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Diabetic nephropathy (DN), a microvascular complication of diabetes, has emerged as an important health problem worldwide. There is strong evidence to suggest that oxidative stress, inflammation, and fibrosis play a pivotal role in the progression of DN. Apigenin has been shown to possess antioxidant, anti-inflammatory, antiapoptotic, antifibrotic, as well as antidiabetic properties. Hence, we evaluated whether apigenin halts the development and progression of DN in streptozotocin (STZ)-induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, and apigenin treatment groups (5-20 mg/kg po, respectively), apigenin per se (20 mg/kg po), and ramipril treatment group (2 mg/kg po). A single injection of STZ (55 mg/kg ip) was administered to all of the groups except control and per se groups to induce type 1 diabetes mellitus. Rats with fasting blood glucose >250 mg/dl were included in the study and randomized to different groups. Thereafter, the protocol was continued for 8 mo in all of the groups. Apigenin (20 mg/kg) treatment attenuated renal dysfunction, oxidative stress, and fibrosis (decreased transforming growth factor-ß1, fibronectin, and type IV collagen) in the diabetic rats. It also significantly prevented MAPK activation, which inhibited inflammation (reduced TNF-α, IL-6, and NF-κB expression) and apoptosis (increased expression of Bcl-2 and decreased Bax and caspase-3). Furthermore, histopathological examination demonstrated reduced inflammation, collagen deposition, and glomerulosclerosis in the renal tissue. In addition, all of these changes were comparable with those produced by ramipril. Hence, apigenin ameliorated renal damage due to DN by suppressing oxidative stress and fibrosis and by inhibiting MAPK pathway.
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Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apigenina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Fibronectinas/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/patologia , Fibrose , Rim/enzimologia , Rim/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ramipril/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , EstreptozocinaRESUMO
There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE). AGE-RAGE activation results in oxidative stress and inflammation. It is well known that this mechanism is involved in the pathogenesis of cardiovascular disease in diabetes. Kaempferol, a dietary flavonoid, is known to possess antioxidant, anti-apoptotic, and anti-inflammatory activities. However, little is known about the effect of kaempferol on myocardial ischemia-reperfusion (IR) injury in diabetic rats. Diabetes was induced in male albino Wistar rats using streptozotocin (70 mg/kg; i.p.), and rats with glucose level >250 mg/dL were considered as diabetic. Diabetic rats were treated with vehicle (2 mL/kg; i.p.) and kaempferol (20 mg/kg; i.p.) daily for a period of 28 days and on the 28th day, ischemia was produced by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed and the heart tissue was processed for biochemical, morphological, and molecular studies. Kaempferol pretreatment significantly reduced hyperglycemia, maintained hemodynamic function, suppressed AGE-RAGE axis activation, normalized oxidative stress, and preserved morphological alterations. In addition, there was decreased level of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NF-κB), inhibition of active c-Jun N-terminal kinase (JNK) and p38 proteins, and activation of Extracellular signal regulated kinase 1/2 (ERK1/2) a prosurvival kinase. Furthermore, it also attenuated apoptosis by reducing the expression of pro-apoptotic proteins (Bax and Caspase-3), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells, and increasing the level of anti-apoptotic protein (Bcl-2). In conclusion, kaempferol attenuated myocardial ischemia-reperfusion injury in diabetic rats by reducing AGE-RAGE/ mitogen activated protein kinase (MAPK) induced oxidative stress and inflammation.
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Diabetes Mellitus Experimental/dietoterapia , Hiperglicemia/dietoterapia , Quempferóis/administração & dosagem , Traumatismo por Reperfusão Miocárdica/dietoterapia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Produtos Finais de Glicação Avançada/genética , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/patologia , Inflamação/dietoterapia , Inflamação/genética , Inflamação/patologia , Interleucina-6/genética , MAP Quinase Quinase 1/genética , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Receptor para Produtos Finais de Glicação Avançada/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genéticaRESUMO
We substantiated the role of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in the protective effect of apigenin against the myocardial infarction (MI) in diabetic rats. Diabetes was induced by intraperitoneal administration of a single dose of streptozotocin (55 mg/kg). The study groups included diabetic rats receiving vehicle, apigenin (75 mg/kg/day, orally), GW9662 (1 mg/kg/day, intraperitoneally), and a combination of apigenin and GW9662 for 14 days. The MI was induced in all the study groups except the diabetic control group by subcutaneous injection of 100 mg/kg/day of isoproterenol on the two terminal days. The diabetes and isoproterenol-induced MI was evident as a reduction in the maximal positive and negative rate of developed left ventricular pressure and an increase in the left ventricular end-diastolic pressure. The activities of creatine kinase on myocardial bundle (CK-MB) and lactate dehydrogenase (LDH) were also reduced. Apigenin treatment prevented the hemodynamic perturbations, restored the left ventricular function and reinstated a balanced redox status. It protected rats against an MI by attenuating myonecrosis, edema, cell death, and oxidative stress. GW9662, a PPAR-γ antagonist reversed the myocardial protection conferred by apigenin. Further, an increase in the PPAR-γ expression in the myocardium of the rats receiving apigenin reinforces the role of PPAR-γ pathway activation in the cardioprotective effects of apigenin.
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Apigenina/farmacologia , Diabetes Mellitus Experimental/prevenção & controle , Infarto do Miocárdio/prevenção & controle , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anilidas/administração & dosagem , Anilidas/farmacologia , Animais , Apigenina/administração & dosagem , Western Blotting , Cardiotônicos/farmacologia , Creatina Quinase Forma MB/metabolismo , Diabetes Mellitus Experimental/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Isoproterenol , L-Lactato Desidrogenase/metabolismo , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/antagonistas & inibidores , Ratos WistarRESUMO
Cisplatin, a platinum compound, is used as a first-line agent against various forms of solid cancers. Nephrotoxicity is an important adverse effect of cisplatin therapy, which involves increased oxidative stress, inflammation, apoptosis, and activation of the mitogen-activated protein kinase (MAPK) pathway. It is well known that the bioactive compounds present in green tea are used to treat various disorders due to their biological activities. With this background, the present study was aimed to investigate the effect of epicatechin gallate (ECG), a green tea polyphenol, in cisplatin-induced nephrotoxicity in rats. To achieve this, ECG (1.25, 2.5, and 5 mg/kg; intraperitoneal (i.p.)) was administered to male albino Wistar rats for the period of 10 days. On the 7th day, a single i.p. injection of cisplatin (8 mg/kg) was injected into rats to produce kidney injury and the animals were then killed on the 10th day. Cisplatin toxicity was associated with enhanced oxidative stress, impaired renal function along with marked tubular necrosis in Histopathology. Furthermore, cisplatin activated the MAPK pathway, which contributed to inflammation and apoptosis in the kidney of treated rats. In contrast, ECG (5 mg/kg) pretreatment normalized cisplatin-induced oxidative stress, renal function, and histopathological changes. ECG also prevented the activation of the MAPK pathway, and attenuated inflammation and apoptosis in rats. These findings suggest that ECG prevented cisplatin-induced oxidative stress, inflammation, and apoptosis by downregulating the MAPK pathway and resulted in improved renal function.
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Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Catequina/análogos & derivados , Cisplatino/antagonistas & inibidores , Cisplatino/toxicidade , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Catequina/farmacologia , Creatinina/sangue , Citocinas/sangue , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos WistarRESUMO
Global cerebral ischemia/reperfusion (I-R) injury often results in an irreparable brain damage like behavioral impairment and neuronal death. This neurological complication involves diverse intricate pathological mechanisms like oxidative stress, inflammation, and apoptosis. Recently, the therapeutic value of plant-based polyphenols has gained researcher's attention. The present study focused on the putative neuroprotective role of negundoside on behavioral and oxidative stress status in an experimental model of global cerebral ischemia and reperfusion-induced brain injury. Negundoside was isolated from the leaves of Vitex negundo Linn. by chromatography for investigating its possible neurobehavioral and neuropharmacological implications. Healthy Balb/C mice of either sex were subjected to 10 min of global cerebral ischemia (GCI) followed by 24-h reperfusion. Mice were pre-treated intraperitoneally with negundoside at varying doses (1, 3, 5, 10, and 15 mg/kg) 60 min before the induction of GCI. Mice were later subjected to a battery of behavioral tests for evaluating memory-related and motor abilities. Elevated plus maze (EPM) was used to determine the anxiety levels and short-term memory whereas motor abilities were evaluated by inclined beam-walking test, rotarod, and lateral push test. TBARS and reduced glutathione (GSH) content in brains were analyzed spectrophotometrically as oxidative stress markers. Behavioral study revealed enhanced anxiety-related responses and motor deficits in I-R injured mice. Additionally, GSH and TBARS levels were found to be altered following I-R-induced neuronal injury. Contrastingly, negundoside administration was able to alleviate the behavioral and biochemical alterations to the normal levels. Together, our findings provide preliminary evidence of neuroprotective role of negundoside against global cerebral ischemia and reperfusion-induced behavioral dysfunction and oxidative damage in mice brain.
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Isquemia Encefálica , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Vitex , Animais , Isquemia Encefálica/tratamento farmacológico , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Parkinson's disease (PD) is a neurological disorder that affects the movement of the human body. It is primarily characterized by reduced dopamine levels in the brain. The causative agent of PD is still unclear but it is generally accepted that α-synuclein has a central role to play. It is also known that gap-junctions and associated connexins are complicated structures that play critical roles in nervous system signaling and associated misfunctioning. Thus, our current article emphasizes how, alongside α-synuclein, ion-channels, gap-junctions, and related connexins, all play vital roles in influencing multiple metabolic activities of the brain during PD. It also highlights that ion-channel and gap-junction disruptions, which are primarily mediated by their structural-functional changes and alterations, have a role in PD. Furthermore, we discussed available drugs and advanced therapeutic interventions that target Parkinson's pathogenesis. In conclusion, it warrants creating better treatments for PD patients. Although, dopaminergic replenishment therapy is useful in treating neurological problems, such therapies are, however, unable to control the degeneration that underpins the disease, thereby declining their overall efficacy. This creates an additional challenge and an untapped scope for neurologists to adopt treatments for PD by targeting the ion-channels and gap-junctions, which is well-reviewed in the present article.
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The emergence of the coronavirus disease-2019 pandemic has led to an outbreak in the world. The SARS-CoV-2 is seventh and latest in coronavirus family with unique exonucleases for repairing any mismatches in newly transcribed genetic material. Therefore, drugs with novel additional mechanisms are required to simultaneously target and eliminate the virus. Thus, a newly deciphered N protein is taken as a target that belongs to SARS-CoV-2. They play a vital role in RNA transcription, viral replication and new virion formation. This study used virtual screening, molecular modeling and docking of the 8987 ligands from Asinex and PubChem databases against this novel target protein. Three hotspot sites having DScore ≥1 (Site 1, Site 2 and Site 3) for ligand binding were selected. Subsequently, high throughput screening, standard precision and extra precision docking process and molecular dynamics concluded three best drugs from two libraries. Two antiviral moieties from Asinex databases (5817 and 6799) have docking scores of -10.29 and -10.156; along with their respective free binding energies (ΔG bind) of -51.96 and -64.36 on Site 3. The third drug, Zidovudine, is from PubChem database with docking scores of -9.75 with its binding free energies (ΔG bind) of -59.43 on Site 3. The RMSD and RMSF were calculated for all the three drugs through molecular dynamics simulation studies for 50 ns. Zidovudine shows a very stable interaction with fluctuation starting at 2.4 Å on 2 ns and remained stable at 3 Å from 13 to 50 ns. Thus, paving the way for further biological validation as a potential treatment.Communicated by Ramaswamy H. Sarma.
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COVID-19 , SARS-CoV-2 , Humanos , Simulação de Acoplamento Molecular , Nucleocapsídeo , Fosfoproteínas , Motivos de Ligação ao RNA , VírionRESUMO
In this study, we applied on-resonance variable delay multiple pulse (onVDMP) MRI to study D-glucose uptake in a mouse model of Alzheimer's disease (AD) tauopathy and demonstrated its feasibility in discriminating AD mice from wild-type mice. The D-glucose uptake in the cortex of AD mice (1.70 ± 1.33%) was significantly reduced compared to that of wild-type mice (5.42 ± 0.70%, p = 0.0051). Also, a slower D-glucose uptake rate was found in the cerebrospinal fluid (CSF) of AD mice (0.08 ± 0.01 min-1) compared to their wild-type counterpart (0.56 ± 0.1 min-1, p < 0.001), which suggests the presence of an impaired glucose transporter on both blood-brain and blood-CSF barriers of these AD mice. Clearance of D-glucose was observed in the CSF of wild-type mice but not AD mice, which suggests dysfunction of the glymphatic system in the AD mice. The results in this study indicate that onVDMP MRI could be a cost-effective and widely available method for simultaneously evaluating glucose transporter and glymphatic function of AD. This study also suggests that tau protein affects the D-glucose uptake and glymphatic impairment in AD at a time point preceding neurofibrillary tangle pathology.
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Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Glucose/metabolismo , Imageamento por Ressonância Magnética/métodos , Proteínas de Transporte de Monossacarídeos/deficiência , Tauopatias/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagem , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia , Análise Custo-Benefício , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Glucose/líquido cefalorraquidiano , Sistema Glinfático/metabolismo , Sistema Glinfático/fisiopatologia , Imageamento por Ressonância Magnética/economia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas de Transporte de Monossacarídeos/metabolismo , Sensibilidade e Especificidade , Tauopatias/patologia , Proteínas tau/metabolismoRESUMO
[This corrects the article DOI: 10.1155/2016/7580731.].
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Cisplatin has been widely used as a first-line agent against various forms of solid cancers. However, nephrotoxicity is the major limiting factor for its clinical use. Several clinical and pre-clinical studies have suggested different strategies for the reduction of cisplatin-induced nephrotoxicity. The present study was conducted to investigate the efficacy of D-Pinitol, against cisplatin-induced nephrotoxicity in Swiss albino mice. A single intraperitoneal injection of cisplatin (20â¯mg/kg) was used to induce nephrotoxicity in mice. Administration of cisplatin in mice is linked with elevated oxidative stress, imbalanced biochemical parameters, apoptosis and stimulation of mitogen-activated protein kinase (MAPK) pathway. D-Pinitol is a member of the flavonoid family and a chief constituent of Sutherlandia fruitesecnce. It was administered with saline water (10, 20, 40â¯mg/kg, p.o.) for seven consecutive days after a single dose of cisplatin. At the end of experiment, animals were sacrificed and biochemical parameters in serum and urine were recorded. Kidneys were isolated for the estimation of tumor necrosis factor-alpha, interleukin-1ß, interlukin-6 levels and histopathological evaluations. It was noted that D-Pinitol significantly ameliorated biochemical levels of serum and urinary creatinine and blood urea nitrogen. Tissue homogenate levels of TNF-α, IL-6, IL-1ß and the renal expression of tissue nitrites were also significantly decreased in D-Pinitol treated mice. These results were supplemented by histopathological findings. This study highlights the potential role of D-Pinitol against cisplatin-induced toxicity, exhibited through favorable alterations in biochemical and histological changes as well as reduction in oxidative stress and cytokine levels.
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Injúria Renal Aguda/prevenção & controle , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Citocinas/metabolismo , Inositol/análogos & derivados , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Catalase/metabolismo , Creatinina/sangue , Creatinina/urina , Glutationa/metabolismo , Inositol/farmacologia , Inositol/uso terapêutico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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-α, IL-6). There were also increased levels of TGF-ß, 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-ß. 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-ß signaling pathways.
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Metformina/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Bleomicina , Peso Corporal/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar , Citocinas/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Masculino , Metformina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/sangue , Fibrose Pulmonar/patologia , Ratos WistarRESUMO
Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.
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[This corrects the article DOI: 10.3389/fphar.2016.00155.].
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We investigated the effect of eplerenone on myocardial infarcted diabetic rats via modulation of the PI3K/Akt pathway and its downstream target GSK-3ß. Diabetes was induced by administration of a single dose of streptozotocin (55 mg/kg IP). Diabetic rats received either eplerenone or PI3k/Akt antagonist (wortmannin) or in combination for 14 days with concurrent administration of isoproterenol (100 mg/kg s.c) on 13th and 14th day. Isoproterenol prompted cardiotoxicity and was demonstrated by a decrease in the maximal positive rate of developed left ventricular pressure, the maximal negative rate of developed left ventricular pressure and an increase in left ventricular end-diastolic pressure along with oxidative stress. Myocardial infarcted diabetic rats exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with eplerenone significantly improved the redox status of the myocardium. Eplerenone markedly inhibited Bax expression, TUNEL-positive cells, and myonecrosis. On the other hand, the administration of eplerenone and wortmanin did not draw out the same effects, when administered concomitantly or individually. Moreover, the rats treated with eplerenone showed increased expression of PI3K/Akt and decreased its downstream target GSK-3ß. The present study confirms the protective effects of eplerenone on myocardial infarction in diabetic rats via modulation of PI3K/Akt pathway and its downstream regulator GSK-3ß.
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Hyperglycemia induced advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) activation is thought to involve in the development of cardiovascular disease in diabetics. Activation of AGE-RAGE axis results in the oxidative stress and inflammation. Mangiferin is found in the bark of mango tree and is known to treat diseases owing to its various biological activities. Thus, this study was designed to evaluate the effect of mangiferin in ischemia-reperfusion (IR) induced myocardial injury in diabetic rats. A single injection of STZ (70 mg/kg; i.p.) was injected to male albino Wistar rats to induce diabetes. After confirmation of diabetes, rats were administered vehicle (2 ml/kg; i.p.) and mangiferin (40 mg/kg; i.p.) for 28 days. On 28th day, left anterior descending coronary artery was ligated for 45 min and then reperfused for 60 min. Mangiferin treatment significantly improved cardiac function, restored antioxidant status, reduced inflammation, apoptosis and maintained myocardial architecture. Furthermore, mangiferin significantly inhibited the activation of AGE-RAGE axis, c-Jun N-terminal kinase (JNK) and p38 and increased the expression of extracellular regulated kinase 1/2 (ERK1/2) in the myocardium. Thus, mangiferin attenuated IR injury in diabetic rats by modulation of AGE-RAGE/MAPK pathways which further prevented oxidative stress, inflammation and apoptosis in the myocardium.
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Fármacos Cardiovasculares/administração & dosagem , Diabetes Mellitus Experimental/complicações , Produtos Finais de Glicação Avançada/metabolismo , Isquemia Miocárdica/complicações , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Xantonas/administração & dosagem , Animais , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases , Masculino , Ratos Wistar , Transdução de Sinais , Resultado do TratamentoRESUMO
Objectives: To determine the optimum range of phenytoin (PHT) and valproate (VAP) levels and find out the critical drug levels below which chances of breakthrough seizures increase in North Indian population. Methodology: A cross-sectional, case-controlled, record-based study was conducted in a quaternary care hospital from September 2018–2019. The case group comprised epilepsy patients on monotherapy with PHT/VAP presenting with breakthrough seizures after at least 6 months of seizure control. Noncompliant, overdose, toxicity, no or partial response, any other psychiatric or neurological disorder, adverse effects, and patients taking two or more antiepileptic drugs were excluded. Results: Data of 100 patients in each group were analyzed. Significantly lower mean levels in cases were observed in PHT (5.74 ± 3.68 mg/L vs. 13.75 ± 4.27 mg/L control) and VAP (24.13 ± 27.39 mg/L vs. 76.37 ± 17.71 mg/L control). A negative correlation of drug levels was observed with age and weight in both the groups. The level/dose ratio in controls (0.05 ± 0.03; 0.09 ± 0.06) was significantly (P < 0.0001) higher than cases (0.02 ± 0.01; 0.02 ± 0.03) in PHT and VAP, respectively. Conclusions: This study identifies the critical levels and level/dose ratio at which the risk of breakthrough seizures increases. A wide level/dose ratio was found in controls, more so in the VAP group. A prospective study with larger group size along with genetic studies should be done to evaluate further.
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BACKGROUND: Myocardial infarction (MI) continues to be associated with high morbidity and mortality worldwide despite the availability of current therapeutic modalities. Kaempferol (KMP), a dietary flavonoid, possesses good antioxidant, immunomodulatory and anti-apoptotic properties and has been evaluated in the present study for its role in mitigating myocardial injury following MI. PURPOSE: In this study, the ability of KMP to protect heart against isoproterenol (ISO) induced oxidative stress and myocardial infarction was evaluated. MATERIAL AND METHODS: Male Wistar rats (n=48) were administered KMP (5, 10 & 20mg/kg/day, i.p.) or vehicle for 15 days with ISO, 85mg/kg, subcutaneously, for 2 consecutive days was also administered at 24h interval on the 13th and 14th days. On the 15th day, rats were anaesthetized and right coronary artery was cannulated to record hemodynamic parameters. Later on blood sample was collected and heart was removed to estimate biochemical, histopathological, ultrastructural and immuohistochemical studies respectively. RESULTS: ISO-treated rats showed a significant reduction in arterial pressure, maximum rate of development of left ventricular pressure and increase in left ventricular end-diastolic pressure. Also, there was a significant decrease in antioxidant enzyme levels such as superoxide dismutase, catalase and glutathione and increase in the level of malondialdehyde and serum TNF-α and IL-6 levels. In addition, the cardiac injury markers such as creatine kinase-MB and lactate dehydrogenase were increased in the serum. Furthermore, immunohistochemistry revealed an increased Bax/Bcl-2 ratio in the myocardium. KMP (5, 10 and 20mg/kg) dose dependently restored hemodynamic, left ventricular functions, decreased cardiac injury marker enzymes in serum, increased antioxidant levels, reduced lipid peroxidation and TNF-α level and apoptosis. Histopathological and ultrastructural studies support the protective effect of KMP in ISO-induced myocardial infarcted rats. CONCLUSION: Thus, the present study revealed that KMP mitigates myocardial damage in ISO-induced cardiac injury by maintaining hemodynamic and biochemical parameters and reducing inflammation owing to its anti-apoptotic, anti-inflammatory and antioxidant activities. It may be concluded that a diet containing KMP may be beneficial in those who are at the risk of myocardial injury.
Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade , Coração/efeitos dos fármacos , Quempferóis/farmacologia , Infarto do Miocárdio/metabolismo , Miocárdio , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Cardiotoxicidade/tratamento farmacológico , Catalase/metabolismo , Glutationa/metabolismo , Interleucina-6/metabolismo , Isoproterenol/toxicidade , Quempferóis/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Modelos Teóricos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular EsquerdaRESUMO
Emblica officinalis Gaertn. belonging to family Euphorbiaceae is commonly known as Indian gooseberry or "Amla" in India. It is used as a 'rejuvenating herb' in traditional system of Indian medicine. It has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic effects. Thus, on the basis of its biological effects, the present study was undertaken to evaluate the protective effect of the dried fruit extract of the E. Officinalis (EO) in cisplatin-induced nephrotoxicity in rats and also to evaluate the mechanism of its nephroprotection. The study was done on male albino Wistar rats. They were divided into six groups (n = 6) viz. control, cisplatin-control, cisplatin and EO (150, 300, and 600 mg/kg; p.o. respectively in different groups) and EO only (600 mg/kg; p.o. only). EO was administered orally to the rats for a period of 10 days and on the 7th day, a single injection of cisplatin (8 mg/kg; i.p.) was administered to the cisplatin-control and EO treatment groups. The rats were sacrificed on the 10th day. Cisplatin-control rats had deranged renal function parameters and the kidney histology confirmed the presence of acute tubular necrosis. Furthermore, there were increased oxidative stress, apoptosis and inflammation along with higher expression of MAPK pathway proteins in the rat kidney from the cisplatin-control group. Contrary to this, EO (600 mg/kg) significantly normalized renal function, bolstered antioxidant status and ameliorated histological alterations. The inflammation and apoptosis were markedly lower in comparison to cisplatin-control rats. Furthermore, EO (600 mg/kg) inhibited MAPK phosphorylation which was instrumental in preserving renal function and morphology. In conclusion, the results of our study demonstrated that EO attenuated cisplatin-induced nephrotoxicity in rats through suppression of MAPK induced inflammation and apoptosis.
RESUMO
Mangiferin, a xanthone glycoside isolated from leaves of Mangifera indica (Anacardiaceae) is known to modulate many biological targets in inflammation and oxidative stress. The present study was designed to investigate whether mangiferin exerts protection against myocardial ischemia-reperfusion (IR) injury and possible role of Mitogen Activated Protein Kinase (MAPKs) and Transforming Growth Factor-ß (TGF-ß) pathways in its cardioprotection. Male albino Wistar rats were treated with mangiferin (40 mg/kg, i.p.) for 15 days. At the end of the treatment protocol, rats were subjected to IR injury consisting of 45 min ischemia followed by 1h reperfusion. IR-control rats caused significant cardiac dysfunction, increased serum cardiac injury markers, lipid peroxidation and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats revealed myocardial necrosis, edema and infiltration of inflammatory cells. However, pretreatment with mangiferin significantly restored myocardial oxidant-antioxidant status, maintained membrane integrity, and attenuated the levels of proinflammatory cytokines, pro-apoptotic proteins and TGF-ß. Furthermore, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. These results suggest that mangiferin protects against myocardial IR injury by modulating MAPK mediated inflammation and apoptosis.
Assuntos
Cardiotônicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miocárdio/patologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Fator de Crescimento Transformador beta/metabolismo , Xantonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Interleucina-6/metabolismo , Masculino , Miocárdio/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular/efeitos dos fármacosRESUMO
Kaempferol (KMP), a dietary flavonoid, has antioxidant, anti-inflammatory, and antiapoptotic effects. Hence, we investigated the effect of KMP in ischemia-reperfusion (IR) model of myocardial injury in rats. We studied male albino Wistar rats that were divided into sham, IR-control, KMP-20 + IR, and KMP 20 per se groups. KMP (20 mg/kg; i.p.) was administered daily to rats for the period of 15 days, and, on the 15th day, ischemia was produced by one-stage ligation of left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed; heart was removed and processed for biochemical, morphological, and molecular studies. KMP pretreatment significantly ameliorated IR injury by maintaining cardiac function, normalizing oxidative stress, and preserving morphological alterations. Furthermore, there was a decrease in the level of inflammatory markers (TNF-α, IL-6, and NFκB), inhibition of active JNK and p38 proteins, and activation of ERK1/ERK2, a prosurvival kinase. Additionally, it also attenuated apoptosis by reducing the expression of proapoptotic proteins (Bax and Caspase-3), TUNEL positive cells, and increased level of antiapoptotic proteins (Bcl-2). In conclusion, KMP protected against IR injury by attenuating inflammation and apoptosis through the modulation of MAPK pathway.