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Obesity is one of the main causes of human cardiovascular and cerebrovascular diseases. Baicalin, a bioactive flavonoid isolated from the herbal medicine Scutellaria baicalensis Georgi, is reported to ameliorate obesity and hyperlipidemia. However, its mechanism remains unclear. Here, we used network pharmacology to explore the potential mechanism of baicalin on a system level. First, we predicted the targets of baicalin and diseases, and then protein-protein interaction (PPI) networks were constructed. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server. Lastly, we confirmed the results of the network analysis by palmitic acid (PA) treated human hepatoma cells (HepG2) in vitro. The results indicated that 37 targets related to obesity treated by baicalin were predicted by network pharmacology, and top 10 related pathways were extracted by the KEGG database. Baicalin treatment could reduce triglyceride (TG) contents and lipid droplet accumulation in PA-treated HepG2 cells. The anti-obesity effects of baicalin might be due to the up-regulation of solute carrier family 2 member 1 (SLC2A1) and down-regulation of tumor necrosis factor (TNF), nuclear factor kappa B subunit 1 (NFKB1), sterol regulatory element binding transcription factor 1 (SREBF1), peroxisome proliferator activated receptor gamma and caspase 3 (CASP3). Our results indicated that baicalin may regulate key inflammatory markers, adipogenesis process, and apoptosis for treatment of obesity.

The selective estrogen receptor modulator raloxifene is widely used in the treatment of postmenopausal osteoporosis, and has cardioprotective properties. However, effects of raloxifene on cardiac ion channels are unclear. The present study was designed to investigate the effects of raloxifene and beta-estradiol on transient outward and ultra-rapid delayed rectifier potassium currents (Ito1 and IKur) in human atrial myocytes with a whole cell patch-clamp technique. Ito1 was inhibited by raloxifene in a concentration-dependent manner with an IC50 of 0.9 microM. Raloxifene at 1 microM decreased Ito1 by 40.2+/-1.9% (at +50 mV, n=14, P0.01 vs control). Time-dependent recovery from inactivation was slowed, and time to peak and time-dependent inactivation of Ito1 were significantly accelerated, while steady-state voltage dependent activation and inactivation of Ito1 were not affected by raloxifene. In addition, raloxifene remarkably suppressed IKur (IC50=0.7 microM). Raloxifene at 1 microM decreased IKur by 57.3+/-3.3% (at +50 mV, n=10, P0.01 vs control). However, beta-estradiol inhibited Ito1 (IC50=10.3 microM) without affecting IKur. The inhibitory effects of raloxifene and beta-estradiol on Ito1 and/or IKur were unaffected by the estrogen receptor antagonist ICI 182,780. Our results indicate that raloxifene directly inhibits the human atrial repolarization potassium currents Ito1 and IKur. Whether raloxifene is beneficial for supraventricular arrhythmias remains to be studied.

Pentamethylquercetin (PMQ) has been shown to possess glucose-lowering properties, but its effect on renal fibrosis in diabetes is still unclear. This study was designed to investigate the effect of PMQ on renal fibrosis and the underlying mechanisms in spontaneous type II diabetic Goto-Kakizaki rats and mesangial cells in high glucose. We found that in Goto-Kakizaki rats, PMQ treatment attenuated glomerular volume, glycogen deposition, renal collagen and fibronectin accumulation, in addition to amelioration of diabetic symptoms, including reduction of urine volume and urine glucose levels. In mesangial cells, PMQ remarkably inhibited the cell proliferation and total collagen accumulation, and suppressed cell hypertrophy. Further experiments showed that PMQ treatment down-regulated the expression of TGF-β1, up-regulated Smad7 and inhibited Smad2/3 activation in vivo and vitro. Our results demonstrated that PMQ ameliorated renal fibrosis in diabetes, which may be associated with suppressed TGF-β/Smads signaling.

Pentamethylquercetin (PMQ), a methylated quercetin derivative, was screened for anti-diabetic effects in neonatally streptozotocin (STZ)-induced diabetic rats (n-STZ diabetic rats). Streptozotocin (90 mg/kg) was administered intraperitoneally to 2-day-old male pups to induce diabetes. PMQ was administered at doses of 2.5, 5, 10 and 20 mg/kg/day orally when the rats were 6 weeks old and continued for 10 consecutive weeks. Body weights were followed. Fasting and fed glucose, triglyceride and insulin levels were monitored periodically at the 6th and 10th week after PMQ treatment. At the end of the study, oral glucose tolerance test was performed, and kidney and liver function parameters were assayed. It was found that PMQ intervention dose-dependently reduced postprandial glucose and triglyceride levels, prevented the onset of overt diabetes, ameliorated polydipsia symptom induced by diabetes, attenuated glucose intolerance, enhanced insulin sensitivity indices and decreased endogenous creatinine clearance rate, urinary albumin excretion rate and blood alanine aminotransferase levels of n-STZ diabetic rats in comparison to their diabetic counterparts. The results from the present study thus suggest that PMQ exhibits great potential as an antidiabetic agent by improving hyperglycemia and reducing the incidence of peripheral complications.

Glycogen synthase kinase-3beta (GSK3beta) is a major negative modulator of cardiac hypertrophy. Here we report that GSK3beta physically and functionally interacts with Smad3. The interaction between GSK3beta and Smad3 may participate in the negative regulation of transforming growth factor beta1 (TGF-beta1) and Angiotensin II-induced transcription and apoptosis. GSK3beta interacted directly with Smad3 to sequester it outside the nucleus and prevent its nuclear translocation. This resulted in the suppression of Smad3-mediated transcriptional activity and gene expression. GSK3beta counteracted the pro-apoptotic effect of Smad3 and attenuated Angiotensin II-induced apoptosis in cardiac myocytes. Furthermore, stimulation of these cells with TGF-beta1 and Angiotensin II led to the endogenous Smad3 disassociating from GSK3beta and inactivating GSK3beta by phosphorylation of its Ser9. These results uncovered a novel mechanism for the GSK3beta negative regulation of TGF-beta1/Smad3 and Angiotensin II/Smad3-mediated transcription and apoptosis by the identification of a crosstalk between GSK3beta and Smad3 signal pathway.