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.

Clinical Evidence-Guided Anti-rheumatoid Arthritis Study of Shuji Tablet in Adjuvant-Induced Arthritis Rats and Mechanism Exploration via Network Pharmacological Approach.

Background: Rheumatoid arthritis (RA) is a kind of chronic autoimmune disease with several tissues damaged. Shuji tablet (SJT) is a prescription approved for treating lumbago and leg pain in the clinic. However, the efficacy of SJT against RA is still unknown. This study aims to evaluate the therapeutic effect of SJT on adjuvant-induced arthritis (AIA) rats and explore the mechanism via a network pharmacological approach. Methods: AIA rats were treated with SJT for 30 days at the dosages of 3.6, 1.8, and 0.9 g/kg, respectively, and the anti-RA effect was determined by measuring paw swelling, systemic symptoms score, arthritis index, and histopathological change. ELISA assay was used to evaluate the level of inflammatory cytokines in serum. The mechanism exploration and target prediction of SJT against RA were performed via a network pharmacological approach. Results: SJT showed excellent alleviation on AIA rats, with evidence of reducing paws swelling, decreasing systemic symptoms score, and arthritis index. Furthermore, SJT significantly reduced the serum cytokines of IL-6, IL-1ß, TNF-α in AIA rats. Histopathological examination showed SJT remarkably reduced synovial hyperplasia, cartilage damage, and inflammatory infiltration in the secondary-side paws. According to network pharmacological analysis, 208 candidate compounds and 445 potential targets of SJT were identified, and 4465 RA therapy-related targets were searched out. Subsequently, 292 target genes of SJT were speculated to be associated with RA treatment, among which the top 5 "response values" targets were STAT3, AKT1, JUN, HSP90AA1, TNF. GO and KEGG enrichment analysis suggested that 45 signaling pathways were associating with SJT treating RA. The top 10 signaling pathways were PI3K-Akt, MAPK, AGE-RAGE pathway in diabetic complications, Ras, HIF-1, TNF, Chemokine, IL-17, FoxO, and Rap1. Conclusion: Our experimental study showed that SJT significantly alleviated rheumatoid arthritis of AIA rats. Network pharmacology showed that the key targets of SJT against RA probably were STAT3, AKT1, JUN, HSP90AA1, TNF, and the potential mechanism was associated with modulation on the signaling pathways of PI3K-Akt, MAPK, Ras, AGE-RAGE, HIF-1, TNF, chemokine, IL-17, FoxO, Rap 1. Our study strongly provides evidence for Shuji tablet in RA therapy and would enlarge its application in the clinic.

Protection of Ficus pandurata Hance against acute alcohol-induced liver damage in mice via suppressing oxidative stress, inflammation, and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ficus pandurata Hance (FPH) is a traditional Chinese herbal medicine, which is commonly used for liver protection in the folk of Southeast China. However, the medicinal part and pharmacological mechanism have not been clarified yet. AIM OF THE STUDY: This study aims to investigate the medicinal part of FPH for liver protection and uncover the potential mechanism. MATERIALS AND METHODS: Acute alcoholic liver damage (ALD) mice model induced by intragastric administration with 50% alcohol was used to evaluate the liver protection of FPH. Different parts of FPH, including the root (FPHR), stem (FPHS), leaf (FPHL), and whole plant (FPHWP), were selected to investigate the liver-protected efficacy and determine which part is the medicinal part. Acute oral toxicity (AOT) test was performed to determine the acute toxicity of FPH on Kunming mice. The liver-protected effect of FPH was determined by evaluating the liver function, liver morphological changes, and liver pathological changes. The underlying mechanism was investigated by evaluating the effect on oxidative stress, inflammation, and apoptosis in liver tissues via ELISA, H&E staining, Western Blot, and TUNEL staining assays. RESULTS: In the screening test for medicinal parts of FPH, all of the extracts from FPHR, FPHS, FPHL, and FPHWP could alleviate the acute ALD of mice, including reducing abnormal levels of AST, ALT, and relative liver weight. Especially, the alleviated efficacies of FPHS and FPHL were better than those of FPHWP and FPHR, showing that the aerial part (FPHAP, including the stem and leaf), is probably the medicinal part of FPH against acute ALD. In the AOT test, FPHAP at the maximum administration dosage (480 g/kg, calculated based on the quantity of crude material) did not induce obvious abnormality and death of mice, and had no significant influence on body weight, as well as the relative organ weight, showing that the maximum tolerated dose (MTD) of FPHAP was 480 g/kg on Kunming mice. In the anti-acute ALD study, FPHAP significantly reduced the levels of AST, ALT, LDH, ROS, MDA, TNF-α, IL-1ß, IL-18, and IL-6, alleviated the morphology of liver injury, increased the levels of SOD and GSH, up-regulated the expressions of Nrf-2, HO-1 and NQO1, and reduced apoptosis of liver cells in acute ALD mice, indicating that FPHAP could significantly alleviate acute ALD by suppressing oxidative stress, inflammation, and apoptosis. CONCLUSIONS: FPH could protect acute alcohol-induced liver damage of mice by suppressing oxidative stress, inflammation, and apoptosis. Our study provides scientific evidence for the therapeutic effect of Ficus pandurata Hance in acute ALD mice and suggests its potential development in humans for liver protection, supporting its traditional application.

Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis, and Oxidative Stress.

SCOPE: Syringaresinol (SYR) is a phenolic compound, which could be found in various cereals and medicinal plants. It exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of SYR on modulating diabetic cardiomyopathy. The present study aimed to investigate the pharmacodynamic effect of SYR on diabetic cardiomyopathy and the underlying molecular mechanism. METHODS AND RESULTS: In STZ-induced type 1 diabetic mice, orally administration with SYR in every other day for 8 weeks significantly improves cardiac dysfunction and preventes cardiac hypertrophy and fibrosis. The macrophage infiltration and oxidative stress biomarkers are also suppressed by SYR without affecting hyperglycemia and body weight. In neonatal cardiomyocytes, high glucose-induced cell apoptosis and fibrosis are potently decreased by SYR, and the inflammatory response and oxidant stress are also alleviated by SYR incubation. Mechanistically, SYR may exert protective effects by restoring suppression of antioxidant kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-E2-related factor 2 (Nrf2) system and abnormal activation of transforming growth factor-ß (TGF-ß)/mothers against decapentaplegic homolog (Smad) signaling pathway in vitro and in vivo. CONCLUSION: The results indicated that SYR could be a potential therapeutic agent for the treatment of diabetic cardiomyopathy by inhibiting inflammation, fibrosis, and oxidative stress. The signaling pathway of Keap1/Nrf2 and TGF-ß/Smad could be used as therapeutic targets for diabetic complications.