JinLiDa granules alleviates cardiac hypertrophy and inflammation in diabetic cardiomyopathy by regulating TP53.

BACKGROUND: JinLiDa granules (JLD) is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus with Qi and Yin deficiency. Clinical evidence has shown that JLD can alleviate diabetic cardiomyopathy, but the exact mechanism is not yet clear. PURPOSE: The purpose of this study was to examine the potential role and mechanism of JLD in the treatment of diabetic cardiomyopathy through network pharmacological analysis and basic experiments. METHODS: The targets of JLD associated with diabetic cardiomyopathy were examined by network pharmacology. Protein interaction analysis was performed on the targets, and the associated pathways were searched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Diabetic mice were treated with low or high doses of JLD by gavage, and AC16 and H9C2 cardiomyocytes exposed to high-glucose conditions were treated with JLD. The analysis results were verified by various experimental techniques to examine molecular mechanisms. RESULTS: Network pharmacological analysis revealed that JLD acted on the tumor suppressor p53 (TP53) during inflammation and fibrosis associated with diabetic cardiomyopathy. The results of basic experiments showed that after JLD treatment, ventricular wall thickening in diabetic mouse hearts was attenuated, cardiac hypertrophy and myocardial inflammation were alleviated, and the expression of cardiac hypertrophy- and inflammation-related factors in cardiomyocytes exposed to a high-glucose environment was decreased. Cardiomyocyte morphology also improved after JLD treatment. TP53 expression and the tumor necrosis factor (TNF) and transforming growth factor beta-1 (TGFß1) signaling pathways were significantly altered, and inhibiting TP53 expression effectively alleviated the activation of the TNF and TGFß1 signaling pathways under high glucose conditions. Overexpression of TP53 activated these signaling pathways. CONCLUSIONS: JLD acted on TP53 to regulate the TNF and TGFß1 signaling pathways, effectively alleviating cardiomyocyte hypertrophy and inflammation in high glucose and diabetic conditions. Our study provides a solid foundation for the future treatment of diabetic cardiomyopathy with JLD.

Effect of Jinlida Granules on Visceral Fat Accumulation in Prediabetic Rats / 中国实验方剂学杂志

ObjectiveTo study the effect of Jinlida granules on visceral fat accumulation and its induced inflammatory response in prediabetic rats. MethodMale SD rats were randomly divided into normal group， model group， Jinlida low-dose group （1.5 g·kg-1）， Jinlida high-dose group （3.0 g·kg-1） and atorvastatin group （10 mg·kg-1）. Prediabetic rat model was established using high-carbohydrate， high-fat diet combined with low-dose streptozotocin （STZ） by multiple small-dose intraperitoneal injections. After 8 weeks of modeling and drug intervention for 13 consecutive weeks， body weight， oral glucose tolerance test（OGTT）， fasting blood glucose （FBG）， fasting insulin （FINS）， insulin resistance index （HOMA-IR）， total cholesterol （TC）， low-density lipoprotein cholesterol （LDL-C） and high-density lipoprotein cholesterol （HDL-C） were measured in each group of rats. The content of visceral fat was quantified by micro-computed tomography （Micro-CT）. Hematoxylin-eosin staining （HE） was used to observe the pathological changes of fat cells. The levels of tumor necrosis factor-α （TNF-α） and interleukin- 6 （IL-6） in rat visceral fat and serum were determined by enzyme linked immunosorbent assay （ELISA）. The expression of macrophage marker CD68 in visceral fat was detected by immunofluorescence and Western blot. ResultCompared with normal group， model group had increased oral glucose tolerance， FBG， FINS， HOMA-IR， TC， LDL-C （P<0.01）， elevated body weight and visceral fat accumulation （P<0.05， P<0.01）， enhanced CD68 protein expression and TNF-α and IL-6 levels （P<0.01）， decreased HDL-C （P<0.01）， and abnormal hypertrophy of adipocytes. Compared with model group， Jinlida high- and low-dose groups lowered oral glucose tolerance， HOMA-IR， TC and LDL-C （P<0.05， P<0.01）， body weight and visceral fat accumulation （P<0.05）， and CD68 protein expression and TNF-α and IL-6 levels （P<0.05， P<0.01） and lessened hypertrophy of fat cells. ConclusionJinlida can improve the insulin resistance in prediabetic rats by reducing visceral fat accumulation and its induced inflammatory response， which provides a new pharmacological basis for clinical treatment of prediabetes by Jinlida granules.

Corrigendum: Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Jinlida Granules on Metabolic Syndrome in Patients With Abnormal Glucose Metabolism.

[This corrects the article DOI: 10.3389/fendo.2020.00415.].

Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Jinlida Granules on Metabolic Syndrome in Patients With Abnormal Glucose Metabolism.

Background: Metabolic syndrome (MS) is a powerful risk factor for cardiovascular and cerebrovascular diseases. Although lifestyle intervention reduces several of the symptoms of the syndrome and cardiovascular risks, the lifestyle intervention that yields the benefits is restrictive. Jinlida is a Chinese patent medicine that has shown activity in type 2 diabetes, which has been approved in China. Preclinical studies in Jinlida granules support an improved role of abnormal glucose and lipids metabolism as well as reducing weight. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for metabolic syndrome in patients with abnormal glucose metabolism. Methods: This study will enroll 880 subjects (aged 18-70 years) who have metabolic syndromes with abnormal glucose metabolism. All the participants in a double-blind, parallel, randomized, placebo-controlled trial, will receive Jinlida or placebo, orally, 9 g/time, three times daily for 2-4 years period on the basis of lifestyle intervention. The primary outcome measure (Incidence of type 2 diabetes) will be assessed during intervention cycles. Adverse events were monitored. All statistical tests will be performed using a two-sided test, and a p ≤ 0.05 (two-sided test) will be considered to be statistically significant results. Discussion: Results from this study will provide evidence on whether incorporating oral Jinlida granules treatment into lifestyle intervention can delay or inhibit the development of diabetes mellitus in metabolic syndrome subjects with abnormal glucose metabolism. Clinical trial registration: Registered at http://www.chictr.org.cn/enIndex.aspx. Trial registration number: ChiCTR1900023241.

Chinese medicine Jinlida granules improve high-fat-diet induced metabolic disorders via activation of brown adipose tissue in mice.

AIMS: Activation of brown adipose tissue (BAT) thermogenesis could contribute to energy expenditure, which is critical for the treatment of obesity and type 2 diabetes mellitus (T2DM). In the present study, we aimed to systematically investigate whether traditional Chinese medication Jinlida (JLD) granules could improve metabolic disorders and activate BAT thermogenesis in C57BL/6 J mice fed with a high-fat diet (HFD). METHODS: In the present study, JLD (3.8 g/kg) in 0.5% of carboxymethyl cellulose (CMC) solution was administrated daily by oral gavage to HFD-induced mice for 15 weeks. The body weight, biochemical analysis, histology analysis, intraperitoneal glucose and insulin tolerance (OGTT and ITT) tests were measured to explore metabolic disorders. Cold tolerance test, real-time PCR (qRT-PCR), immunohistochemistry, and western blot were performed to evaluate BAT function. RESULTS: As results, JLD treatment significantly ameliorated HFD-induced obesity and fat mass gain, maintained glucose and lipid homeostasis, and improved hepatic steatosis and inflammation. More importantly, we observed that JLD markedly activated BAT thermogenesis in HFD-induced obese mice. Moreover, our data confirmed that JLD promoted mitochondrial biogenesis and fatty acid oxidation metabolism in BAT. CONCLUSIONS: These data suggested that JLD could improve metabolic disorders in associated with activation of BAT thermogenesis via enhancement of mitochondrial biogenesis and fatty acid oxidation metabolism, thus providing a new pharmacological evidence for the clinical usage of JLD in T2DM treatment.

Effectiveness of traditional Chinese medicine Jinlida granules as an add-on therapy for type 2 diabetes: A system review and meta-analysis of randomized controlled trials.

BACKGROUND: Jinlida granules are a commonly prescribed oral medication in China used in combination with antidiabetic drugs to lower blood glucose. The aim of this study was to systematically identify and pool the findings of randomized controlled trials evaluating the effectiveness and safety of Jinlida granules as add-on therapy for glycemic control in type 2 diabetes (T2D). METHODS: The China National Knowledge Infrastructure (CNKI), Wang Fang, PubMed, China biology medicine (CBM), and VIP Database for Chinese Technical Periodicals (VIP) databases were searched for papers regarding the effects of Jinlida granules in T2D published before 1 July 2018. A pooled analysis of extracted data was performed using random-effects models. RESULTS: In all, data were retrieved for 15 studies including 1810 individuals. Decreases in HbA1c were greater in groups receiving Jinlida granules as add-on therapy compared with control groups (n = 1820; mean difference - 0.66; 95% confidence interval - 0.72, -0.60; P < 0.00001; I2 = 38%). In addition, Jinlida granules reduced body mass index and had beneficial effects on homeostatic model assessment of ß-cell function and homeostasis model assessment of insulin resistance. No obvious adverse events were reported. CONCLUSIONS: Findings from this meta-analysis demonstrate additional benefits of Jinlida granules as an add-on therapy for T2D and that Jinlida granules are generally safe. Treatment with Jinlida granules provided clinically and statistically significant reductions in fasting plasma glucose, 2-hour post-load glucose, and HbA1c levels in patients with T2D. However, the findings should be interpreted with caution due to the small sample size and study limitations.

Regulatory Effects of Jinlida Granules on Blood Glucose and Related Factors in Mice with Sugar Stress / 中国医科大学学报

Objective To investigate the effect of Jinlida granules on blood glucose level, physiological index, and the nuclear factor-kappa B (NF-κB) pathway in mice. Methods Mice were randomly divided into a positive control group (acarbose group), an experimental group (Jinlida granule group), and a blank control group. The effects of Jinlida granules on blood glucose levels and weights of the mice were measured after single and multiple ingestion of sucrose or starch. The levels of superoxide dismutase and malondialdehyde were measured in mice via enzyme-linked immunosorbent assay. Changes in serum lipids and other indicators were detected using an automatic biochemical analyzer in order to determine the regulatory effect of Jinlida granules on blood lipid levels and liver and kidney damage. Changes in NF-κB, interleukin (IL) -1β, and IL-6 levels were detected via Western blotting. Results Jinlida granules downregulated postprandial blood glucose levels without reducing body weight in mice. Jinlida granules also reduced serum triglyceride concentration without causing damage to the liver or kidneys in mice, showed protective effects on muscle cells, and may reduce activation of the NF-κB pathway. Conclusion Jinlida granules may contribute to ameliorating diabetes.

Curative Efficacy of Metformin Combined with Jinlida Granules in Treatment of Gestational Diabetes Mellitus and Its Effects on Serum VEGF, APN and Hcy Levels / 现代生物医学进展

Objective:To study the curative efficacy of metformin combined with Jinlida granules in the treatment of gestational diabetes mellitus and its effects on the serum vascular endothelial growth factor (VEGF),adiponectin (APN) and homocysteine(Hcy) levels.Methods:94 patients of gestational diabetes mellitus who were treated from July 2014 to July 2016 in our hospital were selected.According to random number table,those patients were divided into the observation group (n=47) and the control group (n=47).On the basis of routine treatment,such as control diet,reasonable exercise and healthy diet,etc,the control group was treated with metformin,while the observation group was combined with Jinlida granules on the basis of the control group.The changes of blood glucose,blood lipid and serum VEGF,APN and Hcy before and after treatment were compared between the two groups,the incidence of maternal complications and neonatal adverse outcomes were compared.Results:Compared with before treatment,the blood glucose,blood lipid of both groups after treatment were significantly improved (P ＜0.05),the fasting plasma glucose (FBG),postprandial 2h blood glucose (2hPG),glycosylated hemoglobin (HbAlc),total cholesterol (TC),triacylglycerol (TG),low density lipoprotein cholesterol(LDL-C) of observation group were significantly lower than those of the control group,the serum high density lipoprotein cholesterol (HDL-C) level was significantly higher than that of the control group(P＜0.05);after treatment,the serum VEGF,APN and Hcy levels were significantly improved than those before treatment in both groups (P＜0.05),and the serum VEGF,and Hcy levels of observation group were lower than those of the control group,the serum APN level was higher than that of the control group (P ＜ 0.05);the incidence of gestational hypertension,hydramnios,cesarean section and premature delivery of observation group was significantly lower than that of the control group (P ＜0.05);the incidence of giant child,neonatal Jaundice and neonatal respiratory distress in the observation group was significantly lower than that of the control group (P＜0.05).Conclusion:Metformin combined with Jinlida granules was effective for the gestational diabetes mellitus,which could effectively control the blood glucose,blood lipid levels and might be related to the regulation of serum VEGF,APN and Hey levels.

The protective effect of Jinlida granules on kidney of type 1 diabetic rats / 第二军医大学学报

Objective To explore the protective effect of Jinlida granuleson kidney tissues of type 1 diabetic rats, and to elucidate the related mechanism. Methods SD rats were intraperitoneally injected with streptozotocin (STZ, 60 mg/kg) to establish type 1 diabetic models. Then the model rats were randomly divided into diabetic model group, low-, medium- and high-dose Jinlida groups (0. 75, 1. 5 and 3. 0 g/kg Jinlida granules, respectively), Jinlida + Tongxinluo (TXL) group (1. 5 g/kg Jinlida granules+ 0. 4 g/kg TXL), metformin group (50 mg/kg metformin), and saxagliptin group (1 mg/kg saxagliptin), with each group containing 5 rats. Five healthy rats served as normal controls. Eight weeks after administration of drugs or placebo, the levels of growth hormone (GH), growth hormone receptor (GHR), insulin-like growth factor 1 (IGF-1), insulin-like growth factor 1 receptor (IGF-1R), and insulin-like growth factor lbinding protein 1 (IGFBP-1) mRNA were detected by real-time quantitative PCR, the expressions of MAPK pathway related proteins and fibronectin (FN) were determined by Western blotting; and H-E staining, Masson staining and PAS staining were used to observe the morphological changes of kidney tissues. Results Compared with the normal control group, the levels of GH, GHR, IGF-1, IGF-1R mRNA and the protein expressions of p-ERK, p-JNK, and FN of kidney tissues were significantly increased (P<0. 01), with cellular proliferation and fibrous deposition seen in the kidney tissues in the diabetic model group. After intervention with midde and high-dose Jinhda granules, the levels of GH, GHR, IGF-1, and IGF-1R mRNA and ratios of p-ERK/ERK, p-JNK/JNK, and FN protein expression were significantly decreased (P<0. 05, P<0. 01), with alleviated kidney tissues fibrosis. Conclusion Jinlida granules can protett kidney tissues of type 1 diabetic rats, which is probably through up-regulating the levels of GH and IGF-l mRNA and inhibiting the activation of the MAPK pathway.

Effects of jinlida granules on renin-angiotensin system in kidney and cardiovascular tissues of diabetic rats / 第二军医大学学报

Objective To evaluate the effects of Jinlida granules on the renin-angiotensin system (RAS) in the kidney, heart and abdominal aorta of experimental diabetic rats, so as to explore the possible mechanism by which Jinlida granules protect the kidney and cardiovascular system. Methods The rats were randomized into 2 groups: normal contronl group (CON group, n=10) and diabetic model group Cn = 20). Rats in the control group were fed with regular chow; those in the diabetic model group were fed with high-fat diet for 4 weeks, and then were administered with streptozotocin (STZ; 30 mg/kg) by intraperitoneal injection to induce diabetic model. Successful diabetic models were further randomized into two groups with 10 in each; Jinlida granules treatment group (DM + JLG group) and non-treatment group (DM group). Rats in DM + JLG group were given Jinlida granules orally (3 g/kg per day) for 8 weeks. Angiotensin I (Ang I) and angiotensin P (Ang II) were measured by enzyme-linked immunosorbent assay (ELISA) in the homogenates of the kidney, heart and abdominal aortas the protein expression of angiotensin II type 1 receptor (ATR) and angiotensin II type 2 receptor (AT2R) was detected by Western blotting analysis. Results Compared with CON group, the kidney mass/body mass(KM/BM), heart mass/body mass (HM/BM), blood glucose (BG), and 24-hour urine proteins (24 h UP) were significantly increased in the DM group (P

Effects of jinlida granules on renin-angiotensin system in kidney and cardiovascular tissues of diabetic rats / 第二军医大学学报

Objective To evaluate the effects of Jinlida granules on the renin-angiotensin system (RAS) in the kidney, heart and abdominal aorta of experimental diabetic rats, so as to explore the possible mechanism by which Jinlida granules protect the kidney and cardiovascular system. Methods The rats were randomized into 2 groups: normal contronl group (CON group, n=10) and diabetic model group Cn = 20). Rats in the control group were fed with regular chow; those in the diabetic model group were fed with high-fat diet for 4 weeks, and then were administered with streptozotocin (STZ; 30 mg/kg) by intraperitoneal injection to induce diabetic model. Successful diabetic models were further randomized into two groups with 10 in each; Jinlida granules treatment group (DM + JLG group) and non-treatment group (DM group). Rats in DM + JLG group were given Jinlida granules orally (3 g/kg per day) for 8 weeks. Angiotensin I (Ang I) and angiotensin P (Ang II) were measured by enzyme-linked immunosorbent assay (ELISA) in the homogenates of the kidney, heart and abdominal aortas the protein expression of angiotensin II type 1 receptor (ATR) and angiotensin II type 2 receptor (AT2R) was detected by Western blotting analysis. Results Compared with CON group, the kidney mass/body mass(KM/BM), heart mass/body mass (HM/BM), blood glucose (BG), and 24-hour urine proteins (24 h UP) were significantly increased in the DM group (P