Insulin stimulus-secretion coupling is triggered by a novel thiazolidinedione/sulfonylurea hybrid in rat pancreatic islets.

New compounds with promising antidiabetic activity were synthesized. For the first time, a portion of the glibenclamide molecule was bound to a part of the core structure of thiazolidinedione to evaluate insulin secretagogue activity. Following studies in our laboratory, 4-{2-[2-(3,4-dichlorophenyl)-4-oxo-1,3-thiazolidin-3-yl]ethyl}benzene-1-sulfonamide (DTEBS) was selected to evaluate glycemia using the glucose tolerance test and insulin secretagogue activity by E.L.I.S.A. The mechanism of action of this compound was studied by 45 Ca2+ influx and whole-cell patch-clamp in rat pancreatic isolated islets. Furthermore, AGE formation in vitro was investigated. We herein show that this novel hybrid compound (DTEBS) exhibits an insulinogenic index and a profile of serum insulin secretion able to maintain glucose homeostasis. Its mechanism of action is mediated by ATP-sensitive potassium channels (KATP) and L-type voltage-dependent calcium channels (VDCC) and by activating protein kinase C and A (PKC and PKA). In addition, the stimulatory action of the compound on calcium influx and insulin secretion indicates that the potentiation of voltage-sensitive K+ currents (Kv) is due to the repolarization phase of the action potential after secretagogue excitation-secretion in pancreatic islets. Furthermore, under these experimental conditions, the compound did not induce toxicity and the in vitro late response of the compound to protein glycation reinforces its use to prevent complications of diabetes. DTEBS exerts an insulin secretagogue effect by triggering KATP, VDCC, and Kv ionic currents, possibly via PKC and PKA pathway signal transduction, in beta-cells. Furthermore, DTEBS may hold potential for delaying the late complications of diabetes.

Mechanism of action of camphoryl-benzene sulfonamide derivative on glucose uptake in adipose tissue.

The aim of the present study was to investigate the mechanism of action of a sulfonamide derivative on glucose uptake in adipose tissue, as well as to characterize the effects of this compound on intestinal disaccharidases and advanced glycation end-products (AGEs) formation. Camphoryl-benzene sulfonamide (CS) was able to stimulate glucose uptake in isolated adipocytes, adipose tissue, and in soleus muscle. The stimulatory effect of the compound (10 µM) on glucose uptake on adipose tissue was blocked by diazoxide, wortmannin, U73122, colchicine, and N-ethylmaleimide. On the other hand, the effects of CS were not blocked by glibenclamide, an inhibitor of the K+ -ATP channel, or even by the inhibitor of protein p38 MAPK, SB 203580. In vivo, this compound reduced intestinal disaccharidase activity, while, in vitro, CS reduced the formation of AGEs at 7, 14, and 28 days of incubation. The stimulatory effect of CS on glucose uptake requires the activation of the K+ -ATP channel, translocation, and fusion of GLUT4 vesicles to the plasma membrane on adipocytes for glucose homeostasis. In addition, the inhibition of disaccharidase activity contributes to the glucose homeostasis in a short-term as well as the remarkable reduction in AGE formation indicates that the CS may prevent of complications of late diabetes.

Antioxidant and anti-inflammatory effect of polysaccharides from Lobophora variegata on zymosan-induced arthritis in rats.

This study analyzes the action of sulfated polysaccharides, fucans, from algae Lobophora variegata on zymosan-induced arthritis in rats. Groups of fucans, obtained after acetone fractionation (0.3-2.0 volumes), were denominated F0.3, F0.5, F0.8, F1, F1.5, and F2. The results that F1 contained a high yield in relation to other fractionated fucans. Chemical and structure analysis of F1 was performed by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies. The in vitro antioxidant activities of the fraction F1 were also observed. Thus, 2 mg/mL of F1 inhibited the phosphomolybdate in the total antioxidant activity assay. The EC(50) values were 0.3 mg/mL and 0.12 mg/mL for superoxide and hydroxyl radicals, respectively. Fucan F1 (25, 50, and 75 mg/kg by body weight), diclofenac sodium (10 mg/kg), and L-NAME (25 mg/kg) were administered intraperitoneally (i.p.) in rats, according to body weight of different groups of animals (n=6). After 6 h, analyses of cell influx and nitrite levels were conducted. Then after 96 h, analysis of edema and concentration of serum TNF-α was carried out along with histopathological analysis. F1 at 25, 50, and 75 mg/kg i.p. by body weight reduced cell influx in 52.1-96.7% and nitric oxide level in 27.2-39% compared with the control group. The reduction of edema and serum TNF-α was observed at 50 mg/kg i.p. (p<0.001). These results suggest that this heterofucan from the brown algae L. variegata has potential anti-inflammatory activity in acute zymosan-induced arthritis in rats and that antioxidant activity promotes modulation in the cellular redox state.

Glucans from the Caripia montagnei mushroom present anti-inflammatory activity.

Caripia montagnei is a basidiomycete species which contains polysaccharides with immunomodulatory properties. An extract of this mushroom underwent removal of the fat content by organic solvent and subsequently proteolysis. The aqueous phase obtained after proteolysis was precipitated with methanol yielding a fraction containing carbohydrates (98.7+/-3.3%) and protein (1.3+/-0.25%). Chemical analysis, infrared spectroscopy and nuclear magnetic resonance (NMR) showed that the carbohydrate fraction contained (63.3+/-4.1) of beta-glucans and proteins (2.2+/-0.3%). These glucans (50mg/kg of body weight) significantly reduced the inflammatory infiltrate produced by thioglycolate-induced peritonitis by 75.5+/-5.2%, when compared to Wy-14643 (60.3+/-6.1%), PFOA (37.8+/-2.8%) and clofibrate (52.2+/-3.2%), p<0.001, which are of the peroxisome proliferator-activated receptor (PPAR-alpha). L-NAME, a nitric oxide synthase inhibitor, reduced the plantar edema in Wistar rats by 91.4+/-1.3% (p<0.001). A significant reduction in nitric oxide (NO) levels was observed in the exudates when the glucans was used in comparison to carrageenan. The C. montagnei glucans did not present signs of inducing cytotoxicity. A decrease in IL-1ra, IL-10 and IFN-gamma in the peritonitis model was observed. Thus, the results suggest that glucans from the C. montagnei mushroom is an effective immunomodulator and may have potential for anti-inflammatory properties.