Bis-Pyrano Prenyl Isoflavone Improves Glucose Homeostasis by Inhibiting Dipeptidyl Peptidase-4 in Hyperglycemic Rats.

Isoflavones widely distributed in plants prevent diabetes. This study investigated the in vivo and in vitro effect of 3',4'-dihydroxy-6″,6″,6″',6″'-tetramethylbis(pyrano[2″,3″:5,6::2″',3″':7,8]isoflavone (bis-pyrano prenyl isoflavone) on glucose homeostasis in hyperglycemic rats. The ethyl acetate fraction from aerial parts of Polygala molluginifolia that contain isoflavones was assayed on glucose tolerance, on in vitro maltase activity and on protein glycation. The isoflavone bis-pyrano prenyl isolated from this fraction was investigated on glucose homeostasis. The in vivo action of the isoflavone exhibits an anti-hyperglycemic effect by improving glucose tolerance, augmenting the liver glycogen, inhibiting maltase activity, and stimulating glucagon-like peptide-1 (GLP-1) and insulin secretion. The in vitro isoflavone inhibits dipeptidyl peptidase-4 (DPP-4) activity since the glucose tolerance was improved in the presence of the isoflavone as much as sitagliptin, an inhibitor of DPP-4. However, the co-incubation with isoflavone and sitagliptin exhibited an additive anti-hyperglycemic action. The isoflavone increased the GLP-1 faster than the positive hyperglycemic group, which shows that the intestine is a potential target. Thus, to clarify the main site of action in which isoflavone improves glucose balance, the in vitro mechanism of action of this compound was tested in intestine using calcium influx as a trigger for the signal pathways for GLP-1 secretion. The isoflavone stimulates calcium influx in intestine and its mechanism involves voltage-dependent calcium channels, phospholipase C, protein kinase C, and stored calcium contributing for GLP-1 secretion. In conclusion, the isoflavone regulates glycaemia by acting mainly in a serum target, the DPP-4 inhibitor. Furthermore, the long-term effect of isoflavone prevents protein glycation. J. Cell. Biochem. 118: 92-103, 2017. © 2016 Wiley Periodicals, Inc.

N-phenylmaleimide derivatives as mimetic agents of the pro-inflammatory process: myeloperoxidase activation.

Myeloperoxidase (MPO) is an important enzyme that catalyzes the reaction between hydrogen peroxide and chloride to generate hypochlorous acid, which oxidizes a range of biomolecules and has been associated with inflammatory diseases. The synthetic compounds N-phenylmaleimide (NFM) and 4-methyl-N-phenylmaleimide (Me-NFM) increased the MPO activity in vitro (of isolated enzyme and in isolated cells after animal treatment) and in vivo assays. MPO-induction may represent a good model system to investigate the molecular and cellular mechanisms of oxidative cell injury induced by activated neutrophils, and the interactions between damaging species involved in the respiratory burst.

Roux-en-Y bypass gastroplasty: markers of oxidative stress 6 months after surgery.

BACKGROUND: This study examined the effect of weight loss on energy intake, vitamin C, E, beta-carotene (diet/blood), reduced glutathione (GSH), C-reactive protein (CRP), thiobarbituric acid reactive substances (TBARS), catalase, and myeloperoxidase, in patients with Roux-en-Y bypass gastroplasty. METHODS: Prospective clinical study with control (C) and bariatric (B) groups (n = 20 each). Age was 38.8 +/- 11.1 (C) and 37.8 +/- 11.2 years (B), and body mass indices (BMI) were 22.4 +/- 2.4 and 48.1 +/- 8.7 kg/m(2), respectively. Group C was assessed on a single occasion and B at three time points (basal period and 3 and 6 months after gastroplasty). RESULTS: BMI was decreased at three (38.3 +/- 1.7, P = 0.018) and 6 months after surgery (34.9 +/- 1.7, P < 0.001). Mean weight loss was 20.53 +/- 1.1 after three and 27.96 +/- 1.3 kg after 6 months. Serum vitamin C and beta-carotene (P < 0.01 and P < 0.001, respectively) were increased at 6 months compared to basal. Basal serum vitamin C (P = 0.001) and beta-carotene (P < 0.001) were lower compared to controls. Serum vitamin E corrected for cholesterol and triglycerides was higher in group B at three (P = 0.01) and 6 months (P = 0.001) and lower at basal (P < 0.001) compared to controls. GSH was higher in controls (P < 0.001) compared to basal. Catalase (P = 0.01) and TBARS (P < 0.001) were higher in group B at 6 months. TBARS were higher (P < 0.001) at basal compared to controls. Myeloperoxidase and CRP decreased in group B after three (P = 0.028, P = 0.010) and 6 months (P < 0.001, P = 0.001), respectively. CONCLUSIONS: Roux-en-Y bypass gastroplasty led to decreased proinflammatory parameters together with increased nutritional antioxidants, catalase, and TBARS, and decreased GSH 6 months after surgery.

The anti-inflammatory modulatory role of Solidago chilensis Meyen in the murine model of the air pouch.

The aim of this study was to investigate the anti-inflammatory efficacy of an aqueous extract (AE), and its butanolic (BuOH) and aqueous residual (AR) fractions, derived from the rhizome of Solidago chilensis in inflammation caused by carrageenan in mice. Solidago chilensis Meyen rhizome was extracted using hot water at 90 degrees C under infusion. The extract was filtered and lyophilized. Part of the aqueous extract was fractionated with n-BuOH, resulting in butanolic (BuOH) and aqueous residual (AR) fractions. Adult Swiss mice were used in the in-vivo experiments. We evaluated the effect of rhizome aqueous extract of Solidago chilensis and these two derived fractions on the inflammation induced by carrageenan in the mouse model of the air pouch. The aqueous extract and its derived fractions significantly inhibited leucocytes, neutrophils, exudation, myeloperoxidase and adenosine deaminase activity, as well as nitric oxide, interleukin-1 beta (IL-1beta), neutrophil chemokine (KC) and tumour necrosis factor-alpha (TNF-alpha) levels (P < 0.05). Indometacin and dexamethasone inhibited all the studied inflammatory parameters (P < 0.01) with the exceptions that indometacin did not inhibit TNF-alpha levels and dexamethasone did not inhibit KC levels (P > 0.05). These results indicate that Solidago chilensis has a significant anti-inflammatory action on acute inflammatory responses and that its inhibitory activity may be due not only to the inhibition of proinflammatory mediators, but also to the inhibition of leucocyte infiltration.

Efficacy of tacrolimus in inhibiting inflammation caused by carrageenan in a murine model of air pouch.

BACKGROUND: Tacrolimus (Tac) is a macrolide immunosuppressant drug isolated from Streptomyces tsukubaensis, widely used in organ transplantation. OBJECTIVE: This study examined the effect of tacrolimus administered by oral route (p.o.) on inflammation in mouse subcutaneous air pouch triggered by carrageenan (Cg 1%). METHODS: The air pouch was induced as described by Benincá et al. [Benincá JP, Montanher AB, Zucolotto SM, Schenkel EP, FrödeTS. Anti-inflammatory effects of the Passiflora edulis: forma flavicarpa Degener inhibition of leukocytes, enzymes and pro-inflammatory cytokine levels in the air pouch model, in mice. Food Chem 2007; 104(3); 1097-1105.]. The inflammatory parameters (leukocytes, exudation, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities, as well as nitrate/nitrate concentrations (NO(x)), interleukin-1 beta (IL-1beta), chemokine to neutrophil (KC) and tumor necrosis factor-alpha (TNF-alpha) levels were analysed 24 h after injection of carrageenan. RESULTS: Tacrolimus, indomethacin and dexamethasone significantly inhibited leukocytes, neutrophils and exudation (P<0.05) when they were administered 0.5 h before inflammation. These drugs, under the same conditions, decreased MPO and ADA activities (P<0.05), NO(x) and IL-1beta levels (P<0.01). Tacrolimus and indomethacin, but not dexamethasone, inhibited KC levels (P<0.01). On the other hand, tacrolimus and dexamethasone, but not indomethacin, decreased TNF-alpha levels (P<0.01). CONCLUSIONS: Results of this study indicate that tacrolimus has an important anti-inflammatory property, showing not only inhibition of pro-inflammatory mediators release, but also inhibition of activated leukocyte infiltration into the site of inflammation. Furthermore, these results showed that most of the anti-inflammatory actions of tacrolimus were similar to those observed in animals treated with either indomethacin or dexamethasone.

Efeito antiinflamatório da ciclosporina a no modelo do lavado broncoalveolar, em camundongos sensibilizados / Anti-inflammatory effect of cyclosporine A in bronchoalveolar lavage model in sensitized mice

Neste estudo utilizou-se o modelo do lavado broncoalveolar ( LBA) induzido pela ova l bumina (OVA 25mg/Kg, s.c.). Neste protocolo experimental os camundongos receberam 1 h antes do desafio, solução de azul de Evans (25mg/Kg, i.v.) para quantificação do exsudato. Os objetivos deste trabalho foram: 1) Caracterizar o modelo do LBA avaliando-se os leucócitos e a exsudação no fluido broncoalveolar e em tecidos e 2) Avaliar os e feitos da ciclosporina A (CLP) sobre os parâmetros inflamatórios estudados. Camundongos albinos Suíços receberam OVA ( 50μg+0,8mg Al(OH)3 + 0,4mL NaCl 0,9 por cento, s.c.) por 21 dias. A última dose (desafio) foi de 50μg/mL, s.c.. O grupo-controle recebeu 0,1 de mL NaCl 0,9 por cento estéril, s.c.. Em outros experimentos, diferentes grupos de animais foram tratados com CLP (10 mg/Kg, i.p.) 0,5 h antes do desafio. Os parâmetros inflamatórios foram avaliados 24 h após o desafio. Os resultados obtidos foram expressos em média ± E.P.M.. As diferenças estatísticas foram determinadas pela análise de variância (ANOVA) e complementados com os testes de Dunnet ou teste “t” de student. Valores de P < 0,05 foram considerados significantes. Nos animais tratados com OVA observou-se aumento dos leucócitos, às custas de mononucleares, e exsudação (P < 0,05). A ciclosporina A inibiu o influxo de leucócitos, às custas de mononucleares, no LBA (P < 0,05) e aumentou a exsudação no rim e no baço (P < 0,01). O modelo do LBA, induzido pela OVA, é um modelo de resposta inflamatória aguda com aumento de leucócitos e exsudação. A ciclosporina A demonstrou efeito antiinflamatório inibindo o influxo de leucócitos no LBA.

In this study we used the bronchoalveolar lavage (BAL) model, of sensitized mice with ovalbumin (25mg/Kg, s.c.). To ana -lyze the exudation 1 h before challenge the animals received 0.2 ml of Evans blue dye (25mg/kg, i.v.). The aim of this study were 1) To characterize the BAL model evaluating the leukocyte and exudationin the BAL and tissues, and 2) To analyze the effect of cyclosporine A (CLP) on the inflammatory parameters described before. The Swiss mice received OVA (50μg + 0,8mg Al(OH)3 + 0,4mL NaCl0.9 percent, s.c.) for 21 days. The last dose (challenge) of OVA was 50μg/mL s.c. The control-group received 0.1mL of sterile saline (NaCl 0.9 percent, s.c.). In another set of experiments, different groups of animals received CLP (10mg/Kg, i.p.) 0,5h before challenge. The inflammatory parameters were analyzed 24h after challenge. The results were expressed by mean ± S.E.M.. The statistical differences between groups were determined by analysis of variance (ANOVA) and complemented with Dunnett or student t tests. Values of P<0.05 were considered significant. In OVA-treated animals (25mg/Kg, s.c.) we observed a significant increase of leukocytes influx, due to mononuclear migration, as well as exudation (P<0.01). The cyclosporine A (CLP) 10mg/Kg, i.p, inhibited the leukocyte influx, due to mononuclear (P<0.05) and a significant increase of exudation in the BAL and organs (kidney and spleen) (P<0.05). The BAL model induced by OVA promotes an acute inflammatory response with significant in crease of leukocytes and exudation. CLP had important anti-inflammatory proprieties, inhibiting priory leukocyte migration into the BAL.