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1.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208534

RESUMO

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Polifenóis/farmacologia , Zea mays/metabolismo , Animais , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , China , Citoproteção/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Células Endoteliais/metabolismo , Glucose/efeitos adversos , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/farmacologia , Polifenóis/química , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(6): 839-846, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34238735

RESUMO

OBJECTIVE: To explore the role of fetuin B-AMPK/ACC signaling pathway in mediating the effect of puerarin on hepatic insulin resistance in mice with type 2 diabetes mellitus (T2DM). OBJECTIVE: Forty C57BL/6J mouse models of T2DM induced by high-fat diet and intraperitoneal injection of streptozotocin were randomized into diabetic model (HFD) group and 3 puerarin groups for treatment with low-, moderate- and high- dose puerarin (50, 100 and 200 mg/kg, respectively), with another 10 mice fed a normal diet as the control group. After treatment for 8 weeks, the mice were examined for fasting blood glucose (FBG), fasting insulin (FINS), liver triglycerides (TG), cholesterol (TC) and free fatty acids (FFA) levels. The expression of fetuin B in the liver was detected by immunohistochemistry. RT-qPCR was used to detect the expressions of fetuin B, AMPK, and ACC mRNA in the liver, and the protein expressions of fetuin B, AMPKα1, ACC, P-AMPKαT183/T172, and P-ACC S79 were determined with Western blotting. OBJECTIVE: Treatment with moderate- and high-dose puerarin significantly lowered TG, TC, FFA and FBG levels in diabetic mice (P < 0.01). Puerarin at all the 3 doses significantly lowered FINS and HOMA-IR of the mice (P < 0.01). In diabetic mice, hepatic expressions of fetuin B and ACC mRNA increased and AMPK mRNA decreased significantly (P < 0.01); the protein expressions of fetuin B and ACC increased while those of AMPKα1, P-AMPKαT183/T172 and P-ACC S79 decreased significantly (P < 0.01). Puerarin dose-dependently inhibited the mRNA and protein expressions of fetuin B and ACC, increased AMPK mRNA and protein expressions of AMPKα1, P-AMPKαT183/ T172, and P-ACC S79, and lowered fetuin B content in the liver of diabetic mice (P < 0.01). OBJECTIVE: Puerarin alleviates insulin resistance and improves glucolipid metabolism in T2DM mice by modulating hepatic fetuin B-AMPK/ACC signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Fetuína-B , Insulina , Isoflavonas , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
3.
Phytomedicine ; 87: 153582, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34091150

RESUMO

BACKGROUND AND PURPOSE: Diosmetin (Dios), a flavonoid compound with multiple pharmacological activities. However, fewer studies have reported its effects on type 2 diabetic mellitus (T2DM). Here, we address the effect of Dios on glucose metabolism and gut microbiota in KK-Ay diabetic mice. METHOD: Wild type C57BL/6 J mice or diabetic KK-Ay mice were treated with vehicle or Dios for one month. The ELISA kit and fluorescence microscope system were respectively employed to the evaluation of serum biochemical indicators and histopathological changes. Liver RNA-Seq and western blot were used to reveal the key signaling pathway. The effects of Dios on gut microbiota was investigated by the 16S rRNA gene sequencing, as well as the relationship between Dios and C. glu on glucose metabolism was explored with the C. glu transplantation. RESULTS: Dios treatment significantly decreased blood glucose and increased serum insulin concentrations. RNA-Seq analysis found that the underlying action mechanism of Dios on T2DM was via modulating glucose metabolism, which was proved by up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation. Besides, Dios treatment reshaped the unbalanced gut microbiota by suppressing the ratio of Firmicutes/Bacteroidetes and markedly increasing the richness of C. glu. Moreover, treatment with C. glu and Dios together could markedly ameliorate glucose metabolism by up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation. CONCLUSIONS: Dios treatment remarkably ameliorated glucose metabolism in KK-Ay diabetic mice by the regulation of C. glu via IRS/PI3K/AKT signaling pathway and reshaped the unbalanced gut microbiota. Our study provided evidence for the application of Dios to the treatment of T2DM.


Assuntos
Corynebacterium glutamicum/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Animais , Glicemia/metabolismo , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Glicogênio/metabolismo , Insulina/sangue , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Ribossômico 16S , Fatores de Transcrição/metabolismo
4.
Ann Palliat Med ; 10(5): 5299-5309, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34107698

RESUMO

BACKGROUND: Substantial studies have demonstrated that fasting therapy (FT) can inhibit the inflammatory response and improve insulin resistance (IR); however, the underlying mechanisms are still unclear. This study aimed to explore the related mechanisms of intermittent FT for the treatment of IR. METHODS: A rat IR model was established through collaboration of a high-fat diet with streptozotocin (STZ) injection. 8 rats were treated with intermittent FT. A positive control group was treated with metformin (MET). Mouse 3T3-L1 pre-adipocytes were cultured and induced into adipocytes in vitro, and were used as the cellular IR model. Blood insulin, glucose, and homeostatic model assessment (HOMA)-IR index were determined. Enzyme-linked immunosorbent assay (ELISA) and western blotting were used to detect inflammatory markers. Oil Red O staining determined the lipid accumulation. An NLRP3 inflammasome agonist served to investigate the effects of FT on IR in 3T3-L1 adipocytes. RESULTS: The high levels of blood insulin, glucose, and HOMA-IR induced by high-fat diet and STZ were significantly decreased by FT. The FT also reduced the level of C-reactive protein (CRP), interleukin (IL)-1ß, IL-18, caspase-1, and increased the expression of glucose transporter 1 (GLUT1), insulin receptor substrate 1 (IRS1), and IRS2 in both the rat models and 3T3-L1 adipocytes. In addition, FT significantly relieved lipid accumulation in the liver of rats. Application of NLRP3 inflammasome agonist weakened the effect of FT on IR in the IR 3T3-L1 adipocytes. CONCLUSIONS: These results suggest that FT can ameliorate the high-fat diet-and STZ-induced IR in rats through inhibition of NLRP3 inflammasome.


Assuntos
Diabetes Mellitus Experimental , Resistência à Insulina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Jejum , Inflamassomos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos
5.
BMC Musculoskelet Disord ; 22(1): 519, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090401

RESUMO

BACKGROUND: Dehydroepiandrosterone (DHEA), an adrenal steroid, has a protective role against diabetes. This study aimed to investigate the in vitro and in vivo protective effects of DHEA against high glucose-induced oxidative stress in tenocytes and tendons. METHODS: Tenocytes from normal Sprague-Dawley rats were cultured in low-glucose (LG) or high-glucose (HG) medium with or without DHEA. The experimental groups were: control group (LG without DHEA), LG with DHEA, HG without DHEA, and HG with DHEA. Reactive oxygen species (ROS) production, apoptosis, and messenger RNA (mRNA) expression of NADPH oxidase (NOX) 1 and 4, and interleukin-6 (IL-6) were determined. Further, diabetic rats were divided into a control group and a DHEA-injected group (DHEA group). NOX1 and NOX4 protein expression and mRNA expression of NOX1, NOX4, IL-6, matrix metalloproteinase (MMP)-2, tissue inhibitors of matrix metalloproteinase (TIMP)-2, and type I and III collagens in the Achilles tendon were determined. RESULTS: In rat tenocytes, DHEA decreased the expression of NOX1 and IL-6, ROS accumulation, and apoptotic cells. In the diabetic rat Achilles tendon, NOX1 protein expression and mRNA expression of NOX1, IL-6, MMP-2, TIMP-2, and type III collagen were significantly lower while type I collagen expression was significantly higher in the DHEA group than in the control group. CONCLUSIONS: DHEA showed antioxidant and anti-inflammatory effects both in vitro and in vivo. Moreover, DHEA improved tendon matrix synthesis and turnover, which are affected by hyperglycemic conditions. DHEA is a potential preventive drug for diabetic tendinopathy.


Assuntos
Diabetes Mellitus Experimental , Tenócitos , Animais , Células Cultivadas , Desidroepiandrosterona/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/toxicidade , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
6.
Gen Physiol Biophys ; 40(3): 221-234, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34100378

RESUMO

Gallic acid is a phenolic compound with biological and pharmacological activities. Therefore, our study aimed to examine whether gallic acid has a beneficial effect against type 2-induced diabetic hepatic injury in rats and attempt to discover its possible intracellular pathways. Adult male rats were subdivided into six groups: Control, DM (diabetes mellitus), GA (gallic acid)+DM, DM+GA, DM+MET (metformin) and DM+GA+MET. Type 2 diabetes mellitus (T2DM) induced a significant increase in the blood glucose, HOMA-IR, liver enzymes, fetuin-A, hepatic triglycerides content with diminished serum insulin and hepatic glycogen content associated with impairment of cellular redox balance. Administration of gallic acid successfully restored all these alterations which was confirmed by marked improvement of the histopathological changes of the liver. Significantly, gallic acid increased the expression of glucagon-like peptide-1 (GLP-1) immunoreactive cells in the terminal ileum with negative correlation observed between fetuin-A and GLP-1 cells. Furthermore, our results discovered that gallic acid could diminish the DM-induced hepatic damage via upregulated hepatic mRNA expression of GLUT-4, Wnt1 and ß-catenin with inhibitory effects on the elevated expression of ERK1/2/NF-κB. In conclusion, this study suggests that gallic acid provides a significant protection against T2DM-mediated liver injury. The use of gallic acid with traditional anti-diabetic drug enhanced its efficiency compared with traditional drug alone.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Ácido Gálico , Peptídeo 1 Semelhante ao Glucagon , Fígado , Sistema de Sinalização das MAP Quinases , Masculino , NF-kappa B , Ratos , Ratos Wistar , Proteína Wnt1 , alfa-2-Glicoproteína-HS , beta Catenina
7.
J Agric Food Chem ; 69(25): 7000-7015, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34139119

RESUMO

High intake of dietary fibers was found to be inversely associated with type-2 diabetes (T2D), whereas the difference among different dietary fibers on T2D remains unclear. Therefore, we have investigated the effects of different dietary fibers on T2D. Nine types of dietary fibers were used to investigate and evaluate their effects on type-2 diabetic rats via physiology, genomics, and metabolomics. We found that supplementation with ß-glucan, arabinogalactan, guar gum, apple pectin, glucomannan, and arabinoxylan significantly reduced the fasting blood glucose, whereas carrageenan, xylan, and xanthan gum did not affect glycemic control in diabetic rats. Also, bioactive dietary fibers (ß-glucan, arabinogalactan, guar gum, and apple pectin) associated with the increased butyric acid level and abundance of beneficial bacteria (Lachnobacterium, Parabacteroides, Faecalibacterium, Akkermansia, and some butyric acid-producing bacteria), as well as improved host metabolism by decreasing 12α-hydroxylated bile acids, acylcarnitines, and amino acids (leucine, phenylalanine, citrulline, etc.), thereby exert beneficial effects on T2D. It was also found that ß-glucan might attenuate insulin resistance via downregulation of Prevotella copri-mediated biosynthesis of branched-chain amino acids in T2D. Together, our study uncovered the effects of different dietary fibers on T2D, along with their potential mechanism.


Assuntos
Diabetes Mellitus Experimental , Microbioma Gastrointestinal , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Fibras na Dieta , Hipoglicemiantes , Prevotella , Ratos
8.
Life Sci ; 278: 119574, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961850

RESUMO

AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Administração Oral , Animais , Área Sob a Curva , Peso Corporal , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Insulina/metabolismo , Veias Jugulares/patologia , Masculino , Metformina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
9.
Free Radic Biol Med ; 171: 112-123, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33992678

RESUMO

Defective autophagy occurred in osteoblasts under stress induced by high glucose and played an essential role in the development of diabetic osteoporosis. Timosaponin BII, a steroidal saponin isolated from the rhizomes of Anemarrhena asphodeloides Bunge, possessed anti-osteoporosis properties. In this study, we investigated the efficacy and mechanism of timosaponin BII on diabetic osteoporosis. Timosaponin BII attenuated the deterioration in the microarchitecture of the tibias in diabetic rats. Furthermore, treatment with timosaponin BII dose-dependently reduced hyperglycemia-induced cell apoptosis in primary osteoblasts from rat calvaria. High glucose-exposed osteoblasts exhibited increased mitochondrial superoxide level, decreased mitochondrial membrane potential and impaired autophagic flux, which was attenuated by timosaponin BII, as evidenced by the upregulation of autophagosome numbers, LC3B puncta formation and Beclin1 expression. The antiapoptotic and antioxidative effect of timosaponin BII were repressed by the autophagy inhibitor 3-methyladenine and enhanced by the autophagy inducer rapamycin. Further studies showed that timosaponin BII suppressed the phosphorylation of mTOR and S6K, as well as the downstream factors NFκB and IκB, consequently activating autophagy and decreasing apoptosis. Of note, coincubation of timosaponin BII with MHY1485, a pharmacological activator of mTOR, diminished the protein expression of Bcl2 induced by timosaponin BII, which was in parallel with decreased autophagy and increased phosphorylation of NFκB and IκB. Overexpression of NFκB reduced timosaponin BII-evoked autophagy and promoted apoptosis. The in vivo results showed that oral administration of timosaponin BII downregulated the phosphorylation of mTOR and NFκB and upregulated Beclin1 expression in the proximal tibias of diabetic rats. These results suggested that timosaponin BII attenuated high glucose-induced oxidative stress and apoptosis through activating autophagy by inhibiting mTOR/NFκB signalling in osteoblasts.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Osteoporose , Saponinas , Animais , Apoptose , Autofagia , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Osteoblastos , Osteoporose/tratamento farmacológico , Ratos , Saponinas/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
10.
FASEB J ; 35(6): e21673, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34042213

RESUMO

Lysophosphatidylinositol (LPI) is a glycero-lysophospholipid and a natural agonist against GPR55. The roles of the LPI/GPR55 axis in the pathogenesis of inflammation have been controversial. In the present study, we attempted to elucidate the roles of the LPI/GPR55 axis in inflammation, especially the secretion of inflammatory cytokines, IL-6 and TNF-α from macrophages. We treated RAW264.7 cells and mouse peritoneal macrophages (MPMs) with LPI and observed that LPI induced the secretion of IL-6 and TNF-α from these cells, as well as the phosphorylation of p38. These responses were inhibited by treatment with CID16020046 (CID), an antagonist against GPR55, or SB202190, an inhibitor of p38 cascade or knockdown of GPR55 with siRNA. Treatment with CID or ML-193, another antagonist against GPR55, attenuated the elevation of inflammatory cytokines in the plasma or tissue of db/db mice and in a septic mouse model induced using lipopolysaccharide, suggesting contributions to the improvement of insulin resistance and protection against organ injuries by treatment with CID or ML-193, respectively. In human subjects, although the serum LPI levels were not different, the levels of LPI in the lipoprotein fractions were lower and the levels in the lipoprotein-depleted fractions were higher in subjects with diabetes. LPI bound to albumin induced the secretion of IL-6 and TNF-α from RAW264.7 cells to a greater degree than LPI bound to LDL or HDL. These results suggest that LPI, especially the albumin-bound form, induced inflammatory cytokines depending on the GPR55/p38 pathway, which might contribute to the pathogenesis of obesity-induced inflammation and acute inflammation.


Assuntos
Albuminas/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Mediadores da Inflamação/metabolismo , Lisofosfolipídeos/farmacologia , Macrófagos/imunologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL
11.
Oxid Med Cell Longev ; 2021: 6657529, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986917

RESUMO

The cardioprotective effect of sevoflurane postconditioning (SPostC) is lost in diabetes that is associated with cardiac phosphatase and tensin homologue on chromosome 10 (PTEN) activation and phosphoinositide 3-kinase (PI3K)/Akt inactivation. T-LAK cell-originated protein kinase (TOPK), a mitogen-activated protein kinase- (MAPKK-) like serine/threonine kinase, has been shown to inactivate PTEN (phosphorylated status), which in turn activates the PI3K/Akt signaling (phosphorylated status). However, the functions of TOPK and molecular mechanism underlying SPostC cardioprotection in nondiabetes but not in diabetes remain unknown. We presumed that SPostC exerts cardioprotective effects by activating PTEN/PI3K/Akt through TOPK in nondiabetes and that impairment of TOPK/PTEN/Akt blocks diabetic heart sensitivity to SPostC. We found that in the nondiabetic C57BL/6 mice, SPostC significantly attenuated postischemic infarct size, oxidative stress, and myocardial apoptosis that was accompanied with enhanced p-TOPK, p-PTEN, and p-Akt. These beneficial effects of SPostC were abolished by either TOPK kinase inhibitor HI-TOPK-032 or PI3K/Akt inhibitor LY294002. Similarly, SPostC remarkably attenuated hypoxia/reoxygenation-induced cardiomyocyte damage and oxidative stress accompanied with increased p-TOPK, p-PTEN, and p-Akt in H9c2 cells exposed to normal glucose, which were canceled by either TOPK inhibition or Akt inhibition. However, either in streptozotocin-induced diabetic mice or in H9c2 cells exposed to high glucose, the cardioprotective effect of SPostC was canceled, accompanied by increased oxidative stress, decreased TOPK phosphorylation, and impaired PTEN/PI3K/Akt signaling. In addition, TOPK overexpression restored posthypoxic p-PTEN and p-Akt and decreased cell death and oxidative stress in H9c2 cells exposed to high glucose, which was blocked by PI3K/Akt inhibition. In summary, SPostC prevented myocardial ischemia/reperfusion injury possibly through TOPK-mediated PTEN/PI3K/Akt activation and impaired activation of this signaling pathway may be responsible for the loss of SPostC cardioprotection by SPostC in diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sevoflurano/farmacologia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/enzimologia , Coração/efeitos dos fármacos , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Inibidores da Agregação Plaquetária/farmacologia , Distribuição Aleatória , Ratos , Transdução de Sinais/efeitos dos fármacos
12.
Xenobiotica ; 51(7): 818-830, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33952086

RESUMO

Diabetes mellitus is a chronic metabolic disorder with multiple complications, patients who receive metformin may have a simultaneous intake of herbal medicine containing rutaecarpine due to cardiovascular protection and hypolipidemic effects of rutaecarpine. There might be drug interactions between metformin and rutaecarpine. This study aimed to investigate the effects of rutaecarpine on the pharmacodynamics and pharmacokinetics of metformin in diabetic rats.The diabetic rat model was induced with high-fat diet and low dose streptozotocin. Metformin with or without rutaecarpine was administered by oral gavage for 42 days. Pharmacodynamics and pharmacokinetics parameters were evaluated.The pharmacodynamics results revealed that co-administration of rutaecarpine with metformin resulted in a remarkable reduction of serum glucose and lipid profiles in diabetic rats compared to metformin treated alone. The pharmacokinetics results showed that co-treatments of rutaecarpine with metformin did not affect the systemic exposure and renal distribution of metformin, but increased metformin concentration in liver. Furthermore, rutaecarpine increased Oct1-mediated metformin uptake into hepatocytes by upregulation of Oct1 expression in the liver.The above data indicate that rutaecarpine enhanced the anti-diabetic effect of metformin, which may be associated with the increased hepatic distribution of metformin through up-regulation of Oct1 in response to rutaecarpine.


Assuntos
Diabetes Mellitus Experimental , Metformina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Alcaloides Indólicos , Fígado , Metformina/farmacologia , Quinazolinas , Ratos , Regulação para Cima
13.
Life Sci ; 278: 119624, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34004254

RESUMO

AIMS: Diabetic nephropathy, a major threat to diabetic patients, is considered as the main reason for end-stage renal disease. Fortunately, incretin-based therapy has been aroused as considerable source to attenuate diabetic renal damage. This study aimed to investigate whether superior protective effects on the progression of diabetic kidney are exerted by glucagon-like peptide-1 analog, exenatide, or dipeptidyl peptidase-4 inhibitor, sitagliptin. MATERIALS AND METHODS: Male Wistar rats were fed high-fat diet for 2 weeks followed by injection of low dose streptozotocin to induce type 2 diabetes mellitus. Four weeks after induction of diabetes, diabetic rats were administered vehicle, exenatide (5 µg/kg/day, SC) or sitagliptin (10 mg/kg/day, orally) for 4 weeks. KEY FINDINGS: Different incretin mimetic agents improved renal function as evident by significant decreases in serum creatinine and urea levels with decline in urinary microalbuminuria and marked improvement in histological alterations. Both treated diabetic rats also exhibited a significant improvement in metabolic intolerance with more pronounced effect of exenatide on glucose regulation. Ameliorated renal oxidative stress alongside significant downregulation in transforming growth factor-beta, tumor necrosis factor-alpha and cleaved-caspase-3 protein expressions in renal tissues were recorded in treated diabetic rats. SIGNIFICANCE: Administration of either exenatide or sitagliptin showed ameliorative effects on early diabetic nephropathy without notable differences between their renal protective effects. However, further clinical studies are still required to ensure their comparative promising effects on the management of renal complication of diabetes.


Assuntos
Caspase 3/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Incretinas/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Caspase 3/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Masculino , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genética
14.
AAPS PharmSciTech ; 22(5): 158, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34009603

RESUMO

The present study was aimed to enhance the mitochondrial function in oxidative stress-induced diabetes. To achieve this, Ficus religiosa L. extract loaded solid lipid nanoparticles (ETNPs) were prepared and functionalized by using triphenylphosphonium. Developed nanoparticles demonstrated desired quality attributes with sustained release for up to 24 h and excellent storage stability for up to 180 days at 40 ± 2°C and 75 ± 5% relative humidity. In vitro cytotoxicity assessment showed no toxicity of ETNPs. Interestingly, oral administration of ETNPs to diabetic rats demonstrated improved mitochondrial function by normalizing the mitochondrial morphology, intracellular calcium ion concentration, complexes I, II, IV, and V activity, mitochondrial membrane potential, and antioxidant levels. Further, reduction in apoptotic markers viz. cytochrome-C, caspase-3, and caspase-9 was observed following the ETNP treatment. Moreover, significant reduction in blood glucose and glycosylated hemoglobin while significant improvement in plasma insulin was observed as compared to the diabetic group following the treatment with developed formulation. Furthermore, histopathology studies confirmed the safety of the developed formulation and thus, data in hand collectively suggest that proposed strategy can be effectively used to improve the mitochondrial function in oxidative stress-induced diabetes along with better control over blood glucose and glycosylated hemoglobin.


Assuntos
Antioxidantes/farmacologia , Ficus/química , Nanopartículas , Compostos Organofosforados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Glicemia/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Citocromos c/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/isolamento & purificação , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar
15.
J Pharm Biomed Anal ; 201: 114139, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000580

RESUMO

Baobab fruit pulp Adansonia digitata (AD) has received attention due to its numerous nutritional and medicinal values. In the current study, tentative identification was performed due to limited information available on its phytochemical composition. Phytochemicals from AD fruit pulp were obtained using successive organic solvent fractionation. The LC-MSMS analysis led to identification of 91 metabolites from methanol, butanol and ethyl acetate extracts. Moreover, 20 compounds were identified in the petroleum ether extract based on high resolution ion masses. In vitro antidiabetic and antioxidant properties of selected extracts were investigated using enzyme activity and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, respectively. Biological screening of the antidiabetic effects of target extracts was performed against streptozotocin-induced diabetes in experimental animals, following daily oral treatment for 3 successive weeks. Serum glucose, insulin, adiponectin, superoxide dismutase (SOD), lipid peroxide, cholesterol and HDL levels were measured. Finally, histopathological and immunohistochemical examinations of pancreas were carried out. Results revealed that animal groups treated daily with butanol (BuOH) and petroleum ether extracts of AD (oil) exhibited a significant improvement in carbohydrate and lipid metabolism as well as antioxidant effect. Both extracts revealed superior effects with respect to the total (TT) and ethyl acetate (EtOAc) extracts. Histopathological and immunohistochemical findings supported these results, showing marked protection of the pancreas. Thus, baobab oil and butanolic extract of the fruit pulp protected animals against STZ-induced diabetic changes, in addition to attenuation of lipid peroxidation, hypercholesterolemia and oxidation.


Assuntos
Adansonia , Diabetes Mellitus Experimental , Animais , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Frutas , Lipidômica , Extratos Vegetais/farmacologia , Ratos
16.
Braz J Biol ; 82: e239378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33978082

RESUMO

The genus Pouteria has been studied because it presents various activities, among which is its anti-inflammatory potential. The effects of Pouteria ramiflora Carbopol gel on the healing of skin wounds in diabetic rats were evaluated by microscopic imaging. Streptozotocin was administered intraperitoneally in animals that had fasted for 12 hours, a situation confirmed by the glycemic index (˃ 240 mg dL-1). An excision on the back of the animals was performed and three groups were formed: Control (Gel), Ethanolic extract (Ext) and Gel + extract 2% (Ext+gel); the histopathological evaluation occurred on the 7th, 14th, 21st and 30th days after the post-operative period. The results of the phytochemical prospecting of P. ramiflora extract demonstrated the major presence of phenolic compounds and flavonoids; the assessment of the inflammatory infiltrate on the 7th day was higher on group Ext and Ext+gel when compared to group Control; on the 14th day control and Ext (p<0.05). The quantification of fibroblasts was higher on the 7th day among the three treatments, control and Ext (p<0.05), on the 21st day. Angiogenesis showed a higher number of vessels in Ext+gel group (p<0.05) on the 7th day; in Control, Ext and Ext+gel (p<0.05) on the 14th day; and Control and Ext (p<0.05)on the 21st day. The histopathological results showed that the formulation Ext+gel was efficient in tissue reparation and decrease in inflammatory cells on the diabetic's animals.


Assuntos
Diabetes Mellitus Experimental , Pouteria , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Flavonoides , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Cicatrização
17.
Food Funct ; 12(8): 3572-3585, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900346

RESUMO

Type 2 diabetic mellitus (T2DM) is a complicated metabolic disorder that is now considered as a major global public health problem. Fucoidan exhibits diverse biological activities, especially prevention of metabolic diseases. In this regard, we herein aimed to reveal the beneficial effect of Sargassum fusiforme fucoidan (SFF) on high-fat diet (HFD) and streptozotocin (STZ) induced T2DM mice. We noted that on the one hand, SFF significantly decreased fasting blood glucose, diet and water intake, and hyperlipidemia, while on the other hand, it improved glucose tolerance. Furthermore, SFF reduced epididymal fat deposition, attenuated the pathological changes in heart and liver tissues, and decreased oxidative stress in diabetic mice. To explore the underlying mechanisms of these ameliorative effects, the gut microbiota was analyzed. Notably, SFF highly enriched benign microbes including Bacteroides, Faecalibacterium and Blautia, as well as increased levels of (R)-carnitine and choline in the colon of diabetic mice. This may be a potential mechanism for alleviating T2DM, thus implying the benefits of SFF as an adjuvant agent for T2DM treatment. Taken together, this study demonstrated a promising application of fucoidan as one of the adjuvant agents for the management of T2DM in the future.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Polissacarídeos/uso terapêutico , Sargassum/química , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia
18.
Biomacromolecules ; 22(5): 1885-1900, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33899465

RESUMO

Diabetes mellitus (DM)-associated impairments in wound healing include prolonged inflammation, the overexpression of matrix metalloproteases (MMPs), and low levels of growth factors at the wound site. To this end, a layer-by-layer scaffold (SL-B-L) made of cross-linked silk fibroin and hyaluronic acid is developed to deliver chlorhexidine, an antimicrobial agent and an MMP-9 inhibitor, along with the PDGF-BB protein. SL-B-L exhibited highly porous morphology. Diabetic rats treated with SL-B-L demonstrated an early wound closure, a fully reconstructed epithelial layer by 14 days, and reduced levels of IL-6, TNF-α, TGF-ß1, and MMP-9. Interestingly, SL-B-L treatment increased angiogenesis, the bioavailability of collagen, DNA content, and VEGF-A levels. Furthermore, enhanced keratinocyte-fibroblast interaction along with ordered collagen deposition was observed in SL-B-L-treated rats. Most interestingly, when compared with a clinically used scaffold SEESKIN+, SL-B-L outperformed in promoting wound healing in a diabetic rat model by regulating the inflammation while delivering growth factor and the MMP-9 inhibitor.


Assuntos
Citocinas , Diabetes Mellitus Experimental , Animais , Clorexidina , Diabetes Mellitus Experimental/tratamento farmacológico , Hidrogéis , Peptídeos e Proteínas de Sinalização Intercelular , Metaloproteinase 9 da Matriz , Ratos , Pele , Fator A de Crescimento do Endotélio Vascular
19.
J Control Release ; 334: 1-10, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33845056

RESUMO

Zwitterionic polymer nanoparticles of diverse morphologies (spherical, cylindrical, and platelet-like) constructed from biocompatible sugar-based polymers are designed to extend the pharmacological activities of short- and long-acting insulin peptides, thereby providing potential for therapeutic systems capable of reducing the frequency of administration and improving patient compliance. Amphiphilic block copolymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline polylactide segments were synthesized, and the respective block length ratios were tuned to allow formation of nanoscopic assemblies having different morphologies. Insulin-loaded nanoparticles had similar sizes and morphologies to the unloaded nanoparticle counterparts. Laser scanning confocal microscopy imaging of three-dimensional spheroids of vascular smooth muscle cells and fibroblasts after treatment with LIVE/DEAD® stain and FITC-insulin-loaded nanoparticles demonstrated high biocompatibility for the nanoconstructs of the various morphologies and significant intracellular uptake of insulin in both cell lines, respectively. Binding of short-acting insulin and long-acting insulin glargine to nanoparticles resulted in extended hypoglycemic activities in rat models of diabetes. Following subcutaneous injection in diabetic rats, insulin- and insulin glargine-loaded nanoparticles of diverse morphologies had demonstrated up to 2.6-fold and 1.7-fold increase in pharmacological availability, in comparison to free insulin and insulin glargine, respectively. All together, the negligible cytotoxicity, immunotoxicity, and minimal cytokine adsorption onto nanoparticles (as have been demonstrated in our previous studies) provide exciting and promising evidence of biocompatible nanoconstructs that are poised for further development toward the management of diabetes.


Assuntos
Diabetes Mellitus Experimental , Nanopartículas , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes , Insulina , Peptídeos , Polímeros , Ratos , Açúcares
20.
Free Radic Biol Med ; 168: 117-128, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33794310

RESUMO

Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological treatment strategies to date. The liver is a major metabolic organ, and hepatic glucose homeostasis is dysregulated in type 1 and type 2 diabetes mellitus. However, the potential of specifically targeting the liver to prevent diabetes has not been fully exploited. In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Sirtuína 3 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose , Fígado/metabolismo , Camundongos , Biogênese de Organelas , Oxidantes , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo
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