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1.
Life Sci ; 284: 119928, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480937

RESUMO

AIMS: Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS: Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS: Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE: Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation.


Assuntos
Berberina/farmacologia , Colo/metabolismo , Diabetes Mellitus Experimental/genética , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Glucose/metabolismo , MicroRNAs/genética , Oligossacarídeos/farmacologia , Animais , Colo/efeitos dos fármacos , Colo/microbiologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , MicroRNAs/metabolismo , Análise de Componente Principal , Ratos Zucker , Reprodutibilidade dos Testes , Transcriptoma/genética
2.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443451

RESUMO

Diabetes mellitus is characterized by tissue oxidative damage and impaired microcirculation, as well as worsened erythrocyte properties. Measurements of erythrocyte deformability together with determination of nitric oxide (NO) production and osmotic resistance were used for the characterization of erythrocyte functionality in lean (control) and obese Zucker diabetic fatty (ZDF) rats of two age categories. Obese ZDF rats correspond to prediabetic (younger) and diabetic (older) animals. As antioxidants were suggested to protect erythrocytes, we also investigated the potential effect of quercetin (20 mg/kg/day for 6 weeks). Erythrocyte deformability was determined by the filtration method and NO production using DAF-2DA fluorescence. For erythrocyte osmotic resistance, we used hemolytic assay. Erythrocyte deformability and NO production deteriorated during aging-both were lower in older ZDF rats than in younger ones. Three-way ANOVA indicates improved erythrocyte deformability after quercetin treatment in older obese ZDF rats only, as it was not modified or deteriorated in both (lean and obese) younger and older lean animals. NO production by erythrocytes increased post treatment in all experimental groups. Our study indicates the potential benefit of quercetin treatment on erythrocyte properties in condition of diabetes mellitus. In addition, our results suggest potential age-dependency of quercetin effects in diabetes that deserve additional research.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eritrócitos/metabolismo , Quercetina/uso terapêutico , Animais , Antioxidantes , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Deformação Eritrocítica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Osmose , Estresse Oxidativo , Quercetina/farmacologia , Ratos Zucker
3.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445250

RESUMO

The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life®, which contains M101 that is extracted from a marine invertebrate, has been used for static cold storage (SCS) and has shown superior results in organ preservation. A total of 36 livers were procured from obese Zucker rats and randomly divided into three groups, i.e., control, SCS-24H and SCS-24H + M101 (M101 at 1 g/L), mimicking the gold standard of organ preservation. Ex situ machine perfusion for 2 h was used to evaluate the quality of the livers. Perfusates were sampled for functional assessment, biochemical analysis and subsequent biopsies were performed for assessment of ischemia-reperfusion markers. Transaminases, GDH and lactate levels at the end of reperfusion were significantly lower in the group preserved with M101 (p < 0.05). Protection from reactive oxygen species (low MDA and higher production of NO2-NO3) and less inflammation (HMGB1) were also observed in this group (p < 0.05). Bcl-1 and caspase-3 were higher in the SCS-24H group (p < 0.05) and presented more histological damage than those preserved with HEMO2life®. These data demonstrate, for the first time, that the addition of HEMO2life® to the preservation solution significantly protects steatotic livers during SCS by decreasing reperfusion injury and improving graft function.


Assuntos
Fígado Gorduroso/metabolismo , Hemoglobinas/farmacologia , Fígado/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Caspase 3/metabolismo , Ciclina D1/metabolismo , Fígado Gorduroso/patologia , Proteína HMGB1/metabolismo , Ácido Láctico/metabolismo , Masculino , Ratos , Ratos Zucker , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transaminases/metabolismo
4.
Nutrients ; 13(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34444713

RESUMO

Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs); and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs; the benefits were independent of alterations in the recipient intestine.


Assuntos
Morte Encefálica , Fígado Gorduroso , Glucose/administração & dosagem , Transplante de Fígado , Fígado/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Emulsões/administração & dosagem , Fígado Gorduroso/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Intestinos/patologia , Intestinos/fisiopatologia , Fígado/patologia , Glicogênio Hepático/metabolismo , Masculino , Obesidade , Fosfolipídeos/metabolismo , Ratos , Ratos Zucker , Doadores de Tecidos
5.
Nutrients ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34444734

RESUMO

Seeds of industrial hemp (Cannabis sativa L.) contain a large amount of protein (26.3%), dietary fiber (27.5%), and fatty acids (33.2%), including linoleic, α-linolenic, and some amount of γ-linolenic acid. In our study, obese male Zucker rats (n = 6) at 8 weeks of age were supplemented for a further 4 weeks with either ground hemp seeds (12% diet) or lipid fractions in the form of hemp seed oil (4% diet). Hemp oil decreased blood plasma HDL-cholesterol (x0.76, p ≤ 0.0001), triglycerides (x0.55, p = 0.01), and calculated atherogenic parameters. Meanwhile, hemp seeds decreased HDL-cholesterol (x0.71, p ≤ 0.0001) and total cholesterol (x0.81, p = 0.006) but not the atherogenic index. The plasma antioxidant capacity of water-soluble compounds was decreased by the seeds (x0.30, p = 0.0015), which in turn was associated with a decrease in plasma uric acid (x0.18, p = 0.03). Dietary hemp seeds also decreased plasma urea (x0.80, p = 0.02), while the oil decreased the plasma total protein (x0.90, p = 0.05). Hemp seeds and the oil decreased lipid peroxidation in the blood plasma and in the heart (reflected as malondialdehyde content), improved contraction to noradrenaline, and up-regulated the sensitivity of potassium channels dependent on ATP and Ca2+. Meanwhile, acetylcholine-induced vasodilation was improved by hemp seeds exclusively. Dietary supplementation with ground hemp seeds was much more beneficial than the oil, which suggests that the lipid fractions are only partially responsible for this effect.


Assuntos
Cannabis , Fenômenos Fisiológicos Cardiovasculares , Suplementos Nutricionais , Obesidade/fisiopatologia , Extratos Vegetais , Sementes , Animais , Antioxidantes , Glicemia , Pressão Sanguínea , Proteínas Sanguíneas/análise , Peroxidação de Lipídeos , Lipídeos/sangue , Masculino , Miocárdio/metabolismo , Ratos , Ratos Zucker , Tromboxano A2/análise , Vasoconstrição , Vasodilatação
6.
Am J Physiol Renal Physiol ; 321(4): F494-F504, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34396787

RESUMO

Impairments in insulin sensitivity can occur in patients with chronic kidney disease (CKD). Correction of metabolic acidosis has been associated with improved insulin sensitivity in CKD, suggesting that metabolic acidosis may directly promote insulin resistance. Despite this, the effect of acid or alkali loading on insulin sensitivity in a rodent model of CKD (remnant kidney) has not been directly investigated. Such studies could better define the relationship between blood pH and insulin sensitivity. We hypothesized that in remnant kidney rats, acid or alkali loading would promote loss of pH homeostasis and consequently decrease insulin sensitivity. To test this hypothesis, we determined the impact of alkali (2 wk) or acid (5-7 days) loading on plasma electrolytes, acid-base balance, and insulin sensitivity in either sham control rats, 2/3 nephrectomized rats, or 5/6 nephrectomized rats. Rats with 5/6 nephrectomy had the greatest response to insulin followed by rats with 2/3 nephrectomy and sham control rats. We found that treatment with 0.1 M sodium bicarbonate solution in drinking water had no effect on insulin sensitivity. Acid loading with 0.1 M ammonium chloride resulted in significant reductions in pH and plasma bicarbonate. However, acidosis did not significantly impair insulin sensitivity. Similar effects were observed in Zucker obese rats with 5/6 nephrectomy. The effect of renal mass reduction on insulin sensitivity could not be explained by reduced insulin clearance or increased plasma insulin levels. We found that renal mass reduction alone increases sensitivity to exogenous insulin in rats and that this is not acutely reversed by the development of acidosis.NEW & NOTEWORTHY Impairments in insulin sensitivity can occur in patients with chronic kidney disease, and previous work has suggested that metabolic acidosis may be the underlying cause. Our study investigated the effect of acid or alkali loading on insulin sensitivity in a rodent model of chronic kidney disease. We found that renal mass reduction increases the blood glucose response to insulin and that this is not acutely reversed by the development of acidosis.


Assuntos
Insulina/sangue , Insulina/farmacologia , Rim/patologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Equilíbrio Ácido-Base , Animais , Creatinina , Teste de Tolerância a Glucose , Resistência à Insulina , Nefrectomia , Obesidade , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Insuficiência Renal Crônica/patologia , Bicarbonato de Sódio/farmacologia , Cloreto de Sódio
7.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069402

RESUMO

The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alternative to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation in rats (4 °C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide, comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessed in a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L) and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35 promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented the formation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP). In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcirculatory disturbances in steatotic grafts during preservation and revascularization. All of these results lead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation. In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, which has already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence, the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a unique solution/perfusate when hypothermic static and preservation strategies are used, either separately or combined, easing the logistics and avoiding the mixture of different solutions/perfusates, especially when fatty liver grafts are used. Further research regarding new therapeutic and pharmacological insights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in static and dynamic graft preservation strategies for clinical liver transplantation purposes.


Assuntos
Transplante de Fígado/métodos , Preservação de Órgãos/métodos , Polietilenoglicóis/farmacologia , Alanina Transaminase/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Criopreservação/métodos , Fígado Gorduroso/metabolismo , Glutationa/metabolismo , Fígado/citologia , Masculino , Microcirculação/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/metabolismo , Soluções para Preservação de Órgãos/farmacologia , Ratos , Ratos Zucker , Manejo de Espécimes/métodos
8.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063487

RESUMO

Conflicting reports exist with regard to the effect of ecdysterone, the predominating representative of steroid hormones in insects and plants, on hepatic and plasma lipid concentrations in different rodent models of obesity, fatty liver, and diabetes, indicating that the effect is dependent on the rodent model used. Here, the hypothesis was tested for the first time that ecdysterone causes lipid-lowering effects in genetically obese Zucker rats. To test this hypothesis, two groups of male obese Zucker rats (n = 8) were fed a nutrient-adequate diet supplemented without or with 0.5 g ecdysterone per kg diet. To study further if ecdysterone is capable of alleviating the strong lipid-synthetic activity in the liver of obese Zucker rats, the study included also two groups of male lean Zucker rats (n = 8) which also received either the ecdysterone-supplemented or the non-supplemented diet. While hepatic and plasma concentrations of triglycerides and cholesterol were markedly higher in the obese compared to the lean rats (p < 0.05), hepatic and plasma triglyceride and cholesterol concentrations did not differ between rats of the same genotype fed the diets without or with ecdysterone. In conclusion, the present study clearly shows that ecdysterone supplementation does not exhibit lipid-lowering actions in the liver and plasma of lean and obese Zucker rats.


Assuntos
Ecdisterona/metabolismo , Ecdisterona/farmacologia , Metabolismo dos Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Obesidade/metabolismo , Animais , Suplementos Nutricionais , Frutosamina/sangue , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Zucker , Reprodutibilidade dos Testes
9.
Nutrients ; 13(5)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064308

RESUMO

Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.


Assuntos
Glicemia/metabolismo , Metabolismo Energético/genética , Homeostase/genética , Obesidade/genética , Receptores para Leptina/deficiência , Animais , Modelos Animais de Doenças , Fígado Gorduroso/genética , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Obesidade/cirurgia , Período Pós-Operatório , Ratos , Ratos Wistar , Ratos Zucker , Perda de Peso/genética
10.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G157-G170, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132111

RESUMO

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.


Assuntos
Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Lipopolissacarídeos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Calgranulina A/metabolismo , Quimiocina CXCL1/metabolismo , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Absorção Intestinal , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Zucker , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Fator de Transcrição STAT3/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Am J Physiol Regul Integr Comp Physiol ; 321(1): R62-R78, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978481

RESUMO

Obese Zucker rats (OZRs) develop hypertension and hyperinsulinemia by 3 mo of age. Male OZRs also have diminished baroreflex-mediated activation of nucleus tractus solitarius (NTS) and bradycardia, which are improved by correcting their hyperglycemia. Conversely, 3-mo-old female OZRs and lean Zucker rats (LZRs) have equivalent baroreflex-mediated bradycardia that is impaired in 6-mo-old OZRs. We hypothesized that 3-mo-old female OZRs maintain NTS activation and baroreflexes coincident with glycemic control. We also hypothesized that 6-mo-old female OZRs develop impaired baroreflexes with hyperglycemia and diminished NTS activation. In 12- to 16-wk-old females, sympathetic nerve activity (SNA) and arterial pressure (AP) were higher in OZRs than LZRs. However, baroreflex-mediated inhibition of SNA and bradycardia were equivalent in female OZRs and LZRs. Unlike deficits in male OZRs, female OZRs and LZRs had no differences in phenylephrine-induced c-Fos expression in NTS or decreases in SNA and AP evoked by glutamate into NTS. Compared with hyperglycemia in male OZRs (217.9 ± 34.4 mg/dL), female OZRs had normal fed blood glucose levels (108.2 ± 1.6 mg/dL in LZRs and 113.6 ± 3.5 mg/dL in OZRs) with emerging glucose intolerance. Conscious 24- to 27-wk-old female OZRs had impaired baroreflex-mediated bradycardia, but fed blood glucose was modestly elevated (124.2 ± 5.2 mg/dL) and phenylephrine-induced c-Fos expression in NTS was comparable to LZRs. These data suggest that better glycemic control in 3-mo-old female OZRs prevents diminished NTS activation and baroreflexes, supporting the notion that hyperglycemia impairs these responses in male OZRs. However, 6-mo-old female OZRs had impaired baroreflex efficacy without diminished NTS activation or pronounced hyperglycemia, suggesting baroreflex deficits develop by different mechanisms in female and male OZRs.


Assuntos
Barorreflexo/fisiologia , Glicemia/metabolismo , Controle Glicêmico , Hipertensão , Obesidade , Envelhecimento , Animais , Colesterol/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperinsulinismo , Insulina/sangue , Masculino , Fenilefrina/farmacologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Zucker , Fatores Sexuais , Sistema Nervoso Simpático , Triglicerídeos/sangue
12.
J Proteomics ; 242: 104255, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-33957313

RESUMO

Hepatic steatosis is a very common response to liver injury and often attributed to metabolic disorders. Prior studies have demonstrated the efficacy of a biotechnologically produced oyster mushroom (Pleurotus sajor-caju, PSC) in alleviating hepatic steatosis in obese Zucker rats. This study aims to elucidate molecular events underlying the anti-steatotic effects of PSC. Tandem mass tag (TMT) peptide labeling coupled with LC-MS/MS/MS was used to quantify and compare proteins in the livers of lean Zucker rats fed a control diet (LC), obese Zucker rats fed the same control diet (OC) and obese Zucker rats fed the control diet supplemented with 5% PSC (OPSC) for 4 weeks. Using this technique 3128 proteins could be quantified, out of which 108 were differentially abundant between the OPSC and OC group. Functional enrichment analysis of the up-regulated proteins showed that these proteins were mainly involved in metabolic processes, while the down-regulated proteins were involved in inflammatory processes. Results from proteomic analysis were successfully validated for two up-regulated (carbonic anhydrase 3, regucalcin) and two down-regulated (cadherin-17, ceruloplasmin) proteins by means of immunoblotting. SIGNIFICANCE: Valorization of low-grade agricultural waste by edible fungi, such as the mushroom Pleurotus sajor-caju (PSC), represents a promising strategy for the production of protein rich biomass since they boast of a unique enzyme system that has the ability to recover nutrients and energy from biodegradable waste. Herein, we describe the metabolic effects of PSC feeding using a combined quantitative proteomics and bioinformatics approach. In total, 108 proteins were identified to be regulated by PSC feeding in the liver of the obese rats. Complementary usage of a bioinformatics approach allowed us to decipher the mechanisms underlying the recently observed lipid-lowering and anti-inflammatory activity of PSC feeding in obese Zucker rats, namely a reduction of fatty acid synthesis, an improvement of hepatoprotective mechanisms and an enhancement of anti-inflammatory effects.


Assuntos
Pleurotus , Animais , Cromatografia Líquida , Lentinula , Fígado , Obesidade , Proteômica , Ratos , Ratos Zucker , Espectrometria de Massas em Tandem
13.
Invest Ophthalmol Vis Sci ; 62(6): 20, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34010957

RESUMO

Purpose: In diabetic subjects, early visual functional alterations such as color vision deficiencies (CVDs) are known to precede clinically apparent diabetic retinopathy. Prominent photoreceptor outer segment degeneration and an increase in the number of retinal dual cones (co-expressing S- and M-opsins simultaneously) have been described in diabetic rat models, suggesting a connection with the development of CVDs. As cone opsin expression is controlled by thyroid hormones, we investigated the diabetic retina in association with thyroid hormone alterations. Methods: In rat models of type 1 and 2 diabetes, dual cones were labeled by immunohistochemistry, and their numbers were analyzed in relation to free triiodothyronine (fT3) and free thyroxine (fT4) levels. Quantification of dual cones was also performed in human postmortem retinas. Additionally, a cross-sectional case-control study was performed where thyroid hormone levels were measured and color vision was assessed with Lanthony desaturated D15 discs. Results: A higher number of dual cones was detectable in diabetic rats, correlating with fT4 levels. Dual cones were also present in postmortem human retinas, with higher numbers in the three diabetic retinas. As expected, age was strongly associated with CVDs in human patients, and the presence of diabetes also increased the risk. However, the current study failed to detect any effect of thyroid hormones on the development of CVDs. Conclusions: Our results point toward the involvement of thyroid homeostasis in the opsin expression changes in diabetic rats and human samples. The evaluation of the possible clinical consequences warrants further research.


Assuntos
Diabetes Mellitus Experimental/sangue , Retinopatia Diabética/sangue , Células Fotorreceptoras Retinianas Cones/patologia , Hormônios Tireóideos/sangue , Adulto , Idoso , Animais , Glicemia/metabolismo , Estudos de Casos e Controles , Visão de Cores/fisiologia , Opsinas dos Cones/metabolismo , Estudos Transversais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/patologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Células Fotorreceptoras Retinianas Cones/metabolismo , Adulto Jovem
14.
Nanoscale ; 13(18): 8452-8466, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33984104

RESUMO

Obesity is one of the most important public health problems that is associated with an array of metabolic disorders linked to cardiovascular disease, stroke, type 2 diabetes, and cancer. A sustained therapeutic approach to stop the escalating prevalence of obesity and its associated metabolic comorbidities remains elusive. Herein, we developed a novel nanocomposite based on mesoporous silica coated cerium oxide (CeO2) nanozymes that reduce the circulating levels of fatty acids and remarkably improve the metabolic phenotype in a model of obese Zucker rats five weeks after its administration. Lipidomic and gene expression analyses showed an amelioration of the hyperlipidemia and of the hepatic and adipose metabolic dysregulations, which was associated with a down-regulation of the hepatic PI3K/mTOR/AKT pathway and a reduction of the M1 proinflammatory cytokine TNF-α. In addition, the coating of the CeO2 maximized its cell antioxidant protective effects and minimized non-hepatic biodistribution. The one-pot synthesis method for the nanocomposite fabrication is implemented entirely in aqueous solution, room temperature and open atmosphere conditions, favoring scalability and offering a safe and translatable lipid-lowering and antioxidant nanomedicine to treat metabolic comorbidities associated with obesity. This approach may be further applied to address other metabolic disorders related to hyperlipidemia, low-grade inflammation and oxidative stress.


Assuntos
Antioxidantes , Diabetes Mellitus Tipo 2 , Animais , Lipídeos , Metaboloma , Obesidade/tratamento farmacológico , Ratos , Ratos Zucker , Dióxido de Silício , Distribuição Tecidual
15.
Molecules ; 26(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947088

RESUMO

This study examined for the first time whether bee bread (BB, consisting of monofloral rape bee pollen) could alleviate lipid derangements and reduced bone quality in Zucker diabetic fatty (ZDF) rats, which are considered an appropriate animal model for type 2 diabetes mellitus (T2DM) investigation. Adult ZDF rats were segregated into four groups: lean non-diabetic rats (L group), obese diabetic rats untreated (C group), and those treated with the BB at two doses (500 and 700 mg/kg body weight, respectively, B1 and B2 groups) for 10 weeks. Significantly reduced levels of total cholesterol and triglyceride were recorded in the B2 group versus the C group. In both BB-treated groups, significantly increased relative volume of trabecular bone and trabecular thickness, enhanced density of secondary osteons, accelerated periosteal bone apposition, and improved blood flow were observed. A positive effect of higher dose of BB on femoral weight and cortical bone thickness was also demonstrated. Our results suggest a promising potential of BB to ameliorate T2DM-related complications associated with lipid and bone damages.


Assuntos
Ração Animal , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Lipídeos/sangue , Obesidade/metabolismo , Obesidade/patologia , Própole/administração & dosagem , Animais , Biomarcadores , Osso e Ossos/diagnóstico por imagem , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Masculino , Obesidade/sangue , Obesidade/etiologia , Ratos , Ratos Zucker , Microtomografia por Raio-X
16.
Chem Pharm Bull (Tokyo) ; 69(4): 333-351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790079

RESUMO

A novel series of 7-substituted-2-[3-(2-furyl)acryloyl]-6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to clarify structure-activity relationships for peroxisome proliferator-activated receptor γ (PPARγ) partial agonist activity and identify more efficacious PPARγ partial agonists with minor adverse effects. Among the derivatives synthesized, compound 26v with a 2-(2,5-dihydropyrrol-1-yl)-5-methyloxazol-4-ylmethoxy group at the 7-position of the tetrahydroisoquinoline structure exhibited stronger PPARγ agonist and antagonist activities (EC50 = 6 nM and IC50 = 101 nM) than previously reported values for compound 1 (EC50 = 13 nM and IC50 = 512 nM). Compound 26v had very weak protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and showed higher oral absorption (Cmax = 11.4 µg/mL and area under the curve (AUC) = 134.7 µg·h/mL) than compound 1 (Cmax = 7.0 µg/mL and AUC = 63.9 µg·h/mL) in male Sprague-Dawley (SD) rats. A computational docking calculation revealed that 26v bound to PPARγ in a similar manner to that of compound 1. In male Zucker fatty rats, 26v and pioglitazone at 10 and 30 mg/kg for 4 weeks similarly reduced plasma triglyceride levels, increased plasma adiponectin levels, and attenuated increases in plasma glucose levels in the oral glucose tolerance test, while only pioglitazone decreased hematocrit values. In conclusion, 6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives provide a novel scaffold for selective PPARγ partial agonists and 26v attenuates insulin resistance possibly by adiponectin enhancements with minor adverse effects.


Assuntos
PPAR gama/agonistas , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Técnicas de Química Sintética , Descoberta de Drogas , Humanos , Masculino , Modelos Moleculares , PPAR gama/metabolismo , Ratos Sprague-Dawley , Ratos Zucker , Tetra-Hidroisoquinolinas/síntese química
17.
Biomolecules ; 11(4)2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924458

RESUMO

Myocardial fibrosis is one of the major complications of long-term diabetes. Hyperglycemia induced cardiomyocyte atrophy is a frequent pathophysiological indicator of diabetic heart. The objective of this study was to investigate the cardioprotective effect of glycyrrhizin (GLC) on myocardial damage in diabetic rats and assess the anti-inflammatory and anti-fibrotic effect of GLC. Our study demonstrates that hyperglycemia can elevate cardiac atrophy in diabetic animals. Type 2 diabetic fatty and the lean control rats were evaluated for cardiac damage and inflammation at 8-12 weeks after the development of diabetes. Western blot and immunohistochemical studies revealed that gap junction protein connexin-43 (CX43), cardiac injury marker troponin I, cardiac muscle specific voltage gated sodium channel NaV1.5 were significantly altered in the diabetic heart. Furthermore, oxidative stress mediator receptor for advanced glycation end-products (RAGE), as well as inflammatory mediator phospho-p38 MAPK and chemokine receptor CXCR4 were increased in the diabetic heart whereas the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), the antioxidant proteins that protect against oxidative damage was reduced. We also observed an increase in the expression of the pleiotropic cytokine, transforming growth factor beta (TGF-ß) in the diabetic heart. GLC treatment exhibited a decrease in the expression of phospho-p38 MAPK, RAGE, NaV1.5 and TGF-ß and it also altered the expression of CX43, CXCR4, Nrf2 and troponin I. These observations suggest that GLC possesses cardioprotective effects in diabetic cardiac atrophy and that these effects could be mediated through activation of Nrf2 and inhibition of CXCR4/SDF1 as well as TGF-ß/p38MAPK signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiomiopatias Diabéticas/tratamento farmacológico , Ácido Glicirrízico/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Cardiotônicos/farmacologia , Linhagem Celular , Conexina 43/metabolismo , Fibrose , Ácido Glicirrízico/farmacologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Zucker , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores CXCR4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Troponina I/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Endocrinol Diabetes Metab ; 4(2): e00193, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33855202

RESUMO

Objectives: Type 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic ß-cell mass. Imeglimin is a first-in-class novel drug candidate that improves glycaemia and glucose-stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate ß-cell dysfunction and protect ß cells in vitro, we postulated that imeglimin could also exert longer term effects to prevent pancreatic ß-cell death and preserve functional ß-cell mass in vivo. Methods: Zucker diabetic fatty (ZDF) male rats were treated by oral gavage with imeglimin at a standard dose of 150 mg/kg or vehicle, twice daily for five weeks. At treatment completion, oral glucose tolerance tests were performed in fasted animals before a thorough histomorphometry and immunohistochemical analysis was conducted on pancreas tissue slices to assess cellular composition and disease status. Results: Imeglimin treatment significantly improved glucose-stimulated insulin secretion (augmentation of the insulinogenic index) and improved glycaemia. Both basal insulinaemia and pancreatic insulin content were also increased by imeglimin. In ZDF control rats, islet structure was disordered with few ß-cells; after imeglimin treatment, islets appeared healthier with more normal morphology in association with a significant increase in insulin-positive ß-cells. The increase in ß-cell mass was associated with a greater degree of ß-cell proliferation in the presence of reduced apoptosis. Unexpectedly, a decrease in as a α-cell mass was also documented due to an apparent antiproliferative effect of imeglimin on this cell type. Conclusion: In male ZDF rats, chronic imeglimin treatment corrects a paramount component of type 2 diabetes progression: progressive loss of functional ß-cell mass. In addition, imeglimin may also moderate a-cell turnover to further ameliorate hyperglycaemia. Cumulatively, these cellular effects suggest that imeglimin may provide for disease modifying effects to preserve functional ß-cell mass.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Células Secretoras de Insulina/patologia , Triazinas/farmacologia , Triazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Intolerância à Glucose/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Ratos Zucker
19.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923282

RESUMO

Several mechanisms may contribute to cardiovascular pathology associated with diabetes, including dysregulation of matrix metalloproteinases (MMPs). Quercetin (QCT) is a substance with preventive effects in treatment of cardiovascular diseases and diabetes. The aim of the present study was to explore effects of chronic QCT administration on changes in heart function in aged lean and obese Zucker Diabetic Fatty (ZDF) rats and that in association with MMPs. Signaling underlying effects of diabetes and QCT were also investigated. In the study, we used one-year-old lean and obese ZDF rats treated for 6 weeks with QCT. Results showed that obesity worsened heart function and this was associated with MMP-2 upregulation, MMP-28 downregulation, and inhibition of superoxide dismutases (SODs). Treatment with QCT did not modulate diabetes-induced changes in heart function and MMPs. However, QCT activated Akt kinase and reversed effects of diabetes on SODs inhibition. In conclusion, worsened heart function due to obesity involved changes in MMP-2 and MMP-28 and attenuation of antioxidant defense by SOD. QCT did not have positive effects on improvement of heart function or modulation of MMPs. Nevertheless, its application mediated activation of adaptive responses against oxidative stress through Akt kinase and prevention of diabetes-induced negative effects on antioxidant defense by SODs.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Metaloproteinase 2 da Matriz/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Envelhecimento , Animais , Antioxidantes/farmacologia , Glicemia/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinases da Matriz Secretadas/genética , Ratos , Ratos Zucker
20.
J Agric Food Chem ; 69(15): 4423-4437, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33835816

RESUMO

Anthocyanins have been reported to possess antidiabetic effects. Recent studies indicate acylated anthocyanins have better stability and antioxidative activity compared to their nonacylated counterparts. This study compared the effects of nonacylated and acylated anthocyanins on hepatic gene expression and metabolic profile in diabetic rats, using full-length transcriptomics and 1H NMR metabolomics. Zucker diabetic fatty (ZDF) rats were fed with nonacylated anthocyanin extract from bilberries (NAAB) or acylated anthocyanin extract from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. Both anthocyanin extracts restored the levels of multiple metabolites (glucose, lactate, alanine, and pyruvate) and expression of genes (G6pac, Pck1, Pklr, and Gck) involved in glycolysis and gluconeogenesis. AAPP decreased the hepatic glutamine level. NAAB regulated the expression of Mgat4a, Gstm6, and Lpl, whereas AAPP modified the expression of Mgat4a, Jun, Fos, and Egr1. This study indicated different effects of AAPP and NAAB on the hepatic transcriptomic and metabolic profiles of diabetic rats.


Assuntos
Antocianinas , Diabetes Mellitus Experimental , Animais , Expressão Gênica , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética , RNA-Seq , Ratos , Ratos Zucker
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