RESUMO
Pulmonary fibrosis has been recently linked to metabolic dysregulation. Silica-induced pulmonary fibrosis in rats was employed by the current study to explore the effects of trimetazidine (a metabolic modulator-antianginal drug; TMZ) on silica-induced pulmonary fibrosis. Pulmonary fibrosis was induced by intranasal instillation of silica (50 mg/100 µl/rat) in TMZ versus vehicle-treated rats. Body weights of rats, weights of lungs, and wet-to-dry lung weights were determined. Various parameters were also measured in serum, bronchoalveolar lavage fluid (BALF) in addition to lung tissue homogenates. Moreover, histopathological examination of sectioned lungs for lesion score and distribution and histochemical detection of myeloperoxidase (MPO) in lung tissues were also performed. No significant differences were observed in body weight gains, lung coefficients, lung weights, and wet-to-dry lung weight in silica versus control rats. Elevated lactate levels in serum and lung homogenates were significantly attenuated by TMZ. In addition, lactate dehydrogenase activity, transforming growth factor-ß, and total proteins in BALF were significantly normalized with TMZ. Moreover, TMZ significantly increased reduced glutathione and adenosine triphosphate levels and decreased nitrate/nitrite and hydroxyproline content in lungs of silica-treated rats. Histopathological examination of lungs revealed more than 56% reduction in lesion score and distribution by TMZ. MPO expression in lungs of silica-treated rats was also significantly attenuated by TMZ. TMZ attenuates silica-induced pulmonary fibrosis, an effect that could be mediated by suppressing anaerobic glycolysis-induced excessive lactate production. Regulation of oxidative stress could also play a role in TMZ-promoted protective effects.
Assuntos
Substâncias Protetoras/farmacologia , Fibrose Pulmonar , Trimetazidina , Animais , Líquido da Lavagem Broncoalveolar/química , Lactatos/análise , Lactatos/metabolismo , Lactatos/farmacologia , Pulmão/metabolismo , Substâncias Protetoras/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Ratos , Dióxido de Silício/análise , Dióxido de Silício/toxicidade , Trimetazidina/farmacologia , Trimetazidina/uso terapêuticoRESUMO
Activation of nuclear factor erythroid 2-related factor 2 (Nrf2, a transcription factor) and/or inhibition of mammalian target of rapamycin (mTOR) are implicated in the suppression of vascular smooth muscle cell (VSMC) proliferation. The present study has examined the likely regulatory effects of sulforaphane (SFN, an antioxidant) on Nrf2 activation and platelet-derived growth factor (PDGF)-induced mTOR signaling in VSMCs. Using human aortic VSMCs, nuclear extraction and siRNA-mediated downregulation studies were performed to determine the role of Nrf2 on SFN regulation of PDGF-induced proliferative signaling. Immunoprecipitation and/or immunoblot studies were carried out to determine how SFN regulates PDGF-induced mTOR/p70S6K/S6 versus ERK and Akt signaling. Immunohistochemical analysis was performed to determine SFN regulation of S6 phosphorylation in the injured mouse femoral artery. SFN (5µM) inhibits PDGF-induced activation of mTOR without affecting mTOR association with raptor in VSMCs. While SFN inhibits PDGF-induced phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTOR), it does not affect ERK or Akt phosphorylation. In addition, SFN diminishes exaggerated phosphorylation of S6 ribosomal protein (a downstream target of p70S6K) in VSMCs in vitro and in the neointimal layer of injured artery in vivo. Although SFN promotes Nrf2 accumulation to upregulate cytoprotective genes (e.g., heme oxygenase-1 and thioredoxin-1), downregulation of endogenous Nrf2 by target-specific siRNA reveals an Nrf2-independent effect for SFN-mediated inhibition of mTOR/p70S6K/S6 signaling and suppression of VSMC proliferation. Strategies that utilize local delivery of SFN at the lesion site may limit restenosis after angioplasty by targeting mTOR/p70S6K/S6 axis in VSMCs independent of Nrf2 activation.
Assuntos
Antioxidantes/farmacologia , Isotiocianatos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , SulfóxidosRESUMO
Hypoadiponectinemia is associated with an increased risk of coronary artery disease. Although adiponectin replenishment mitigates neointimal hyperplasia and atherosclerosis in mouse models, adiponectin therapy has been hampered in a clinical setting due to its large molecular size. Recent studies demonstrate that AdipoRon (a small-molecule adiponectin receptor agonist) improves glycemic control in type 2 diabetic mice and attenuates postischemic cardiac injury in adiponectin-deficient mice, in part, through activation of AMP-activated protein kinase (AMPK). To date, it remains unknown as to whether AdipoRon regulates vascular smooth muscle cell (VSMC) proliferation, which plays a major role in neointima formation. In the present study, oral administration of AdipoRon (50mg/kg) in C57BL/6J mice significantly diminished arterial injury-induced neointima formation by â¼57%. Under in vitro conditions, AdipoRon treatment led to significant inhibition of platelet-derived growth factor (PDGF)-induced VSMC proliferation, DNA synthesis, and cyclin D1 expression. While AdipoRon induced a rapid and sustained activation of AMPK, it also diminished basal and PDGF-induced phosphorylation of mTOR and its downstream targets, including p70S6K/S6 and 4E-BP1. However, siRNA-mediated AMPK downregulation showed persistent inhibition of p70S6K/S6 and 4E-BP1 phosphorylation, indicating AMPK-independent effects for AdipoRon inhibition of mTOR signaling. In addition, AdipoRon treatment resulted in a sustained and transient decrease in PDGF-induced phosphorylation of Akt and ERK, respectively. Furthermore, PDGF receptor-ß tyrosine phosphorylation, which controls the phosphorylation state of Akt and ERK, was diminished upon AdipoRon treatment. Together, the present findings suggest that orally-administered AdipoRon has the potential to limit restenosis after angioplasty by targeting mTOR signaling independent of AMPK activation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Neointima/tratamento farmacológico , Piperidinas/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Adiponectina/agonistas , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/lesões , Artérias/metabolismo , Artérias/patologia , Linhagem Celular , Humanos , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Neointima/metabolismo , Neointima/patologia , Receptores de Adiponectina/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVES: Sacubitril-valsartan, a recently approved treatment for heart failure, has shown some promise as a possible therapeutic option for diabetes mellitus. It is still not clear whether those beneficial effects are comparable to valsartan effects. In this work, we aimed at investigating Sacubitril-valsartan effect on metabolic changes in a model of high-fat high fructose diet-induced diabetes mellitus, in comparison to the metabolic changes induced by valsartan only. METHODS: Rats were ad libitum fed with either standard chow plus tap water for drinking (controls) or 60% beef tallow and 10% fructose drinking water (diseased) for 11 weeks. Starting in week 9, each group was subdivided into four, namely vehicle, pioglitazone, Sacubitril-valsartan and valsartan. Treatments were administered from weeks 9 to 11, while rats were maintained in their respective diet groups. KEY FINDINGS: Sacubitril-valsartan treatment significantly decreased daily food intake, body weight and epididymal white adipose weight, and normalized insulin and glycosylated haemoglobin in high-fat high fructose. Both valsartan and Sacubitril-valsartan only attenuated the elevated fasting blood glucose levels, glucose, insulin and pyruvate tolerance and increased protein kinase B phosphorylation in diseased rats. CONCLUSIONS: Sacubitril-valsartan may be an effective modulator of diabetes mellitus-associated metabolic aberration, superiorly compared to valsartan only.
Assuntos
Insuficiência Cardíaca , Doenças Metabólicas , Bovinos , Ratos , Animais , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Valsartana/farmacologia , Valsartana/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Compostos de Bifenilo/uso terapêutico , Combinação de Medicamentos , Insulina , Doenças Metabólicas/tratamento farmacológicoRESUMO
Transgender individuals that undergo gender-affirming hormone therapy may experience discrimination in the health care setting with a lack of access to medical personnel competent in transgender medicine. Recent evidence suggests that gender-affirming hormone therapy is associated with an increased risk of cardiovascular diseases and cardiovascular risk factors. A recent statement from the American Heart Association reinforces the importance of cardiovascular-focused clinical management and the necessity for more research into the impact of gender-affirming hormone therapy. With this in mind, this review will highlight the known cardiovascular risk factors associated with gender-affirming hormone therapy and identify potential molecular mechanisms determined from the limited animal studies that explore the role of cross-sex steroids on cardiovascular risk. The lack of data in this understudied population requires future clinical and basic research studies to inform and educate clinicians and their transgender patient population to promote precision medicine for their care to improve their quality of life.
Assuntos
Doenças Cardiovasculares , Pessoas Transgênero , Transexualidade , Humanos , Qualidade de Vida , Hormônios Esteroides Gonadais , Transexualidade/terapia , Doenças Cardiovasculares/epidemiologia , HormôniosRESUMO
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women at reproductive age. PCOS diagnosis (Rotterdam criteria) is based on the presence of two out of three criteria; clinical and/or biochemical hyperandrogenism, oligo- or an-ovulation and polycystic ovaries. PCOS women suffer from a constellation of reproductive and metabolic abnormalities including obesity and insulin resistance. PCOS women also have increased blood pressure and increased risk of cardiovascular diseases (CVD). In-utero, offspring of PCOS women are exposed to altered maternal hormonal environment and maternal obesity (for most of PCOS women). Offspring of PCOS women could also be subject to genetic susceptibility, the transgenerational transmission of some of the PCOS traits or epigenetic changes. Offspring of PCOS women are commonly reported to have an abnormal birth weight, which is also a risk factor for developing CVD and hypertension later in life. Although studies have focused on the growth pattern, reproductive and metabolic health of children of PCOS women, very limited number of studies have addressed the risk of hypertension and CVD in those offspring particularly as they age. The current narrative review is designed to summarize the available literature (both human studies and experimental animal studies) and highlight the gaps in addressing hypertension and CVD risks in offspring of PCOS women or hyperandrogenemic female animal models.
Assuntos
Doenças Cardiovasculares , Hiperandrogenismo , Hipertensão , Resistência à Insulina , Síndrome do Ovário Policístico , Animais , Criança , Feminino , Humanos , Gravidez , Síndrome do Ovário Policístico/diagnóstico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/complicações , Hiperandrogenismo/complicações , Hiperandrogenismo/diagnóstico , Hipertensão/complicaçõesRESUMO
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 10%. PCOS is diagnosed by the presence of at least two of these three criteria: hyperandrogenemia, oligo- or anovulation, and polycystic ovaries. The most common type (80%) of PCOS includes hyperandrogenemia. PCOS is also characterized by obesity or overweight (in 80% of US women with PCOS), insulin resistance with elevated plasma insulin but not necessarily hyperglycemia, dyslipidemia, proteinuria, and elevated BP. Although elevated compared with age-matched controls, BP may not reach levels considered treatable according to the current clinical hypertension guidelines. However, it is well known that elevated BP, even modestly so, increases the risk of cardiovascular disease. We have developed a model of hyperandrogenemia in rodents that mimics the characteristics of PCOS in women, with increases in body weight, insulin resistance, dyslipidemia, andproteinuria and elevated BP. This review discusses potential mechanisms responsible for the elevated BP in the adult and aging PCOS rat model that may be extrapolated to women with PCOS.
Assuntos
Anovulação , Hiperandrogenismo , Resistência à Insulina , Insulinas , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Hiperandrogenismo/diagnóstico , Síndrome do Ovário Policístico/diagnóstico , RatosRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by reproductive and metabolic dysfunction, and elevated blood pressure (BP). The cardiometabolic consequences of maternal hyperandrogenemia on offspring, either as adults or with aging, have not been well studied. We previously found that male offspring of hyperandrogenemic female (HAF) rats, a model of PCOS, are normotensive but have an exaggerated pressor response to angiotensin (Ang) II. METHOD: In this study, the hypothesis was tested that adult and aging female offspring of HAF rats develop a metabolic and hypertensive phenotype. Control and HAF rats were implanted prepubertally with placebo or dihydrotestosterone pellets, which continued throughout pregnancy and lactation. RESULTS: Female offspring of HAF dams had lower birth weight than female control offspring. Although female HAF offspring (aged 16-24 weeks) had no differences in intrarenal Ang II, plasma lipids or proteinuria, they did have lower intrarenal Ang (1-7) and lower nitrate/nitrite excretion than controls. Adult HAF offspring had similar baseline BP as controls, but had an attenuated pressor response to Ang II. With aging (16-20âmonths), female HAF offspring remained normotensive with an attenuated pressor response to Ang II and high salt diet but more proteinuria and higher intrarenal Ang(1-7) than controls. CONCLUSION: Taken together, these data suggest that female HAF offspring are protected from developing hypertension, but may be at risk for renal injury with aging. Future studies are necessary to determine whether adult and postmenopausal offspring of PCOS women are at increased risk for cardiovascular dysfunction.Graphical abstract:http://links.lww.com/HJH/B820.
Assuntos
Hiperandrogenismo , Hipertensão , Síndrome do Ovário Policístico , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/fisiologia , Feminino , Humanos , Hiperandrogenismo/complicações , Hiperandrogenismo/metabolismo , Rim , Masculino , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismo , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Polycystic ovary syndrome (PCOS) in women is characterized by hyperandrogenemia, obesity, and oligo- or anovulation. In addition, women with PCOS are often obese, with insulin resistance, hyperlipidemia, and elevated blood pressure. The cardiometabolic consequences for the male offspring of maternal hyperandrogenemia are unclear. The present studies tested the hypothesis that male offspring of a rat model of PCOS would develop cardiometabolic disease as adults. Female Sprague-Dawley rats (hyperandrogenemic females (HAF)) were implanted with dihydrotestosterone or placebo pellets (controls) at 4 weeks of age, and were mated at 10-12 weeks and allowed to lactate their offspring after birth. Body weights in male HAF offspring were lower at birth than in controls until postnatal day 4, but body weights remained similar between male control and HAF offspring from 2 to 8 weeks of age. However, at 16 weeks of age, body weight was lower in HAF male offspring, but there were no differences in fat mass or lean mass factored for body weight in HAF males, compared to controls. Plasma total cholesterol and HDL and proteinuria were higher and nitrate/nitrite excretion was lower in male HAF offspring than in controls. Baseline blood pressure was similar between HAF male offspring and controls, but HAF offspring had an exaggerated pressor response to angiotensin II infusion. These data suggest that adult sons of PCOS mothers may be at increased risk of cardiometabolic disease.
Assuntos
Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Hiperandrogenismo/sangue , Síndrome Metabólica/sangue , Síndrome do Ovário Policístico/sangue , Animais , Feminino , Hiperandrogenismo/complicações , Hiperandrogenismo/patologia , Hipertensão/sangue , Hipertensão/etiologia , Hipertensão/patologia , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/patologia , Obesidade/sangue , Obesidade/etiologia , Obesidade/patologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/patologia , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Imatinib, a PDGF receptor tyrosine kinase inhibitor, has been shown to suppress intimal hyperplasia in different animal models under normal metabolic milieu, diabetic, and/or hypercholesterolemic conditions. However, the impact of imatinib treatment on injury-induced neointimal hyperplasia has not yet been investigated in the setting of insulin resistance without frank diabetes. Using a mouse model of high fat diet (HFD)-induced insulin resistance and guidewire-induced arterial injury, the present study demonstrates that intraperitoneal administration of imatinib (25 mg/kg/day) for ~3 weeks resulted in a marked attenuation of neointimal hyperplasia (intima/media ratio) by ~78% (n = 6-9 per group; P < 0.05). Imatinib treatment also led to significant improvements in key metabolic parameters. In particular, imatinib improved insulin resistance and glucose tolerance, as revealed by complete inhibition of HFD-induced increase in HOMA-IR index and AUCIPGTT, respectively. In addition, imatinib treatment led to diminutions in HFD-induced increases in plasma total cholesterol and triglycerides by ~73% and ~59%, respectively. Furthermore, imatinib decreased HFD-induced increase in visceral fat accumulation by ~51% (as determined by epididymal white adipose tissue weight). Importantly, imatinib treatment in HFD-fed mice enhanced plasma levels of high-molecular-weight adiponectin by ~2-fold without affecting total adiponectin. However, there were no significant changes in mean arterial pressure in insulin-resistant state or after imatinib exposure, as measured by tail-cuff method. Together, the present findings suggest that targeting PDGF receptor tyrosine kinase using imatinib may provide a realistic treatment option to prevent injury-induced neointimal hyperplasia and diet-induced insulin resistance in obesity.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Artéria Femoral/efeitos dos fármacos , Mesilato de Imatinib/uso terapêutico , Resistência à Insulina , Neointima/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Hiperplasia/tratamento farmacológico , Hiperplasia/etiologia , Hiperplasia/patologia , Mesilato de Imatinib/farmacologia , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neointima/metabolismo , Neointima/patologia , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Grape (Vitis vinifera) leaf extracts (GLEs) are known to be rich in phenolic compounds that exert potent antioxidant effects. Given the vulnerability of the liver to oxidative damage, antioxidants have been proposed as therapeutic agents and coadjuvant drugs to ameliorate liver pathologies. The current study was designed to characterize secondary metabolites and investigate the hepatoprotective effects of GLE and its underlying mechanisms. The secondary metabolites were profiled using HPLC-PDA-ESI-MS, and forty-five compounds were tentatively identified. In experimental in vivo design, liver injury was induced by oral administration of high doses of ethanol (EtOH) for 12 days to male Sprague Dawley rats that were split into five different groups. Blood samples and livers were then collected, and used for various biochemical, immunohistochemical, and histopathological analyses. Results showed that GLE-attenuated liver injury and promoted marked hepatic antioxidant effects, in addition to suppressing the increased heat-shock protein-70 expression. Moreover, GLE suppressed EtOH-induced expression of nuclear factor-κB (NF-B) p65 subunit and proinflammatory cytokine tumor necrosis factor-α. Caspase-3 and survivin were enhanced by EtOH intake and suppressed by GLE intake. Finally, EtOH-induced histopathological changes in liver sections were markedly normalized by GLE. In conclusion, our results suggested that GLE interferes with NF-B signaling and induces antioxidant effects, which both play a role in attenuating apoptosis and associated liver injury in a model of EtOH-induced liver damage in rats.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Etanol/efeitos adversos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Vitis/química , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased ACE (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.
Assuntos
Hiperandrogenismo , Hipertensão , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade , Síndrome do Ovário Policístico , Pós-Menopausa/fisiologia , Receptor de Endotelina B/metabolismo , Animais , Pressão Sanguínea/fisiologia , Feminino , Regulação da Expressão Gênica , Hiperandrogenismo/etiologia , Hiperandrogenismo/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Rim/metabolismo , Obesidade/metabolismo , Obesidade/prevenção & controle , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Fatores de Proteção , Ratos , Sistema Renina-Angiotensina/fisiologiaRESUMO
The purpose of this work was to compare the influences of sulforaphane (SFN) to those of the standard insulin sensitizer pioglitazone (PIO) on high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, hepatosteatosis, and vascular dysfunction in rats. Male Sprague Dawley rats (150-200 g) were fed on a standard diet (control) or a high fructose diet (HFrD, 60% w/w fructose) for 60 days. From day 16, two subgroups of HFrD-fed rats received either SFN (0.5 mg/kg/day, orally) or PIO (5 mg/kg/day, orally) along with HFrD until the end of the experiment. Fructose-fed rats showed significant decreases in food intake, body weight and feeding efficiency; effects that were not altered by either treatment. Data from insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and HOMA-IR and HOMA-ß indices demonstrated impaired insulin sensitivity and glucose utilization in HFrD-fed rats. SFN and PIO treatments significantly reduced OGTTAUC (Glass's Delta values = 1.12 and 0.84, respectively), decreased ITTAUC (Glass's Delta values = 1.05 and 0.71, respectively), significantly diminished HOMA-IR index (by 55.6% and 77.6%, respectively), and increased HOMA-ß value (by 1.8 and 1.3 fold, respectively) compared to the HFrD rats. Moreover, SFN and PIO ameliorated hepatic oxidative stress and reduced serum levels of C-reactive protein and lactate dehydrogenase in HFrD-fed rats. Furthermore, SFN and PIO administrations improved insulin resistance-associated heaptosteatosis and enhanced vascular responsiveness to acetylcholine-induced relaxations. However, only SFN was able to enhance serum HDL-C levels in HFrD group. These finding suggests that SFN elicited insulin-sensitizing, hepatoprotective, and vasculoprotective effects in HFrD insulin-resistant rats that were comparable to those exerted by PIO.
Assuntos
Aorta Torácica/efeitos dos fármacos , Dislipidemias/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Isotiocianatos/uso terapêutico , Pioglitazona/uso terapêutico , Animais , Aorta Torácica/fisiologia , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/análise , Dislipidemias/sangue , Dislipidemias/patologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Frutose/administração & dosagem , L-Lactato Desidrogenase/sangue , Masculino , Ratos Sprague-Dawley , SulfóxidosRESUMO
Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., ß-hydroxybutyrate; ßOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9â¯days resulted in significant decreases in weight gain (â¼19.5% ↓) and caloric intake (â¼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (â¼37% ↑). Importantly, ethanol increased systemic ßOHB concentration (â¼8-fold ↑) with significant decreases in blood glucose (â¼4-fold ↓) and plasma insulin and HOMA-IR index (â¼3-fold ↓). In addition, ethanol enhanced hepatic ßOHB content (â¼5-fold ↑) and hmgcs2 mRNA expression (â¼3.7-fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (â¼4-fold ↓). Furthermore, ethanol intake led to significant decreases in the mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3ß, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/genética , Cetose/metabolismo , Glicogênio Hepático/metabolismo , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Regulação para Baixo , Etanol , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Corpos Cetônicos/metabolismo , Cetose/sangue , Cetose/induzido quimicamente , Masculino , Camundongos Knockout , FosforilaçãoRESUMO
Diet-induced obesity (DIO) is commonly associated with hyperleptinemia and leptin resistance. Leptin acts centrally to inhibit food intake and increase energy expenditure, thereby preventing body weight gain. Resistance to the biological effects of leptin represents a major obstacle in utilizing exogenously administered leptin as a treatment option for obesity. Of importance, recent studies demonstrate that naturally occurring compounds improve leptin sensitivity in DIO mice, as revealed by anorectic and body weight-lowering effects. To date, the role of sulforaphane (SFN, an isothiocyanate derived from cruciferous vegetables) on leptin responsiveness has not been examined, in spite of its known beneficial effects toward lowering body weight gain in DIO. In the present study, we determined the extent to which SFN regulates leptin responsiveness in high-fat high-sucrose (HFHS) diet-fed obese mice. SFN treatment (0.5â¯mg/kg/day, s.c.) for 23 days in HFHS-fed mice improved the responsiveness to intraperitoneally-injected leptin by promoting significant decreases in cumulative food intake and body weight gain. A single leptin injection (2â¯mg/kg; i.p.) resulted in significant decreases in food intake at 24â¯h and 38â¯h time points. In addition, a triple leptin injection (1â¯mg/kg/day, 3 days; i.p.) led to significant decreases in food intake at 14â¯h, 24â¯h, 38â¯h, 48â¯h, and 62â¯h time points. Furthermore, single and triple leptin injections prevented body weight gain at 38â¯h and 62â¯h time points, respectively. The present findings suggest that intervention with SFN, a naturally occurring isothiocyanate, has the potential to improve leptin responsiveness in DIO.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Isotiocianatos/farmacologia , Leptina/farmacologia , Obesidade/induzido quimicamente , Obesidade/metabolismo , Sacarose/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , SulfóxidosRESUMO
Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5mg/Kg/day) for~3weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by~60%; n=5-8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by~52%, ↓ plasma leptin by~42%, ↓ plasma insulin by~63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by~73%], glucose tolerance (↓ AUCGTT by~24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by~23% (n=5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n=3-4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Isotiocianatos/uso terapêutico , Leptina/antagonistas & inibidores , Músculo Liso Vascular/efeitos dos fármacos , Neointima/prevenção & controle , Obesidade/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Aorta , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dieta Ocidental/efeitos adversos , Artéria Femoral/lesões , Humanos , Injeções Subcutâneas , Resistência à Insulina , Isotiocianatos/administração & dosagem , Isotiocianatos/farmacologia , Leptina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Neointima/imunologia , Neointima/metabolismo , Neointima/patologia , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Sulfóxidos , Aumento de Peso/efeitos dos fármacosRESUMO
This study investigates the possible protective effects of levocetirizine against fructose-induced insulin resistance, hepatic steatosis and vascular dysfunction, in comparison to pioglitazone, a standard insulin sensitizer. Male Sprague Dawley rats (150-200 g) were divided into 4 groups. Three groups were fed on high fructose diets (HFD) containing 60% w/w fructose, while the fourth control group was fed on standard laboratory food for 8 weeks. AUCOGTT, AUCITT, fasting glucose, HOMA-IR, hepatic glutathione (GSH) and malondialdehyde (MDA) levels, serum total cholesterol, LDL-C, C-reactive protein (CRP) level and lactate dehydrogenase (LDH) activity and liver steatosis scores were significantly higher in HFD group compared to control group. Moreover, body weight gain, food intake, feeding efficiency, HOMA-ß, Emax and pEC50 of acetylcholine-induced relaxations of aortic rings and hepatic superoxide dismutase (SOD) activity were significantly lower in HFD group than in control group. Treatment with levocetirizine caused significant decreases in AUCOGTT, AUCITT, HOMA-IR, hepatic GSH and MDA levels and serum CRP level and LDH activity and significant increases in hepatic SOD activity and HOMA-ß when compared with the HFD group. Although levocetirizine failed to alter TC and LDL-C levels, it produced a significant increase in HDL-C level relative to control group. Levocetirizine was also able to improve acetylcholine-induced relaxations of aortic rings, indicating a protective effect against insulin resistance-induced endothelial damage comparable to that offered by pioglitazone. Moreover, levocetirizine substantially attenuated insulin resistance-associated liver macrovesicular steatosis. These findings demonstrate that levocetirizine ameliorates insulin resistance, improves glucose tolerance and attenuates insulin resistance-linked hepatic steatosis and vascular damage.
Assuntos
Cetirizina/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Resistência à Insulina , Substâncias Protetoras/uso terapêutico , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/análise , Cetirizina/farmacologia , Dieta , Ingestão de Alimentos/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Frutose , Teste de Tolerância a Glucose , Glutationa/metabolismo , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Insulina/sangue , L-Lactato Desidrogenase/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Vasodilatação/efeitos dos fármacosRESUMO
This study was designed to compare the inhibitory effects of thymoquinone (TQ) and curcumin (CMN) on the biological changes associating asthma. TQ appeared to exhibit greater inhibitory effects on the aggregation of inflammatory cells in bronchoalveolar lavage (BAL) fluid and in lung tissues. We also measured the effects of the two agents on serum IgE and the changes in the mRNA levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1). Serum IgE was significantly decreased by TQ and CMN with TQ being more potent. Also, TQ showed superior inhibitory effects on iNOS and TGF-ß1. Meanwhile, CMN was more potent in inhibiting mRNA expression of TNF-α. These results suggest that TQ is more potent in inhibiting the inflammatory changes associating asthma. On the other hand, CMN was a less potent inhibitor of all measured parameters, despite its superior inhibitory effect on TNF-α mRNA levels.