RÉSUMÉ
Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor A(VEGF-A) modulates tumor EC response to exclude T-cells are not well understood. Here, we demonstrate that EC-specific deletion of small GTPase Rap1B, previously implicated in normal angiogenesis, restricts tumor growth in endothelial-specific Rap1B-knockout (Rap1BiΔEC) mice. EC-specific Rap1B deletion inhibits angiogenesis, but also leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T-cells. Depletion of CD8+ T-cells restored tumor growth in Rap1BiΔEC mice. Mechanistically, global transcriptome and functional analyses indicated upregulation of signaling by a tumor cytokine, TNF-α, and increased NF-κB transcription in Rap1B-deficient ECs. Rap1B-deficiency led to elevated proinflammatory chemokine and Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was elevated in tumor ECs from Rap1BiΔEC mice. Significantly, Rap1B deletion prevented VEGF-A-induced immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-A-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-A-dependent desensitization of EC to proinflammatory stimuli. Significantly, they identify EC Rap1B as a potential novel vascular target in cancer immunotherapy.
Sujet(s)
Lymphocytes T CD8+ , Cellules endothéliales , Tumeurs , Protéines G rap , Animaux , Souris , Lymphocytes T CD8+/immunologie , Immunosuppression thérapeutique , Tumeurs/vascularisation , Tumeurs/génétique , Tumeurs/immunologie , Microenvironnement tumoral/génétique , Microenvironnement tumoral/immunologie , Facteur de nécrose tumorale alpha/génétique , Facteur de nécrose tumorale alpha/immunologie , Facteur de croissance endothéliale vasculaire de type A/génétique , Facteur de croissance endothéliale vasculaire de type A/immunologie , Cellules endothéliales/immunologie , Cellules endothéliales/physiologie , Facteur de transcription NF-kappa B/génétique , Facteur de transcription NF-kappa B/immunologie , Protéines G rap/génétique , Protéines G rap/immunologieRÉSUMÉ
Recent studies indicate cell death is the hallmark of cardiac pathology in myocardial infarction and diabetes. The AMP-activated protein kinase (AMPK) signalling pathway is considered a putative salvaging phenomenon, plays a decisive role in almost all cellular, metabolic, and survival functions, and therefore entails precise regulation of its activity. AMPK regulates various programmed cell death depending on the stimuli and context, including autophagy, apoptosis, necroptosis, and ferroptosis. There is substantial evidence suggesting that AMPK is down-regulated in cardiac tissues of animals and humans with type 2 diabetes or metabolic syndrome compared to non-diabetic control and that stimulation of AMPK (physiological or pharmacological) can ameliorate diabetes-associated cardiovascular complications, such as myocardial ischemia-reperfusion injury. Furthermore, AMPK is an exciting therapeutic target for developing novel drug candidates to treat cell death in diabetes-associated myocardial ischemia-reperfusion injury. Therefore, in this review, we summarized how AMPK regulates autophagic, apoptotic, necroptotic, and ferroptosis pathways in the context of myocardial ischemia-reperfusion injury in the presence and absence of diabetes.
Sujet(s)
Diabète de type 2 , Lésion de reperfusion myocardique , Humains , Animaux , Lésion de reperfusion myocardique/métabolisme , AMP-Activated Protein Kinases/métabolisme , Diabète de type 2/complications , Autophagie , ApoptoseRÉSUMÉ
[This corrects the article DOI: 10.3389/fcell.2021.687598.].
RÉSUMÉ
Small GTPase Rap1 plays a prominent role in endothelial cell (EC) homeostasis by promoting NO release. Endothelial deletion of the two highly homologous Rap1 isoforms, Rap1A and Rap1B, leads to endothelial dysfunction ex vivo and hypertension in vivo. Mechanistically, we showed that Rap1B promotes NO release in response to shear flow by promoting mechanosensing complex formation involving VEGFR2 and Akt activation. However, the specific contribution of the Rap1A isoform to NO release and the underlying molecular mechanisms through which the two Rap1 isoforms control endothelial function are unknown. Here, we demonstrate that endothelial dysfunction resulting from knockout of both Rap1A and Rap1B isoforms is ameliorated by exogenous L-Arg administration to rescue NO-dependent vasorelaxation and blood pressure. We confirmed that Rap1B is rapidly activated in response to agonists that trigger eNOS activation, and its deletion in ECs attenuates eNOS activation, as detected by decreased Ser1177 phosphorylation. Somewhat surprising was the finding that EC deletion of Rap1A does not lead to impaired agonist-induced vasorelaxation ex vivo. Mechanistically, the deletion of Rap1A led to elevated eNOS phosphorylation both at the inhibitory, T495, and the activating Ser1177 residues. These findings indicate that the two Rap1 isoforms act via distinct signaling pathways: while Rap1B directly positively regulates eNOS activation, Rap1A prevents negative regulation of eNOS. Notably, the combined deficiency of Rap1A and Rap1B has a severe effect on eNOS activity and NO release with an in vivo impact on endothelial function and vascular homeostasis.
RÉSUMÉ
OBJECTIVE: Small GTPase Rap1 (Ras-association proximate 1) is a novel, positive regulator of NO release and endothelial function with a potentially key role in mechanosensing of atheroprotective, laminar flow. Our objective was to delineate the role of Rap1 in the progression of atherosclerosis and its specific functions in the presence and absence of laminar flow, to better define its role in endothelial mechanisms contributing to plaque formation and atherogenesis. Approach and Results: In a mouse atherosclerosis model, endothelial Rap1B deletion exacerbates atherosclerotic plaque formation. In the thoracic aorta, where laminar shear stress-induced NO is otherwise atheroprotective, plaque area is increased in Athero-Rap1BiΔEC (atherogenic endothelial cell-specific, tamoxifen-inducible Rap1A+Rap1B knockout) mice. Endothelial Rap1 deficiency also leads to increased plaque size, leukocyte accumulation, and increased CAM (cell adhesion molecule) expression in atheroprone areas, whereas vascular permeability is unchanged. In endothelial cells, in the absence of protective laminar flow, Rap1 deficiency leads to an increased proinflammatory TNF-α (tumor necrosis factor alpha) signaling and increased NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and elevated inflammatory receptor expression. Interestingly, this increased signaling to NF-κB activation is corrected by AKTVIII-an inhibitor of Akt (protein kinase B) translocation to the membrane. Together, these data implicate Rap1 in restricting Akt-dependent signaling, preventing excessive cytokine receptor signaling and proinflammatory NF-κB activation. CONCLUSIONS: Via 2 distinct mechanisms, endothelial Rap1 protects from the atherosclerosis progression in the presence and absence of laminar flow; Rap1-stimulated NO release predominates in laminar flow, and restriction of proinflammatory signaling predominates in the absence of laminar flow. Our studies provide novel insights into the mechanisms underlying endothelial homeostasis and reveal the importance of Rap1 signaling in cardiovascular disease.
Sujet(s)
Aorte/métabolisme , Maladies de l'aorte/prévention et contrôle , Athérosclérose/prévention et contrôle , Cellules endothéliales/métabolisme , Médiateurs de l'inflammation/métabolisme , Inflammation/prévention et contrôle , Protéines G rap/métabolisme , Animaux , Aorte/anatomopathologie , Maladies de l'aorte/génétique , Maladies de l'aorte/métabolisme , Maladies de l'aorte/anatomopathologie , Athérosclérose/génétique , Athérosclérose/métabolisme , Athérosclérose/anatomopathologie , Cellules cultivées , Cytokines/métabolisme , Alimentation riche en graisse , Modèles animaux de maladie humaine , Évolution de la maladie , Cellules endothéliales/anatomopathologie , Femelle , Humains , Inflammation/génétique , Inflammation/métabolisme , Inflammation/anatomopathologie , Leucocytes/métabolisme , Mâle , Souris de lignée C57BL , Souris invalidées pour les gènes ApoE , Facteur de transcription NF-kappa B/métabolisme , Monoxyde d'azote/métabolisme , Plaque d'athérosclérose , Transduction du signal , Protéines G rap/génétique , Protéines G rap1/génétique , Protéines G rap1/métabolismeRÉSUMÉ
Myocardial ischemic postconditioning- (IPo-) mediated cardioprotection against myocardial ischemia-reperfusion (IR) injury needs the activation of signal transducer and activator of transcription 3 (STAT3), which involves adiponectin (APN). APN confers its biological effects through AMP-activated protein kinase- (AMPK-) dependent and AMPK-independent pathways. However, the role of AMPK in APN-mediated STAT3 activation in IPo cardioprotection is unknown. We hypothesized that APN-mediated STAT3 activation in IPo is AMPK-independent and that APN through AMPK-dependent STAT3 activation facilitates IPo cardioprotection. Here, Sprague-Dawley rats were subjected to myocardial IR without or with IPo and/or APN. APN or IPo significantly improved postischemic cardiac function and reduced myocardial injury and oxidative stress, and their combination further attenuated postischemic myocardial injuries. APN or its combination with IPo but not IPo alone significantly increased AMPK activation and both nuclear and mitochondrial STAT3 activation, while IPo significantly enhanced mitochondrial but not nuclear STAT3 activation. In primarily isolated cardiomyocytes, recombined globular APN (gAd), hypoxic postconditioning (HPo), or their combination significantly attenuated hypoxia/reoxygenation-induced cell injury and increased nuclear and/or mitochondrial STAT3 activation. STAT3 inhibition had no impact on gAd or gAd in combination with HPo-induced AMPK activation but abolished their cellular protective effects. AMPK inhibition did not affect HPo cardioprotection but abolished gAd cardioprotection and disabled gAd to facilitate/enhance HPo cardioprotection and STAT3 activation. These results suggest that APN confers cardioprotection through AMPK-dependent and AMPK-independent STAT3 activation, while IPo confers cardioprotection through AMPK-independent mitochondrial STAT3 activation. Joint use of APN and IPo synergistically attenuated myocardial IR injury by activating STAT3 via distinct signaling pathways.
Sujet(s)
AMP-Activated Protein Kinases/métabolisme , Adiponectine/pharmacologie , Cardiotoniques/métabolisme , Noyau de la cellule/métabolisme , Mitochondries/métabolisme , Facteur de transcription STAT-3/métabolisme , AMP-Activated Protein Kinases/antagonistes et inhibiteurs , Animaux , Hypoxie cellulaire/effets des médicaments et des substances chimiques , Noyau de la cellule/effets des médicaments et des substances chimiques , Activation enzymatique/effets des médicaments et des substances chimiques , Hémodynamique/effets des médicaments et des substances chimiques , Postconditionnement ischémique , Mâle , Mitochondries/effets des médicaments et des substances chimiques , Myocarde/enzymologie , Myocarde/anatomopathologie , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/métabolisme , Myocytes cardiaques/anatomopathologie , Rat Sprague-Dawley , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Ca2+ is a universal intracellular signal. The modulation of cytoplasmic Ca2+ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation-contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers-cyclic adenosine monophosphate (cAMP), Ca2+, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca2+ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca2+ signaling when activated by mechanisms involving Ca2+ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca2+ levels. It does so by regulating the activity of Ca2+ signaling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca2+ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer's disease, hypertension, and atherosclerosis, among other diseases.
Sujet(s)
Signalisation calcique/génétique , Calcium/métabolisme , Cardiomégalie/métabolisme , Maladies neurodégénératives/métabolisme , Protéines G rap1/métabolisme , Animaux , Ca(2+) Mg(2+)-ATPase/génétique , Ca(2+) Mg(2+)-ATPase/métabolisme , Ca(2+) Mg(2+)-ATPase/physiologie , Cardiomégalie/génétique , AMP cyclique/métabolisme , Diglycéride/métabolisme , Endothélium/métabolisme , Endothélium/physiologie , Humains , Intégrines/génétique , Intégrines/métabolisme , Muscles lisses vasculaires/métabolisme , Maladies neurodégénératives/génétique , Récepteurs de type Toll/immunologie , Vasodilatation/génétique , Vasodilatation/physiologie , Protéines G rap1/génétiqueRÉSUMÉ
Chronic consumption of unhealthy diet and sedentary lifestyle induces fatty liver and metabolic complications. Adipocytes get overloaded with lipid succeeding low-grade inflammation and disrupting adipokine release. This research aims to investigate the effect of sitagliptin on white adipose tissue inflammation, adipokine level, metabolic syndrome, and fatty liver through 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. In sixteen weeks of the experimental protocol, Swiss albino mice were kept in a standard environment and were fed 60% high-fat diet and 20% fructose water (HFFW) where they developed metabolic syndrome features, adipose tissue inflammation, and altered adipokine profile. Sitagliptin was administered for the last eight weeks. They were allocated to following six groups, control diet with regular water (1), HFFW only (2), HFFW and metformin 100â¯mg/kg (3), HFFW and sitagliptin 10â¯mg/kg (4), HFFW and sitagliptin 20â¯mg/kg (5), and HFFW and sitagliptin 30â¯mg/kg (6). Fasting serum insulin (FSI), glucagon-like peptide-1 (GLP-1), adipokines (adiponectin and leptin), serum lipid profile, hepatic lipid content, and white adipose tissue inflammation were assessed. Protein expression of P-AMPK, P-Acetyl co-a carboxylase (ACC), and mRNA expression of fatty acid metabolism genes were also evaluated in the liver. Sitagliptin significantly and effectively reversed metabolic syndrome complexity. FSI and GLP-1 levels were improved. A significant reduction in hepatic lipid content and oxidative stress was also observed. Also, sitagliptin significantly ameliorated adipose tissue inflammation and adiponectin levels at 20â¯mg/kg and 30â¯mg/kg. P-AMPK and P-ACC expression increased significantly. Moreover, expression of fatty acid synthesis genes was down-regulated, and fatty acid oxidation genes were up-regulated. Sitagliptin significantly ameliorated obesity-induced adipose tissue inflammation, metabolic syndrome, and fatty liver via regulation of adiponectin and AMPK levels in obese mice. Also, increased GLP-1 levels would have induced insulin-independent effects on adipose tissue and liver.
Sujet(s)
AMP-Activated Protein Kinases/métabolisme , Adiponectine/métabolisme , Stéatose hépatique/traitement médicamenteux , Inflammation/traitement médicamenteux , Syndrome métabolique X/traitement médicamenteux , Phosphate de sitagliptine/pharmacologie , Tissu adipeux blanc/effets des médicaments et des substances chimiques , Tissu adipeux blanc/métabolisme , Animaux , Inflammation/métabolisme , Métabolisme lipidique/effets des médicaments et des substances chimiques , Foie/effets des médicaments et des substances chimiques , Foie/anatomopathologie , Mâle , Souris , Stress oxydatif/effets des médicaments et des substances chimiquesRÉSUMÉ
In the whole world, the principal cause of end-stage renal disease is diabetic nephropathy (DN), which is one of the most relentless complications of diabetes. However, there is a shortfall of compelling DN treatments and the mechanism potentially able to alleviate renal injury remains ambiguous. In this experiment, we estimated the preventive actions of tetramethylpyrazine (TMP) on DN in rats and further investigated the underlying mechanism. The different doses of TMP (100â¯mg/kg, 150â¯mg/kg and 200â¯mg/kg) were orally given each day for 8 weeks in streptozotocin (STZ) - nicotinamide (NCT) - induced type-2 diabetic (T2D) rats. The metabolic parameters of diabetes, blood urea nitrogen (BUN), serum creatinine (SCR), urinary protein and oxidative stress parameters were assessed. Microstructural changes in kidney were observed, and the expression of Akt signalling pathway proteins was measured by western blotting. TMP administration in T2D rats improved diabetic condition, as demonstrated by significant (Pâ¯<â¯0.05) increase of body weight and fasting serum insulin (FSI) level, reduction of fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c) level and regulation of lipid profile and oral glucose tolerance in a dose-dependent manner. TMP treatment also reduced BUN, SCR, urinary protein and oxidative stress and prevented renal injury in diabetic rats. TMP activated Akt signalling pathway, increased the levels of p-Akt and Bcl-2, and diminished the expressions of p-GSK-3ß, Bax and cleaved caspase-3. In conclusion, TMP ameliorates diabetic nephropathy in T2D rats by initiating the Akt signalling, improving the metabolic markers of diabetes and suppressing oxidative stress.
Sujet(s)
Diabète expérimental/traitement médicamenteux , Diabète de type 2/traitement médicamenteux , Néphropathies diabétiques/traitement médicamenteux , Défaillance rénale chronique/traitement médicamenteux , Agents protecteurs/usage thérapeutique , Protéines proto-oncogènes c-akt/métabolisme , Pyrazines/usage thérapeutique , Animaux , Diabète expérimental/métabolisme , Diabète expérimental/anatomopathologie , Diabète de type 2/métabolisme , Diabète de type 2/anatomopathologie , Néphropathies diabétiques/métabolisme , Néphropathies diabétiques/anatomopathologie , Rein/effets des médicaments et des substances chimiques , Rein/anatomopathologie , Défaillance rénale chronique/métabolisme , Défaillance rénale chronique/anatomopathologie , Mâle , Stress oxydatif/effets des médicaments et des substances chimiques , Agents protecteurs/pharmacologie , Pyrazines/pharmacologie , Rat Wistar , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
AIMS: The present experiment was conceptualised to explore the therapeutic response of tetramethylpyrazine (TMP), a major active constituent of Ligusticum chuanxiong, a Chinese traditional medicinal plant, in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes in rats and to identify the possible mechanism of action. MAIN METHODS: Dose-reliant effect of oral treatment of TMP (100, 150 and 200â¯mg/kg/day) for 28â¯days was evaluated by calculating the alteration in body weight, level of fasting blood glucose (FBG), plasma insulin, homeostasis model assessment (HOMA), serum lipids, oral glucose & intraperitoneal insulin tolerance and glycosylated haemoglobin in HFD-STZ-induced type-2 diabetic (T2D) rats and underlying molecular mechanisms of TMP was also studied. KEY FINDINGS: TMP treatment prominently reduced the level of FBG, glycosylated haemoglobin and revived body weight gain and level of serum insulin dose-dependently in diabetic rats. TMP treatment considerably improved insulin resistance, as observed in oral glucose tolerance and insulin tolerance tests. Moreover, dose-dependent reduction in the level of pro-inflammatory cytokines, C-reactive protein (CRP) and interleukin-6 (IL-6) was observed and their level was found to be significantly reduced in highest dose TMP (200â¯mg/kg) treated diabetic rats, pointing towards TMP mediated recovery of insulin signalling and a decrease in insulin resistance. The expressions of p-PI3K-p85/p-Akt/GLUT-4 were also significantly up-regulated by TMP (200â¯mg/kg), suggesting the connection of the PI3K/Akt signal pathway in the anti-hyperglycemic action of TMP. SIGNIFICANCE: These findings suggest that TMP may be used as a potential agent for type-2 diabetes treatment.
Sujet(s)
Diabète expérimental/prévention et contrôle , Diabète de type 2/prévention et contrôle , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Transporteur de glucose de type 4/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Pyrazines/pharmacologie , Animaux , Glycémie , Diabète expérimental/étiologie , Diabète expérimental/métabolisme , Diabète expérimental/anatomopathologie , Diabète de type 2/étiologie , Diabète de type 2/métabolisme , Diabète de type 2/anatomopathologie , Alimentation riche en graisse/effets indésirables , Modèles animaux de maladie humaine , Transporteur de glucose de type 4/génétique , Mâle , Phosphatidylinositol 3-kinases/génétique , Protéines proto-oncogènes c-akt/génétique , Rats , Rat Wistar , Transduction du signal , Vasodilatateurs/pharmacologieRÉSUMÉ
BACKGROUND/AIMS: Pterostilbene (PT) exerts antidiabetic effects by decreasing blood glucose and modulating lipid metabolism and has been shown to attenuate myocardial ischemia-reperfusion (IR) injury in non-diabetic subjects. However, whether PT can protect against myocardial IR injury in diabetes is unknown. AMPK stimulation is indispensable in offering cardioprotection against myocardial IR injury in diabetes by limiting cardiac apoptosis. Thus, we hypothesized that PT may confer protection against myocardial IR injury in diabetes via AMPK activation. METHODS: Sprague-Dawley rats at eight weeks of diabetes induction (induced by an intravenous dose of 65 mg/kg streptozotocin) were administered with vehicle or PT (20 and 40 mg/kg/day, p.o.) for four weeks (starting from week 9 to 12). At the end of week 12, myocardial IR injury was induced by subjecting the diabetic rats to 30 minutes of coronary artery ligation and followed by 2 hours of reperfusion. In in vitro studies, rat primary cardiomyocytes were incubated with low glucose (LG, 5.5 mM) or high glucose (HG, 30 mM) and exposed to 45 minutes hypoxia and 2 hours reoxygenation in the presence or absence of PT (0.5 µM) or the AMPK inhibitor compound C (CC, 5 µM). RESULTS: PT significantly reduced post-ischemic cardiac infarct size, oxidative stress, plasma lactate dehydrogenase (LDH), creatine kinase-MB levels and apoptosis in diabetic rats. In cardiomyocytes, PT decreased hypoxia/ reoxygenation-induced oxidative stress, attenuated LDH and cleaved caspase3/caspase3 ratio and increased Bcl-2/Bax ratio and AMPK phosphorylation. However, CC administration blunted the cardioprotective effects of PT both in vivo and in vitro. CONCLUSION: Suppressing cardiac oxidative stress and apoptosis via AMPK stimulation may represent a primary mechanism whereby pterostilbene attenuates diabetic myocardial IR injury.
Sujet(s)
AMP-Activated Protein Kinases/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Lésion de reperfusion myocardique/prévention et contrôle , Stress oxydatif/effets des médicaments et des substances chimiques , Stilbènes/pharmacologie , AMP-Activated Protein Kinases/antagonistes et inhibiteurs , Animaux , Caspase-3 , Hypoxie cellulaire , Cellules cultivées , Vaisseaux coronaires/traumatismes , MB Creatine kinase/sang , Diabète expérimental/induit chimiquement , Diabète expérimental/anatomopathologie , Glucose/pharmacologie , L-Lactate dehydrogenase/sang , Mâle , Lésion de reperfusion myocardique/étiologie , Lésion de reperfusion myocardique/métabolisme , Myocytes cardiaques/cytologie , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/métabolisme , Phosphorylation/effets des médicaments et des substances chimiques , Protéines proto-oncogènes c-bcl-2/métabolisme , Rats , Rat Sprague-Dawley , Espèces réactives de l'oxygène/métabolisme , Stilbènes/usage thérapeutique , Streptozocine/toxicité , Protéine Bax/métabolismeRÉSUMÉ
PURPOSE: Oxidative stress has a pivotal role in the pathogenesis of diabetes-associated cardiovascular problems, which has remained a primary cause of the increased morbidity and mortality in diabetic patients. It is of paramount importance to prevent the diabetes-associated cardiac complications by reducing oxidative stress with the help of nutritional or pharmacological agents. Pterostilbene (PT), the primary antioxidant in blueberries, has recently gained attention for its promising health benefits in metabolic and cardiac diseases. However, the mechanism whereby PT reduces diabetic cardiac complications is currently unknown. METHODS: Sprague-Dawley rats were fed with 65% fructose diet with or without PT (20 mg kg-1 day-1) for 8 weeks. Heart rate and blood pressure were measured by tail-cuff apparatus. Real-time PCR and western blot experiments were executed to quantify the expression levels of mRNA and protein, respectively. RESULTS: Fructose-fed rats demonstrated cardiac hypertrophy, hypertension, enhanced myocardial oxidative stress, inflammation and increased NF-κB expression. Administration of PT significantly decreased cardiac hypertrophy, hypertension, oxidative stress, inflammation, NF-κB expression and NLRP3 inflammasome. We demonstrated that PT improved mitochondrial biogenesis as evidenced by increased protein expression of PGC-1α, complex III and complex V in fructose-fed diabetic rats. Further, PT increased protein expressions of AMPK, Nrf2, HO-1 in cardiac tissues, which may account for the prevention of cardiac oxidative stress and inflammation in fructose-fed rats. CONCLUSIONS: Collectively, PT reduced cardiac oxidative stress and inflammation in diabetic rats through stimulation of AMPK/Nrf2/HO-1 signalling.
Sujet(s)
AMP-Activated Protein Kinases/métabolisme , Anti-inflammatoires/pharmacologie , Antioxydants/pharmacologie , Diabète/traitement médicamenteux , Cardiomyopathies diabétiques/prévention et contrôle , Fructose , Heme oxygenase (decyclizing)/métabolisme , Inflammation/prévention et contrôle , Myocarde/enzymologie , Facteur-2 apparenté à NF-E2/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Stilbènes/pharmacologie , Animaux , Glycémie/effets des médicaments et des substances chimiques , Glycémie/métabolisme , Diabète/sang , Diabète/enzymologie , Cardiomyopathies diabétiques/enzymologie , Cardiomyopathies diabétiques/anatomopathologie , Cardiomyopathies diabétiques/physiopathologie , Modèles animaux de maladie humaine , Hémodynamique/effets des médicaments et des substances chimiques , Inflammasomes/métabolisme , Inflammation/enzymologie , Médiateurs de l'inflammation/métabolisme , Mâle , Mitochondries du myocarde/effets des médicaments et des substances chimiques , Mitochondries du myocarde/enzymologie , Mitochondries du myocarde/anatomopathologie , Myocarde/anatomopathologie , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Rat Sprague-Dawley , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Mammalian Rap1, the most conserved telomere-interacting protein, beyond its role within nucleus for the maintenance of telomeric functions, is also well known for its pleiotropic functions in various physiological and pathological conditions associated with metabolism, inflammation and oxidative stress. For all these, nowadays Rap1 is the subject of critical investigations aimed to unveil its molecular signaling pathways and to scrutinize the applicability of its modulation as a promising therapeutic strategy with clinical relevance. However, the underlying intimate mechanisms of Rap1 are not extensively studied, but any modulation of this protein level has been associated with pathologies like inflammation, oxidative stress and deregulated metabolism. This is considerably important in light of the recent discovery of Rap1 modulation in diseases like cancer and cardiac metabolic disorders. In this review, we focus on both the telomeric and nontelomeric functions of Rap1 and its modulation in various health risks, especially on the heart.
Sujet(s)
Réparation de l'ADN , ADN/génétique , Cardiomyopathies diabétiques/génétique , Homéostasie des télomères , Protéines télomériques/génétique , Télomère/métabolisme , Animaux , ADN/métabolisme , Cardiomyopathies diabétiques/métabolisme , Cardiomyopathies diabétiques/anatomopathologie , Régulation de l'expression des gènes , Humains , Voies et réseaux métaboliques/génétique , Souris , Stress oxydatif , Liaison aux protéines , Complexe shelterine , Transduction du signal , Télomère/ultrastructure , Protéines télomériques/composition chimique , Protéines télomériques/métabolismeRÉSUMÉ
AIMS: The present investigation was designed to explore the effectiveness of pterostilbene (PT) on insulin resistance, metabolic syndrome and oxidative stress in fructose-fed insulin resistant rats. MAIN METHODS: Age-matched, male Sprague-Dawley rats (330±30g body weight) were allocated into five groups (n=10). Control (C) group received 65% cornstarch, and the diabetic (D) group received 65% fructose for eight weeks. The third group (D+PT20) received 65% fructose and PT 20mg/kg/day for eight weeks. The fourth group (D+PT40) received 65% fructose and PT 40mg/kg/day for eight weeks. The fifth group (D+M) received 65% fructose and metformin (M) 100mg/kg/day for eight weeks. PT was dissolved in 10% ß-cyclodextrin and given orally to rats. Several biochemical parameters were determined to assess the PT efficacy against insulin resistance, metabolic complications, and hepatic oxidative stress. KEY FINDINGS: Significantly high HOMA-IR (p<0.001) values in D group compared to C group indicate the presence of insulin resistance. Significantly high levels of TBARS (p<0.001) and decreased levels of SOD (p<0.001) and GSH (p<0.001) in hepatic tissues of D group indicate oxidative stress associated with insulin resistance. Pterostilbene treatment to fructose-fed diabetic rats significantly decreased HOMA-IR (p<0.001) values. Furthermore, PT treatment significantly decreased hepatic TBARS (p<0.001) and increased SOD (p<0.001) and GSH (p<0.001) levels in fructose-fed diabetic rats. SIGNIFICANCE: Current study reveals that PT is successful in ameliorating glycemic control, insulin sensitivity while diminishing metabolic disturbances and hepatic oxidative stress in a fructose-induced T2DM rat model.
Sujet(s)
Diabète expérimental/traitement médicamenteux , Diabète de type 2/traitement médicamenteux , Insulinorésistance , Stress oxydatif/effets des médicaments et des substances chimiques , Stilbènes/pharmacologie , Animaux , Glycémie/effets des médicaments et des substances chimiques , Diabète expérimental/physiopathologie , Diabète de type 2/physiopathologie , Fructose/administration et posologie , Mâle , Syndrome métabolique X/traitement médicamenteux , Metformine/pharmacologie , Rats , Rat Sprague-Dawley , Stilbènes/administration et posologie , Superoxide dismutase/métabolisme , Substances réactives à l'acide thiobarbiturique/métabolisme , Cyclodextrines bêta/composition chimiqueRÉSUMÉ
The present study explored the potential causal link between ischemia-driven cyclooxygenase-2 (COX-2) expression and enhanced apoptosis during myocardial ischemia/reperfusion (I/R) by using H9C2 cardiomyocytes and primary rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R). The results showed that H/R resulted in higher COX-2 expression than that of controls, which was prevented by pretreatment with Helenalin (NFκB specific inhibitor). Furthermore, pretreatment with NS398 (COX-2 specific inhibitor) significantly attenuated H/R-induced cell injury [lower lactate dehydrogenase (LDH) leakage and enhanced cell viability] and apoptosis (higher Bcl2 expression and lower level of cleaved caspases-3 and TUNEL-positive cells) in cardiomyocytes. The amelioration of posthypoxic apoptotic cell death was paralleled by significant attenuation of H/R-induced increases in proinflammatory cytokines [interleukin 6 (IL6) and tumor necrosis factor (TNFα)] and reactive oxygen species (ROS) production and by higher protein expression of phosphorylated Akt and inducible nitric oxide synthase (iNOS) and enhanced nitric oxide production. Moreover, the application of LY294002 (Akt-specific inhibitor) or 1400W (iNOS-selective inhibitor) cancelled the cellular protective effects of NS398. Findings from the current study suggest that activation of NFκB during cardiomyocyte H/R induces the expression of COX-2 and that higher COX-2 expression during H/R exacerbates cardiomyocyte H/R injury via mechanisms that involve cross talks among inflammation, ROS, and Akt/iNOS/NO signaling.
Sujet(s)
Inhibiteurs de la cyclooxygénase 2/pharmacologie , Myocytes cardiaques/effets des médicaments et des substances chimiques , Nitric oxide synthase type II/métabolisme , Apoptose , Hypoxie cellulaire , Protéines proto-oncogènes c-akt/métabolisme , Transduction du signalRÉSUMÉ
OBJECTIVE: The current study was designed to explore anxiolytic, antidepressant, and antistress actions of Cinnamomum tamala (CT) leaves (aqueous extract) in rats. MATERIALS AND METHODS: Behavioral procedures of anxiety, depression, and stress were assessed in rats. CT (100, 200, and 400 mg/kg) was given once a daily for 7 days via oral route and the efficacy was matched by those elicited by lorazepam (1 mg/kg, p.o.), imipramine (10 mg/kg, p.o.), and Withania somnifera (100 mg/kg, p.o.) for anxiolytic, antidepressant, and antistress studies, respectively. Standard drugs were given 1 time, 30 min preceding the behavioral trials. RESULTS: One-way analysis of variance followed by Newman-Keuls multiple comparison test was employed to analyze the results. P < 0.05 was considered statistically significant as compared to control. CT at 400 mg/kg produced an antianxiety effect equivalent to lorazepam, in the elevated plus maze, open field, and social interaction tests among selected doses of the CT. CT at 400 mg/kg also induced an antidepressant activity similar to imipramine, in the behavioral despair, learned helplessness test, and tail suspension among selected doses of the CT. Moreover, CT at 400 mg/kg produced a significant antistress effect comparable to W. somnifera in water immersion-restraint stress by decreasing ulcer index, adrenal gland weight, and by normalizing the plasma levels of corticosterone, glucose, cholesterol, and triglyceride levels when related to stress control. CONCLUSION: The study shows that among the different CT doses, CT at 400 mg/kg possesses significant anxiolytic, antidepressant, and anti-stress effects and has therapeutic beneficial for the management of psychological ailments.
Sujet(s)
Anxiolytiques/usage thérapeutique , Antidépresseurs/usage thérapeutique , Anxiété/traitement médicamenteux , Cinnamomum , Dépression/traitement médicamenteux , Extraits de plantes/usage thérapeutique , Stress psychologique/traitement médicamenteux , Animaux , Anxiolytiques/pharmacologie , Antidépresseurs/pharmacologie , Anxiété/sang , Comportement animal/effets des médicaments et des substances chimiques , Glycémie/analyse , Cholestérol/sang , Corticostérone/sang , Dépression/sang , Comportement d'exploration/effets des médicaments et des substances chimiques , Femelle , Suspension des membres postérieurs , Imipramine/usage thérapeutique , Relations interpersonnelles , Lorazépam/usage thérapeutique , Mâle , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Phytothérapie , Extraits de plantes/pharmacologie , Feuilles de plante , Rat Wistar , Contention physique , Stress psychologique/sang , Triglycéride/sang , WithaniaRÉSUMÉ
Pterostilbene (PS) is a well-recognized antioxidant that primarily exists in blueberries, grapevines and heartwood of red sandalwood. Interest in this compound has been renewed in recent years, and studies have found that PS possesses an array of pharmacological properties, including chemopreventive, antiinflammatory, antidiabetic, antidyslipidemic, antiatherosclerotic and neuroprotective effects. However, the greater in vivo bioavailability of PS, as compared to resveratrol, is an added advantage for its efficacy. This review provides a summary regarding the sources, pharmacokinetic aspects and pharmacodynamics of PS, with a focus on the molecular mechanisms underlying its protective effects against cancer, brain injuries and heart disease. Studies regarding the safety profile of PS have also been included. Based on the presently available evidence, we conclude that PS represents an active phytonutrient and a potential drug with pleiotropic health applications.
Sujet(s)
Stilbènes/pharmacologie , Animaux , Maladies cardiovasculaires/traitement médicamenteux , Maladies cardiovasculaires/anatomopathologie , Maladies du système nerveux central/traitement médicamenteux , Maladies du système nerveux central/anatomopathologie , Humains , Tumeurs/traitement médicamenteux , Sécurité , Stilbènes/effets indésirables , Stilbènes/pharmacocinétique , Stilbènes/usage thérapeutiqueRÉSUMÉ
Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to attract attention. In this review, we focus on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis.