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Chemotherapy-induced cognitive impairment (CICI) is a novel clinical condition characterized by memory, learning, and motor function deficits. Oxidative stress and inflammation are potential factors contributing to chemotherapy's adverse effects on the brain. Inhibition of soluble epoxide hydrolase (sEH) has been proven effective in neuroinflammation and reversal of memory impairment. The research aims to evaluate the memory protective effect of sEH inhibitor and dual inhibitor of sEH and COX and compare its impact with herbal extracts with known nootropic activity in an animal model of CICI. In vitro sEH, the inhibitory activity of hydroalcoholic extracts of Sizygium aromaticum, Nigella sativa, and Mesua ferrea was tested on murine and human sEH enzyme as per the protocol, and IC50 was determined. Cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and fluorouracil (5 mg/kg) combination (CMF) were administered intraperitoneally to induce CICI. The known herbal sEH inhibitor, Lepidium meyenii and the dual inhibitor of COX and sEH (PTUPB) were tested for their protective effect in the CICI model. The herbal formulation with known nootropic activity viz Bacopa monnieri and commercial formulation (Mentat) were also used to compare the efficacy in the CICI model. Behavioral parameter such as cognitive function was assessed by Morris Water Maze besides investigating oxidative stress (GSH and LPO) and inflammatory (TNFα, IL-6, BDNF and COX-2) markers in the brain. CMF-induced CICI, which was associated with increased oxidative stress and inflammation in the brain. However, treatment with PTUPB or herbal extracts inhibiting sEH preserved spatial memory via ameliorating oxidative stress and inflammation. S. aromaticum and N. sativa inhibited COX2, but M. Ferrea did not affect COX2 activity. Lepidium meyenii was the least effective, and mentat showed superior activity over Bacopa monnieri in preserving memory. Compared to untreated animals, the mice treated with PTUPB or hydroalcoholic extracts showed a discernible improvement in cognitive function in CICI.
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Comprometimento Cognitivo Relacionado à Quimioterapia , Fármacos Neuroprotetores , Nootrópicos , Humanos , Camundongos , Animais , Ciclo-Oxigenase 2 , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Epóxido Hidrolases , InflamaçãoRESUMO
Cardiovascular disease is the leading cause of morbidity and mortality world-wide. Recently, the role of inflammation in the progression of diseases has significantly attracted considerable attention. In addition, various comorbidities, including diabetes, obesity, etc. exacerbate inflammation in the cardiovascular system, which ultimately leads to heart failure. Furthermore, cytokines released from specialized immune cells are key mediators of cardiac inflammation. Here, in this review article, we focused on the role of selected immune cells and cytokines (both pro-inflammatory and anti-inflammatory) in the regulation of cardiac inflammation and ultimately in cardiovascular diseases. While IL-1ß, IL-6, TNFα, and IFNγ are associated with cardiac inflammation; IL-10, TGFß, etc. are associated with resolution of inflammation and cardiac repair. IL-10 reduces cardiovascular inflammation and protects the cardiovascular system via interaction with SMAD2, p53, HuR, miR-375 and miR-21 pathway. In addition, we also highlighted recent advancements in the management of cardiac inflammation, including clinical trials of anti-inflammatory molecules to alleviate cardiovascular diseases.
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Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Animais , Coração , Humanos , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológicoRESUMO
BACKGROUND: Pharmacological inhibition of soluble epoxide hydrolase (sEH) enhances the synaptic function in the CNS and has a protective role in cognitive decline. We hypothesized that the sEH inhibitor TPPU might prevent the diabetes-induced decline in learning and memory which is associated with an alteration in the level of neurotransmitters and oxidative stress. METHODS: Type 1 diabetes was induced in rats and the animals were treated with TPPU for 8 weeks. The learning and memory functions were assessed by the Barnes maze and a step-down test. Indicators of oxidative stress, levels of neurotransmitters, and activity of acetylcholinesterase were measured in the discrete regions of the brain. RESULTS: Our results revealed that treatment with TPPU significantly improves learning and memory performance in diabetic rats along with decreasing the level of blood sugar. Moreover, treatment with TPPU significantly prevented the diabetes-induced alteration in levels of neurotransmitters, the activity of acetylcholinesterase and preserved anti-oxidant defence system. CONCLUSION: Inhibition of the sEH alleviates diabetes-induced decline in learning and memory.
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Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Animais , Complicações do Diabetes/enzimologia , Diabetes Mellitus Tipo 1/enzimologia , Epóxido Hidrolases/metabolismo , Masculino , Transtornos da Memória/enzimologia , Transtornos da Memória/etiologia , Ratos , Ratos WistarRESUMO
Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 enzymes, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in a mouse model of periodontitis induced by infection with Aggregatibacter actinomycetemcomitans Oral treatment of wild-type mice with TPPU and sEH knockout (KO) animals showed reduced bone loss induced by A. actinomycetemcomitans This was associated with decreased expression of key osteoclastogenic molecules, receptor activator of nuclear factor-κB/RANK ligand/osteoprotegerin, and the chemokine monocyte chemotactic protein 1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and c-Jun N-terminal kinase known to be activated in response to inflammatory signals were abrogated after TPPU treatment or in sEH KO mice. Moreover, endoplasmic reticulum stress was elevated in periodontal disease but was abrogated after TPPU treatment and in sEH knockout mice. Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis.
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Perda do Osso Alveolar/metabolismo , Apoptose/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Periodontite/diagnóstico por imagem , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-α (TNF-α) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-α, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-α Thus sEHI might be useful in the management of NSAID-induced ulcers.
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Diclofenaco/efeitos adversos , Epóxido Hidrolases/antagonistas & inibidores , Intestinos/efeitos dos fármacos , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Úlcera/induzido quimicamente , Úlcera/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Citoproteção/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Técnicas de Inativação de Genes , Mucosa Intestinal/metabolismo , Intestinos/patologia , Masculino , Camundongos , Peroxidase/metabolismo , Compostos de Fenilureia/uso terapêutico , Piperidinas/uso terapêutico , Solubilidade , Fator de Necrose Tumoral alfa/sangue , Úlcera/metabolismo , Úlcera/patologiaRESUMO
Soluble epoxide hydrolase (sEH) inhibitors have been reported to improve penile erection; therefore, sEH could be useful for management of erectile dysfunction. Methanolic and aqueous extracts of 30 Indian medicinal plants were screened for their sEH inhibition potential. Fifteen extracts showed >50% inhibition when screened at 50 µg/mL in sEH inhibition assay. Methanolic extract of Moringa oleifera Lam. (Moringaceae) seeds (MEMO) was most potent with IC50 1.7 ± 0.1 µg/mL and was selected for in vitro studies on isolated rat corpus cavernosum smooth muscle and in vivo sexual behaviour studies on healthy and diabetic rats. Rats were divided into five groups, each containing six animals and treated orally with either water, vehicle (1% Tween-20), MEMO (45 and 90 mg/kg/day for 21 days), and standard drug, sildenafil (5 mg/kg/day for 7 days). An equal number of female rats were used, and the effect of MEMO and sildenafil was compared with that of vehicle. MEMO significantly relaxed isolated rat corpus cavernosum smooth muscle at 0.1-100 µg/mL in vitro and significantly increased (p < 0.05) sexual activity, intracavernous pressure/mean arterial pressure in normal and diabetic rats. The increase in erectile function of rats by MEMO could be because of its sEH inhibitory activity. Copyright © 2016 John Wiley & Sons, Ltd.
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Afrodisíacos/farmacologia , Epóxido Hidrolases/fisiologia , Moringa oleifera , Ereção Peniana/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Epóxido Hidrolases/antagonistas & inibidores , Feminino , Pressão Intracraniana/efeitos dos fármacos , Masculino , RatosRESUMO
Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7 days)+TPPU (3mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME+TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.
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Analgésicos/farmacologia , Dinoprostona/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Compostos de Epóxi/farmacologia , Omeprazol/farmacologia , Dor/tratamento farmacológico , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Epóxido Hidrolases/metabolismo , Hiperalgesia/metabolismo , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Dor/metabolismo , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Among several known RNA modifications, N6-methyladenosine (m6A) is the most studied RNA epitranscriptomic modification and controls multiple cellular functions during development, differentiation, and disease. Current research advancements have made it possible to examine the regulatory mechanisms associated with RNA methylation and reveal its functional consequences in the pathobiology of many diseases, including heart failure. m6A methylation has been described both on coding (mRNA) and non-coding RNA species including rRNA, tRNA, small nuclear RNA and circular RNAs. The protein components which catalyze the m6A methylation are termed methyltransferase or 'm6A writers'. The family of proteins that recognize this methylation are termed 'm6A readers' and finally the enzymes involved in the removal of a methyl group from RNA are known as demethylases or 'm6A erasers'. At the cellular level, different components of methylation machinery are tightly regulated by many factors to maintain the m6A methylation dynamics. The m6A methylation process impacts different stages of mRNA metabolism and the biogenesis of long non-coding RNA and miRNA. Although, mRNA methylation was initially described in the 1970s, its regulatory roles in various diseases, including cardiovascular diseases are broadly unexplored. Recent investigations suggest the important role of m6A mRNA methylation in both hypertrophic and ischaemic heart diseases. In the present review, we evaluate the significance of m6A methylation in the cardiovascular system, in cardiac homeostasis and disease, all of which may help to improve therapeutic intervention for the treatment of heart failure. RNA methylation in cardiovascular diseases: altered m6A RNA (coding and non-coding RNA) methylation is identified during different cardiovascular diseases. Increased cardiac hypertrophy is observed following METTL3 overexpression. In contrast, reduced FTO level was seen in mice following myocardial infarction. Increased cardiac fibroblasts activation or increased atherosclerotic plaques were also co-related with m6A RNA methylation.
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Doenças Cardiovasculares , Sistema Cardiovascular , Insuficiência Cardíaca , RNA Longo não Codificante , Animais , Biologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/terapia , Sistema Cardiovascular/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Background: Endothelial cells (ECs) play a critical role in the maintenance of vascular homeostasis and in heart function. It was shown that activated fibroblast-derived exosomes impair cardiomyocyte function in hypertrophic heart, but their effect on ECs is not yet clear. Thus, we hypothesized that activated cardiac fibroblast-derived exosomes (FB-Exo) mediate EC dysfunction, and therefore modulation of FB-exosomal contents may improve endothelial function. Methods and Results: Exosomes were isolated from cardiac fibroblast (FB)-conditioned media and characterized by nanoparticle tracking analysis and electron microscopy. ECs were isolated from mouse heart. ECs were treated with exosomes isolated from FB-conditioned media, following FB culture with TGF-ß1 (TGF-ß1-FB-Exo) or PBS (control) treatment. TGF-ß1 significantly activated fibroblasts as shown by increase in collagen type1 α1 (COL1α1), periostin (POSTN), and fibronectin (FN1) gene expression and increase in Smad2/3 and p38 phosphorylation. Impaired endothelial cell function (as characterized by a decrease in tube formation and cell migration along with reduced VEGF-A, Hif1α, CD31, and angiopoietin1 gene expression) was observed in TGF-ß1-FB-Exo treated cells. Furthermore, TGF-ß1-FB-Exo treated ECs showed reduced cell proliferation and increased apoptosis as compared to control cells. TGF-ß1-FB-Exo cargo analysis revealed an alteration in fibrosis-associated miRNAs, including a significant increase in miR-200a-3p level. Interestingly, miR-200a-3p inhibition in activated FBs, alleviated TGF-ß1-FB-Exo-mediated endothelial dysfunction. Conclusions: Taken together, this study demonstrates an important role of miR-200a-3p enriched within activated fibroblast-derived exosomes on endothelial cell biology and function.
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BACKGROUND: Endothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. The molecular mechanism for endothelial dysfunction in the heart is still not clearly understood. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury. METHODS AND RESULTS: ECs were treated with ischemic insults (lipopolysaccharide and 1% hypoxia) to determine the role of ALKBH5 in ECs angiogenesis. siRNA mediated ALKBH5 gene silencing was used for examining the loss of function. In this study, we report that ALKBH5 levels are upregulated following ischemia and are associated with maintaining ischemia-induced ECs angiogenesis. To decipher the mechanism of action, we found that ALKBH5 is required to maintain eNOS phosphorylation and SPHK1 protein levels. ALKBH5 silencing alone or with ischemic stress significantly increased SPHK1 m6A mRNA methylation. In contrast, METTL3 (RNA methyltransferase) overexpression resulted in the reduced expression of SPHK1. CONCLUSION: We reported that ALKBH5 helps in the maintenance of angiogenesis in endothelial cells following acute ischemic stress via reduced SPHK1 m6A methylation and downstream eNOS-AKT signaling.
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While iron is a nutrient metal, iron overload can result in multiple organ failures. Iron chelators, such as deferoxamine, are commonly used to ameliorate iron overload conditions. However, their uses are limited due to poor pharmacokinetics and adverse effects. Many novel chelator formulations have been developed to overcome these drawbacks. In this review, we have discussed various nanochelators, including linear and branched polymers, dendrimers, polyrotaxane, micelles, nanogels, polymeric nanoparticles and liposomes. Although these research efforts have mainly been focused on nanochelators with longer half-lives, prolonged residence of polymers in the body could raise potential safety issues. We also discussed recent advances in nanochelation technologies, including mechanism-based, long-acting nanochelators.
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BACKGROUND: Myocardial injury due to ischemia-reperfusion (IR) is aggravated in diabetes which is associated with oxidative stress. Alleviating oxidative stress via use of antioxidants has been shown to be effective at minimizing myocardial cell death and improving cardiac function. The aim of the present study was to evaluate the cardioprotective effect of phloroglucinol against myocardial reperfusion injury (MRI) in diabetic rats. METHODS: Diabetes was induced in female rats with streptozotocin (50 mg/kg). The diabetic rats were orally treated with phloroglucinol (100 and 200 mg/kg daily for 28 days). After treatment the hearts were isolated and mounted on a Langendorff apparatus. The hearts were subjected to 15 minutes of IR to induce myocardial damage. Cardiac functions including heart rate (HR), resting and developed tension, and rate of change of contraction (+dP/dt max) were recorded. Cardiac injury biomarkers lactate dehydrogenase (LDH) and creatine kinase (CK-MB) were measured in the heart perfusate. Levels of the antioxidant enzymes reduced glutathione (GSH) and malondialdehyde (MDA) were measured. Hematoxylin and eosin (H&E) staining was also performed. RESULTS: After IR injury, a decrease in HR and +dP/dt max in hearts from diabetic rat was seen compared to healthy rat hearts, which was reversed by phloroglucinol treatment. Myocardial infarct size, measured by H&E staining, was increased in diabetic rats compared to healthy rats and an increase in the activity of LDH and CK-MB in the heart perfusate in diabetic rats was decreased by phloroglucinol treatment. An increase in MDA levels and a decrease in levels of antioxidant enzymes were observed in diabetic rats, which was reversed with phloroglucinol treatment. CONCLUSION: Phloroglucinol treatment has potential therapeutic promise in the treatment of MRI in diabetes.
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Diabetes-induced male sexual dysfunction is associated with endothelial dysfunction. Inhibition of soluble epoxide hydrolase (sEH) is known to improve endothelial function in diabetes. Therefore, we hypothesized that sEH inhibitor (sEHI), [trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid] / t-TUCB can restore the male sexual function in diabetic rat. After one week of administration of diabetogenic agent STZ (52 mg/kg i.p) injection, diabetic rats were treated with t-TUCB (0.1 and 0.3 mg/kg, p.o) or vehicle for 8 weeks. The sexual behaviour parameters of the animals were evaluated at the end of dosing period. The levels of testosterone and glucose in serum, and sperm were quantified. Effect of treatment on weight of reproductive organs and histopathology of penile tissue was evaluated. Diabetes had a negative effect on male sexual function, weight of sexual organs and production of sperm with a parallel decrease in the level of testosterone. The sEHI, t-TUCB, significantly preserved the sexual function and minimized an increase in the level of blood glucose in diabetic rats. It also prevented a decrease in the level of testosterone and sperm in diabetic rats, in comparison to diabetic control rats. Further, diabetes induced distortion of corpus cavernosum was attenuated by t-TUCB. Based on our findings, sEHI may delay the development of sexual dysfunction in diabetes.
Assuntos
Benzoatos/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Disfunções Sexuais Fisiológicas/prevenção & controle , Animais , Endotélio Vascular/efeitos dos fármacos , Genitália Masculina/efeitos dos fármacos , Genitália Masculina/patologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Ratos Wistar , Comportamento Sexual Animal/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/enzimologia , Disfunções Sexuais Fisiológicas/etiologia , Estreptozocina , Testosterona/sangueRESUMO
Diabetes is a risk factor for Alzheimer's disease and it is associated with significant memory loss. In the present study, we hypothesized that the soluble epoxide hydrolase (sEH) inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea (also known as TPPU) could alleviate diabetes-aggravated Alzheimer's disease-like symptoms by improving memory and cognition, and reducing the oxidative stress and inflammation associated with this condition. Also, we evaluated the effect of edaravone, an antioxidant on diabetes-induced Alzheimer's-like complications and the additive effect of docosahexaenoic acid (DHA) on the efficacy of TPPU. Diabetes was induced in male Sprague-Dawley rats by intraperitoneally administering streptozotocin (STZ). Six weeks after induction of diabetes, animals were either treated with vehicle, edaravone (3 or 10 mg/kg), TPPU (1 mg/kg) or TPPU (1 mg/kg) + DHA (100 mg/kg) for 2 weeks. The results demonstrate that the treatments increased the memory response of diabetic rats, in comparison to untreated diabetic rats. Indeed, DHA + TPPU were more effective than TPPU alone in reducing the symptoms monitored. All drug treatments reduced oxidative stress and minimized inflammation in the brain of diabetic rats. Expression of the amyloid precursor protein (APP) was increased in the brain of diabetic rats. Treatment with edaravone (10 mg/kg), TPPU or TPPU + DHA minimized the level of APP. The activity of acetylcholinesterase (AChE) which metabolizes acetylcholine was increased in the brain of diabetic rats. All the treatments except edaravone (3 mg/kg) were effective in decreasing the activity of AChE and TPPU + DHA was more efficacious than TPPU alone. Intriguingly, the histological changes in hippocampus after treatment with TPPU + DHA showed significant protection of neurons against STZ-induced neuronal damage. Overall, we found that DHA improved the efficacy of TPPU in increasing neuronal survival and memory, decreasing oxidative stress and inflammation possibly by stabilizing anti-inflammatory and neuroprotective epoxides of DHA. In the future, further evaluating the detailed mechanisms of action of sEH inhibitor and DHA could help to develop a strategy for the management of Alzheimer's-like complications in diabetes.
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Metabolic abnormalities including hyperglycemia, hyperlipidemia, and oxidative-nitrosative stress are involved in the progression of diabetic neuropathy. In the present study, we targeted oxidative-nitrosative stress using nebivolol, a ß1-receptor antagonist with vasodilator and antioxidant property, to evaluate its neuroprotective effect in streptozotocin-induced diabetic neuropathy in rats. Diabetic neuropathy develops within 4-6 weeks after administration of streptozotocin (55 mg/kg, i.p.). Therefore, after confirmation of diabetes, subtherapeutic doses of nebivolol (1 and 2 mg/kg, p.o./day) were given to diabetic rats for 8 weeks. Nebivolol treatment significantly improved thermal hyperalgesia, grip strength, and motor coordination. Nebivolol also reduced levels of malondialdehyde, tumor necrosis factor-α, and nitrite in diabetes. Moreover, nebivolol increased the levels of superoxide dismutase and catalase in sciatic nerve homogenate of diabetic rats. Further, nebivolol exerted positive effects on lipid profile, sciatic nerve's morphological changes and nerve conduction velocity in diabetic rats. Results of the present study suggest the neuroprotective effect of nebivolol through its antioxidant, nitric oxide-potentiating, and antihyperlipidemic activity.
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Antagonistas Adrenérgicos beta/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Nebivolol/uso terapêutico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/metabolismo , Masculino , Nebivolol/farmacologia , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Estreptozocina/toxicidadeRESUMO
Aims: Activation and expression of large conductance calcium and voltage-activated potassium channel (BKCa) by pharmacological agents have been implicated in cardioprotection from ischemia-reperfusion (IR) injury possibly by regulating mitochondrial function. Given the non-specific effects of pharmacological agents, it is not clear whether activation of BKCa is critical to cardioprotection. In this study, we aimed to decipher the mechanistic role of BKCa in cardioprotection from IR injury by genetically activating BKCa channels. Methods and Results: Hearts from adult (3 months old) wild-type mice (C57/BL6) and mice expressing genetically activated BKCa (Tg-BKCa R207Q, referred as Tg-BKCa) along with wild-type BKCa were subjected to 20 min of ischemia and 30 min of reperfusion with or without ischemic preconditioning (IPC, 2 times for 2.5 min interval each). Left ventricular developed pressure (LVDP) was recorded using Millar's Mikrotip® catheter connected to ADInstrument data acquisition system. Myocardial infarction was quantified by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Our results demonstrated that Tg-BKCa mice are protected from IR injury, and BKCa also contributes to IPC-mediated cardioprotection. Cardiac function parameters were also measured by echocardiography and no differences were observed in left ventricular ejection fraction, fractional shortening and aortic velocities. Amplex Red® was used to assess reactive oxygen species (ROS) production in isolated mitochondria by spectrofluorometry. We found that genetic activation of BKCa reduces ROS after IR stress. Adult cardiomyocytes and mitochondria from Tg-BKCa mice were isolated and labeled with Anti-BKCa antibodies. Images acquired via confocal microscopy revealed localization of cardiac BKCa in the mitochondria. Conclusions: Activation of BKCa is essential for recovery of cardiac function after IR injury and is likely a factor in IPC mediated cardioprotection. Genetic activation of BKCa reduces ROS produced by complex I and complex II/III in Tg-BKCa mice after IR, and IPC further decreases it. These results implicate BKCa-mediated cardioprotection, in part, by reducing mitochondrial ROS production. Localization of Tg-BKCa in adult cardiomyocytes of transgenic mice was similar to BKCa in wild-type mice.
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AIMS: This research was conducted to evaluate the hypothesis that gastric ulcers caused by the NSAID diclofenac sodium (DCF) can be prevented by the soluble epoxide hydrolase inhibitor TPPU. MAIN METHODS: Mice were administered a single dose of 10, 30 or 100mg/kg of DCF. Once an ulcerative dose of DCF was chosen, mice were pretreated with TPPU for 7days at 0.1mg/kg to evaluate anti-ulcer effects of the sEH inhibitor on anatomy, histopathology, pH, inflammatory markers and epithelial apoptosis of stomachs. KEY FINDINGS: Diclofenac caused ulceration of the stomach at a dose of 100mg/kg and a time post dose of 6h. Ulcers generated under these conditions were associated with a significant increase in the levels of TNF-α and IL-6 in serum and increased apoptosis compared to control mice. Pretreatment with TPPU resulted in a decrease of ulceration in mice treated with DCF with a significant decrease in the level of apoptosis, TNF-α and IL-6 in the serum in comparison to diclofenac-treated mice. TPPU did not affect the pH of the stomach, whereas omeprazole elevated the pH of the stomach as expected. A similar anti-ulcer effect was observed in sEH gene knockout mice treated with DCF. SIGNIFICANCE: The sEH inhibitor TPPU decreases the NSAID-induced stomach ulcers.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Diclofenaco/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Úlcera Gástrica/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antiulcerosos/farmacologia , Apoptose/efeitos dos fármacos , Diclofenaco/administração & dosagem , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/genética , Deleção de Genes , Concentração de Íons de Hidrogênio , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Omeprazol/farmacologia , Úlcera Gástrica/patologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangueRESUMO
INTRODUCTION: Diabetes-induced sexual dysfunction is associated with an increase in oxidative stress. Scavengers of reactive oxygen species (ROS) have been shown to reduce oxidative stress and aid in the management of sexual dysfunction in diabetes. AIM: The aim of the study was to test the hypothesis that antioxidant, which scavenge ROS and reduce formation of advanced glycation end products (AGEs), can potentiate efficacy of phosphodiesterase type 5 inhibitors in diabetes-induced sexual dysfunction that is associated with oxidative stress. MATERIALS AND METHODS: Effect of phloroglucinol and sildenafil on serum glucose level, sexual function, penile smooth muscle : collagen ratio, and phenylephrine precontracted corpus cavernosum smooth muscle (CCSM) was studied. The ability of phloroglucinol to reduce the formation of AGEs and its ability to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) was also evaluated. MAIN OUTCOME MEASURES: Antioxidant potential of phloroglucinol was studied in addition to its effect on diabetes-induced sexual dysfunction in presence and absence of sildenafil. RESULTS: Phloroglucinol (50 mg/kg, p.o.) significantly decreased serum glucose level and increased sexual function in streptozotocin-induced diabetic rats when compared with diabetic control rats. Sildenafil (5 mg/kg, p.o.) had no effect on glycemia but significantly increased sexual function of diabetic rats. Coadministration of phloroglucinol increased the efficacy of sildenafil by improving sexual function. Treatment of diabetic rats with phloroglucinol + sildenafil maintained smooth muscle : collagen levels similar to that of normal rat penile tissue. Phloroglucinol decreased formation of AGEs and significantly scavenged DPPH radical activity in vitro. Sildenafil relaxed isolated CCSM of normal rat and diabetic rat significantly, but phloroglucinol did not show any significant effect. Phloroglucinol also inhibited human CYP3A4 enzyme activity in vitro. CONCLUSION: Phloroglucinol coadministration increases efficacy of sildenafil in diabetes-induced sexual dysfunction. However, further studies are required to ascertain the benefits of phloroglucinol owing to its undesirable CYP3A4 inhibition activity.
RESUMO
BACKGROUND: Diabetes induced sexual dysfunction is a leading cause of male sexual disorder and an early indicator of cardiovascular complication. Reactive oxygen species generated in body during diabetes is a main causative factor for erectile dysfunction, a sexual dysfunction. Adjuvant antioxidant therapy along with phosphodiesterases type 5 enzyme inhibitor (PDE5i) is more effective than PDE5i alone. OBJECTIVE: The aim of the study was to investigate efficacy of ellagic acid a known antioxidant and sildenafil in diabetes induced erectile dysfunction. MATERIALS AND METHODS: Type 1 diabetes was induced in male rats and rats were treated with ellagic acid (50 mg/kg, p.o.) and a combination of ellagic acid (50 mg/kg, p.o.) and sildenafil (5 mg/kg, p.o.), a PDE5i for 28 days. Sexual function was observed in diabetic rat and compared with those of treatment group and normal rats. Effect of ellagic acid was studied on advanced glycation end products (AGE) and isolated rat corpus cavernosum in vitro. RESULTS: Sexual function of diabetic rats was found to be reduced and ellegic acid treatment could preserve sexual function of diabetic rats to some extent. Ellagic acid + sildenafil treatment was more efficient in management of diabetes induced sexual dysfunction. Ellagic acid inhibited (AGE) in vitro implying its role in reducing oxidative stress in diabetes. The polyphenol could not increase sexual function in normal rats and relax isolated rat corpus cavernosum smooth muscle significantly. CONCLUSION: The study proves usefulness of adjuvant antioxidant therapy in the management of erectile dysfunction in diabetes.
RESUMO
OBJECTIVE: Cinnamomum cassia has been suggested in Ayurveda for the management of sexual dysfunction. This research work was conducted to shed some light on the mechanism of action of the extract, and evaluate the efficacy of its methanol extract in age induced sexual dysfunction in male Wistar rats. Secondary objective of the project was to study the effect of treatment on sperm parameters and smooth muscle:collagen level in rat penile tissue. METHODS: Young and aged male rats were treated with methanol extract of Cinnamomum cassia at a dose of 100 mg/kg and sexual behavior was observed on 28th day in presence of female rats in estrous phase. Sildenafil was used as standard medicine. Effect of treatment was studied on epididymal sperm parameters, and Massons trichrome staining of rat penile tissues was performed to know the level of smooth muscle:collagen. RESULTS: The treatment significantly increased sexual function in aged rats that had decreased in comparison to young rats, but did not have any significant effect on sperm count, live and defective sperm percentage. However, treatment induced an increase in smooth muscle level and a decrease in collagen level in the aged rat penile tissue in comparison to that of age matched control. CONCLUSION: Based on our studies, we found that Cinnamomum cassia extract was effective in management of sexual dysfunction in aged rats and hence we propose a possible mechanism of action for Cinnamomum cassia which could be responsible for restoring sexual activity in aged rat.