Background High blood glucose levels in diabetes lead to vascular inflammation which accelerates atherosclerosis. Herein, Morin was orally administered in male Wistar rats, at the dose of 40 mg/kg for 28 days, and on the 27th and 28th day, ISO was administered to designate groups at the dose of 85 mg/kg s.c., to induce myocardial infarction. Results Free radical generation, including ROS, in diabetes following ISO administration, leads to the activation of both intrinsic and extrinsic pathways of apoptosis. Morin significantly ( p ≤ 0.05) reduced oxidative stress (GSH, MDA, SOD), cardiac injury markers (CK-MB, LDH), inflammation (TNF, IL-6), and apoptosis (Bax, BCl 2 , Caspase-3). In addition, it also reduced insulin and blood glucose levels. Akt/eNOS, Nrf2/HO-1, MAPK signaling pathways, and Insulin signal transduction pathways were positively modulated by morin pre-treatment. Conclusions Morin attenuated oxidative stress and inflammation and also modified the activity of various molecular pathways to mitigate cardiomyocyte damage during ISO-induced MI in diabetic rats.

Objective: It is important to address the impact of rising incidence of mortality and morbidity associated with myocardial infarction (MI). There is need to explore new safer and efficacious drugs with novel mechanisms to manage MI. Morin, (2-(2,4-Dihydroxyphenyl)-3, is a bioflavanoid which is found in Maclura cochinchinensis, Maclura tinctoria, Maclura pomifera and leaves of Psidium guajava. It possesses good anti-apoptotic, anti-inflammatory, and antioxidant activity. Hence, we have evaluated the cardio-protective effect of Morin in Myocardial Ischemia-Reperfusion (IR) injury model of rat. Design and method: Male albino Wistar rats were pre-treated with Morin (40 and 80 mg/kg; p.o.) for 28 days and on the 29th day, the chest cavity was opened and myocardial ishemia was induced for 45 minutes by ligatiing the LAD coronary artery. Thereafter, reperfusion was carried out for 60 minutes. The hemodynamic parameters as well as left ventricular pressures (±LV dp/dt and LVEDP) were recorded throughout the ischemia and reperfusion. At the end of the procedure, the blood and heart were collected for evaluation of cardiac-injury markers, antioxidant-oxidant parameters, inflammatory markets, histopathological evaluation and molecular signalling pathway protein expressions. Results: Morin pretreatment for 28 days at 40 mg/kg and 80 mg/kg doses significantly controlled hemodynamic parameters, reduced cardiac injury markers, inflammation and apoptosis and reduced oxidative stress and mitigated histological changes following IR injury in rat heart. Morin also downregulated expression of pro-inflammatory and pro-apoptotic SAPK pathway proteins (p38 and JNK), and upregulated the survival kinase protein expression i.e. RISK pathway (ERK, eNOS). Conclusions: Morin reduced myocardial oxidative stress, inflammation and apoptosis in ischemia-reperfusion induced cardiac injury through upregulation of RISK and downregulation of SAPK pathways proteins.

Myocardial infarction (MI) is irreversible damage to the myocardial tissue caused by prolonged ischemia/hypoxia, subsequently leading to loss of contractile function and myocardial damage. However, after a perilous period, ischemia-reperfusion (IR) itself causes the generation of oxygen free radicals, disturbance in cation homeostasis, depletion of cellular energy stores, and activation of innate and adaptive immune responses. The present study employed Abatacept (ABT), which is an anti-inflammatory drug, originally used as an antirheumatic response agent. To investigate the cardioprotective potential of ABT, primarily, the dose was optimized in a chemically induced model of myocardial necrosis. Thereafter, ABT optimized the dose of 5 mg/kg s.c. OD was investigated for its cardioprotective potential in a surgical model of myocardial IR injury, where animals (n = 30) were randomized into five groups: Sham, IR-C, Telmi10 + IR (Telmisartan, 10 mg/kg oral OD), ABT5 + IR, ABT perse. ABT and telmisartan were administered for 21 days. On the 21st day, animals were subjected to LAD coronary artery occlusion for 60 min, followed by reperfusion for 45 min. Further, the cardioprotective potential was assessed through hemodynamic parameters, oxidant–antioxidant biochemical enzymatic parameters, cardiac injury, inflammatory markers, histopathological analysis, TUNEL assay, and immunohistochemical evaluation, followed by immunoblotting to explore signaling pathways. The statistics were performed by one-way analysis of variance, followed by the Tukey comparison post hoc tests. Noteworthy, 21 days of ABT pretreatment amended the hemodynamic and ventricular functions in the rat models of MI. The cardioprotective potential of ABT is accompanied by inhibiting MAP kinase signaling and modulating Nrf-2/HO-1 proteins downstream signaling cascade. Overall, the present work bolsters the previously known anti-inflammatory role of ABT in MI and contributes a mechanistic insight and application of clinically approved drugs in averting the activation of inflammatory response.

Abstract Purpose: Diabetes is a risk factor that predisposes to atherosclerotic cardiovascular diseases. The risk of myocardial infarction in diabetes is 3-4 times higher. In diabetes, high blood glucose levels lead to vascular inflammation which accelerates atherosclerosis. Hence, we evaluate the mechanism involved in the cardioprotective action of Morin in diabetic rats. Methods: In male Wistar rats, streptozotocin (70 mg/kg; i.p.) was administered to induce diabetes and, rats with fasting blood glucose levels >400 mg/dl were considered diabetic and included in the study. These rats were divided into five groups (n=8), i.e., Normal; Diabetic-control; Diabetes+Isoproterenol (ISO); Diabetes+ISO+Morin and, Diabetes+Morin. Morin was orally administered at the dose of 40 mg/kg for 28 days and on the 27 th and 28 th day ISO was administered to designate groups at the dose of 85mg/kg s.c., to induce myocardial infarction. Results: Free radical generation in diabetes as well as the rush of ROS following ISO administration leads to activation of the intrinsic as well as extrinsic pathways of apoptosis. Morin significantly (p≤0.05) reduced oxidative stress (áGSH, âMDA, áSOD), cardiac injury markers (âCK-MB, âLDH), inflammation (âTNF, âIL-6) and apoptosis (âBax, áBCl 2 , áCaspase-3). In addition, it also reduced serum insulin and blood glucose levels. Histopathology showed cardio-protection with morin. Akt/eNOS, Nrf2/HO-1, MAPK signalling pathways and Insulin signal transduction pathways were positively modulated by Morin pre-treatment. It also significantly modulated NLRP3 inflammasome formation. Conclusion : Morin attenuated oxidative stress and inflammation and also modified expression of various molecular pathways to mitigate cardiomyocyte damage during ISO induced MI in diabetic rats.

Abstract Cardiac hypertrophy is the enlargement of cardiomyocytes in response to persistent release of catecholamine which further leads to cardiac fibrosis. Chrysin, flavonoid from honey, is well known for its multifarious properties like antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic. To investigate the cardioprotective potential of chrysin against isoproterenol (ISO), cardiac hypertrophy and fibrosis are induced in rats. Acclimatised male albino Wistar rats were divided into seven groups (n 6): normal (carboxymethyl cellulose at 0·5 % p.o.; as vehicle), hypertrophy control (ISO 3 mg/kg, s.c.), CHY15 + H, CHY30 + H & CHY60 + H (chrysin; p.o.15, 30 and 60 mg/kg respectively + ISO at 3 mg/kg, s.c.), CHY60 (chrysin 60 mg/kg in per se) and LST + H (losartan 10 mg/kg p.o. + ISO 3 mg/kg, s.c.) were treated for 28 d. After the dosing schedule on day 29, haemodynamic parameters were recorded, after that blood and heart were excised for biochemical, histological, ultra-structural and molecular evaluations. ISO administration significantly increases heart weight:body weight ratio, pro-oxidants, inflammatory and cardiac injury markers. Further, histopathological, ultra-structural and molecular studies confirmed deteriorative changes due to ISO administration. Pre-treatment with chrysin of 60 mg/kg reversed the ISO-induced damage to myocardium and prevent cardiac hypertrophy and fibrosis through various anti-inflammatory, anti-apoptotic, antioxidant and anti-fibrotic pathways. Data demonstrated that chrysin attenuated myocardial hypertrophy and prevented fibrosis via activation of transforming growth factor-beta (TGF-β)/Smad signalling pathway.

Objective: The present study was designed to evaluate the effect of apigenin on progression and development of diabetic nephropathy in diabetic rats. Design and method: Adult male albino Wistar rats were divided into 7 groups: control, diabetic control, apigenin treatment groups (5–20 mg/kg; p.o.), ramipril (2 mg/kg; p.o.) and apigenin per se (20 mg/kg) group. Except control and per se groups, type 1 diabetes in other groups were induced by a single injection of streptozotocin (55 mg/kg; i.p). After confirmation of diabetes (FBG>250 mg/dl), rats were randomly divided into different treatment groups and observed for period of 8 months. Results: After 8 months, STZ resulted in attenuation of renal function (increased BUN and serum creatinine), increased oxidative stress and inflammation (increased cytokines and NF-kappa B) in the diabetic rats. In addition, there was fibrosis (increased transforming growth factor, fibronectin and type IV collagen), apoptosis (increased bax, caspase-3 and decreased bcl-2) and activation of MAPK pathway in diabetic-control group. These results were further supported by histopathological examination, which revealed presence of inflammation, collagen deposition and glomerulosclerosis in renal tissue of diabetic rats. In contrast, pre-treatment with apigenin significantly ameliorated STZ-induced functional and pathological changes in diabetic rats. In addition, it attenuated fibrosis, inflammation and apoptosis and also prevented activation of MAPK pathway in diabetic rats. All these protective effects were comparable to the ramipril treated group. Conclusions: Apigenin ameliorated oxidative stress, inflammation, apoptosis and fibrosis in diabetic rats by attenuation of MAPK pathway and prevented diabetic complication in diabetic rats.

Objective: The injurious effects of restoration of coronary blood flow following myocardial infarction is a major concern as reperfusion predisposes to myocardial injury. Mangiferin is a polyphenolic antioxidant present in the bark, fruits, roots and leaves of Mangifera indica Linn (Anacardiaceae). It is known to modulate biological targets in inflammation & oxidative stress. It also possesses anti-oxidant, anti-apoptotic; anti-atherogenic and anti-diabetic actions. Hence, we hypothesized that the anti-oxidative, anti-inflammatory, and anti-apoptotic effects of mangiferin may also be involved in the prevention of IR injury. Design and method: Male albino Wistar rats were divided into four groups i.e. sham, IR-control, Mangiferin-40 + IR and Mangiferin 40 per se. Mangiferin was administered at a dose of 40 mg/kg, intraperitoneally for 15 days. On the 15th day, myocardial IR injury was induced by occluding the left anterior descending coronary artery for 45 minutes followed by reperfusion for 60 minutes. At the end of the surgical procedure, the rats were sacrificed, the hearts excised and processed. Results: IR-control rats showed significant cardiac dysfunction along with a raised serum cardiac injury markers, and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats showed myocardial necrosis, edema and inflammatory cell infiltration. Pre-treatment with mangiferin significantly suppressed myocardial oxidative damage, maintained membrane integrity, and attenuated the levels of pro-inflammatory cytokines, pro-apoptotic proteins and TGF-beta. Additionally, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. Conclusions: Mangiferin ameliorates myocardial IR injury by alleviating oxidative stress mediated apoptosis and modulating MAPK mediated inflammation.

BACKGROUND:The activation of Nrf2/HO-1 pathway has been shown to protect against cisplatin- induced nephrotoxicity by reducing oxidative stress. Berberine (Ber), an isoquinoline alkaloid, has demonstrated antioxidant, anti-inflammatory and anti-apoptotic activities in various experimental models.AIM:To check the effect of Ber on cisplatin-induced nephrotoxicity and to explore the involved mechanism.METHODS:Adult male Wistar rats were divided into 6 groups: Normal, cisplatin-control, treatment groups and per se group. Normal saline and Ber (20, 40 and 80 mg/kg; p.o.) was administered to rats for 10 days. A single intraperitoneal injection of cisplatin (8 mg/kg) was injected on 7th day to induced nephrotoxicity. On 10th day, rats were sacrificed, the kidney was removed and stored for the estimation of various parameters.RESULTS:As compared to cisplatin-control group, Ber pretreatment improved renal function system and preserved renal architecture. It also diminished oxidative stress by upregulating the expression of Nrf2/HO-1 proteins. In addition, Ber attenuated the cisplatin mediated inflammation and apoptosis. Furthermore, it also reduced the phosphorylation of p38/JNK and PARP/Beclin-1 expression in the kidney.CONCLUSION:Ber attenuated renal injury by activating Nrf2/HO-1 and inhibiting JNK/p38MAPKs/ PARP/Beclin-1 expression which prevented oxidative stress, inflammation, apoptosis and autophagy in renal tissue.

Background: Free radicals generated during injury lead to the development of various diseases such as diabetes, myocardial infarction, cerebrovascular disease, and cancer. Antioxidants present in plants can prevent the deleterious effect of these free radicals. Among various plants, Leucaena leucocephala is a mimosoid, fast-growing, nitrogen-fixing small tree having pods with various medicinal properties. Objective: Hence, the present study was designed to determine the bioactive potential of ethanolic and methanolic extracts of L. leucocephala pod seeds. Materials and Methods: We have assessed the antioxidant and antibacterial activities of the extract. In addition, the presence of various metabolites and other compounds was also evaluated though gas chromatography-mass spectrometry (GC-MS) analysis. Results: The results indicated that the methanol extract had relatively higher antibacterial and antioxidant properties than ethanol extract. Furthermore, GC-MS data revealed the presence of various active constituents in the methanolic extract. Conclusion: Thus, the bioactive potential of various compounds present in methanol extracts of plant parts could be responsible for its antibacterial and antioxidant properties.

Objective: To assess the pharmacological and molecular effects of erdosteine in ISO induced myocardial necrosis in rats Design and method: To optimize the effect of erdosteine against experimental model of myocardial necrosis, male albino Wistar rats were divided into eight groups (n = 6) i.e. normal, ISO-control (ISO-C), erdosteine treatment with ISO. Rats in treatment groups were administered erdosteine orally for 28 days, whereas in normal and ISO-C group, 1% CMC was administered orally at 2 ml/kg/day for 28 days. Two consecutive doses of ISO 85 mg/kg, s.c. were given to ISO-C and erdosteine treatment groups on 27th and 28th day at 24 h interval. On 29th day, hemodynamic parameters were recorded and animals were sacrificed to excise their heart for measurement of various parameters. Results: In ISO-C rats, significantly increased levels of inflammatory markers, pro-oxidants and structural damage was observed as compared to normal group. Furthermore, immunohistochemistry revealed an increased expression of apoptotic proteins and decreased expression of anti-apoptotic protein which was further confirmed through TUNEL assay. Pretreatment with erdosteine at 80 mg/kg and 160 mg/kg reversed the deleterious effects of isoproterenol and normalized myocardial architecture. Erdosteine showed anti-inflammatory and anti-apoptotic activities through inhibition of MAPK pathway. Furthermore, erdosteine partially activated transcription factor Nrf-2 and HO-1 expressions showing the anti-oxidant potential of erdosteine. Conclusions: Thus, this study revealed the new use of an old drug and concluded the protective effect of erdosteine in ISO-induced myocardial necrosis through combined effect of MAPK and Nrf-2/HO-1 pathway.

Cisplatin has been confined due to the reported cases of nephrotoxicity. In the present study, an active xanthone, Mangiferin (from Mangifera indica) was investigated for its defensive role in cisplatin-induced nephrotoxicity. Male wistar albino rats were divided into six groups i.e., group 1 (normal); group 2 (cisplatin control); group 3, 4, and 5 (mangiferin 10, 20, and 40 mg/kg, i.p.); and per se (40 mg/kg; i.p.). The treatment was given for 10 days. On day 7, single dose of cisplatin 8 mg/kg i.p. was administered to induce nephrotoxicity in all groups except normal and per se. On day 11, animals were anesthetized, blood was taken from heart and serum was separated. Thereafter, rats were sacrificed and kidneys were isolated and preserved for histopathological, ultrastructural, immunohistochemical, and western blot analysis. Cisplatin control group showed significant impairment in renal function due to increased inflammation and oxidative stress which was also confirmed by histopathology and MAPK pathway proteins expression. However, pretreatment with mangiferin 20 and 40 mg/kg significantly reversed the renal function along with the structural changes and the levels of antioxidants. Mangiferin treatment attenuated DNA damage and apoptotic pathway.

Oxidative stress plays a major role in myocardial injury. Morin, a bioflavonoid has known to possess various biological activities in previous studies. Hence, this study evaluated the cardioprotective mechanism(s) of Morin against isoproterenol induced myocardial necrosis in rats. Male albino Wistar rats were divided into five groups (n = 8) i.e., I (normal), II (ISO-control), III, IV and V (morin 20, 40 and 80 mg/kg respectively). Groups III, IV and V were treated orally with daily doses of Morin accordingly for 28 days. On 26th and 27th day, a single injection of isoproterenol was injected (85 mg/kg s.c.) at 24 h interval to induce myocardial necrosis in group II, III, IV and V. On 28th day, hemodynamic parameters were evaluated, animals were euthanised and heart was excised for measurement of various parameters. In ISO-control rats, there was deterioration of hemodynamic parameters, decreased anti-oxidants levels, increased cardiac injury markers and pro-inflammatory cytokines (TNF-α and IL-6). Also, there was increased level of Bax, Caspase-3, p-JNK, p-38 and NF-κB and decreased expression of Bcl-2 and p-ERK1/2 in ISO-C group. Morin dose-dependently improved hemodynamic profile, increased anti-oxidant levels, normalized myocardial architecture and reduced inflammatory markers and apoptosis. Furthermore, immunoblot analysis of MAPK pathway proteins demonstrated the mechanism responsible for anti-apoptotic and anti-inflammatory potential of morin. Thus, this study substantiated the beneficial effect of Morin by virtue of its modulation of MAPK pathway in myocardial injury.

Hesperidin (HES), a flavanone glycoside, predominant in citrus fruits, has an agonistic activity on peroxisome proliferator-activated receptor gamma (PPAR-gamma). PPAR-gamma is an inhibitor of cardiac hypertrophy (CH) signaling pathways. In this study, we investigated the cardioprotective effect of HES in isoproterenol (ISO)-induced CH through PPAR-gamma agonistic activity. For this, male albino Wistar rats were divided into six groups (n = 6), that is, normal, ISO-control, HES treatment group (200 mg kg(-1); p.o.), HES per se (200 mg kg(-1); p.o.), enalapril treatment group (30 mg kg(-1); p.o.), and combination group (HES 200 mg kg(-1); p.o.+enalapril 30 mg kg(-1); p.o.). ISO (3 mg kg(-1); s.c.) was administered to all groups except normal and per se to induce CH. HES or enalapril treatment of 28 days significantly attenuated pathological changes, improved cardiac hemodynamics, suppressed oxidative stress, and apoptosis along with an increased PPAR-gamma expression. The combination of enalapril with HES exhibited an effect similar to that of HES or enalapril alone on all the aforementioned parameters. Therefore, HES may be further evaluated as a promising molecule for the alleviation of CH.

[This corrects the article DOI: 10.3389/fphar.2016.00155.].

Background: Metformin, a commonly used oral antidiabetic agent, is known to possess pleiotropic antioxidant, anti-inflammatory and anti-fibrotic effects. In this study, we evaluated the effect of metformin on pulmonary fibrosis and the mechanism underlying its effect. Methods: Pulmonary fibrosis was induced experimentally with bleomycin (0.035 U/g, i.p.) given twice weekly for four weeks. Metformin (125, 250 and 500 mg/kg/day, p.o) was given seven days prior to first injection of bleomycin and continued till 28 days after starting bleomycin injection. Prednisolone (5 mg/kg/day, p.o) was the standard control. Results: Administration of bleomycin caused pulmonary fibrosis in rats as evidenced by characteristic structural changes in histopathology, increased inflammatory cells in bronchoalveolar lavage fluid, elevated lipid peroxidation marker, depleted endogenous antioxidants and increased inflammatory mediators (TNF-alpha, IL-6). There were also increased levels of TGF-beta, Smad2/3, ERK1/2, p38, JNK, fibronectin, hydroxyproline and type I collagen in bleomycin-control group. All these changes were ameliorated by high dose metformin. It restored structural, biochemical and molecular changes towards normal. This protective effect may be attributed to activation of AMPK by metformin, with consequent reduction in oxidative stress and TGF-beta. Moreover, this protective effect was superior to prednisolone as metformin had additional antioxidant and antifibrotic properties. Conclusion: These data suggest that metformin protects against bleomycin-induced pulmonary fibrosis through activation of AMPK and amelioration of TGF-beta signaling pathways.

Objectives: Chronic hyperglycemia in diabetes predisposes to myocardial infarction (MI). The production of advanced glycation end products (AGEs) in diabetes stimulates the receptor for AGE (RAGE) to produce oxidative stress and inflammation which causes myocardial damage. Kaempferol, a polyphenolic compound, has good anti-oxidant and anti-inflammatory properties. Hence, we evaluated the ameliorative effect of kaempferol on myocardial injury in diabetic rats. Methods: Streptozotocin (70 mg/kg; i.p.) was used to induce diabetes in rats. The rats with glucose level > 250 mg/dL were considered as diabetic. The diabetic rats were treated with either kaempferol (20 mg/kg; i.p.) or vehicle (2 mL/kg; i.p.) daily for 28 days and thereafter ischemia was produced in rats by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After the surgery, rats were sacrificed and the heart tissue was processed for biochemical, molecular and morphological studies. Results: Pretreatment with kaempferol significantly reduced hyperglycemia and oxidative stress by suppressing AGE-RAGE axis activation. The levels of inflammatory markers (TNF-α, IL-6, and NF-κβ) were significantly decreased and also, the myocardial morphololgy was well preserved. Further, active c-Jun N-terminal kinase (JNK) and p38 proteins were inhibited and Extracellular signal regulated kinase 1/2 (ERK1/2) was activated. Kaempferol attenuated apoptosis by reducing the expression of TUNEL positive cells, pro-apoptotic proteins (Bax and Caspase-3) and increasing the levels of anti-apoptotic protein (Bcl-2). Conclusion: Kaempferol ameliorated myocardial ischemia-reperfusion injury in diabetic rats by suppressing mitogen activated protein kinase (MAPK) pathway and AGE-RAGE axis activation.

Objectives: Diabetes mellitus is a major metabolic disorder characterized by hyperglycemia resulting from defective insulin secretion and/or response. Diabetic nephropathy is one of the major micro-vascular complications of Diabetes mellitus which results due to inflammatory phenomenon, fibrosis and oxidative stresses. Apigenin (4',5, 7-trihydroxyflavone), a plant derived flavonoid possess anti-inflammatory, anti-fibrotic and anti-diabetic properties was used to evaluate its effect in streptozotocin induced diabetic rats to scrutinize its efficacy in halting the progression of diabetic nephropathy. Methods: Male Wistar rats were divided into 5 groups (n = 8) i.e. I (normal), II (diabetes- control), III (Apigenin 20 mg/kg i.p.), IV (Ramipril 2 mg/kg p.o.) and V (Apigenin 20 mg/kg per se) for a duration of 8 months. All groups were administered single injection of STZ (55 mg/kg i.p.) to induce diabetic mellitus. Different parameters were used for confirmation of their effect. Results: Apigenin (20 mg/kg) on treatment was observed to attenuate oxidative stress, renal dysfunction and fibrosis (decreased fibronectine, TGF-β1 and type IV collagen) in diabetic rats. Histopathological studies demonstrated reduction in collagen deposition, inflammation and glomerulosclerosis in renal tissue of rats. Also Apigenin suppressed inflammation by inhibiting MAPK activation and decrease apoptosis. All changes were comparable to the ramipril group. Conclusion: This study substantiated the beneficial effect of Apigenin by virtue of anti-oxidative, anti-inflammatory and anti-apoptotic properties. Hence, Apigenin imparts diabetic nephropathy induced by streptozotocin.