RESUMO
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-ß (Aß) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO4 intake in experimental rats. Thirty adult male Wistar rats (140-160 g) were used in this study. AD was first induced in rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO4 intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO4 induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO4-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.
Assuntos
Doença de Alzheimer , Pentoxifilina , Ratos , Masculino , Animais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Donepezila , Secretases da Proteína Precursora do Amiloide/metabolismo , Sulfato de Cobre , Pentoxifilina/efeitos adversos , Proteína X Associada a bcl-2 , Acetilcolinesterase/metabolismo , Fator de Necrose Tumoral alfa , Ratos Wistar , Ácido Aspártico Endopeptidases/efeitos adversos , Ácido Aspártico Endopeptidases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Modelos Animais de DoençasRESUMO
The current study aimed to investigate the effect of orally administered raspberry ketone (RK) on ameliorating nonalcoholic fatty liver disease (NAFLD) induced in rats by high-fat high-fructose diet (HFFD) in comparison to calorie restriction (CR) regimen. Thirty male Wistar rats were divided into two experimental groups; one was fed normal chow diet (NCD, n = 6) for 15 weeks to serve as normal control group and the other group was fed HFFD (n = 24) for 7 weeks to induce NAFLD. After induction, rats in the HFFD group were randomly allocated into four groups (n = 6 rats each). One group continued on HFFD feeding for 8 weeks (NAFLD control group). The remaining 3 groups received NCD, calorie-restricted diet, or NCD along with RK (55 mg/kg/day, orally) for 8 weeks. Like CR, RK effectively attenuated NAFLD and ameliorated the changes attained by HFFD. RK upregulated the expression of the phosphorylated AMP-activated protein kinase (P-AMPK) and fatty acid oxidation factors; peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase-1 (CPT-1) and downregulated lipogenic factors; sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) in the hepatic tissue. Also, RK improved lipid profile parameters, liver enzymes and both body and liver tissue weights. Altogether, these findings suggest that oral administration of RK, along with normal diet, ameliorated NAFLD in a way similar to CR. This approach could be an alternative to CR in the management of NAFLD, overcoming the poor compliance to long term CR regimen.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Doenças não Transmissíveis , Masculino , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Quinases Ativadas por AMP , Ratos Wistar , FrutoseRESUMO
OBJECTIVES: To investigate the therapeutic role of calorie-restricted diet (CR) and raspberry ketone (RK) in non-alcoholic fatty liver disease (NAFLD) and the implication of sphingosine kinase-1 (SphK1)/sphingosine-1-phosphate (S1P) and toll-like receptor 4 (TLR4) signalling. METHODS: NAFLD was induced by feeding rats high-fat-fructose-diet (HFFD) for 6 weeks. Rats were then randomly assigned to three groups (n = 6 each); NAFLD group continued on HFFD for another 8 weeks. CR group was switched to CR diet (25% calorie restriction) for 8 weeks and RK group was switched to normal diet and received RK (55 mg/kg/day; orally) for 8 weeks. Another six rats were used as normal control. KEY FINDINGS: HFFD induced a state of NAFLD indicated by increased fat deposition in liver tissue along with dyslipidemia, elevated liver enzymes, oxidative stress and inflammation. Either CR diet or RK reversed these changes and decreased HFFD-induced elevation of hepatic SphK1, S1P, S1PR1 and TLR4. Of notice, RK along with a normal calorie diet was even better than CR alone in most studied parameters. CONCLUSIONS: SphK1/S1P and TLR4 are interconnected and related to the establishment of HFFD-induced NAFLD and can be modulated by RK. Supplementation of RK without calorie restriction to patients with NAFLD unable to follow CR diet to achieve their treatment goals would be a promising therapeutic modality.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Ratos , Dieta Hiperlipídica , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfatos/metabolismo , Esfingosina/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.
Assuntos
Doença de Alzheimer , Lesões Encefálicas , Disfunção Cognitiva , Ratos , Masculino , Animais , Donepezila/efeitos adversos , Cobre , Sulfato de Cobre/efeitos adversos , Sulfato de Cobre/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/farmacologia , Secretases da Proteína Precursora do Amiloide/uso terapêutico , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Acetilcolinesterase/metabolismo , Sulfatos/metabolismo , Sulfatos/farmacologia , Sulfatos/uso terapêutico , Proteína X Associada a bcl-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ratos Wistar , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/farmacologia , Ácido Aspártico Endopeptidases/uso terapêutico , Lesões Encefálicas/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Vitaminas/farmacologia , Encéfalo , Disfunção Cognitiva/induzido quimicamenteRESUMO
The release of inflammatory cytokines, namely tumor necrosis factor-α (TNF-α), plays an important role in the pathogenesis of cardiomyopathy. TNF-α increases in plasma and in myocardium of heart failure patients. We aimed to investigate the role of TNF-α inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats. DCM was induced in rats by doxorubicin (DOX; 3.5 mg. kg-1 , i.p) twice weekly for 3 weeks (21 mg. kg-1 cumulative dose). DCM rats were treated with RPL (1 mg. kg-1 orally, daily), IFX (5 mg. kg-1 ; i.p. once) or their combination for 4 weeks starting next day of last DOX dose. Echocardiography was conducted followed by a collection of blood and left ventricle (LV) for biochemical and histological investigations. DCM rats revealed deteriorated cardiac function (increased CK-MB activity, LVIDs, LVIDd, ESV, and EDV, while decreased EF% and FS%), hypertrophy (increased HW/TL, ß-MHC, and α-actin), inflammation (increased IL-1ß, IL-6, and TNF-α). The activation of Wnt/ß-catenin along with increased gene expression of RAS components (RENIN, ACE, and AT1) were evident. LV architecture also revealed abnormalities and some degree of fibrosis. Treatment with RPL and/or IFX suppressed TNF-α and consequently improved most of these parameters suppressing Wnt/ß-catenin/RAS axis. Combined RPL and IFX treatment was the best among all treatments. In conclusion, Wnt/ß-catenin/RAS axis is implicated in DOX-induced cardiomyopathy. The upstream TNF-α was proved for the first time in-vivo to stimulate this axis where its inhibition by RPL or IFX prevented DCM. Targeting this axis at two points using RPL and IFX showed better therapeutic efficacy.
Assuntos
Cardiomiopatias , Infliximab , Fator de Necrose Tumoral alfa , Animais , Ratos , beta Catenina/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Doxorrubicina/efeitos adversos , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
OBJECTIVES: Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/ß-catenin signalling in CKD. METHODS: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX. KEY FINDINGS: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1ß, Wnt1, active ß-catenin/total ß-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy. CONCLUSIONS: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/ß-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/ß-catenin signalling and its downstream targets.
Assuntos
Fosfolipases A/antagonistas & inibidores , Insuficiência Renal Crônica , Sistema Renina-Angiotensina/efeitos dos fármacos , Triterpenos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Wolfiporia , Animais , Cistatina C/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Testes de Função Renal/métodos , Proteínas Klotho/metabolismo , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismoRESUMO
Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation-contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.
Assuntos
Doxorrubicina/efeitos adversos , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Proteínas de Membrana/genética , MicroRNAs/genética , Triterpenos/farmacologia , Animais , Cardiomegalia/diagnóstico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Testes de Função Cardíaca , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de SinaisRESUMO
Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.
Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fitoestrógenos/farmacologia , Resveratrol/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo , Calcificação Vascular/tratamento farmacológico , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Feminino , Osteogênese/efeitos dos fármacos , Ovariectomia , Pós-Menopausa , Ratos , Sirtuína 1/genética , Calcificação Vascular/patologiaRESUMO
Increased fructose consumption is among bad nutritional habits that contribute to increased incidence of neurodegenerative diseases. We proposed that coffee, the most popular beverage worldwide, may protect against the progression of Alzheimer's disease (AD). We investigated the protective potential of decaffeinated green coffee bean extract (GCBE) and the possible potentiation of pioglitazone (PIO) effects by decaffeinated GCBE in fructose-induced AD in rats. Twenty-four rats [12-untreated and 12-pre-treated (for 4 weeks) with GCBE] consumed drinking water supplemented with 10% fructose for 18 weeks. Twelve of these rats (6-GCBE-untreated and 6-GCBE-pre-treated) were treated orally with PIO starting on the 13th week for 6 weeks. Prophylactic administration of GCBE attenuated oxidative damage (increased cortical reduced glutathione and superoxide dismutase activity), while decreased malondialdehyde. It retarded the activation of acetylcholine esterase, increased acetylcholine level in the cortex of fructose-induced AD. It also impeded the upregulation of beta-secretase-1and the accumulation of Aß plaques that were induced by fructose drinking. With PIO therapy, GCBE showed better effects alleviating oxidative stress and Aß extracellular plaques formation, while improving cholinergic activity, learning, and memory ability. In conclusions, the consumption of GCBE may protect against the development of AD and delay the progression of AD when given with PIO. PRACTICAL APPLICATIONS: Decaffeinated dietary supplement of green coffee bean extract attenuated the deleterious consequences of fructose-induced Alzheimer's disease in rats. It improved the antioxidant status and cortical cholinergic activity, while hindered the changes responsible for amyloid plaque formation. It also improved the impaired learning and memory. These results, if confirmed by clinical studies, may recommend the consumption of decaffeinated green coffee beans extract as dietary supplement or as a regular beverage to protect against AD in individuals with family history or early signs of AD. With pioglitazone, such dietary supplement improved pioglitazone efficacy and delayed the progression of AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Animais , Antioxidantes , Café , Frutose , Pioglitazona , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , RatosRESUMO
Radiation-induced multiple organ injury, including γ-radiation nephropathy, is the most common. Even with dose fractionation strategy, residual late side effects are inevitable. Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and erythropoietin (EPO) have shown to be effective in treating chronic kidney disease and associated anemia. This study aimed to evaluate the effect of BM-MSCs and/or EPO in fractionated γ-irradiation induced kidney damage in rats. Adult male Wistar rats were randomized into 2 groups; normal and 8 Gy (fractionated dose of 2 Gy for 4 days) γ-irradiated rats. Animal from both groups were subdivided to receive the following treatments: BM-MSCs (1 × 106 cells/rat, i.v - once), EPO (100 IU/kg, i.p - every other day for 30 days) or their combined treatment (BM-MSCs and EPO). γ-Irradiated rats showed a noticeable elevation in serum urea and creatinine, kidney malondialdehyde (MDA) and caspase 3 activity. They also revealed significant drop in kidney glutathione (GSH) and Bcl2 protein contents. Conspicuously, they revealed down-regulation of renal EPO signaling (EPO, EPOR, pJAK2, pPI3K and pAkt). Conversely, groups treated with BM-MSCs and/or EPO revealed significant modulation in most tested parameters and appeared to be effective in minimizing the hazard effects of radiation. In conclusion, BM-MSCs and/or EPO exhibited therapeutic potentials against nephrotoxicity induced by fractionated dose of γ-irradiation. An effect mediated by antioxidant and non-hematopoietic EPO downstream anti-apoptotic signaling (PI3K/Akt) pathway. EPO potentiate the repair capabilities of BM-MSCs making this combined treatment a promising therapeutic strategy to overcome radiotherapy-induced kidney damage.
Assuntos
Apoptose , Eritropoetina/uso terapêutico , Rim/efeitos da radiação , Transplante de Células-Tronco Mesenquimais , Lesões Experimentais por Radiação/terapia , Animais , Apoptose/efeitos dos fármacos , Terapia Combinada , Creatinina/sangue , Raios gama/efeitos adversos , Masculino , Ratos , Ratos Wistar , Ureia/sangueRESUMO
Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate ß-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can regulate Wnt/ß-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/ß-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-α, interleukin-6 (IL-6), interleukin-1ß (IL1ß). DOX decreased the renal expression of klotho which in turn increased Wnt1, active ß-catenin/total ß-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-α was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active ß-catenin/total ß-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/ß-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/ß-catenin/renin angiotensin axis.
Assuntos
Infliximab/uso terapêutico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Infliximab/farmacologia , Masculino , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Sistema Renina-Angiotensina/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Via de Sinalização Wnt/fisiologiaRESUMO
OBJECTIVES: To investigate the protective effect of vanillin in cisplatin (CP)-induced nephrotoxicity in rats and elucidate the role of nrf-2 and its downstream antioxidant molecules. METHODS: Rats received vanillin (100 mg/kg orally) for 10 constitutive days and CP (7.5 mg/kg, once, ip) on day 6 of vanillin administration. KEY FINDINGS: Cisplatin suppressed body weight gain, increased serum urea and creatinine and renal malondialdehyde and nitric oxide while decreased renal total antioxidant capacity. Up-regulation of NADPH oxidase-4 (NOX-4) was marked in renal tissue of CP-treated rats along with down-regulation of the antioxidant genes (nuclear factor erythroid 2-related factor2 (NRF2) and haem oxygenase-1(HO-1)). Increased tumour necrosis factor-α and decreased interleukin-10 with increased myeloperoxidase activity were apparent in renal tissue of CP-treated rats along with marked tubular injury, neutrophil infiltration and increased apoptosis (caspase-3) and some degree of interstitial fibrosis. Vanillin prophylactic administration prevented the deterioration of kidney function, oxidative and nitrosative stress. It also suppressed NOX-4 and up-regulated NRF2 and HO-1 expression in renal tissue. Inflammation, apoptosis and tubular injury were also inhibited by vanillin. CONCLUSIONS: The antioxidant mechanism by which vanillin protected against CP-induced nephrotoxicity involved the inhibition of NOX-4 along with the stimulation of Nrf2/HO-1 signalling pathway. These in turn inhibited inflammation and apoptosis.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzaldeídos/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cisplatino , Modelos Animais de Doenças , Fibrose , Rim/enzimologia , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/enzimologia , Nefropatias/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de SinaisRESUMO
Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3ß (GS3Kß) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Café , Resistência à Insulina , Insulina/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Pioglitazona/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Transdução de SinaisRESUMO
The hypolipidemic effect of 10-DHGD was previously reported owing to its anti-inflammatory and anti-oxidant properties. We further investigated the anti-inflammatory role of 10-DHGD in modulating atherogenicity by targeting proproteinconvertasesubtilisinkexin-9 (PCSK-9). Rabbits fed high cholesterol diet (HCD) containing 0.2% w/w cholesterol for12-weeks received either 10-DHGD (10-mg/kg), pentoxifylline (PTX, 40-mg/kg) or their combination concurrently with HCD. Lipid profile, serum PCSK-9, macrophage migration inhibitory factor (MIF), aorta tumor necrosis factor- alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. Atherogenicity and increased PCSK-9, MIF and TNF-α and GAGs (p < 0.001) was proved HCD-fed rabbits. The concurrent administration of 10-DHGD or PTX with HCD feeding prevented this atheogenicity by modulating the release of PCSK-9, inflammatory markers and GAGs. The combined PTX and 10-DHGD in HCD fed rabbits not only lowered hyperlipidemia, but also targeted arterial inflammation to a better extent. In conclusion PTX and 10-DHGD can prevent hyperlipidemia and associated inflammatory process modifying factors predisposing to atherosclerosis.
Assuntos
Glicosaminoglicanos/metabolismo , Guaiacol/análogos & derivados , Hiperlipidemias/prevenção & controle , Pentoxifilina/farmacologia , Pró-Proteína Convertase 9/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Aterosclerose/prevenção & controle , Colesterol , Guaiacol/farmacologia , Masculino , Pró-Proteína Convertase 9/sangue , CoelhosRESUMO
10-Dehydrogingerdione (10-DHGD) was previously reported to possess a hypolipidemic, anti-inflammatory and anti-oxidant properties in hyperlipidemic rabbit model. In this study, we investigated a possible new role for 10-DHGD in modulating atherogenic lipid profile by targeting proprotein convertase subtilisin kexin-9 (PCSK-9). Cholesterol (0.2% w/w)-fed rabbits received either atorvastatin (20 mg/kg) or 10-DHGD (10 mg/kg) for 12 weeks along with cholesterol feeding (HCD). Lipid profile, serum PCSK-9 and macrophage migration inhibitory factor (MIF), and aorta level of tumor necrosis factor-alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. HCD-fed rabbits revealed an atherogenic lipid profile along with increased serum level of PCSK-9 (p < 0.001) and increased serum MIF and aortic TNF-α and GAGs (p < 0.001). 10-DHGD administration to HCD-fed rabbits prevented this atheogenicity by modulating the release of PCSK-9, inflammation extent (serum MIF and aortic TNF-α) and GAGs. These results provide new insights on the hypolipidemic potential of 10-DHGD. The effects of 10-DHGD was superior to that of atorvastatin in most studied parameters modulating atherogenicity. 10-DHGD is found to be able to suppress the release of PCSK-9, decrease aortic expression of GAGs in cholesterol-fed rabbits and halt the inflammation extent. These effects may provide new insights on the hypolipidemic potential of 10-DHGD.
Assuntos
Glicosaminoglicanos/metabolismo , Guaiacol/análogos & derivados , Hiperlipidemias/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiologia , Aterosclerose/metabolismo , Atorvastatina/farmacologia , Colesterol/metabolismo , Guaiacol/metabolismo , Guaiacol/farmacologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Lipídeos/sangue , Masculino , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/metabolismo , Coelhos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100µM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX.
Assuntos
Apoptose/efeitos dos fármacos , Benzaldeídos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Ehrlich/tratamento farmacológico , Doxorrubicina/uso terapêutico , Animais , Benzaldeídos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Caspase 9/metabolismo , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Células MCF-7 , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: Hydrogen sulfide (H2S) can protect against hepatic ischemia-reperfusion injury (HIR). However, it is unknown whether it can protect against HIR in insulin resistance. This study investigated the protective effects of silymarin against HIR in a rat model of insulin resistance and the possible involvement of endogenous H2S. MATERIALS AND METHODS: Insulin resistance was first established using 10% fructose in drinking water for 10 weeks. HIR was conducted in fructose-fed rats treated with saline or silymarin (100 mg/kg), 15 min before HIR (30 min ischemia, followed by 1 h reperfusion). Insulin resistance and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), total nitrites (NO2(-)), and H2S were measured. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), hydroxyproline, H2S synthesizing activity, and mRNA expression of cystathionine ß-synthase (CBS) or cystathionine γ-lyase (CSE) were determined. Additionally, histopathological examination involved H&E, Sirius red, and caspase-3 immunostaining. RESULTS: Fructose-induced insulin resistance increased serum ALT, TNF-α, H2S and H2S synthesizing activity, and hepatic MDA, hydroxyproline, and CSE mRNA and decreased NO2(-) and GSH. These changes exacerbated the HIR injury in which endogenous H2S production was auxiliary increased. Silymarin preconditioning decreased ALT, AST, MDA, NO2(-), TNF-α, and TNF-α/IL-10 ratio, increased GSH, IL-10, improved hepatic architecture, and lowered caspase-3 immunostaining. Serum H2S, its hepatic synthesizing activity, and CSE and CBS mRNA expressions were all suppressed by silymarin pretreatment. CONCLUSIONS: The increases in endogenous H2S exacerbate HIR injury, whereas silymarin preconditioning protected against HIR in insulin resistant rats via powerful antioxidant, anti-inflammatory, and antiapoptotic effects along with suppressing H2S production.
Assuntos
Antioxidantes/uso terapêutico , Sulfeto de Hidrogênio/sangue , Resistência à Insulina , Hepatopatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Silimarina/uso terapêutico , Animais , Apoptose , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fibrose , Frutose , Fígado/enzimologia , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Estresse Oxidativo , Fitoterapia , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
Organs subjected to chronic injuries may develop tissue fibrosis. Several factors contribute to the combat injurious stimuli to repair, heal and alleviate any disturbance. Secretion of chemokines, migration of inflammatory cells to the affected site and activation of fibroblast for production of extracellular matrix (ECM) are examples. Recently, few studies have delt with 10-dehydrogingerdione (10-DHGD), one of the active constituent of ginger extracts that has been published. This constituent proved to be potent antioxidant, anti-inflammatory, cholesterol ester transfer protein (CETP) inhibitor, indeed, a hypolipemic agent. It has been selected in the present study as a natural anti-inflammatory agent to combat inflammation, nephrotoxicity and renal fibrosis-induced by cisplatin. Renal fibrosis state demonstrated a significant increase in creatinine, urea, nuclear factor kappa (NF-kB), insulin like growth factor I (IGF-I), fibroblast growth factor-23 (FGF-23) along with a significant decrease of hepatocytes growth factor (HGF), renal glutathione (GSH) and in confirm to histopathological examination of kidney tissue. Administration of 10-DHGD orally daily for 4 weeks resulted in a significant improvement of both the biomarkers studied in addition to the histopathological profile of the renal tissues. CONCLUSION: 10-DHGD exhibited a marked anti-inflammatory potential, alleviated to a great extent of nephrotoxicity and renal fibrosis induced by cisplatin.
Assuntos
Cisplatino/efeitos adversos , Guaiacol/análogos & derivados , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Animais , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fibrose , Guaiacol/farmacologia , Guaiacol/uso terapêutico , Fator de Crescimento de Hepatócito/sangue , Inflamação/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Nefropatias/sangue , Testes de Função Renal , Masculino , NF-kappa B/sangue , Ratos WistarRESUMO
Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.