RESUMO
Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.
Assuntos
Intolerância à Glucose , Inibidores de Hidroximetilglutaril-CoA Redutases , Resistência à Insulina , Microbiota , Humanos , Animais , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon , Intolerância à Glucose/tratamento farmacológico , Ácidos e Sais Biliares , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed, and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, was decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared with vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.
Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/tratamento farmacológico , Obesidade/metabolismo , Ácido Ursodesoxicólico/análogos & derivados , Animais , Dieta Hiperlipídica/métodos , Estresse do Retículo Endoplasmático/fisiologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/farmacologiaRESUMO
Statin therapy plays an important role in stabilizing and regressing coronary artery plaques. Omega-3 supplements also have anti-inflammatory and antioxidant effects on coronary plaques. However, the effect of omega-3 supplementation on the basis of statin therapy on the stability and composition of plaques, is still unclear. We searched for randomized controlled trials published prior to November 2020 in the PubMed, Embase and Cochrane databases. Finally, eight studies using different imaging techniques to evaluate coronary atherosclerotic plaque, including optical coherence tomography (OCT), coronary CT angiography (cCTA) and intravascular ultrasound (IB-IVUS), met our inclusion criteria. We pooled data extracted from the included studies using the standardized mean difference (SMD) or mean difference (MD) of the random effects model. Compared with statin treatment alone, the combined treatment further delayed the progression of total plaque volume [SMD -0.36, 95% confidence interval (CI) -0.64 to -0.08, pâ¯=â¯0.01] and fiber content (SMD -0.40, 95% CI -0.68 to -0.13, pâ¯=â¯0.004). The plasma high-sensitivity C-reactive protein (hs-CRP) level of patients in the combination treatment group was significantly lower than that of the patients in the statin treatment group alone (SMD -0.30, 95% CI -0.59 to -0.01, pâ¯=â¯0.04). In addition, the combined use of omega-3 further increases the fibrous cap thickness (FCT) of the plaque with an MD of 29.45 µm. There were no significant differences in plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), or lipid content in plaques between the two groups. Omega-3 combined with statins is superior to the statin treatment group in stabilizing and promoting coronary plaque regression and may help to further reduce the occurrence of cardiovascular events.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Proteína C-Reativa/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Angiografia por Tomografia Computadorizada , Doença da Artéria Coronariana/diagnóstico por imagem , Quimioterapia Combinada , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Tomografia de Coerência Óptica , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
This study explored whether zinc supplementation alleviates diabetic endothelial dysfunction and the possible mechanisms underlying. We found that high glucose exposure significantly increased reactive oxygen species (ROS) and decreased guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and tetrahydrobiopterin (BH4) levels in bovine aortic endothelial cells (BAECs) in a time-dependent manner. High glucose increased zinc release from GTPCH1 in a similar trend. Zinc supplementation restored GTPCH1 and BH4 levels and blocked ROS accumulation in both BACEs and wild type GTPCH1 transfected HEK293â¯cells, but not in the zinc-free C141R mutant of GTPCH1 transfected ones. In vivo experiments showed that exogenous supplementation of zinc to streptozotocin (STZ)-induced diabetic mice partially improved the impaired maximal endothelium-dependent vasorelaxation, reversed the aberrant reduction of GTPCH1 and BH4, and suppressed the elevation of ROS in the aortas. In conclusion, our study demonstrated a novel mechanism that via GTPCH1 restoration zinc supplementation exerts a protective benefit on diabetic endothelial dysfunction.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Suplementos Nutricionais , Endotélio Vascular/fisiopatologia , GTP Cicloidrolase/metabolismo , Zinco/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Bovinos , Endotélio Vascular/efeitos dos fármacos , GTP Cicloidrolase/deficiência , Deleção de Genes , Glucose/toxicidade , Humanos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Allergic asthma and atherosclerosis represent different directions of inflammatory responses of CD4+ T cells, and allergic asthma accelerates atherosclerosis formation. Curcumin could ameliorate the progression of both atherosclerosis and allergic asthma. PURPOSE: We aimed to investigate the roles of curcumin in asthma-accelerated atherosclerosis plaque formation, and the change of CD4+ T-cell subsets in this process. METHODS: Six to eight-week-old apolipoprotein E-/- (apoE-/-) mice were sensitized and challenged by ovalbumin (OVA) to establish an allergic asthma model, and then received curcumin or vehicle treatment for 8 weeks. RESULTS: The accelerated atherosclerosis was induced by allergic asthma accompanied by increased T helper cell (Th)2 and Th17 cells and decreased regulatory T cells (Tregs) in the spleen. After the 8-week treatment with curcumin, the lesion areas in the aortic root in asthmatic mice significantly improved, and the elevated Th2 and Th17 cells significantly decreased, but Tregs markedly increased. Although curcumin treatment markedly reduced the interleukin (IL)-4 and IL-13 in serum and spleen, the elevated IL-17A did not decrease. Moreover, Th1 cells showed no significant change between different groups. The mRNA expression levels of M1 macrophage-related inflammatory factors IL-6, iNOS and IL-1ß were markedly elevated in the spleens of asthmatic mice, but significantly decreased after the 8-week treatment with curcumin. CONCLUSION: Curcumin ameliorated the aggravation of atherosclerotic lesions and stabilised plaque by modulating the balance of Th2/Tregs in asthmatic apoE-/- mice.
Assuntos
Asma/complicações , Aterosclerose/tratamento farmacológico , Curcumina/farmacologia , Linfócitos T Reguladores/citologia , Células Th2/citologia , Animais , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Ovalbumina , Placa Aterosclerótica/tratamento farmacológico , Células Th1 , Células Th17RESUMO
We explored whether pu-erh tea consumption ameliorates atherosclerosis and the possible mechanism for its effects in apolipoprotein E-deficient (ApoE-/-) mice. Our data showed that pu-erh tea consumption markedly reduced early fatty streak formation and the advanced fibrofatty plaque sizes. Additionally, the mean proportion of inflammatory macrophages in the plaque decreased, and the number of apoptotic macrophages increased significantly. NF-κB activity in peritoneal macrophages decreased by 75.6% compared to the controls, similar with the levels of IL-6, IL-12, and TNF-α expression. The tea extract increased the apoptosis of RAW264.7 cells by decreasing NF-κB activation and reducing the inflammatory cytokine expression. In conclusion, pu-erh tea ameliorates atherosclerosis progress by alleviating the chronic inflammatory state by reducing NF-κB activation and promoting macrophage apoptosis in atherosclerotic plaques.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Macrófagos/metabolismo , NF-kappa B/metabolismo , Chá/química , Animais , Apoptose , Camundongos , Camundongos Knockout para ApoERESUMO
Salt, promoting oxidative stress, contributes to insulin resistance, whereas K, inhibiting oxidative stress, improves insulin sensitivity. Oxidative stress activation of NLRP3 inflammasome is a central player in the induction of insulin resistance. Therefore, we hypothesised that NLRP3 inflammasome may mediate the effects of salt and K on insulin resistance. In all, fifty normotensive subjects were recruited from a rural community of Northern China. The protocol included a low-salt diet for 7 d, then a high-salt diet for 7 d and a high-salt diet with K supplementation for another 7 d. In addition, THP-1 cells were cultured in different levels of Na with and without K. The results showed that salt loading elevated fasting blood glucose, insulin and C-peptide levels, as well as insulin resistance, whereas K supplementation reversed them. Meanwhile, additional K reversed the active effects of high salt on NLRP3 inflammasome in both the subjects and THP-1 cells, and the change of insulin resistance index notably related with the alteration of plasma IL-1ß, the index of NLRP3 inflammasome activation, during intervention in the subjects. Additional K ameliorated oxidative stress induced by high salt in both the subjects and cultured THP-1 cells, and the change of oxidative stress related with the alteration of plasma IL-1ß during intervention in the subjects. In vitro, antioxidant N-acetyl-l-cysteine significantly prevented the active effects of high Na or oxidant Rosup on NLRP3 inflammasome, so did K. Our study indicates that oxidative stress modulation of NLRP3 inflammasome may be involved in the impacts of Na and K on insulin resistance.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Inflamassomos/fisiologia , Resistência à Insulina/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Potássio/administração & dosagem , Sódio na Dieta/administração & dosagem , Adulto , Idoso , Povo Asiático , Glicemia/análise , Peptídeo C/sangue , Células Cultivadas , China , Dieta , Interações Medicamentosas , Feminino , Humanos , Insulina/sangue , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , População Rural , Células THP-1/efeitos dos fármacosRESUMO
BACKGROUND: Dietary sodium and potassium affect the fluctuation in blood pressure (BP) and renal function. Corin, with its enzymatic activity to convert pro-atrial natriuretic peptide (pro-ANP) to biologically active ANP, regulates BP, cardiac, and renal functions. We investigated whether corin expression responds to a high-salt (HS) diet to regulate salt and water balance. METHODS: Forty-two volunteers followed 3 sequential diets for 7 days each: a low-salt (LS) diet (3.0 g/day NaCl), a HS diet (18.0 g/day NaCl), followed by an HS diet with K+ supplementation (HS + K+) (18.0 g/day NaCl and 4.5 g/day KCl). RESULTS: Corin level was higher with the HS diet than the LS and HS + K+ diets and was positively correlated with systolic BP (SBP) and 24-hour urinary Na+ and microalbumin (U-mALB) excretion. In rodents, serum and renal levels of corin were transiently increased with the HS diet and were decreased if the HS diet was continued for up to 7 days. HS loading increased SBP, 24-hour urinary Na+, U-mALB excretion, and the expression of proprotein convertase subtilisin/kexin-6 (PCSK6), a corin activator. Knockdown of PCSK6 or corin in high salt-treated M1-cortical collecting duct (M1-CCD) cells increased the expression of aquaporin 2 (AQP2) and ß-epithelial Na+ channel (ß-ENaC). CONCLUSIONS: Short-term HS may induce the PCSK6-corin-ANP-AQP2/ß-ENaC pathway in the kidney. Enhanced serum corin level in humans and rodents is positively correlated with HS-induced SBP and 24-hour urinary Na+ and U-mALB excretion, which suggests that corin is involved in the salt-water balance in response to HS intake. CLINICAL TRIALS REGISTRATION: Public Trials Registry Number NCT02915315.
Assuntos
Dieta Hipossódica , Rim/enzimologia , Potássio na Dieta/administração & dosagem , Serina Endopeptidases/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Equilíbrio Hidroeletrolítico , Adaptação Fisiológica , Adulto , Albuminúria/enzimologia , Albuminúria/fisiopatologia , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Pressão Sanguínea , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Feminino , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Natriurese , Potássio na Dieta/efeitos adversos , Potássio na Dieta/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Ratos Sprague-Dawley , Serina Endopeptidases/genética , Cloreto de Sódio na Dieta/efeitos adversos , Cloreto de Sódio na Dieta/metabolismo , Fatores de Tempo , Regulação para CimaRESUMO
Background High dietary salt intake contributes to the development of autoimmune/inflammatory diseases including metabolic syndrome (MetS) which potassium supplementation can potentially reverse. T helper (Th) 17 cells as well as its production interleukin (IL)-17A are involved in the pathogenesis of MetS. The polarization of Th17 cells and enhanced IL-17A production induced by high salt might increase the risk of autoimmune/inflammatory diseases. Methods 45 normotensive subjects (aged 29 to 65 years) were enrolled from a rural community of Northern China at random. All of the participants were maintained on a low-salt (3 g/day) diet for 7 days, a high-salt (18 g/day) diet for 7 days, and then a high-salt diet with potassium supplementation (4.5 g/day, KCl) for another 7 days. Insulin resistance (IR) was determined based on the homeostasis model assessment index (HOMA-IR). Results Participants exhibited increased plasma insulin level, as well as progressed HOMA-IR, during a high-salt diet intervention, which potassium supplementation reversed. Moreover, after salt loading, the plasma IL-17A concentrations increased significantly (4.2±2.1 pg/mL to 9.7±5.1 pg/mL; P<0.01), whereas dropped considerably when dietary potassium was supplemented (9.7±5.1 pg/mL to 2.0±0.9 pg/mL; P<0.001). Statistically significant correlations were found between changes in HOMA-IR and changes in plasma IL-17A concentrations during the interventions (low- to high-salt: r=0.642, P<0.01; high-salt to potassium supplementation: r=0.703, P<0.01). Based on multivariate regression analysis, plasma IL-17A showed as an independent predictor of IR. Conclusions The amelioration of salt-loading-induced IR by potassium supplementation in participants may be related to the reduction in plasma IL-17A concentration.
Assuntos
Suplementos Nutricionais , Resistência à Insulina , Insulina/sangue , Interleucina-17/sangue , Potássio/administração & dosagem , Cloreto de Sódio na Dieta/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cloreto de Sódio na Dieta/administração & dosagem , Células Th17/metabolismoRESUMO
The mechanism by which high-salt and low-potassium diet contributes to hypertension remains poorly understood. Plasma homocysteine (Hcys) is recognized as a primary mediator of blood pressure (BP) response to some diets. Therefore, the present study tried to investigate whether plasma Hcys and BP could be regulated by salt loading in normotensive salt-sensitive (SS) persons, and further explored whether potassium supplementation could reverse the effect. We enrolled 47 normotensive subjects, aged 29-65 years. The protocol included 7 days on a low-salt diet (3g/day, NaCl), 7 days on a high-salt diet (18g/day), and then a high-salt diet with potassium supplementation (4.5g/day) for 7 days. After high-salt intake, BP was significantly increased and potassium supplementation lowered it in the SS group. Plasma Hcys were higher in SS subjects than in salt-resistant (SR) subjects after salt loading (34.4 ± 17.0 µmol/L versus 19.16 ± 6.4 µmol/L, P < 0.01). Plasma Hcys in SS subjects was increased on a high-salt diet than on a low-salt diet (34.4 ± 17.0 µmol/L versus 16.5 ± 8.3 µmol/L, P < 0.01), but plasma Hcys was ameliorated by potassium supplementation (34.4 ± 17.0 µmol/L versus 20.9 ± 10.4 µmol/L, P < 0.01). In SS subjects, the change of mean arterial blood pressure (MBP) correlated significantly and positively with the alteration of plasma Hcys during low-salt to high-salt intake and high-salt to high-salt with potassium supplementation (r = 0.75, P < 0.001; r = 0.74, P < 0.001, respectively). Our results indicate that Hcys may partly mediate the impact of high-salt intake and potassium supplementation on BP in SS subjects.
Assuntos
Pressão Arterial/efeitos dos fármacos , Homocisteína/sangue , Potássio na Dieta/farmacologia , Cloreto de Sódio na Dieta/farmacologia , Adulto , Idoso , Dieta Hipossódica , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cloreto de Sódio na Dieta/administração & dosagemRESUMO
BACKGROUND AND OBJECTIVE: Salt-sensitive (SS) patients more frequently showed a nondipper blood pressure pattern and were associated with more serious target organ damage than non-SS patients. We aimed to investigate whether potassium supplement can improve the blunted nocturnal blood pressure fall in SS patients exposed to a high-salt diet. PATIENTS AND METHODS: Approximately 49 normotensive and mildly hypertensive Chinese patients received a study protocol of a 3 days of baseline examination, 7 days of a low-salt diet (3 g NaCl/day), 7 days of a high-salt diet (18 g NaCl/day), and 7 days of a high-salt diet with a potassium supplement (18 g NaCl and 4.5 g KCl/day). The 24 h ambulatory blood pressure was determined at the end of each period. RESULTS: A total of 14 patients were classified as SS according to the at least 10% increase in their 24-h mean arterial pressure after high-salt loading. The night-to-day blood pressure ratio was significantly higher in SS patients than in non-SS patients during the high-salt loading period (systolic 0.96±0.01 vs. 0.89±0.01, P<0.01; diastolic 0.96±0.01 vs. 0.92±0.01, P<0.05). Compared with the high-salt loading period, the night-to-day blood pressure ratio was significantly reversed by potassium supplement in SS patients (systolic 0.91±0.01 vs. 0.96±0.01, P<0.05; diastolic 0.91±0.01 vs. 0.96±0.01, P<0.05). CONCLUSION: Potassium supplement can improve the blunted nocturnal blood pressure fall in SS patients exposed to a high-salt diet, but the related mechanism needs to be studied further.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Suplementos Nutricionais , Potássio/administração & dosagem , Cloreto de Sódio na Dieta/administração & dosagem , Adulto , Povo Asiático , Monitorização Ambulatorial da Pressão Arterial , Dieta Hipossódica , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from a traditional Chinese herb pogostemonis herba. Literatures have proven that PA could inhibit inflammatory responses in various inflammatory disease models. However, whether PA could protect against atherosclerosis, a chronic vascular inflammation, is unknown. In this study, we sought to explore this issue in atherosclerosis-prone apolipoprotein E knockout mice fed an atherogenic diet, with or without daily PA intragastrical administration (40mg/kg). Our results showed that PA administration did not change plasma lipids metabolism, however, it significantly attenuated atherosclerotic plaque burdens in both the aorta and the aortic root. The lesional macrophage content, shown as Mac2 positive areas, was reduced, while the lesional smooth muscle cell and collagen content, shown as α-SMA positive areas and by Sirius red staining, respectively, was not affected in PA-treated mice, compared with non-treated controls. Aortic mRNA expression of macrophage inflammatory cytokines, including MCP-1, iNOS, IL-1ß, IL-6, CXCL9 and CXCL11, was also reduced in PA-treated mice. Therefore, we demonstrated that PA could attenuate atherosclerosis, possibly by inhibiting macrophage infiltration and its inflammatory responses.
Assuntos
Aterosclerose/tratamento farmacológico , Inflamação/patologia , Macrófagos/patologia , Sesquiterpenos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Placa Aterosclerótica/patologia , Sesquiterpenos/farmacologiaRESUMO
High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1ß, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1ß, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension.
Assuntos
Antioxidantes/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Hipertensão/tratamento farmacológico , Núcleo Hipotalâmico Paraventricular/metabolismo , Ubiquinona/análogos & derivados , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Interleucina-1beta/metabolismo , NADPH Oxidase 2/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Sais/toxicidade , Superóxido Dismutase-1/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Ubiquinona/administração & dosagemRESUMO
High salt intake contributes to the development of autoimmune/inflammatory diseases, while potassium supplementation antagonizes the effects. Interleukin (IL)-17A are tightly related with autoimmune/inflammatory diseases. Thus, we explored the effects and underlying molecular mechanism of high salt and potassium supplementation on IL-17A production in T lymphocytes. Forty-nine healthy participants received a low-salt, high-salt, followed by a high-salt diet plus potassium supplement for 7 days, respectively. Human T lymphocyte Jurkat cells were treated with different concentrations of NaCl and KCl. In the participants, IL-17A levels in plasma and in peripheral blood mononuclear cells (PBMC) were significantly increased after a high-salt diet, which was dramatically reversed when potassium was supplemented. In Jurkat cells, the addition of 40 mM NaCl markedly enhanced IL-17A production and the expression of phosphorylated p38/mitogen-activated protein kinase (MAPK) and its downstream target, serum/glucocorticoid-regulated kinase (SGK)1, whereas combined treatment with additional 2 mM KCl significantly decreased them. Respective inhibition of p38/MAPK and SGK1 suppressed IL-17A expression induced by NaCl, and KCl inhibited IL-17A production induced by specific activator of p38/MAPK. We conclude potassium supplementation has a blocking effect on IL-17A production in T lymphocytes induced by salt loading. This protective effect is mediated through the direct suppression of p38/MAPK-SGK1 pathway.
Assuntos
Suplementos Nutricionais , Proteínas Imediatamente Precoces/metabolismo , Interleucina-17/biossíntese , Potássio/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Western Blotting , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Imediatamente Precoces/genética , Interleucina-17/sangue , Interleucina-17/genética , Células Jurkat , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Potássio/administração & dosagem , Proteínas Serina-Treonina Quinases/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Cloreto de Sódio/administração & dosagem , Linfócitos T/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Renalase is currently the only known amine oxidase in the blood that can metabolize catecholamines and regulate sympathetic activity. High salt intake is associated with high blood pressure (BP), possibly through the modulation of renalase expression and secretion, whereas potassium can reverse the high salt-mediated increase in blood pressure. However, whether potassium could also modulate BP through renalase is unclear. In this study, we aim to investigate how salt intake and potassium supplementation affect the level of renalase in rats. Eighteen salt-sensitive (SS) and 18 SS-13BN rats were divided into six groups, receiving normal salt (0.3% NaCl), high salt (8% NaCl) and high salt/potassium (8% NaCl and 8% KCl) dietary intervention for four weeks. At the end of experiments, blood and kidneys were collected for analysis. mRNA level of renalase was measured by quantitative real-time PCR and protein level was determined by Western blot. We found that mRNA and protein levels of renalase in the kidneys of SS and SS-13BN rats were significantly decreased (P < 0.05) after high salt intervention, whereas dopamine in plasma was increased (P < 0.05) compared with rats received normal salt, suggesting that salt may induce salt-sensitive hypertension through inhibition of renalase expression. We also found increased mRNA level and protein level of renalase, decreased catecholamine levels in plasma, and decreased BP in SS rats treated with high salt/potassium, compared with that of the high salt SS group. Taken together, the salt-induced increase and potassium-induced decrease in BP could be mediated through renalase. More studies are needed to confirm our findings and understand the underlying mechanisms.
Assuntos
Dieta/métodos , Rim/patologia , Monoaminoxidase/análise , Monoaminoxidase/sangue , Potássio/administração & dosagem , Sais/administração & dosagem , Animais , Análise Química do Sangue , Pressão Sanguínea , Western Blotting , Catecolaminas/sangue , Dopamina/sangue , Perfilação da Expressão Gênica , Masculino , RNA Mensageiro/análise , Ratos Endogâmicos Dahl , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND/AIMS: Serum/Glucocorticoid Regulated Kinase 1 (SGK1) plays a significant role in regulating renal Na(+) reabsorption, K(+) secretion, and blood pressure (BP). This study aimed to assess the association of common genetic variants in the SGK1 gene with BP responses to controlled dietary sodium or potassium interventions. METHODS: A total of 334 subjects from 124 families were recruited from the rural areas of northern China. After a three-day baseline observation, they were sequentially maintained a seven-day low-sodium diet (3g/day of NaCl or 51.3 mmol/day of sodium), a seven-day high-sodium diet (18 g/day of NaCl or 307.8 mmol/day of sodium) and a seven-day high-sodium plus potassium supplementation intervention (4.5 g/day of KCl or 60 mmol/day of potassium). Six single-nucleotide polymorphisms (SNPs) in the SGK1 gene were selected. RESULTS: After adjustment for multiple testing, SNP rs9376026 was significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-sodium intervention (P = 0.018 and 0.022, respectively). However, the associations between selected SNPs in the SGK1 gene and BP responses to high-sodium or high-sodium plus potassium-supplementation intervention did not reach statistical significance. In addition, SNP rs9389154 and two other SNPs (rs1763509 and rs9376026) were associated respectively with systolic BP (SBP) and DBP at baseline (P = 0.040, 0.032, and 0.031, respectively). SNP rs3813344 was significantly associated with SBP, DBP, and MAP (P = 0.049, 0.015 and 0.018, respectively). CONCLUSION: Our study indicates that the genetic polymorphism in the SGK1 gene is significantly associated with BP responses to dietary sodium intervention.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Proteínas Imediatamente Precoces/genética , Potássio na Dieta/farmacologia , Proteínas Serina-Treonina Quinases/genética , Sódio na Dieta/farmacologia , Adolescente , Adulto , Pressão Arterial/efeitos dos fármacos , China/epidemiologia , Dieta , Dieta Hipossódica , Família , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Pré-Hipertensão/genética , População Rural , Adulto JovemRESUMO
AIMS: To address the underlying mechanisms by which curcumin facilitates M2 phenotype polarization of macrophages and its roles in the protective effects during experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: The expression of classic M2 markers, including macrophage mannose receptor (MMR), arginase-1 (Arg-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ) was upregulated in curcumin-treated Raw264.7 macrophages. Curcumin increased interleukin-4 (IL-4) and interleukin-13 (IL-13) mRNA expression and protein secretion. Curcumin notably increased STAT6 phosphorylation. Leflunomide, a STAT6 inhibitor, and IL-4 and/or IL-13 neutralizing antibodies antagonized the induction of MMR, Arg-1 and PPAR-γ by curcumin in Raw264.7 cells. In vivo, 6-week old male Lewis rats were used to induce EAM and orally administrated with curcumin or corn oil for 3weeks after myosin injection. Cardiac functional parameters, including left ventricular fractional shortening (LVFS), ejection fraction (EF), left ventricular end-systolic diameter (LVEDs) and heart rate (HR) were significantly improved by curcumin treatment. Curcumin also reduced the inflammatory cell infiltration and myocardial mRNA levels of interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS). Meanwhile, the myocardial mRNA levels of MMR and Arg-1 were markedly up-regulated by curcumin. Immunofluorescence assay showed that the number of CD68(+) MMR(+) and CD68(+) Arg-1(+) double positive macrophages in curcumin-treated myocardial tissue was significantly higher than untreated control. The number of CD68(+) iNOS(+) double positive macrophages was increased obviously in EAM group, but decreased markedly by curcumin treatment. CONCLUSIONS: Taken together, these results show that curcumin induces macrophage M2 polarization by secretion of IL-4 and/or IL-13. Curcumin ameliorates EAM by reducing infiltration inflammatory macrophages and by polarizing M0 and M1 macrophages to M2 phenotype.
Assuntos
Cardiotônicos/farmacologia , Curcumina/farmacologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Animais , Linhagem Celular , Polaridade Celular , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Interleucina-13/genética , Interleucina-4/genética , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Miocardite/tratamento farmacológico , Miocardite/imunologia , Miocardite/patologia , Miocárdio/imunologia , Miocárdio/patologia , Ratos Endogâmicos Lew , Fator de Transcrição STAT6/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: The aim of our study was to assess the effects of altered salt and potassium intake on urinary renalase and serum dopamine levels in humans. METHODS: Forty-two subjects (2865 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for an additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). RESULTS: Urinary renalase excretions were significantly higher during the high-salt diet intervention than during the low-salt diet. During high-potassium intake, urinary renalase excretions were not significantly different from the high-salt diet, whereas they were significantly higher than the low-salt levels. Serum dopamine levels exhibited similar trends across the interventions. Additionally, a significant positive relationship was observed between the urine renalase and serum dopamine among the different dietary interventions. Also, 24-hour urinary sodium excretion positively correlated with urine renalase and serum dopamine in the whole population. CONCLUSIONS: The present study indicates that dietary salt intake and potassium supplementation increase urinary renalase and serum dopamine levels in Chinese subjects.
Assuntos
Pressão Sanguínea/fisiologia , Dopamina/sangue , Monoaminoxidase/urina , Potássio/administração & dosagem , Cloreto de Sódio na Dieta/administração & dosagem , Adulto , Idoso , Povo Asiático , China , Feminino , Humanos , Hipertensão/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , População Rural , Cloreto de Sódio na Dieta/urinaRESUMO
BACKGROUND/AIMS: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies indicate that common variations in the gene with RNLS are associated with hypertension. The aim of this study was to examine the association between genetic variants in RNLS and blood pressure (BP) responses to strict dietary interventions of salt and potassium intake. METHODS: A total of 334 subjects from 124 families were selected and sequentially maintained on a low-salt diet for 7 days (3.0 g/day, NaCl), then a high-salt diet for 7 days (18.0 g/day, NaCl), high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). RESULTS: SNPs rs919115 and rs792205 of the RNLS gene were significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) responses to high-salt intervention. In addition, rs12356177 was significantly associated with systolic BP (SBP) and DBP responses to low-salt diet, and SBP, DBP or MAP during the high-salt intervention. Unfortunately, no associations for the 7 RNLS SNPs with BP response to high-salt diet with potassium supplementation reached nominal statistical significance. CONCLUSIONS: This family-based study indicates that genetic variants in the RNLS gene are significantly associated with BP responses to dietary salt intake.
Assuntos
Pressão Sanguínea/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Monoaminoxidase/genética , Potássio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Renalase, a recently discovered enzyme released by the kidneys, breaks down blood-borne catecholamines and may thus regulate blood pressure (BP). Animal studies have suggested that high levels of dietary salt might reduce blood and kidney renalase levels. We conducted a randomized trial to assess the effects of altered salt and potassium intake on serum renalase levels and the relationship between serum renalase levels and BP in humans.Forty-two subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl).Serum renalase levels were significantly higher than baseline levels during the low-salt diet intervention period. Renalase levels decreased with the change from the low-salt to high-salt diet, whereas dietary potassium prevented the decrease in serum renalase induced by the high-salt diet. There was a significant inverse correlation between the serum renalase level and 24-h urinary sodium excretion. No significant correlation was found between the renalase level and BP among the different dietary interventions.The present study indicates that variations in dietary salt intake and potassium supplementation affect the serum renalase concentration in Chinese subjects.