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1.
Wei Sheng Yan Jiu ; 49(5): 785-822, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070825

RESUMO

OBJECTIVE: Establish the prokaryotic expression system of Amuc_1100 protein from Akkermansia muciniphila, and analyze the effects of this protein on the body weight, blood glucose, intestinal barrier function and Akkermansia muciniphila abundance in rats fed with high-fat diet combined streptozotocin(STZ)injection. METHODS: PCR product of Amuc_1100 Gene(Gene ID: 34174504) was linked to the double enzyme-digested pET-26 b plasmid vector. The recombinant expression plasmid pET-26 b-Amuc_1100 then transformed into E. Coli BL21. The verified clones through sequence analysis were induced by the addition of IPTG. High-fat diet rats were interfered with the purified protein at high and low doses. The changes of body weight, blood glucose, intestinal barrier function and Akkermansia muciniphila abundance were analyzed. RESULTS: The recombinant expression plasmid pET-26 b-Amuc_1100 was successfully constructed. The sequencing result showed 100% similarity to the Amuc_1100 gene in GenBank. The molecular weight of the protein obtained was 42 kDa. The intervention of Amuc_1100 protein can reduce the weight of rats fed with high-fat diet combined STZ injection to some extent, improve barrier function and increase the abundance of Akkermansia muciniphila in intestine. CONCLUSION: The prokaryotic expression system of Amuc_1100 protein was successfully constructed, which has a certain regulatory effect on rats fed with high-fat diet combined STZ injection.


Assuntos
Dieta Hiperlipídica , Escherichia coli , Animais , Dieta Hiperlipídica/efeitos adversos , Escherichia coli/genética , Ratos , Estreptozocina/toxicidade , Verrucomicrobia
2.
PLoS One ; 15(8): e0237669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810137

RESUMO

Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sobrevivência Celular/genética , Células Secretoras de Insulina/patologia , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Técnicas de Silenciamento de Genes , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Ratos , Estreptozocina/toxicidade , Tunicamicina/toxicidade
3.
PLoS One ; 15(8): e0237660, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841254

RESUMO

This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin. The animals were distributed as follow: Non-Hyperglycemic (NH), Non Hyperglycemic with Ligature (NH-L), Treated Non Hyperglycemic (TNH), Treated Non Hyperglycemic with Ligature Treated (TNH-L), Hyperglycemic (H), Treated Hyperglycemic (TH), Hyperglycemic with Ligature (H-L), Treated Hyperglycemic with Ligature (TH-L). At 40th day after induction of hyperglycemia, the groups NH-L, TNH-L, H-L, TH-L received a ligature to induce periodontitis. On the 69th, the TNH, TNH-L, TH, TH-L groups received metformin until the end of the study. Bone repair was evaluated at histometric and the expression levels of Sox9, RunX2 and Osterix. Analysis of the ex-vivo expression of TNF-α, IFN-γ, IL-12, IL-4, TGF-ß, IL-10, IL-6 and IL-17 were also evaluated. Metformin partially reverse induced bone loss in NH and H animals. Lower OPG/RANKL, increased OCN and TRAP expression were observed in hyperglycemic animals, and treatment with metformin partially reversed hyperglycemia on the OPG/RANKL, OPN and TRAP expression in the periodontitis. The expression of SOX9 and RunX2 were also decreased by hyperglycemia and metformin treatment. Increased ex vivo levels of TNF-α, IL-6, IL-4, IL-10 and IL-17 was observed. Hyperglycemia promoted increased IL-10 levels compared to non-hyperglycemic ones. Treatment of NH with metformin was able to mediate increased levels of TNF-α, IL-10 and IL-17, whereas for H an increase of TNF-α and IL-17 was detected in the 24- or 48-hour after stimulation with LPS. Ligature was able to induce increased levels of TNF-α and IL-17 in both NH and H. This study revealed the negative impact of hyperglycemia and/or treatment with metformin in the bone repair via inhibition of transcription factors associated with osteoblastic differentiation.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hiperglicemia/complicações , Metformina/administração & dosagem , Periodontite/prevenção & controle , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Processo Alveolar/citologia , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/metabolismo , Processo Alveolar/patologia , Animais , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Osteoblastos/fisiologia , Periodontite/etiologia , Periodontite/metabolismo , Ratos , Estreptozocina/toxicidade , Fatores de Transcrição/metabolismo
4.
Plast Reconstr Surg ; 145(5): 942e-950e, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32332536

RESUMO

BACKGROUND: Chronic inflammation associated with delayed diabetic wound healing is induced by disturbed polarization of macrophages derived mainly from predisposed progenitor cells in bone marrow. Docosahexaenoic acid plays a critical role in regulating the function of macrophage progenitor cells. The authors evaluated whether docosahexaenoic acid accelerates diabetic wound healing in rats. METHODS: Streptozotocin-induced diabetic rats divided into control and docosahexaenoic acid-treated groups (n = 10) were subjected to paired dorsal skin wounds. Docosahexaenoic acid (100 mg/kg per day) was orally supplemented 2 weeks before wounding until termination. The wound healing process was recorded 0, 7, and 14 days after wounding. At day 7, blood perfusion was measured by laser Doppler perfusion imaging; angiogenesis was compared using immunofluorescent CD31 and α-smooth muscle actin staining; macrophage polarization was detected using immunofluorescence for CD68, CD206, and inducible nitric oxide synthase. Hematoxylin and eosin staining was used to examine wound healing at day 14. Activation status of macrophages derived from bone marrow cells in normal, diabetic, and docosahexaenoic acid-treated diabetic rats was determined in vitro using Western blotting and enzyme-linked immunosorbent assay. RESULTS: Docosahexaenoic acid significantly accelerated wound healing 7 and 14 days (p < 0.01) after wounding. Increased vessel densities (1.96-fold; p < 0.001) and blood perfusion (2.56-fold; p < 0.001) were observed in docosahexaenoic acid-treated wounds. Immunofluorescence revealed more CD206 and fewer inducible nitric oxide synthase-positive macrophages (p < 0.001) in treated wounds. Furthermore, macrophages derived from diabetic rats expressed higher levels of inducible nitric oxide synthase and tumor necrosis factor-α and lower arginase-1 and interleukin-10 (p < 0.05). CONCLUSION: Docosahexaenoic acid accelerates diabetic wound healing at least in part by restoring impaired plasticity of macrophage progenitor cells.


Assuntos
Diabetes Mellitus Experimental/complicações , Ácidos Docosa-Hexaenoicos/administração & dosagem , Macrófagos/imunologia , Células-Tronco/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Administração Oral , Animais , Plasticidade Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Humanos , Masculino , Ratos , Pele/lesões , Células-Tronco/fisiologia , Estreptozocina/toxicidade , Fatores de Tempo , Cicatrização/imunologia
5.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165764, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32169506

RESUMO

Recent studies have shown that laboratory murine autoimmunity models under the same environment display different outcomes. We established diabetic nephropathy model mice under the same environment using the classic streptozotocin method. Renal dysfunction was different among the mice. Proteinuria was more significant in the severe proteinuria group (SP) than in the mild proteinuria group (MP). We hypothesized a role for the gut microbiota in the outcome and reproducibility of induced DN models. 16S rDNA gene sequencing technology was used to analyze the differences in the gut microbiota between the two groups. Here, through fecal microbiota transplantation (FMT) and gas chromatography mass spectrometry (GC-MS), we verified the role of the gut microbiota and its short-chain fatty acid (SCFA) generation in DN mouse renal dysfunction. In the SP group, there was a reduced abundance of Firmicutes (P < 0.0001), and the dominant genus Allobaculum [linear discriminant analysis (LDA) >3, P < 0.05] was positively correlated with body weight (Rho = 0.767, P < 0.01) and blood glucose content (Rho = 0.648, P < 0.05), while the dominant genus Anaerosporobacter (LDA > 3, P < 0.05) was positively correlated with 24-hour urinary protein content (Rho = 0.773, P < 0.01). In the MP group, the dominant genus Blautia (LDA > 3, P < 0.05) was negatively correlated with 24-hour urinary protein content (Rho = -0.829, P < 0.05). The results indicated that Allobaculum and Anaerosporobacter may worsen renal function, while Blautia may be a protective factor in DN. These findings suggested that the gut microbiota may contribute to the heterogeneity of the induced response since we observed potential disease-associated microbial taxonomies and correlations with DN.


Assuntos
Nefropatias Diabéticas/microbiologia , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/genética , Rim/metabolismo , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/patogenicidade , Glicemia/genética , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Rim/microbiologia , Rim/patologia , Camundongos , RNA Ribossômico 16S/genética , Índice de Gravidade de Doença , Estreptozocina/toxicidade
6.
Proc Natl Acad Sci U S A ; 117(14): 7990-8000, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32198206

RESUMO

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.


Assuntos
Fibrilação Atrial/metabolismo , Remodelamento Atrial/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Insulina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/imunologia , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Átrios do Coração/citologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Humanos , Insulina/administração & dosagem , Insulina/genética , Canal de Potássio Kv1.5/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , Cultura Primária de Células , Sódio/metabolismo , Estreptozocina/toxicidade
7.
Oxid Med Cell Longev ; 2020: 9316751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104544

RESUMO

The current study was carried out to evaluate the ameliorative effect of fucoidan against aflatoxicosis-induced hepatorenal toxicity in streptozotocin-induced diabetic rats. Sixty-four Wister albino male rats were randomly assigned into eight groups (8 rats each) that received normal saline, fucoidan (FUC) at 100 mg/kg/day orally for 4 weeks, streptozotocin (STZ) at 50 mg/kg/i.p. single dose, STZ plus FUC, aflatoxin B1 (AFB1) at 50 µg/kg/i.p. after one month of the beginning of the experiment for 2 weeks, AFB1 plus FUC, STZ plus AFB1, or STZ plus AFB1 and FUC. Injection of rats with STZ induced hyperglycemia. Rats with STZ-induced diabetes, with or without AFB1 intoxication, had significantly elevated activities of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and levels of serum urea, creatinine, cholesterol, 8-oxo-2'-deoxyguanosine, interleukin-1ß, interleukin-6, and tumor necrosis factor-α. In addition, these rats exhibited increased lipid peroxidation and reduced glutathione concentration and activities of superoxide dismutase, catalase, and glutathione peroxidase enzymes in the hepatic and renal tissues. In contrast, administration of FUC to diabetic rats, with or without AFB1 intoxication, ameliorated the altered serum parameters, reduced oxidative stress, DNA damage, and inflammatory biomarkers, and enhanced the antioxidant defense system in the hepatic and renal tissues. These results indicated that FUC ameliorated diabetes and AFB1-induced hepatorenal injuries through alleviating oxidative stress, DNA damage, and inflammation.


Assuntos
Aflatoxina B1/toxicidade , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Polissacarídeos/uso terapêutico , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Dano ao DNA/efeitos dos fármacos , Glutationa/metabolismo , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo
8.
Oxid Med Cell Longev ; 2020: 9585047, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104545

RESUMO

Quercetin, a flavonoid found in fruits and vegetables, is widely distributed as a secondary metabolite in the plant kingdom. Oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The present study investigated the effects of quercetin dietary supplementation on streptozotocin- (STZ-) induced hyperglycemic Arbor Acre (AA) broilers by determining the levels of fasting blood glucose (FBG), fasting insulin (FINS), biochemical indicators, oxidative stress markers, inflammatory cytokines content, antioxidant enzymes activities in tissues, and mRNA expression of genes relating to the insulin signaling pathway. Three hundred one-day-old healthy AA broilers were randomly assigned into 5 treatments; A, control healthy broilers; B, STZ-induced broilers; C, STZ-induced broiler dietary supplemented with 0.02% quercetin; D, STZ-induced broiler dietary supplemented with 0.04% quercetin; and E, STZ-induced broiler dietary supplemented with 0.06% quercetin. The results showed that quercetin supplementation relieved the side effects of STZ-induced oxidative stress by changing activities of antioxidant enzymes, decreasing malondialdehyde (MDA) and nitric oxide (NO) levels, activating expression of genes relating to PI3K/PKB signaling pathway that modulate glucose metabolism and reduce oxidative damage, thereby decreasing FBG and increasing FINS levels. These findings suggest that quercetin exhibits a protective effect in STZ-induced hyperglycemic AA broilers via decreasing oxidative stress.


Assuntos
Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Quercetina/uso terapêutico , Estreptozocina/toxicidade , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Galinhas , Suplementos Nutricionais , Hiperglicemia/metabolismo , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos
9.
PLoS One ; 15(2): e0228750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032367

RESUMO

OBJECTIVE: Accumulating epidemiological studies have demonstrated that diabetes is an important risk factor for dementia. However, the underlying pathological and molecular mechanisms, and effective treatment, have not been fully elucidated. Herein, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, on diabetes-related cognitive impairment. METHOD: Streptozotocin (STZ)-induced diabetic mice were treated with linagliptin (3 mg/kg/24 h) for 17 weeks. The radial arm water maze test was performed, followed by evaluation of oxidative stress using DNP-MRI and the expression of NAD(P)H oxidase components and proinflammatory cytokines and of microglial activity. RESULTS: Administration of linagliptin did not affect the plasma glucose and body weight of diabetic mice; however, it improved cognitive impairment. Additionally, linagliptin reduced oxidative stress and the mRNA expression of NAD(P)H oxidase component and TNF-α, and the number and body area of microglia, all of which were significantly increased in diabetic mice. CONCLUSIONS: Linagliptin may have a beneficial effect on diabetes-related dementia by inhibiting oxidative stress and microglial activation, independently of glucose-lowering.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Linagliptina/farmacologia , Microglia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Inibidores da Dipeptidil Peptidase IV/farmacologia , Linagliptina/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/efeitos dos fármacos , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estreptozocina/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Psychopharmacology (Berl) ; 237(4): 1131-1145, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912189

RESUMO

RATIONALE: Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain. OBJECTIVES: The aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions. METHODS: Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall-Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively. RESULTS: Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of α-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels. CONCLUSIONS: Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; ß2-adrenoceptors; D1-, D2/D3-dopaminergic receptors; and δ-opioid receptors. The results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy-induced pain.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Reboxetina/uso terapêutico , Receptores Opioides delta/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/induzido quimicamente , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/sangue , Neuralgia/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Reboxetina/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Estreptozocina/toxicidade
11.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936547

RESUMO

Curcumin is the main secondary metabolite of Curcuma longa and other Curcuma spp, and has been reported to have some potential in preventing and treating some physiological disorders. This study investigated the effect of curcumin in inhibiting high-fat diet and streptozotocin (STZ)-induced hyperglycemia and hyperlipidemia in rats. Twenty-six male Sprague-Dawley (SD) rats (170-190 g) were randomly divided into a standard food pellet diet group (Control group), a high-fat diet and streptozotocin group (HF + STZ group), and a high-fat diet combined with curcumin and STZ group (HF + Cur + STZ group). Compared with the HF + STZ group, the HF + Cur + STZ group exhibited significantly reduced fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (AST), and aspartate transaminase (ALT) levels, as well as liver coefficients. In the livers of these rats, the expression of malondialdehyde (MDA) and Bax was downregulated, whereas that of superoxide dismutase (SOD) and Bcl-2 was upregulated. Moreover, the liver histology of these rats was improved and resembled that of the control rats. These results suggest that curcumin prevents high-fat diet and STZ-induced hyperglycemia and hyperlipidemia, mainly via anti-oxidant and anti-apoptotic mechanisms in the liver.


Assuntos
Curcumina/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Extratos Vegetais/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia , Curcuma/química , Dieta Hiperlipídica/efeitos adversos , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/patologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Extratos Vegetais/química , Ratos , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo , Triglicerídeos/sangue
12.
Eur J Vasc Endovasc Surg ; 59(1): 117-127, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31732468

RESUMO

OBJECTIVE: Diabetes mellitus has reached epidemic proportions. Foot ulceration is a multifactorial complication of diabetes associated with marked morbidity and mortality. Innate immune Toll-like receptor 4 (TLR4) mediated inflammation has been implicated in the systemic pathogenesis of diabetes and may contribute to impairment of wound healing. This study investigates the effect of high glucose and hypoxic conditions on TLR4 activation and signalling in vitro and in vivo. METHODS: Fibroblasts cultured at physiological glucose concentration (5.5 mM) were exposed to glucose concentrations from 0 mM to 25 mM, with duplicates placed in a hypoxic chamber. TLR4 inhibition was assessed in the 25 mM glucose groups. Diabetes was induced in wild type (WT) and TLR4 knockout (KO) C57BL/6 mice by intraperitoneal injection of low dose streptozocin (STZ). Hindlimb ischaemia was induced by femoral artery ligation four weeks post streptozocin, and a full thickness 4 mm skin wound inflicted below the knee. Wound healing was assessed via digital planimetry on days 3, 7, and 14 post surgery. RESULTS: Hypoxic and high glucose (25 mM) conditions led to an increase in TLR4 protein expression, apoptosis, and interleukin (IL)-6 release. Inhibition with a TLR4 neutralising antibody and specific TLR4 antagonist ameliorated the effects of high glucose and ischaemia (p < .05). In vivo, wound healing was significantly impaired in the diabetic ischaemic group at day 14 (p < .05). Diabetic ischaemic wounds in TLR4 KO mice exhibited significantly improved healing rates compared with those in WT mice at all time points. CONCLUSION: Hypoxia stimulates upregulation of TLR4 protein expression and this effect is exaggerated by hyperglycaemia. In TLR4 KO mice, there is a significant improvement in the healing of diabetic ischaemic wounds compared with WT. It is suggested that a synergistic effect between hypoxia and hyperglycaemia impairing wound healing exists, through TLR4 mediated inflammation.


Assuntos
Pé Diabético/patologia , Hiperglicemia/complicações , Isquemia/complicações , Receptor 4 Toll-Like/metabolismo , Cicatrização/fisiologia , Animais , Hipóxia Celular/fisiologia , Células Cultivadas , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Pé Diabético/etiologia , Modelos Animais de Doenças , Fibroblastos , Humanos , Hiperglicemia/sangue , Hiperglicemia/fisiopatologia , Interleucina-6/metabolismo , Isquemia/sangue , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Transdução de Sinais/fisiologia , Pele/citologia , Estreptozocina/toxicidade , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Regulação para Cima
13.
J Surg Res ; 246: 213-223, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31606511

RESUMO

BACKGROUND: For patients with diabetes mellitus, excessive and long-lasting inflammatory reactions at the wound site commonly lead to the delayed refractory wound healing. The polarization of macrophages in terms of M1 and M2 phenotypes is closely related to the production of inflammatory cytokines. Quercetin is traditionally recognized to have anti-inflammatory effect; however, whether quercetin modulates macrophage polarization from M1 to M2 and thus promotes diabetic wound healing remain unknown. MATERIALS AND METHODS: Wounded male diabetic rats were equally divided into five groups: model group, solvent control group (10% DMSO), and three drug groups treated with quercetin (Q) at concentrations of 10 mg/mL (Q-LD [low dose]), 20 mg/mL (Q-MD [medium dose]), and 40 mg/mL (Q-HD [high dose]), respectively. The anti-inflammatory effect of quercetin on diabetic wounds was observed. Immunohistochemistry and quantificational real-time polymerase chain reaction were applied to test the changes in macrophage polarization and inflammatory responses. RESULTS: The wound contraction was fastest in Q-HD group. Hematoxylin and eosin (H&E) and Masson's trichrome staining revealed that fibroblast distribution and collagen deposition in quercetin-treated groups were significantly higher than those in the model group. Immunohistochemistry tests showed more CD206-positive cells and less iNOS-positive cells in quercetin-treated groups. Furthermore, the levels of proinflammatory factors in quercetin-treated groups were lower than those in the model group, whereas the levels of the anti-inflammatory factors and angiogenesis-related factors were relatively higher. CONCLUSIONS: In short, quercetin inhibits inflammatory reactions via modulating macrophage polarization switching from M1 to M2 phenotype, thereby accelerating the diabetic wound repair.


Assuntos
Diabetes Mellitus Experimental/complicações , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Quercetina/administração & dosagem , Pele/lesões , Cicatrização/efeitos dos fármacos , Administração Cutânea , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Relação Dose-Resposta a Droga , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Ratos , Pele/imunologia , Pele/patologia , Estreptozocina/toxicidade , Resultado do Tratamento , Cicatrização/imunologia
14.
Life Sci ; 241: 117154, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31857087

RESUMO

AIM: Insulin resistance and neuroinflammation play roles in Alzheimer's (AD) etiology. Insulin receptors (IR) are developmentally expressed in neurons as well as astrocytes. Moreover, prolonged stress can induce brain insulin resistance and astrogliosis. Also, prenatal stress could advance AD-related abnormalities in a transgenic model of AD. Besides, postnatal maternal care (PMC) has antagonistic effects on prenatal stress (PS)-induced neuronal and immunological malfunctions. Using an icv-STZ subclinical model of sAD, we assessed PS and/or abnormal PMC impacts on advancing sAD-like pathology in adult male rats. We also sought astrocyte- and/or neuron-oriented change in central insulin programming. MAIN METHODS: Pregnant rats were exposed to PS. Thereafter, a group of pups was fostered onto unstressed mothers and the others remained intact. Real-time RT-PCR- for hippocampal IR, Tau, and ChAT transcripts- and immunohistochemistry analysis- for GFAP+ astrocytes- were performed at the first- and forth-postnatal-week, respectively. The other animals received icv-STZ0.5 mg/kg in adulthood and subjected to cognitive tests, molecular, and histological experiments at appropriate time-point post-injection. KEY FINDINGS: PS could advance sAD-related symptoms in icv-STZ-treated animals. PS changed expression levels of hippocampal IR in one-week-old and 5.5-month-old offspring. PS could worsen cognitive, molecular and histological impairments of icv-STZ. Adequate PMC prevented some destructive effects of PS. SIGNIFICANCE: PS can potentially change central insulin programming and induce long-lasting astrogliosis in rat hippocampus. PS-related cognitive and histological pathologies can rescue by PMC probably via IR-dependent pathways. Astrocyte involvement in AD-like neuropathology observed in stressed-animals needs more detailed investigations.


Assuntos
Doença de Alzheimer/patologia , Comportamento Animal , Modelos Animais de Doenças , Resistência à Insulina , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estreptozocina/toxicidade , Estresse Psicológico/complicações , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Infusões Intraventriculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Gravidez , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Transdução de Sinais , Estreptozocina/administração & dosagem
15.
Proc Natl Acad Sci U S A ; 117(1): 448-453, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871187

RESUMO

Voltage-gated calcium 3.1 (CaV3.1) channels are absent in healthy mouse ß cells and mediate minor T-type Ca2+ currents in healthy rat and human ß cells but become evident under diabetic conditions. Whether more active CaV3.1 channels affect insulin secretion and glucose homeostasis remains enigmatic. We addressed this question by enhancing de novo expression of ß cell CaV3.1 channels and exploring the consequent impacts on dynamic insulin secretion and glucose homeostasis as well as underlying molecular mechanisms with a series of in vitro and in vivo approaches. We now demonstrate that a recombinant adenovirus encoding enhanced green fluorescent protein-CaV3.1 subunit (Ad-EGFP-CaV3.1) efficiently transduced rat and human islets as well as dispersed islet cells. The resulting CaV3.1 channels conducted typical T-type Ca2+ currents, leading to an enhanced basal cytosolic-free Ca2+ concentration ([Ca2+]i). Ad-EGFP-CaV3.1-transduced islets released significantly less insulin under both the basal and first phases following glucose stimulation and could no longer normalize hyperglycemia in recipient rats rendered diabetic by streptozotocin treatment. Furthermore, Ad-EGFP-CaV3.1 transduction reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting CaV3.1 channels or the Ca2+-dependent phosphatase calcineurin. Enhanced expression of ß cell CaV3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+ influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of ß cell exocytotic proteins. The present work thus suggests an elevated expression of CaV3.1 channels plays a significant role in diabetes pathogenesis.


Assuntos
Canais de Cálcio Tipo T/metabolismo , Diabetes Mellitus Experimental/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Animais , Células COS , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/genética , Núcleo Celular/metabolismo , Chlorocebus aethiops , Citosol/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Exocitose/efeitos dos fármacos , Estudos de Viabilidade , Feminino , Proteínas de Fluorescência Verde/genética , Células HEK293 , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/transplante , Masculino , Pessoa de Meia-Idade , Fosforilação , Cultura Primária de Células , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estreptozocina/toxicidade , Proteínas de Transporte Vesicular/metabolismo , Adulto Jovem
16.
Carbohydr Polym ; 229: 115534, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826396

RESUMO

As a new platform of systems biology, metabolomics provides a powerful approach to discover therapeutic biomarkers and mechanism of metabolic disease. Type 2 diabetes mellitus (T2DM) is a global metabolic disease, thus, a urinary metabolomics profiling was analyzed to study the anti-diabetic effects and mechanism of stachyose (ST) on high-fat diet- and low dose streptozotocinc-induced T2DM rats. The results showed that ST treatment regulated the level of insulin, low-density lipoprotein cholesterol, and triglycerides, which demonstrates improvement in T2DM on ST treatment. Urinary samples from the ST and T2DM group were enrolled in metabolomics study, 21 differential metabolites were identified from urinary metabolomics analysis, indicating that the ST treatment partly exerted the anti-diabetes activity by regulating energy metabolism, gut microbiota changes and inflammation. A metabolomics strategy is both suitable and reliable for exploring the anti-diabetes effects and understanding the mechanisms of ST treatment against T2DM.


Assuntos
Biomarcadores/urina , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metabolômica , Oligossacarídeos/uso terapêutico , Animais , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Análise Discriminante , Metabolismo Energético/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Histamina/urina , Hipoglicemiantes/farmacologia , Insulina/sangue , Análise dos Mínimos Quadrados , Masculino , Oligossacarídeos/farmacologia , Análise de Componente Principal , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Triglicerídeos/sangue
17.
J Ethnopharmacol ; 247: 112273, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31586692

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Luohanguo (LHG), a traditional Chinese medicine, could clear heat, moisten the lung, soothe the throat, restore the voice, and lubricate intestine and open the bowels. LHG has been utilized for the treatment of sore throats and hyperglycemia in folk medicine as a homology of medicine and food. The hypoglycemic pharmacology of LHG has attracted considerable attention, and mogrosides have been considered to be active ingredients against diabetes mellitus. We have found that these mogrosides could be metabolized into their secondary glycosides containing 1-3 glucose residues in type 2 diabetes mellitus (T2DM) rats in previous studies. These metabolites may be the antidiabetic components of LHG in vivo. Thus far, no reports have been found on reducing blood glucose of mogrosides containing 1-3 glucose residues. AIMS OF THE STUDY: The aim of this study was to confirm that mogrosides containing 1-3 glucose residues were the active components of LHG for antidiabetic effects and to understand their potential mechanisms of action. MATERIALS AND METHODS: First, the special fraction of mogrosides containing 1-3 glucose residues was separated from a 50% ethanol extract of LHG, and the chemical components were identified by ultra-performance liquid chromatography (UPLC) and named low-polar Siraitia grosvenorii glycosides (L-SGgly). Second, the antidiabetic effects of L-SGgly were evaluated by HFD/STZ-induced (high-fat diet and streptozocin) obese T2DM rats by indexing fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance, and then compared with other fractions in the separation process. The changes in serum lipid levels were also detected. Finally, possible mechanisms of antidiabetic activity of L-SGgly were identified as increasing GLP-1 levels and activating liver AMPK in T2DM rats. RESULTS: The chemical analysis of L-SGgly showed that they contain 11-oxomogroside V, mogroside V, mogroside III, mogroside IIE, mogroside IIIA1, mogroside IIA1, and mogroside IA1, respectively. The total content of the mogrosides in L-SGgly was 54.4%, including 15.7% mogroside IIA1 and 12.6% mogroside IA1. L-SGgly showed excellent effects on obese T2DM rats compared with the other fractions of LHG extract, including significantly reducing the levels of FBG (p < 0.001) and modifying insulin resistance (p < 0.05). Meanwhile, they could significantly decrease the content of triglyceride (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and free fatty acid (p < 0.001) and increase the content of high-density lipoprotein cholesterol (p < 0.001) in serum of T2DM rats. Moreover, L-SGgly can significantly increase (p < 0.01) GLP-1 levels and decrease (p < 0.01) IL-6 levels in T2DM rat serum. AMPK-activating activity in T2DM rats was also upregulated by L-SGgly, but no statistical significance was shown. CONCLUSION: L-SGgly, fractions separated from LHG extract, were verified to have obvious anti-hyperglycemic and anti-hyperlipidemic effects on T2DM rats. Furthermore, L-SGgly regulated insulin secretion in T2DM rats by increasing GLP-1 levels. These findings provide an explanation for the antidiabetic role of LHG.


Assuntos
Cucurbitaceae/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Obesidade/tratamento farmacológico , Triterpenos/farmacologia , Administração Oral , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Fracionamento Químico , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicosídeos/análise , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/análise , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/análise , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/uso terapêutico , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Obesidade/sangue , Obesidade/etiologia , Ratos , Estreptozocina/toxicidade , Triterpenos/análise , Triterpenos/isolamento & purificação , Triterpenos/uso terapêutico
18.
J Ethnopharmacol ; 247: 112275, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31589966

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is a terrible microvascular disorder causing blindness. Retinal inflammation is the early stage in DR, which is believed to play a crucial role in the development of it. Shengpuhuang-tang (ST), a traditional herbal formula, which has effective treatment of fundus bleeding disorder. ST exerts protective effects against DR in rats, but its underlying mechanism of this efficacy remains unknown. Thus, the objective of this study is to examine the mechanism and the efficacy of ST on retinal inflammation in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The administration of ST was initiated at 4 weeks after diabetes induction and continued for 12 weeks. Retinal vessel permeability was evaluated by using FITC-dextran and Evans blue. Retinal leukostasis was evaluated with FITC-coupled concanavalin A lectin (ConA). Moreover, western blotting was performed to detect TNF-α, ICAM-1 and the relative expression levels of IκBα, IKKß, and p65 in vivo. RESULTS: The results showed that the retinal inflammation in streptozotocin-induced diabetic rats was significantly decreased by ST. ST could decreased the expression levels of TNF-α, ICAM-1 and inhibited the expression of p-IKKß, p-p65 and IκBα. It could also inhibited the nuclear transfer of p65. CONCLUSIONS: In conclusion, these data suggested that ST may have potential treatment strategies against early stage of diabetic retinopathy through NF-κB pathway.


Assuntos
Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Leucostasia/tratamento farmacológico , Vasos Retinianos/efeitos dos fármacos , Administração Oral , Animais , Capilares/efeitos dos fármacos , Capilares/metabolismo , Capilares/patologia , Permeabilidade Capilar/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Leucostasia/etiologia , Masculino , NF-kappa B/imunologia , NF-kappa B/metabolismo , Ratos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Estreptozocina/toxicidade
19.
J Ethnopharmacol ; 247: 112257, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31589968

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hydrolea zeylanica L. Vahl. (Hydroleaceae) is an aquatic medicinal plant used as leafy vegetable in some parts of India. In south Odisha and Hazaribag district of Jharkhand, India, decoction of leaves is used as household remedy for diabetes. To our knowledge, no prior studies have examined the antidiabetic activity of H. zeylanica to validate its ethnomedicinal claim. PURPOSE: With this aim in mind, we examined the bioactivity of hydroalcohol fraction of leaves of H. zeylanica (HAHZ) in streptozotocin-induced oxidative stress in diabetic rats. MATERIALS AND METHODS: In vitro antidiabetic and free radical scavenging activities of different fractions of H. zeylanica were performed. The most effective bioactive fraction e.g. HAHZ was considered for kinetic studies to understand the mode of inhibition of α-glucosidase and α-amylase. To understand the chemical composition, GC-MS/MS and LC-MS/MS analysis of HAHZ were performed. To find out the molecular mechanism of action of HAHZ, streptozotocin-induced oxidative stress and metabolic changes in diabetic rats were studied. RESULTS: HAHZ demonstrated significantly higher radical scavenging and antidiabetic activities. Kinetic analysis revealed that HAHZ inhibited α-glucosidase competitively, and α-amylase mixed competitively. To understand the chemical composition, GC-MS/MS and LC-MS/MS analysis of HAHZ identified 32 compounds and among which R-limonene (0.52%), perillartine (0.41%), N-formyl-L-lysine (1.49%), limonen-6-ol, pivalate (1.43%), lidocaine (1.70%) and gamolenic acid (2.80%) were reported to have antioxidant and antidiabetic activities. HAHZ-400 mg/kg showed significant (p < 0.001) improvement in serum markers (SGOT, SGPT, ALP, total bilirubin, total protein, triglycerides, total cholesterol, HDL-C, LDL-C) and oxidative markers (MDA, SOD, CAT, GSH) in serum, liver and pancreas at effective dose dependent manner. In histopathological observation, HAHZ-400 mg/kg showed marked improvement in restoring cellular architecture of liver and pancreas. CONCLUSION: In diabetic rats, the improvement in glycemic control mechanism was achieved upon stimulating insulin secretion by R-limonene, perillartine, N-formyl-L-lysine, limonen-6-ol, pivalate, lidocaine and gamolenic acid of HAHZ.


Assuntos
Organismos Aquáticos/química , Diabetes Mellitus Experimental/tratamento farmacológico , Depuradores de Radicais Livres/farmacologia , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Solanales/química , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Etnofarmacologia , Feminino , Depuradores de Radicais Livres/isolamento & purificação , Depuradores de Radicais Livres/uso terapêutico , Humanos , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/uso terapêutico , Índia , Insulina/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Ratos , Estreptozocina/toxicidade
20.
Eur Rev Med Pharmacol Sci ; 23(23): 10482-10488, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31841202

RESUMO

OBJECTIVE: The aim of this study was to clarify the potential function of transforming growth factor-ß1/serum/glucocorticoid-regulated kinase 1 (TGF-ß1/SGK1) pathway in diabetic nephropathy-induced tubulointerstitial fibrosis. MATERIALS AND METHODS: Type 2 diabetes mellitus (T2DM) model was successfully established in rats by high-sucrose-high-fat diet combined with streptozotocin (STZ) induction. Subsequently, blood glucose level, renal function and pathological changes in kidneys of T2DM and control rats were evaluated. Western blot and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) were conducted to determine the protein and mRNA expression levels of TGF-ß1, SGK1, fibronectin (FN) and α-smooth muscle actin (α-SMA) in rat kidney tissues, respectively. RESULTS: Blood glucose (BG), glycosylated hemoglobin (GHb), serum creatinine (Scr) and blood urea nitrogen (BUN) in T2DM rats were significantly higher than those of control rats (p<0.05). The morphology of glomeruli and renal tubules in rats of control group were normal. In contrast, T2DM rats showed significant lesions in glomeruli, renal tubules, and renal interstitium. Furthermore, the relative expression levels of TGF-ß1, SGK1, FN, and α-SMA in kidney tissues of T2DM rats were remarkably higher than those of controls (p<0.05). CONCLUSIONS: The TGF-ß1/SGK1 pathway is closely related to tubulointerstitial fibrosis in T2DM rats.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/patologia , Proteínas Imediatamente Precoces/metabolismo , Túbulos Renais/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Fibrose , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Estreptozocina/toxicidade
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