salvianolic-acid-a and Diabetes-Mellitus--Type-2

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes (T2DM). Decreased mitochondrial abundance and function were found in white adipose tissue (WAT) of T2DM patients. Therefore, promoting WAT mitochondrial biogenesis and improving adipocyte metabolism may be strategies to prevent and reverse T2DM. Salvianolic acid A (SAA) has been found to exert anti-diabetic and lipid disorder-improving effects. However whether SAA benefits mitochondrial biogenesis and function in adipose tissue is unclear. Here, we evaluated SAA's effect on mitochondrial biogenesis and function in 3T3-L1 adipocytes and investigated its potential regulatory mechanism. Results showed that SAA treatment significantly promoted the transcription and expression of peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Meanwhile, SAA treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) quantity, mitochondrial mass, and expression of mitochondrial respiratory chain enzyme complexes III and complex IV. These enhancements were accompanied by enhanced phosphorylation of AMPK and ACC and were suppressed by Compound C, a specific AMPK inhibitor. Furthermore, SAA treatment improved adipocytes mitochondrial respiration and stimulated ATP generation. These findings indicate that SAA exerts a potential therapeutic capacity against adipocytes mitochondrial dysfunction in diabetes by activating the AMPK-PGC-1α pathway.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Caffeic Acids; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Humans; Lactates; Mice; Mitochondria; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Platelets in patients with type 2 diabetes mellitus (DM2) are characterized by increased activation and aggregation, which tends to be associated with a high morbidity and mortality due to cardiovascular disease (CVD). Moreover, a large proportion of DM2 patients show an inadequate response to standard antiplatelet treatments, contributing to recurrent cardiovascular events. In our previous study, we indicated that Salvianolic acid A (SAA) presents an antiplatelet effect in healthy volunteers. However, whether it can inhibit "activated platelets" with a pathologic status has not been explored. Therefore, this study was designed to investigate the antiplatelet effect of SAA and its diabetic complication-related difference in DM2.. Forty patients diagnosed with DM2 from January 2018 to April 2018 were recruited. Fibrinogen-binding (PAC-1) and P-selectin (CD62p) flow cytometry reagents were measured under resting and stimulated conditions by flow cytometry, while agonist-induced platelet aggregation was conducted by light transmission aggregometry. Before all these measurements were conducted, all platelet samples were preincubated with a vehicle or SAA for 10 min. Additionally, the diabetic complication-related difference in the antiplatelet effect of SAA was further studied in enrolled patients.. The expressions of PAC-1 and CD62p were elevated in DM2, as well as the maximal platelet aggregation. In addition, SAA decreased the expressions of PAC-1 and CD62p, which were enhanced by ADP and thrombin (all P < 0.01). It also reduced the platelet aggregation induced by ADP (P < 0.001) and thrombin (P < 0.05). Comparing the antiplatelet effect of SAA on DM2, with and without diabetic complications, no statistically significant difference was found (all P > 0.05).. The present study demonstrated that SAA can inhibit platelet activation and aggregation in patients with DM2, and the inhibition did not abate for the existence of diabetic complications.

Topics: Aged; Biomarkers; Blood Platelets; Caffeic Acids; Diabetes Mellitus, Type 2; Female; Humans; Lactates; Male; Middle Aged; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors

Topics: Alkenes; Animals; Atherosclerosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Inflammasomes; Lipids; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Polyphenols; Rats; Rats, Zucker

α-Glucosidase (AG) is an important drug target for the treatment of type 2 diabetes mellitus in humans due to the potential effect of down regulating glucose absorption in patients. In our previous study, salvianolic acid A (SAA) was found to exhibit potent AG inhibitory activity, whereas the interaction mechanism was still ambiguous. Herein, the interaction mechanism of SAA and AG was investigated by multi-spectroscopic methods along with molecular docking. As a result, it was found that SAA reversibly inhibited AG in a competitive manner with IC

Topics: alpha-Glucosidases; Caffeic Acids; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Kinetics; Lactates; Molecular Docking Simulation; Protein Binding; Thermodynamics

Glomerular endothelium dysfunction leads to the progression of renal architectonic and functional abnormalities in early-stage diabetic nephropathy (DN). Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) are proved to play important roles in diabetic nephropathy. This study investigated the role of Salvianolic acid A (SalA) on early-stage DN and its possible underlying mechanism.. In vitro AGEs formation and breaking rate were measured to illustrate the effect of SalA on AGEs. Type 2 diabetic nephropathy rats were induced by high-fat diet and low-dose streptozocin (STZ). After eight-week treatment with SalA 1 mg/kg/day, 24h-urine protein, creatinine clearance was tested and renal structural injury was assessed by PAS and PASM staining. Primary glomerular endothelial cell permeability was evaluated after exposed to AGEs. AGEs-induced RhoA/ROCK and subsequently activated disarrange of cytoskeleton were assessed by western blot and immunofluorescence.. Biochemical assay and histological examination demonstrated that SalA markedly reduced endothelium loss and glomerular hyperfiltration, suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced urinary albumin and ameliorated renal function. Further investigation suggested that SalA exerted its renoprotective effects through inhibiting AGE-RAGE signaling. It not only inhibited formation of AGEs and increased its breaking in vitro, but also reduced AGEs accumulation in vivo and downregulated RAGE expression. SalA restored glomerular endothelial permeability through suppressing AGEs-induced rearrangement of actin cytoskeleton via AGE-RAGE-RhoA/ ROCK pathway. Moreover, SalA attenuated oxidative stress induced by AGEs, subsequently alleviated inflammation and restored the disturbed autophagy in glomerular endothelial cell and diabetic rats via AGE-RAGE-Nox4 axis.. Our study indicated that SalA restored glomerular endothelial function and alleviated renal structural deterioration through inhibiting AGE-RAGE, thus effectively ameliorated early-stage diabetic nephropathy. SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.

Topics: Animals; Caffeic Acids; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drugs, Chinese Herbal; Endothelium; Glycation End Products, Advanced; Kidney Glomerulus; Lactates; Male; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Signal Transduction

Cardiovascular complications represent a leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). During such complicated progression, subtle variations in the cardiovascular risk (CVR)-related biomarkers have been used to identify cardiovascular disease at the incipient stage. In this study we attempt to integrally characterize the progression of cardiovascular complications and to assess the beneficial effects of metformin combined with salvianolic acid A (Sal A), in Goto-Kakizaki (GK) rats with spontaneous T2DM. The rats were treated with metformin (200 mg·kg

Topics: Alkenes; Animals; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Progression; Drug Therapy, Combination; Hypoglycemic Agents; Metformin; Models, Biological; Polyphenols; Rats, Wistar

Salvianolic acid A (SalA) is the main efficacious, water-soluble constituent of Salvia miltiorrhiza Bunge. This study evaluated the effects of SalA on plantar microcirculation and peripheral nerve dysfunction in streptozotocin (STZ )-induced type 2 diabetic rats. The rats were given a high-fat and high-sucrose diet for a month followed by intraperitoneal injection of STZ (30 mg/kg). Oral administration of SalA (1 and 3mg/kg, respectively) was performed daily for 10 weeks after modeling. Diabetic rats were given a high-fat diet, while age-matched healthy rats were given a standard chow. Plantar microcirculation was measured by Laser Doppler flowmetry, and peripheral nerve function was measured with regard to pain withdrawal latency and motor nerve conduction velocity. The results show that the plantar blood perfusion and vasodilation reactivities decreased significantly, and latency of pain withdrawal and motor nerve conduction velocity rose in diabetic rats compared with the normal control group. SalA increased peripheral blood perfusion and vascular activities; improved peripheral nerve function; and decreased AGEs levels, vascular eNOS expression, and blood glucose, lipid, vWF and malondialdehyde levels in diabetic rats. The beneficial effects of SalA on plantar microcirculation and peripheral nerve function in diabetic rats might be attributed to improvements in lipid and glucose metabolism in diabetic rats, the inhibition of AGEs formation and the development of oxidative stress-related nervous and vascular damage. Based on these findings, we proposed that therapeutic use of SalA to prevent the development of diabetic foot problems.

Topics: Animals; Aorta; Blood Glucose; Body Weight; Caffeic Acids; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Foot; Foot; Glycation End Products, Advanced; Hyperemia; Lactates; Lipid Metabolism; Male; Malondialdehyde; Microcirculation; Motor Activity; Nitric Oxide Synthase Type III; Pain; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Reaction Time; Survival Rate; von Willebrand Factor