Elucidation of the anti-ß-cell dedifferentiation mechanism of a modified Da Chaihu Decoction by an integrative approach of network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Da Chaihu decoction (MDCH) is a traditional Chinese herbal prescription that has been used in the clinic to treat type 2 diabetes (T2D). Previous studies have confirmed that MDCH improves glycemic and lipid metabolism, enhances pancreatic function, and alleviates insulin resistance in patients with T2D and diabetic rats. Evidence has demonstrated that MDCH protects pancreatic ß cells via regulating the gene expression of sirtuin 1 (SIRT1) and forkhead box protein O1 (FOXO1). However, the detailed mechanism remains unclear. AIM OF THE STUDY: Dedifferentiation of pancreatic ß cells mediated by FOXO1 has been recognized as the main pathogenesis of T2D. This study aims to investigate the therapeutic effects of MDCH on T2D in vitro and in vivo to elucidate the potential molecular mechanisms. MATERIALS AND METHODS: To predict the key targets of MDCH in treating T2D, network pharmacology methods were used. A T2D model was induced in diet-induced obese (DIO) C57BL/6 mice with a single intraperitoneal injection of streptozotocin. Glucose metabolism indicators (oral glucose tolerance test, insulin tolerance test), lipid metabolism indicators (total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol), inflammatory factors (C-reactive protein, interleukin 6, tumor necrosis factor alpha), oxidative stress indicators (total antioxidant capacity, superoxide dismutase, malondialdehyde), and hematoxylin and eosin staining were analyzed to evaluate the therapeutic effect of MDCH on T2D. Immunofluorescence staining and quantification of FOXO1, pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), octamer-binding protein 4 (OCT4), neurogenin 3 (Ngn3), insulin, and SIRT1, and Western blot analysis of insulin, SIRT1, and FOXO1 were performed to investigate the mechanism by which MDCH inhibited pancreatic ß-cell dedifferentiation. RESULTS: The chemical ingredients identified in MDCH were predicted to be important for signaling pathways related to lipid metabolism and insulin resistance, including lipids in atherosclerosis, the advanced glycation end product receptor of the advanced glycation end product signaling pathway, and the FOXO signaling pathway. Experimental studies showed that MDCH improved glucose and lipid metabolism in T2D mice, alleviated inflammation and oxidative stress damage, and reduced pancreatic pathological damage. Furthermore, MDCH upregulated the expression levels of SIRT1, FOXO1, PDX1, and NKX6.1, while downregulating the expression levels of OCT4 and Ngn3, which indicated that MDCH inhibited pancreatic dedifferentiation of ß cells. CONCLUSIONS: MDCH has therapeutic effects on T2D, through regulating the SIRT1/FOXO1 signaling pathway to inhibit pancreatic ß-cell dedifferentiation, which has not been reported previously.

Excess dietary zinc drives a Cushing's-like syndrome in ovariectomized mice - Implications for postmenopausal obesity.

Postmenopausal women have an increased risk of obesity, but the underlying cause is not clear. We unexpectedly found that excess dietary zinc induced severe obesity and a Cushing's-like syndrome without increased food intake in ovariectomized (Ovx) but not in sham-operated mice. Zinc accumulated in the adrenal glands and inhibited adrenal 17,20-lyase activity and steroid synthesis. As adrenal steroids are the only source of estrogen in Ovx mice, estrogen deficiency induced adrenal hyperplasia, glucocorticoid overproduction, and consequent development of a Cushing's-like syndrome. Adrenal steroid supplementation prevented the effects of zinc. Plasma zinc was positively correlated with cortisol level and negatively correlated with the levels of adrenal steroids and estrogen in obese postmenopausal women. The finding of a link between dietary zinc, estrogen deficiency, and postmenopausal obesity, implies that postmenopausal obesity might be prevented by supplementation with a adrenal steroid and avoiding excess dietary zinc.

The Effect of Berberine on Metabolic Profiles in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Rhizoma Coptidis is an herb that has been frequently used in many traditional formulas for the treatment of diabetic mellitus (DM) over thousands of years. Berberine, the main active component of Rhizoma Coptidis, has been demonstrated to have the potential effect of hypoglycemia. To determine the potential advantages of berberine for diabetic care, we conducted this systematic review and meta-analysis to examine the efficacy and safety of berberine in the treatment of patients with type 2 DM. METHODS: Eight databases including PubMed, Embase, Web of Science, the Cochrane library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Database (SinoMed), Wanfang Database, and Chinese VIP Information was searched for randomized controlled trials (RCTs) reporting clinical data regarding the use of berberine for the treatment of DM. Publication qualities were also considered to augment the credibility of the evidence. Glycemic metabolisms were the main factors studied, including glycosylated hemoglobin (HbA1c), fasting plasm glucose (FPG), and 2-hour postprandial blood glucose (2hPG). Insulin resistance was estimated by fasting blood insulin (FINS), homeostasis model assessment-insulin resistance (HOMA-IR), and body mass index (BMI). Lipid profiles were also assessed, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), along with inflammation factors such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Serum creatinine (Scr), blood urea nitrogen (BUN), and adverse events were applied to evaluate the safety of berberine. RESULTS: Forty-six trials were assessed. Analysis of berberine applied alone or with standard diabetic therapies versus the control group revealed significant reductions in HbA1c (MD = -0.73; 95% CI (-0.97, -0.51)), FPG (MD = -0.86, 95% CI (-1.10, -0.62)), and 2hPG (MD = -1.26, 95% CI (-1.64, -0.89)). Improved insulin resistance was assessed by lowering FINS (MD = -2.05, 95% CI (-2.62, -1.48)), HOMA-IR (MD = -0.71, 95% CI (-1.03, -0.39)), and BMI (MD = -1.07, 95% CI (-1.76, -0.37)). Lipid metabolisms were also ameliorated via the reduction of TG (MD = -0.5, 95% CI (-0.61, -0.39)), TC (MD = 0.64, 95% CI (-0.78, -0.49)), and LDL (MD = 0.86, 95% CI (-1.06, -0.65)) and the upregulation of HDL (MD = 0.17, 95% CI (0.09, 0.25)). Additionally, berberine improved the inflammation factor. CONCLUSION: There is strong evidence supporting the clinical efficacy and safety of berberine in the treatment of DM, especially as an adjunctive therapy. In the future, this may be used to guide targeted clinical use of berberine and the development of medications seeking to treat patients with T2DM and dyslipidemia.

Chinese herbal medicine Shenzhuo Formula treatment in patients with macroalbuminuria secondary to diabetic kidney disease: study protocol for a randomized controlled trial.

BACKGROUND: Diabetic kidney disease (DKD) is a serious complication associated with diabetes mellitus and can cause end-stage renal disease (ESRD). Traditional Chinese medicine (TCM) is widely used in China to treat DKD, and in particular microalbuminuria and macroalbuminuria. This study will address the efficacy and safety of Shenzhuo Formula (SZF), a frequently prescribed TCM, in DKD patients with macroalbuminuria. METHODS/DESIGN: This study is a 24-week, randomized, multi-center, double-blinded, double-dummy, controlled, clinical trial that will include 120 DKD patients aged 18 to 80 years old with a 24-h urinary protein (24-h UP) level of between 0.5 g and 3 g and serum creatinine (SCr) ≤ 133 µmol/L (1.5 mg/dL) and compare SZF to irbesartan. The 24-h UP change from baseline to week 24 will represent the primary endpoint with secondary endpoints including SCr, estimated glomerular filtration rate (eGFR), TCM symptoms, urinary albumin excretion rate (UAER), etc. Safety assessments will also be evaluated. DISCUSSION: This study will provide initial evidence regarding the efficacy and safety of SZF relative to irbesartan in the treatment of DKD patients with macroalbuminuria. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-ICR-15006311 . Registered on 15 April 2015.

Retrospective analysis of the overt proteinuria diabetic kidney disease in the treatment of modified Shenzhuo formula for 2 years.

The objective of the present study was to evaluate the 2-year effectiveness of modified Shenzhuo formula in the treatment of overt proteinuria diabetic kidney disease (DKD).Patients diagnosed with type 2 DKD in the clinical research database of Prof Xiaolin Tong (>20,000 data points) with >1-year follow-up were screened for this study. Patients' demographic data, chief complaint, present illness, past history, allergic history, personal history, family history, test results, tongue images, pulse information, and prescription information at 1, 1.5, and 2 years of follow-up were analyzed. EpiData3.1 was used to establish the electronic database of this research and SPSS v20.0 (SPSS Inc, Chicago, IL) was used for performing statistical analyses.The patients' common main symptoms of overt proteinuria DKD were weak breath and fatigue, numbness of limbs, insomnia, blurred vision, nocturia, edema, low backache, constipation, itchy skin ulcer, and chills. The average 24-hour urinary protein of patients treated with modified Shenzhuo formula was statistically significantly lower than baseline values at 1, 1.5, and 2 years (0.66 g, 95% confidence interval [CI] [-0.95, -0.41]; 1.00 g, 95% CI [-1.67, 0.38]; 1.11 g, 95% CI [-1.79, -0.57]). There are no statistically significant differences between the glomerular filtration rate at the baseline and that after modified Shenzhuo formula intervention. Statistically significant reductions in serum triglyceride and glycosylated hemoglobin values and systolic blood pressure also were recorded. Other indexes, including serum creatinine, blood urea nitrogen, diastolic blood pressure, cholesterol, high-density lipoprotein, and low-density lipoproteins, did not differ between baseline and post-treatment time points.Modified Shenzhuo formula could reduce 24-hour urinary protein excretion in patients with DKD. The formula maybe had the potential advantages on glomerular filtration rate, creatinine reciprocal, blood lipid levels, etc.

Diabetic kidney disease treated with a modified Shenzhuo formula derived from Traditional Chinese Medicine: a case report.

INTRODUCTION: Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus and is the leading cause of end-stage renal disease. DKD seriously affects the quality of life of patients and brings heavy economic burden to the country. At present, the pathogenesis of DKD is not entirely clear, and clinical treatment is mainly to control blood glucose and lower blood pressure and urine protein. However, the clinical effect is not satisfactory. CASE PRESENTATION: A female patient, aged 72 years, first visited our hospital endocrinology clinic, and was diagnosed with DKD. She suffered from fatigue, cold sensation in the lower extremities, convulsion of the lower limbs and frequent urination at night. She had a dark purple tongue with white and yellow fur and sublingual varices. Accessory examinations showed that her fasting blood glucose was 5.7 mmol/L, serum creatinine 159 µmol/L, blood urea nitrogen 13.6 µmol/L, blood uric acid 493 µmol/L, and blood pressure 138/65 mm Hg. The patient received Traditional Chinese Medicine treatment of the modified Shenzhuo formula [Huangqi (Radix Astragali Mongolici), Dahuang (Radix Et Rhizoma Rhei Palmati), Shuizhi (Hirudo) and Danshen (Radix Salviae Miltiorrhizae)] for 7 years and achieved good results. CONCLUSION: This case provides a specific treatment plan and an effective reference for clinical application of Traditional Chinese Medicine for treating DKD. This may be an alternative treatment for DKD.

Assessment of the Reporting Quality of Placebo-controlled Randomized Trials on the Treatment of Type 2 Diabetes With Traditional Chinese Medicine in Mainland China: A PRISMA-Compliant Systematic Review.

Placebo-controlled randomized trials are often used to evaluate the absolute effect of new treatments and are considered gold standard for clinical trials. No studies, however, have yet been conducted evaluating the reporting quality of placebo-controlled randomized trials. The current study aims to assess the reporting quality of placebo-controlled randomized trials on treatment of diabetes with Traditional Chinese Medicine (TCM) in Mainland China and to provide recommendations for improvements.China National Knowledge Infrastructure database, Wanfang database, China Biology Medicine database, and VIP database were searched for placebo-controlled randomized trials on treatment of diabetes with TCM. Review, animal experiment, and randomized controlled trials without placebo control were excluded. According to Consolidated Standards of Reporting Trials (CONSORT) 2010 checklists items, each item was given a yes or no depending on whether it was reported or not.A total of 68 articles were included. The reporting percentage in each article ranged from 24.3% to 73%, and 30.9% articles reported more than 50% of the items. Seven of the 37 items were reported more than 90% of the items, whereas 7 items were not mentioned at all. The average reporting for "title and abstract," "introduction," "methods," "results," "discussion," and "other information" was 43.4%, 78.7%, 40.1%, 49.9%, 71.1%, and 17.2%, respectively. The percentage of each section had increased after 2010. In addition, the reporting of multiple study centers, funding, placebo species, informed consent forms, and ethical approvals were 14.7%, 50%, 36.85%, 33.8%, and 4.4%, respectively.Although a scoring system was created according to the CONSORT 2010 checklist, it was not designed as an assessment tool. According to CONSORT 2010, the reporting quality of placebo-controlled randomized trials on the treatment of diabetes with TCM improved after 2010. Future improvements, however, are still needed, particularly in methods sections.

Application of Herbal Medicines with Bitter Flavor and Cold Property on Treating Diabetes Mellitus.

Diabetes mellitus has been a global pandemic. Traditional Chinese Medicine has been used on diabetes mellitus for thousands of years and the modern Chinese medicine studies have found a curative effect of herbal medicine with bitter flavor and cold property on diabetes. This review will introduce the theory summary of flavor and property in TCM, argument basis, the evidences from clinical trails and animal experiments, the possible antidiabetic mechanisms, and advantages on lowering glucose of herbal medicines with bitter flavor and cold property and take rhizome, Chinese rhubarb, and Momordica charantia, the three herbal medicines with bitter flavor and cold property, as examples to illustrate the exact antidiabetic effect. It is hoped that this review can provide some ideas and inspiration for the treatment of diabetes with herbal medicine.

Innovative Thoughts on Treating Diabetes from the Perspective of Traditional Chinese Medicine.

The rapidly increasing incidence of diabetes mellitus (DM) is becoming a major public health issue. As one of the important parts in complementary and alternative therapies, traditional Chinese medicine (TCM) is promising in treating DM. In this review, we summarize new thoughts on treating DM that aim to improve the clinical efficacy of TCM from the perspectives of principle, methods, formula, herbs, and doses. Our approach is as follows: principle: we use a combination of symptoms, syndromes, and diseases as a new mode for treating diabetes; methods: emphasizing heat-clearing in the early and middle stage of T2DM and invigorating blood circulation throughout the whole process of T2DM are two innovative methods to treat T2DM; formulas and herbs: choosing formulas and herbs based on the combination of TCM theory and current medicine. We will emphasize four strategies to help doctors choose formulas and herbs, including treatment based on syndrome differentiation, choosing herbs of bitter and sour flavors to counteract sweet flavor, choosing formulas and herbs aimed at main symptoms, and using modern pharmacological achievements in clinical practice; dose: reasonable drug dose plays an important role in the treatment of DM and a close relationship exists between dose and clinical efficacy.

[Systematic review of efficacy and safety of shenmai injection for chronic heart failure].

The paper is to evaluate the efficacy and safety of Shenmai injection for chronic heart failure, retrieving the Pubmed, CBM, CNKI, Wanfang database and VIP database to comprehensively collect all types research report of Shenmai injection for chronic heart failure (CHF). Particularly wishing to point out, randomized controlled trials are include for the evaluation of effectiveness, which are statistically analyzed and evaluated by Rev-Man 5. 2. The current studies show that the improvement rate of NYHA classification of cardiac function of CHF patients and their related indexes figure such as LVEF, SV, CO, BNP, 6 min walking test value are all improved by the combination of Shenmai injection and foundation treatment. However, HR is almost no improvement. Meanwhile, serious ADR/AE of Shenmai injection for CHF isn't appear.

Syndrome Differentiation of Diabetes by the Traditional Chinese Medicine according to Evidence-Based Medicine and Expert Consensus Opinion.

In Chinese medicine, diabetes belongs to the category of "Xiaoke disease (disease with symptoms of frequent drinking and urination)"; in the traditional sense, its pathogenesis is "Yin deficiency and dryness-heat." However, over time, changes in the social environment and lifestyle have also changed the use of traditional Chinese medicine (TCM) in diabetes. In this study, we performed diabetes syndrome differentiation using TCM according to evidence-based medicine and expert consensus opinion.

[Tissue culture of Vinca minor and determination of vincamine].

OBJECTIVE: To study tissue culture of Vinca minor and determine the content of vincamine. METHOD: Leaf blades, stalks, root segment of V. minor were used as explants to study the effect of 2, 4-D,6-BA,NAA on its callus induction and vincamine contents in the orthogonal design experiment. In the peak period of callus formation, vincamine content in callus of V. minor and sterile plants was determined by HPLC. The experimental data was statistically analyzed. RESULT: The content of 6-BA and NAA had no significant effect on its callus induction. But the content of 2, 4-D had significant effect on its callus induction. Within 20,40,60 d, the content of vincamine in sterile plant was (0.015 +/- 0.003)%, (0.097 +/- 0.001)% , (0.113 +/- 0.06)%, respectively. In the peak period of callus formation, vincamine content in callus of leaf blades, stalks, root segment was (0.024 +/- 0.0025)%, (0.016 +/- 0.0015)%, (0.010 +/- 0.0015)%, respectively. To 30 days of subculture, vincamine content in callus of leaf blades, stalks, root segment was (0.041 +/- 0.002)%, (0.019 +/- 0001)%, (0.016 +/- 0.002)%, respectively. CONCLUSION: The optimal hormone combination for callus initiation was MS +2, 4-D 1.0 mg x L(-1) +6-BA 0.5 mg x L(-1) + NAA 0.5 mg x L(-1). In different growth periods, vincamine content in sterile plants is significantly different. From different explants in callus vincamine content is different, in which leaves callus is significantly higher than that of stems, roots produced callus organization.