Fufang Fanshiliu Decoction Revealed the Antidiabetic Effect through Modulating Inflammatory Response and Gut Microbiota Composition.

Background: Diabetes mellitus brings serious threats and financial burdens to human beings worldwide. Fufang Fanshiliu decoction (FFSLD), a traditional Chinese medicine formula showing great antidiabetic effects, has been used in clinics for many years. Objective: This study aims to explore the underlying therapeutic mechanisms of FFSLD in Type II diabetes mellitus (T2DM). Methods: Sprague-Dawley rats induced by high-fat diet feeding combined with streptozotocin injection were used to establish the T2DM model. All rats were randomly divided into 6 groups: control, model, metformin, high dosage, middle dosage, and low dosage of FFSLD. After 4 weeks of treatment, serum, intestinal mucosa, and fecal samples were collected for further analysis. ELISA was used to detect the diabetic-related serum indicators and proinflammation cytokines. Gene or protein expressions of mitogen-activated protein kinase (MAPK), interleukin 1 beta (IL-1ß), transforming growth factor-beta (TGF-ß), and tumor necrosis factor-alpha (TNF-α) in intestinal mucosa were analyzed by quantitative real-time polymerase chain reaction (RT-PCR) or western blot. 16s rRNA gene sequencing was used to detect the changes of gut microbiome in these groups. Intestinal gut microbiota (GM) composition was further analyzed according to the sequencing libraries. Results: FFSLD effectively recovered the diabetic-related biochemical indexes by reducing fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), insulin, and increasing high-density lipoprotein cholesterol (HDL-C). Furthermore, FFSLD significantly ameliorated the abnormal levels of proinflammation cytokines including IL-1ß, IL-6, TNF-α, and TGF-ß. In addition, the GM compositions of rats in control, model, and FFSLD treated groups were different. FFSLD significantly increased the relative abundance of Lactobacillus, Akkermansia, and Proteus, and reduced the relative abundance of Alistipes, Desulfovibrio, and Helicobacter. Moreover, these changed bacteria were closely related to the diabetic-related serum indicators and proinflammatory cytokines. Conclusion: These results suggest that FFSLD alleviates diabetic symptoms in T2DM rats through regulating GM composition and inhibiting inflammatory response, which clarify the therapeutic mechanism of FFSLD on T2DM and provide a theoretical basis for its further clinical application.

Alleviation of Fufang Fanshiliu decoction on type II diabetes mellitus by reducing insulin resistance: A comprehensive network prediction and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Fanshiliu decoction (FFSLD) is a Chinese herbal medicine prescription that has been used in type 2 diabetes mellitus (T2DM), while the underlying mechanism remains unclear. AIM OF THE STUDY: To validate the efficacy and explore the potential mechanisms of FFSLD in treating T2DM via integrating a network pharmacological approach and experimental evaluation. MATERIALS AND METHODS: T2DM mice model induced by high-fat diet feeding combined with streptozotocin injection was selected to investigate the alleviation of FFSLD against T2DM, via detecting the levels of glucose, insulin, glucagon (GC), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Network pharmacological analysis was used to predict the potential mechanisms, including the pharmacokinetics and drug-likeness screening, active ingredients and potential targets prediction, network analysis, and enrichment analysis. The candidate bioactive molecules of FFSLD, and targets information excavated through TCMSP, Uniprot, GeneCards, OMIM databases, were combined for comprehensive analysis by constructing "drug-compound-target-disease" and "protein-protein interaction" networks. Enrichment analysis was performed via Gene Ontology (GO) and Koto Encyclopedia of Genes and Genomes (KEGG) databases. HepG2 insulin-resistance (IR) cells model induced by high glucose was used to verify the potential mechanisms of FFSLD against T2DM which were predicted by the network pharmacology. RESULTS: The animal study showed that FFSLD significantly decreased the blood glucose, and reversed the abnormal levels of insulin, GC, TG, TC, HDL-C, and LDL-C in T2DM mice. Network pharmacological analysis indicated that 106 active compounds of FFSLD might be correlated with 628 targets in treating T2DM, and the mechanism would probably be related to insulin resistance that harbored a high response value (P = 5.88844 E-33) though regulating Akt1, ESR1, oxidoreductase activity, and JAK/STAT signalings. Experimental validation showed that FFSLD reduced the ROS level, up-regulated the expressions of p-AKT, Nrf-2, and ESR1, and down-regulated the expressions of JAK2, STAT3, and Keap-1 in the HepG2-IR cells model. CONCLUSIONS: This study demonstrated that the therapeutic effect of FFSLD on T2DM was related to IR alleviation. The underlying mechanisms were associated with the regulation of PI3K/AKT, JAK/STAT, oxidative stress, and ESR signaling pathways.

The Efficacy and Safety of Chinese Medicine Fufang Zhenzhu Tiaozhi Capsule (FTZ) in the Treatment of Diabetic Coronary Heart Disease: Study Protocol for Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Diabetic coronary heart disease (DCHD), the main macrovascular complication of type 2 diabetes mellitus (T2DM), is greatly harmful to T2DM patients. Traditional Chinese medicine (TCM) is an alternative and effective therapy to delay the development of macrovascular diseases, but the existing evidence of its efficacy and safety is insufficient. The aim of this multicenter, randomized, double-blind, placebo-controlled trial is to evaluate the efficacy and safety of Chinese Medicine Fufang Zhenzhu Tiaozhi capsule (FTZ) in treating DCHD. PATIENTS AND METHODS: This study includes a 2-week run-in, 52-week treatment, and 52-week post-treatment follow-up. A total of 160 participants will be recruited and randomized into two groups. The treatment group will receive FTZ and basic treatment, while the control group will receive the placebo and basic treatment. The primary outcome is the combined outcome including the major adverse cardiovascular events, coronary restenosis, and unplanned revascularization. The combined secondary outcomes include all-cause mortality, acute coronary syndrome, ischemic stroke, heart failure, unplanned re-hospitalization mainly caused by acute complications of diabetes, other thromboembolic events, and TCM symptom indicators. The safety outcomes and adverse events will also be evaluated in this trial. DISCUSSION: This trial evaluates the clinical effectiveness and safety of FTZ in patients with DCHD. The results are important to further explore the effectiveness of the comprehensive strategy "Tiao Gan Qi Shu Hua Zhuo" (modulating Gan, trigging key metabolic system to resolve pathogenic factors such as phlegm retention and dampness) in the prevention and control of glucolipid metabolic disorders (GLMD) including DCHD and T2DM. On the other hand, this study is the first trial of FTZ to observe cardiovascular outcomes through long-term follow-up after treatment of DCHD, which is of great value. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry on April 07, 2019 (No. ChiCTR1900022345).