to investigate the renoprotective effects of RH and DSS in vitro and in vivo, and the underlying mechanism. A total of 5/6 nephrectomy rats and HK-2 cells were subjected to chronic renal injury. The combination of RH and DSS conferred a protective effect, as shown by a significant improvement in the renal function, blood supply, and fibrotic degree. Proinflammatory cytokines and adhesion molecules were suppressed by RH and DSS through NK-κB signaling. The combination also inhibited apoptosis by up-regulating Bcl-2 and down-regulating Bax. Inhibiting the TGF-ß/Smad3 pathway was at least in part involved in the antifibrotic mechanism of the combination treatment of RH and DSS. This study demonstrates for the first time the renoprotective effect and the mechanism of RH and DSS combination on chronic renal injury. It could provide experimental evidence to support the rationality of the combinatorial use of TCM in clinical practices.

Insulinotropic effect of Chikusetsu saponin IVa in diabetic rats and pancreatic ß-cells.

ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has traditionally been used as the medicine considered alleviating several disorders including diabetes mellitus (DM). Chikusetsu saponin IVa (CHS) has been defined as a major active ingredient of triterpenoid saponins extracted from Aralia taibaiensis. The scientific evidence of anti-diabetic effect for CHS remains unknown and the purpose of our study was to study its hypoglycemic and insulin secretagogue activities. MATERIALS AND METHODS: In vivo studies were performed on type 2 diabetic mellitus (T2DM) rats given CHS for 28 days to test the antihyperglycemic activity. The in vitro effects and possible mechanisms of CHS on the insulin secretion in pancreatic ß-cell line ßTC3 were determined. RESULTS: Oral administration of CHS dose-dependently increased the level of serum insulin and decreased the rise in blood glucose level in an in vivo treatment. In vitro, CHS potently stimulated the release of insulin from ßTC3 cells at both basal and stimulatory glucose concentrations, the effect which was changed by the removal of extracellular Ca(2+). Two methods showed that CHS enhanced the intracellular calcium levels in ßTC3 cells. CHS was capable of enhancing the phosphorylation of extracellular signal-regulated protein kinases C (PKC), which could be reversed by a PKC inhibitor (RO320432), and the insulin secretion induced by CHS was also inhibited by RO320432. Further study also showed that the insulinotropic effect, intracellular calcium levels and the phosphorylation of PKC were reduced by inhibiting G protein-coupled receptor 40 (GPR40) by a GPR40 inhibitor (DC126026). CONCLUSION: These observations suggest that the signaling of CHS-induced insulin secretion from ßTC3 cells via GPR40 mediated calcium and PKC pathways and thus CHS might be developed into a new potential for therapeutic agent used in T2DM patients.

Saponins from Aralia taibaiensis attenuate D-galactose-induced aging in rats by activating FOXO3a and Nrf2 pathways.

Reactive oxygen species (ROS) are closely related to the aging process. In our previous studies, we found that the saponins from Aralia taibaiensis have potent antioxidant activity, suggesting the potential protective activity on the aging. However, the protective effect of the saponins and the possible underlying molecular mechanism remain unknown. In the present study, we employed a D-galactose-induced aging rat model to investigate the protective effect of the saponins. We found that D-galactose treatment induced obvious aging-related changes such as the decreased thymus and spleen coefficients, the increased advanced glycation end products (AGEs) level, senescence-associated ß-galactosidase (SAß-gal) activity, and malondialdehyde (MDA) level. Further results showed that Forkhead box O3a (FOXO3a), nuclear factor-erythroid 2-related factor 2 (Nrf2), and their targeted antioxidants such as superoxide dismutase 2 (SOD2), catalase (CAT), glutathione reductase (GR), glutathione (GSH), glutamate-cysteine ligase (GCL), and heme oxygenase 1 (HO-1) were all inhibited in the aging rats induced by D-galactose treatment. Saponins supplementation showed effective protection on these changes. These results demonstrate that saponins from Aralia taibaiensis attenuate the D-galactose-induced rat aging. By activating FOXO3a and Nrf2 pathways, saponins increase their downstream multiple antioxidants expression and function, at least in part contributing to the protection on the D-galactose-induced aging in rats.

Antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis in experimental type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has multiple pharmacological activities, including relieving rheumatism, promoting blood circulation to arrest pain, inducing diuresis to reduce edema, and antidiabetic action. It has long been used as a folk medicine for the treatment of traumatic injury, rheumatic arthralgia, nephritis, edema, hepatitis and diabetes mellitus in China. AIM OF STUDY: To evaluate the antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis (SAT) in experimental type 2 diabetic mellitus (T2DM) rats. MATERIALS AND METHODS: Acute toxicity was studied in rats to determine the safe oral dose of SAT. Then, SAT was given orally to normal and streptozotocin-nicotinamide induced T2DM rats at 80, 160 and 320 mg/kg doses for a series of 28 days to determine the antihyperglycemic activity. Glibenclamide (600 µg/kg), a standard antidiabetic drug, was used as a positive control drug. At the end of treatment, biochemical parameters and antioxidant levels were measured to evaluate the hypolipidemic and antioxidant activities of SAT. RESULTS: Oral administration of SAT did not exhibit toxicity and death at a dose not more than 2000 mg/kg. SAT dose-dependently improved the symptoms of polydipsia, polyuria, polyphagia and weight loss in diabetic rats. Compared with diabetic control group, administration of 320 mg/kg SAT resulted in significant (P<0.05) fall in the levels of fasting blood glucose, glycosylated hemoglobin, creatinine, urea, alanine transarninase, aspartate aminotransferase, total cholesterol, triglycerides, low density lipoprotein cholesterol and malondialdehyde, but significant (P<0.05) increase in the levels of serum insulin, superoxide dismutase and reduced glutathione. However, SAT did not have any effect on the normal rats. CONCLUSIONS: SAT had excellent antihyperglycemic, hypolipidemic and antioxidant activities in T2DM rats and might be a promising drug in the therapy of diabetes mellitus and its complications.

NADPH oxidase-mitochondria axis-derived ROS mediate arsenite-induced HIF-1α stabilization by inhibiting prolyl hydroxylases activity.

Arsenic exposure has been shown to induce hypoxia inducible factor 1α (HIF-1α) accumulation, however the underlying mechanism remains unknown. In the present study, we tested the hypothesis that arsenic exposure triggered the interaction between NADPH oxidase and mitochondria to promote reactive oxygen species (ROS) production, which inactivate prolyl hydroxylases (PHDs) activity, leading to the stabilization of HIF-1α protein. Exposure of human immortalized liver cell line HL-7702 cells to arsenite induced HIF-1α accumulation in a dose-dependent manner, which was abolished by SOD mimetic MnTMPyP. Inhibition of NADPH oxidase with diphenyleneiodonium chloride (DPI) or inhibition of mitochondrial respiratory chain with rotenone significantly blocked arsenite-induced ROS production, and the mitochondria appeared to be the major source of ROS production. Arsenite treatment inhibited HIF-1α hydroxylation by prolyl hydroxylases (PHDs) and increased HIF-1α stabilization, but did not affect HIF-1α mRNA expression and Akt activation. Supplementation of ascorbate or Fe(II) completely abolished arsenite-induced PHDs inhibition and HIF-1α stabilization. In conclusion, these results define a unique mechanism of HIF-1α accumulation following arsenic exposure, that is, arsenic activates NADPH oxidase-mitochondria axis to produce ROS, which deplete intracellular ascorbate and Fe(II) to inactivate PHDs, leading to HIF-1α stabilization.

Dissection of mechanisms of a chinese medicinal formula: danhong injection therapy for myocardial ischemia/reperfusion injury in vivo and in vitro.

Traditional Chinese medicine uses a systemic treatment approach, targeting multiple etiological factors simultaneously. Danhong injection (DHI), a very popular Chinese medicine injection, is reported to be effective for many cardiovascular conditions. The primary active ingredients of DHI, and their systemic and interrelated mechanism have not been evaluated in an established myocardial ischemia/reperfusion (MI/R) model. We identified the main active constituents in DHI, including hydroxysafflor yellow A (A), salvianolic acid B (B), and danshensu (C), by HPLC fingerprint analysis and assessed their effect on MI/R rats and cardiomyocytes. These 3 compounds and DHI all decreased the levels of IL-1, TNF- α , and MDA, increased those of IL-10 and SOD activity in vivo and in vitro, and had antiapoptotic effects, as shown by flow cytometric analysis and TUNEL assay. Moreover, these compounds increased phosphorylation of Akt and ERK1/2 in cardiomyocytes. Interestingly, we found compound A exerted a more prominent anti-inflammatory effect than B and C, by decreasing NF- κ B levels; compound B had more powerful antioxidative capacity than A and C, by increasing Nrf2 expression; compound C had stronger antiapoptotic ability than A and B, by lowering caspase-3 activity. Our results elucidate the mechanisms by which DHI protects against MI/R induced injury.

Triterpenoid saponins with anti-myocardial ischemia activity from the whole plants of Clematis tangutica.

Four new triterpenoid saponins named clematangosides A-D (1-4) along with six known saponins (5-10) were isolated from the whole plants of Clematis tangutica. Their structures were determined by extensive spectral analysis and chemical evidences. All saponins were evaluated for their protective effects in hypoxia-induced myocardial injury model. Compounds 2-4, 6, and 10 exhibited anti-myocardial ischemia activities with ED50 values in the range of 75.77-127.22 µM.

Safflor yellow A protects neonatal rat cardiomyocytes against anoxia/reoxygenation injury in vitro.

AIM: To investigate the effects of safflor yellow A (SYA), a flavonoid extracted from Carthamus tinctorius L, on cultured rat cardiomyocytes exposed to anoxia/reoxygenation (A/R). METHODS: Primary cultured neonatal rat cardiomyocytes were exposed to anoxia for 3 h followed by reoxygenation for 6 h. The cell viability was measured using MTT assay. The releases of lactate dehydrogenase (LDH) and creatine kinase (CK), level of malondialdehyde (MDA), and activities of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were analyzed. Hoechst 33258 staining and changes in Bcl-2/Bax ratio and caspase 3 activity were used to examine A/R-induced apoptosis. RESULTS: The A/R exposure markedly decreased the viability of cardiomyocytes, suppressed the activities of SOD, GSH, CAT and GSH-Px, and Bcl-2 protein expression. Meanwhile, the A/R exposure markedly increased the release of LDH and CK, and MDA production in the cardiomyocytes, and increased the rate of apoptosis, caspase 3 activity, Bax protein expression. Pretreatment with SYA (40, 60 and 80 nmol/L) concentration-dependently blocked the A/R-induced changes in the cardiomyocytes. Pretreatment of the cardiomyocytes with the antioxidant N-acetylcysteine (NAC, 200 µmol/L) produced protective effects that were comparable to those caused by SYA (80 nmol/L). CONCLUSION: SYA protects cultured rat cardiomyocytes against A/R injury, maybe via inhibiting cellular oxidative stress and apoptosis.

Ethyl pyruvate protects rats from phosgene-induced pulmonary edema by inhibiting cyclooxygenase2 and inducible nitric oxide synthase expression.

Phosgene is a poorly water-soluble gas penetrating the lower respiratory tract which can induce acute lung injury characterized by a latent phase of fatal pulmonary edema. Pulmonary edema caused by phosgene is believed to be a consequence of oxidative stress and inflammatory responses. Ethyl pyruvate (EP) has been demonstrated to have anti-inflammatory and anti-oxidative properties in vivo and in vitro. The potential therapeutic role of EP in phosgene-induced pulmonary edema has not been addressed so far. In the present study, we aim to investigate the protective effects of EP on phosgene-induced pulmonary edema and the underlying mechanisms. Rats were administered with EP (40 mg kg(-1)) and RAW264.7 cells were also incubated with it (0, 2, 5 or 10 µm) immediately after phosgene (400 ppm, 1 min) or air exposure. Wet-to-dry lung weight ratio (W:D ratio), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, cyclooxygenase2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and mitogen-activated protein kinases activities (MAPKs) were measured. Our results showed that EP treatment attenuated phosgene-induced pulmonary edema and decreased the level of NO and PGE(2) dose-dependently. Furthermore, EP significantly reduced COX-2 expression, iNOS expression and MAPK activation induced by phosgene. Moreover, specific inhibitors of MAPKs reduced COX-2 and iNOS expression induced by phosgene. These findings suggested that EP has a protective role against phosgene-induced pulmonary edema, which is mediated in part by inhibiting MAPK activation and subsequently down-regulating COX-2 and iNOS expression as well as decreasing the production of NO and PGE(2).

Insulin-secretagogue activity of eleven plant extracts and twelve pure compounds isolated from Aralia taibaiensis.

AIMS: To investigate the insulinogenic activities of the eleven saponins enriched traditional Chinese medicine (TCM) extracts. MAIN METHODS: Radioimmunoassay and trypan blue exclusion assay were used to investigate the insulinogenic activity and cytotoxic effects respectively. KEY FINDINGS: The total saponin extract of Aralia taibaiensis (sAT) exhibited highest insulinogenic activity and no cytotoxicity was recorded. Twelve pure compounds from sAT stimulated insulin secretion from a mouse insulinoma ßTC3 cells in a concentration-dependent manner. TA35 outperformed the other compounds which suggested that the active insulinogenic ingredient of sAT was probably TA35. In addition, both sAT and TA35 markedly potentiated glucose-induced insulin secretion. SIGNIFICANCE: Our study is the first to show that sAT dramatically stimulated insulin secretion and its antidiabetic activity may be related to its high saponin content. These findings suggested that sAT and the compound TA35 isolated from sAT may provide novel therapeutic tools for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

Study on the characteristics of pectin-ketoprofen for colon targeting in rats.

Pectin-ketoprofen (PT-KP) prodrug with the potential for colon targeted delivery has been evaluated. A sensitive HPLC method was established for the determination of concentration of ketoprofen (KP) in rats. This method was also used to evaluate the colon targeting property of PT-KP. KP or PT-KP was given to rats by oral administration at a dosage of 10mg/kg. Plasma and the different parts of gastrointestinal (GI) tract were taken after 2, 4, 6, 8, 10 and 12h of oral administration of KP or PT-KP to rats and the concentration of KP was measured by HPLC. Preliminary experiments show KP distributes mainly in stomach, proximal small intestine and distal small intestine. However, KP released from PT-KP mainly distributes in cecum and colon. Therefore, this approach suggests that PT-KP prodrug has a good colon targeting property.