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1.
Nutrients ; 13(8)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34444827

RESUMO

Cutaneous wound healing comprises a complex systemic network. Probiotics, naturally extracted substances, medicine, and chemical compounds have been used for wound healing, but the application of postbiotics as therapeutic agents has yet to be explored. Our study shows potential beneficial effects of heat-killed Lactococcus chungangensis CAU 1447 on type 1 diabetic mice. The postbiotic strain significantly decreased the skin wound size. The activity of myeloperoxidase secreted from neutrophils also decreased. The molecular mechanism of wound healing was adjusted by important mediators, growth factors, chemokines, and cytokines. These elements regulated the anti-inflammatory activity and accelerated wound healing. To determine the role of the postbiotic in wound repair, we showed a similar taxonomic pattern as compared to the diabetic mice using skin microbiome analysis. These findings demonstrated that heat-killed Lactococcus chungangensis CAU 1447 had beneficial effects on wound healing and can be utilized as postbiotic therapeutic agents.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Lactococcus/química , Probióticos/uso terapêutico , Pele/efeitos dos fármacos , Cicatrização , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Temperatura Alta , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lactococcus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/análise , Pele/patologia , Estreptozocina/efeitos adversos
2.
Sci Rep ; 11(1): 15027, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294853

RESUMO

Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) plays a role in various diseases. Here, the anti-diabetic effects of NAG-1 were evaluated using a high-fat diet/streptozotocin-induced diabetic mouse model. NAG-1-overexpressing transgenic (NAG-1 Tg) mice exhibited lower body weight, fasting blood glucose levels, and serum insulin levels than wild-type (WT) mice. The homeostatic model assessment of insulin resistance scores of NAG-1 Tg mice were lower than those of WT mice. Hematoxylin and eosin staining revealed a smaller lipid droplet size in the adipose tissues, lower lipid accumulation in the hepatocytes, and larger beta cell area in the pancreas of NAG-1 Tg mice than in those of WT mice. Immunohistochemical analysis revealed downregulated expression of cleaved caspase-3, an apoptosis marker, in the beta cells of NAG-1 Tg mice. Adiponectin and leptin mRNA levels were upregulated and downregulated in NAG-1 Tg mice, respectively. Additionally, the expression of IRS1/PI3K/AKT signaling pathway components, especially Foxo1, which regulates gluconeogenesis in the muscle and white adipose tissue, was downregulated in NAG-1 Tg mice. Furthermore, NAG-1 overexpression promoted the expression of As160 in both muscles and adipocytes, and the mRNA levels of the NLRP3 pathway members were downregulated in NAG-1 Tg mice. Our findings suggest that NAG-1 expression alleviates diabetes in mice.


Assuntos
Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Suscetibilidade a Doenças , Fator 15 de Diferenciação de Crescimento/genética , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/etiologia , Dislipidemias/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Fator 15 de Diferenciação de Crescimento/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Pâncreas/metabolismo , Pâncreas/patologia , Transdução de Sinais , Estreptozocina/efeitos adversos
3.
Sci Rep ; 11(1): 12924, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155273

RESUMO

Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson's trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.


Assuntos
Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Frutose/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , eIF-2 Quinase/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Metabolismo Energético/efeitos dos fármacos , Fibrose , Indóis/química , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Wistar
4.
Biomolecules ; 11(5)2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066859

RESUMO

Diabetic foot wound healing is a major clinical problem due to impaired angiogenesis and bacterial infection. Therefore, an effective regenerative dressing is desiderated with the function of promoting revascularization and anti-bacteria. Herein, a multifunctional injectable composite hydrogel was prepared by incorporation of the cerium-containing bioactive glass (Ce-BG) into Gelatin methacryloyl (GelMA) hydrogel. The Ce-BG was synthesized by combining sol-gel method with template method, which maintained spherical shape, chemical structure and phase constitution of bioactive glass (BG). The Ce-BG/GelMA hydrogels had good cytocompatibility, promoted endothelial cells migration and tube formation by releasing Si ion. In vitro antibacterial tests showed that 5 mol % CeO2-containing bioactive glass/GelMA (5/G) composite hydrogel exhibited excellent antibacterial properties. In vivo study demonstrated that the 5/G hydrogel could significantly improve wound healing in diabetic rats by accelerating the formation of granulation tissue, collagen deposition and angiogenesis. All in all, these results indicate that the 5/G hydrogel could enhance diabetic wound healing. Therefore, the development of multifunctional materials with antibacterial and angiogenic functions is of great significance to promote the repair of diabetic wound healing.


Assuntos
Antibacterianos/administração & dosagem , Cério/administração & dosagem , Diabetes Mellitus Experimental/complicações , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Cério/química , Cério/farmacologia , Colágeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Gelatina/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrogéis , Nanopartículas Metálicas , Metacrilatos/química , Camundongos , Ratos , Estreptozocina/efeitos adversos
5.
Int J Biol Macromol ; 185: 350-368, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34171251

RESUMO

Injectable hydrogel with multifunctional tunable properties comprising biocompatibility, anti-oxidative, anti-bacterial, and/or anti-infection are highly preferred to efficiently promote diabetic wound repair and its development remains a challenge. In this study, we report hyaluronic acid and Pullulan-based injectable hydrogel loaded with curcumin that could potentiate reepithelization, increase angiogenesis, and collagen deposition at wound microenvironment to endorse healing cascade compared to other treatment groups. The physical interaction and self-assembly of hyaluronic acid-Pullulan-grafted-pluronic F127 injectable hydrogel were confirmed using nuclear magnetic resonance (1H NMR) and Fourier transformed infrared spectroscopy (FT-IR), and cytocompatibility was confirmed by fibroblast viability assay. The CUR-laden hyaluronic acid-Pullulan-g-F127 injectable hydrogel promptly undergoes a sol-gel transition and has proved to potentiate wound healing in a streptozotocin-induced diabetic rat model by promoting 93% of wound closure compared to other groups having 35%, 38%, and 62%. The comparative in vivo study and histological examination was conducted which demonstrated an expeditious recovery rate by significantly reducing the wound healing days i.e. 35 days in a control group, 33 days in the CUR suspension group, 21 days in unloaded injectable, and 13 days was observed in CUR loaded hydrogel group. Furthermore, we suggest that the injectable hydrogel laden with CUR showed a prompt wound healing potential by increasing the cell proliferation and serves as a drug delivery platform for sustained and targeted delivery of hydrophobic moieties.


Assuntos
Curcumina/administração & dosagem , Complicações do Diabetes/tratamento farmacológico , Glucanos/química , Ácido Hialurônico/administração & dosagem , Cicatrização/efeitos dos fármacos , Células 3T3-L1 , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Hidrogéis , Injeções , Masculino , Camundongos , Tamanho da Partícula , Coelhos , Ratos , Reologia , Estreptozocina/efeitos adversos
6.
J Nutr Biochem ; 96: 108748, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34051305

RESUMO

EGCG and quercetin are flavonoids which usually co-exist in edible plants and they exhibit anti-diabetes effects. This study aimed to explore the mechanisms by which quercetin and EGCG synergistically protected pancreatic ß-cells from streptozotocin-induced apoptosis. EGCG, quercetin, and their combinations (both 15 µM) all reversed STZ-induced cells damage and enhanced glucose-stimulated insulin secretion, with the combination being more effective than a single compound. At the molecular level, the EGCG-quercetin combination upregulated BCL-2 expression and caused a greater reduction in miR-16-5p level than EGCG alone or quercetin alone. Overexpression of miR-16-5p could offset the down-regulated apoptotic genes caused by the synergistic action of the combination. These findings suggest that EGCG and quercetin exert synergistic anti-diabetes effect, possibly via decreasing the expression of miR-16-5p that targets directly BCL-2. This is the first report on a miRNA-based mechanism underlying the synergistic protective effect of EGCG and quercetin against pancreatic cell damage.


Assuntos
Catequina/análogos & derivados , Células Secretoras de Insulina/efeitos dos fármacos , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Quercetina/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Catequina/farmacologia , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/patologia , Camundongos , Estreptozocina/efeitos adversos , Regulação para Cima/efeitos dos fármacos
7.
Nanotechnology ; 32(34)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34057430

RESUMO

Atherosclerosis is a macrophage-related inflammatory disease that remains a leading cause of death worldwide. Magnetic iron oxide (IO) nanocrystals are clinically used as magnetic resonance imaging contrast agents and their application as a detection agent for macrophages in arterial lesions has been studied extensively. We recently fabricated heparin-modified calcium phosphate (CaP) nanoparticles loaded with a large number of IO nanocrystals via coprecipitation from a supersaturated CaP solution supplemented with heparin and ferucarbotran (IO nanocrystals coated with carboxydextran). In this study, we further increased the content of IO nanocrystals in the heparin-modified IO-CaP composite nanoparticles by increasing the ferucarbotran concentration in the supersaturated CaP solution. The increase in nanoparticle IO content caused a decrease in particle diameter without impairing its dispersibility; the nanoparticles remained dispersed in water for up to 2 h due to electrostatic repulsion between particles due to the surface modification with heparin. The nanoparticles were more effectively taken up by murine RAW264.7 macrophages compared to free ferucarbotran without showing significant cytotoxicity. A preliminaryin vivostudy showed that the nanoparticles injected intravenously into mice delivered more IO nanocrystals to macrophage-rich carotid arterial lesions than free ferucarbotran. Our nanoparticles have potential as a delivery agent of IO nanocrystals to macrophages in arterial lesions.


Assuntos
Aterosclerose/tratamento farmacológico , Fosfatos de Cálcio/administração & dosagem , Compostos Férricos/química , Estreptozocina/efeitos adversos , Administração Intravenosa , Animais , Aterosclerose/etiologia , Fosfatos de Cálcio/síntese química , Fosfatos de Cálcio/química , Fosfatos de Cálcio/farmacologia , Dextranos/química , Modelos Animais de Doenças , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanopartículas de Magnetita/química , Masculino , Camundongos , Nanocompostos , Células RAW 264.7 , Resultado do Tratamento
8.
J Pharmacol Sci ; 146(1): 10-20, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33858650

RESUMO

Diabetic nephropathy is a serious complication of diabetes. Hyperoside has been widely reported to ameliorate diabetes-associated disease. The current study is designed to explore the mechanism of hyperoside in diabetic nephropathy. In the present study, high glucose was used to treat podocytes. Diabetic nephropathy mice models were established by high-fat feeding followed by multiple low dose injections of streptozocin. Western blot analysis was conducted for detection of extracellular matrix accumulation, inflammatory response and cell apoptosis. We found out that hyperoside improved high glucose-induced cell injury. Additionally, hyperoside prevented mice with diabetic nephropathy from diabetic symptoms and renal dysfunction. Mechanistically, hyperoside inhibited the mRNA and protein expression of APC. MiR-499-5p was found to be an upstream negative mediator of APC, and hyperoside induced the upregulation of miR-499-5p. MiR-499-5p bound with the 3' untranslated region of APC to inhibit its expression. Finally, rescue assays revealed that the suppressive effects of miR-499-5p overexpression on renal dysfunction were rescued by upregulation of APC in mice with diabetic nephropathy. In conclusion, these findings indicated that hyperoside ameliorates diabetic nephropathy via targeting the miR-499-5p/APC axis, suggesting that hyperoside may offer a potential tactic for diabetic nephropathy treatment.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Quercetina/análogos & derivados , Estreptozocina/efeitos adversos , Animais , Células Cultivadas , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Podócitos , Quercetina/farmacologia , Quercetina/uso terapêutico
9.
Am J Pathol ; 191(5): 838-856, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33705752

RESUMO

Growing evidence shows that the lungs are an unavoidable target organ of diabetic complications. However, the pathologic mechanisms of diabetic lung injury are still controversial. This study demonstrated the dysbiosis of the gut and lung microbiome, pulmonary alveolar wall thickening, and fibrotic change in streptozotocin-induced diabetic mice and antibiotic-induced gut dysbiosis mice compared with controls. In both animal models, the NF-κB signaling pathway was activated in the lungs. Enhanced pulmonary alveolar well thickening and fibrotic change appeared in the lungs of transgenic mice expressing a constitutively active NF-κB mutant compared with wild type. When lincomycin hydrochloride-induced gut dysbiosis was ameliorated by fecal microbiota transplant, enhanced inflammatory response in the intestine and pulmonary fibrotic change in the lungs were significantly decreased compared with lincomycin hydrochloride-treated mice. Furthermore, the application of fecal microbiota transplant and baicalin could also redress the microbial dysbiosis of the gut and lungs in streptozotocin-induced diabetic mice. Taken together, these data suggest that multiple as yet undefined factors related to microbial dysbiosis of gut and lungs cause pulmonary fibrogenesis associated with diabetes mellitus through an NF-κB signaling pathway.


Assuntos
Diabetes Mellitus Experimental/complicações , Disbiose/complicações , Microbiota , NF-kappa B/metabolismo , Fibrose Pulmonar/microbiologia , Transdução de Sinais , Animais , Anti-Infecciosos/administração & dosagem , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/patologia , Disbiose/terapia , Transplante de Microbiota Fecal , Flavonoides/administração & dosagem , Microbioma Gastrointestinal , Intestinos/microbiologia , Intestinos/patologia , Lincomicina/efeitos adversos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/terapia , Estreptozocina/efeitos adversos
10.
J Cereb Blood Flow Metab ; 41(9): 2344-2355, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33657898

RESUMO

Alzheimer's disease (AD) is a very common neurodegenerative disorder. Although a majority of the AD cases are sporadic, most of the studies are conducted using transgenic models. Intracerebroventricular (ICV) administered streptozotocin (STZ) animals have been used to explore mechanisms in sporadic AD. In this study, we have investigated memory and neurometabolism of ICV-STZ-administered C57BL6/J mice. The neuronal and astroglial metabolic activity was measured in 1H-[13C]-NMR spectrum of cortical and hippocampal tissue extracts of mice infused with [1,6-13C2]glucose and [2-13C]acetate, respectively. STZ-administered mice exhibited reduced (p = 0.00002) recognition index for memory. The levels of creatine, GABA, glutamate and NAA were reduced (p ≤ 0.04), while that of myo-inositol was increased (p < 0.05) in STZ-treated mice. There was a significant (p ≤ 0.014) reduction in aspartate-C3, glutamate-C4/C3, GABA-C2 and glutamine-C4 labeling from [1,6-13C2]glucose. This resulted in decreased rate of glucose oxidation in the cerebral cortex (0.64 ± 0.05 vs. 0.77 ± 0.05 µmol/g/min, p = 0.0008) and hippocampus (0.60 ± 0.04 vs. 0.73 ± 0.07 µmol/g/min, p = 0.001) of STZ-treated mice, due to similar reductions of glucose oxidation in glutamatergic and GABAergic neurons. Additionally, reduced glutamine-C4 labeling points towards compromised synaptic neurotransmission in STZ-treated mice. These data suggest that the ICV-STZ model exhibits neurometabolic deficits typically observed in AD, and its utility in understanding the mechanism of sporadic AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/metabolismo , Metabolismo Energético/genética , Espectroscopia de Ressonância Magnética/métodos , Estreptozocina/efeitos adversos , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos
11.
Environ Health Prev Med ; 26(1): 38, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752586

RESUMO

BACKGROUND: Periploca aphylla is used by local population and indigenous medicine practitioners as stomachic, tonic, antitumor, antiulcer, and for treatment of inflammatory disorders. The aim of this study was to evaluate antidiabetic effect of the extract of P. aphylla and to investigate antioxidant and hypolipidemic activity in streptozotocin (STZ)-induced diabetic rats. METHODS: The present research was conducted to evaluate the antihyperglycemic potential of methanol extract of P. aphylla (PAM) and subfractions n-hexane (PAH), chloroform (PAC), ethyl acetate (PAE), n-butanol (PAB), and aqueous (PAA) in glucose-overloaded hyperglycemic Sprague-Dawley rats. Based on the efficacy, PAB (200 mg/kg and 400 mg/kg) was tested for its antidiabetic activity in STZ-induced diabetic rats. Diabetes was induced via intraperitoneal injection of STZ (55 mg/kg) in rat. Blood glucose values were taken weekly. HPLC-DAD analysis of PAB was carried out for the presence of various polyphenols. RESULTS: HPLC-DAD analysis of PAB recorded the presence of rutin, catechin, caffeic acid, and myricetin. Oral administration of PAB at doses of 200 and 400 mg/kg for 21 days significantly restored (P < 0.01) body weight (%) and relative liver and relative kidney weight of diabetic rats. Diabetic control rats showed significant elevation (P < 0.01) of AST, ALT, ALP, LDH, total cholesterol, triglycerides, LDL, creatinine, total bilirubin, and BUN while reduced (P < 0.01) level of glucose, total protein, albumin, insulin, and HDL in serum. Count of blood cells and hematological parameters were altered in diabetic rats. Further, glutathione peroxidase, catalase, superoxide dismutase, glutathione reductase, and total soluble protein concentration decreased while concentration of thiobarbituric acid reactive substances and percent DNA damages increased (P < 0.01) in liver and renal tissues of diabetic rats. Histopathological damage scores increased in liver and kidney tissues of diabetic rats. Intake of PAB (400 mg/kg) resulted in significant improvement (P < 0.01) of above parameters, and results were comparable to that of standard drug glibenclamide. CONCLUSION: The result suggests the antihyperglycemic, antioxidant, and anti-inflammatory activities of PAB treatment in STZ-compelled diabetic rat. PAB might be used as new therapeutic agent in diabetic patients to manage diabetes and decrease the complications.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Periploca/química , Compostos Fitoquímicos/administração & dosagem , Extratos Vegetais/administração & dosagem , 1-Butanol/química , Administração Oral , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Relação Dose-Resposta a Droga , Hipoglicemiantes/química , Masculino , Compostos Fitoquímicos/química , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Estreptozocina/efeitos adversos
12.
J Ayub Med Coll Abbottabad ; 33(1): 134-138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33774970

RESUMO

BACKGROUND: The adrenal gland is one of the major endocrine glands involved not only in different physiological functions, but also in response to stress This study was done to asses the effects of L-arginine and insulin on streptozotocin (STZ) induced adrenal gland damage in albino rats. METHODS: This laboratory based experimental study on animals was undertaken in the Anatomy department of Basic Medical Sciences Institute (BMSI), Jinnah postgraduate Medical Center (JPMC), Karachi, from February to March 2018. Forty adult, healthy male albino rats were placed into 4 groups (10 each). Group A was taken as control. Group B was given STZ. Group C and D were given STZ as in group B with insulin and L-arginine respectively. Absolute and relative weight of adrenal glands was measured at the end of the study. Tissues from adrenal glands were processed and stained with Haematoxylin and Eosin for the morphometric study. RESULTS: The absolute as well as relative adrenal weight of animals was significantly raised in group B in comparison to control, although showed a significant recovery in group C and D animals when insulin and L-arginine were added to STZ. Haematoxylin and Eosin (H&E) stained sections of adrenal cortex of STZ treated Group B showed reduced width of zona glomerulosa, with increased width of zona fasciculata and zona reticularis when compared to control. The width of these zones of adrenal cortex recovered to a significant extent when group C and D tissue sections were compared with STZ- treated group B tissue sections. CONCLUSIONS: This study highlighted the protective effect of L-arginine on adrenal gland weight and histology in streptozotocin induced adrenal gland damage, which was comparable to insulin.


Assuntos
Glândulas Suprarrenais , Arginina/farmacologia , Insulina/farmacologia , Substâncias Protetoras/farmacologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Masculino , Ratos , Estreptozocina/efeitos adversos
13.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525535

RESUMO

Polycystic ovarian syndrome (PCOS) is a common reproductive endocrine disorder in reproductive-age women. Due to its various pathophysiological properties and clinical heterophenotypes, the mechanism of PCOS pathogenesis is still unclear. Several animal models have been used to study PCOS and allow the exploration of the specific mechanism underlying PCOS. We focused on streptozotocin (STZ) to develop a non-steroidal and non-diabetic PCOS model. We administered multiple STZ injections to female C57BL/6 mice (3-4 weeks old) at different concentrations: STZ-15 (15 mg/kg), STZ-30 (30 mg/kg), and STZ-60 (60 mg/kg) treatments. During the experimental period, we analyzed body weight, blood glucose levels, and estrous cycle pattern. Furthermore, five weeks after STZ administration, we examined hormone levels and the morphology of ovarian tissues. Mice in the STZ-15 group did not show differences in body weights, blood glucose level, insulin level, and insulin tolerance compared to wild-type and control groups whereas those in the STZ-60 group presented a typical diabetes phenotype. In the case of the STZ-30 group, only increased blood glucose level was observed. Total testosterone levels were significantly elevated in STZ-15 and STZ-30 groups. Luteinizing hormone (LH) and estradiol levels were not significantly changed in the STZ-treated groups. The number of ovarian antral follicles and atretic follicles significantly increased in the ovary of mice in the STZ-15 and STZ-30 groups. All STZ-treated groups manifested irregular estrus cycles. However, the patterns of estrous cycles were different between mice treated with different STZ concentrations. We found that PI3K-AKT and IRS-1 signaling in the ovary was enhanced by low doses of STZ treatment. Taken together, our finding indicates that multiple injections of STZ at low doses induce PCOS features in mice without induction of diabetes features.


Assuntos
Proteínas Substratos do Receptor de Insulina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Síndrome do Ovário Policístico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estreptozocina/efeitos adversos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estradiol/metabolismo , Ciclo Estral , Feminino , Humanos , Hormônio Luteinizante/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Testosterona/metabolismo
14.
Biomed Pharmacother ; 134: 111105, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33338750

RESUMO

Diabetes mellitus is a common metabolic disease leading to hyperglycemia due to insufficient pancreatic insulin production or effect. Amine oxidase copper containing 3 (AOC3) is an enzyme that belongs to the semicarbazide-sensitive amine oxidase family, which may be a novel therapeutic target to treat diabetic complications. We aimed to explore the effects of AOC3 inhibition and to test the actions of our novel AOC3 inhibitor multi-target drug candidate, SZV 1287, compared to a selective reference compound, LJP 1207, in an 8-week long insulin-controlled streptozotocin (STZ)-induced (60 mg/kg i.p.) rat diabetes model. Both AOC3 inhibitors (20 mg/kg, daily s.c. injections) were protective against STZ-induced pancreatic beta cell damage determined by insulin immunohistochemistry and radioimmunoassay, neuropathic cold hypersensitivity measured by paw withdrawal latency decrease from 0 °C water, and retinal dysfunction detected by electroretinography. SZV 1287 showed greater inhibitory effects on beta cell damage, and reduced retinal apoptosis shown by histochemistry. Mechanical hypersensitivity measured by aesthesiometry, cardiac dysfunction and nitrosative stress determined by echocardiography and immunohistochemistry/Western blot, respectively, serum Na+, K+, fructosamine, and urine microalbumin, creatinine, total protein/creatinine ratio alterations did not develop in response to diabetes. None of these parameters were influenced by the treatments except for SZV 1287 reducing serum fructosamine and LJP 1207 increasing urine creatinine. We provide the first evidence for protective effects of AOC3 inhibition on STZ-induced pancreatic beta cell damage, neuropathic cold hypersensitivity and diabetic retinal dysfunction. Long-term treatment with our novel multi-target analgesic candidate, SZV 1287, is safe and effective also under diabetic conditions.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Oxazóis/farmacologia , Oximas/farmacologia , Amina Oxidase (contendo Cobre)/metabolismo , Analgésicos/farmacologia , Animais , Moléculas de Adesão Celular/metabolismo , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/prevenção & controle , Nefropatias Diabéticas/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Humanos , Hidrazinas/farmacologia , Insulina/metabolismo , Células Secretoras de Insulina , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina/efeitos adversos
15.
Carbohydr Polym ; 254: 117312, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357875

RESUMO

Vitexin of Ficus deltoidea exhibits intestinal α-glucosidase inhibitory and blood glucose lowering effects. This study designs oral intestinal-specific alginate nanoparticulate system of vitexin. Nanospray-dried alginate, alginate/stearic acid and alginate-C18 conjugate nanoparticles were prepared. Stearic acid was adopted to hydrophobize the matrix and minimize premature vitexin release in stomach, whereas C-18 conjugate as immobilized fatty acid to sustain hydrophobic effect and drug release. Nanoparticles were compacted with polyethylene glycol (PEG 3000, 10,000 and 20,000). The physicochemical, drug release, in vivo blood glucose lowering and intestinal vitexin content of nanoparticles and compact were determined. Hydrophobization of alginate nanoparticles promoted premature vitexin release. Compaction of nanoparticles with PEG minimized vitexin release in the stomach, with stearic acid loaded nanoparticles exhibiting a higher vitexin release in the intestine. The introduction of stearic acid reduced vitexin-alginate interaction, conferred alginate-stearic acid mismatch, and dispersive stearic acid-induced particle breakdown with intestinal vitexin release. Use of PEG 10,000 in compaction brought about PEG-nanoparticles interaction that negated initial vitexin release. The PEG dissolution in intestinal phase subsequently enabled particle breakdown and vitexin release. The PEG compacted nanoparticles exhibited oral intestinal-specific vitexin release, with positive blood glucose lowering and enhanced intestinal vitexin content in vivo.


Assuntos
Alginatos/química , Apigenina/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Toxinas Bacterianas/administração & dosagem , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/química , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Proteínas Hemolisinas/administração & dosagem , Hipoglicemiantes/administração & dosagem , Nanopartículas/química , Administração Oral , Alginatos/metabolismo , Animais , Apigenina/química , Proteínas de Bactérias/química , Toxinas Bacterianas/química , Diabetes Mellitus Experimental/induzido quimicamente , Liberação Controlada de Fármacos , Ficus/química , Inibidores de Glicosídeo Hidrolases/química , Proteínas Hemolisinas/química , Ligação de Hidrogênio , Hipoglicemiantes/química , Masculino , Tamanho da Partícula , Polietilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Ácidos Esteáricos/química , Estreptozocina/efeitos adversos , alfa-Glucosidases/metabolismo
16.
Mol Med Rep ; 22(6): 5472-5478, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174004

RESUMO

Although insulin is known to affect neointimal hyperplasia via distinct signaling pathways, how neointimal hyperplasia is affected in insulin­deficient type 1 diabetes remains unknown. The aim of the current study was to investigate two major signaling branches of insulin action regulating neointimal hyperplasia following arterial injury in type 1 diabetes with or without exogenous insulin administration. Rats were treated with vehicle (control group), streptozotocin (STZ) alone (STZ group; uncontrolled type 1 diabetes) or STZ followed by insulin (STZ + I group; controlled type 1 diabetes). Subsequently, a type 1 diabetic rat model of carotid artery balloon injury was established. Following this, the intima­to­media area ratios were examined for evidence of neointimal hyperplasia in the carotid arteries of the rats by performing hematoxylin­eosin staining. Furthermore, the protein expression of extracellular signal­regulated kinase (ERK), phosphorylated (p­) ERK, protein kinase B (Akt) and p­Akt in the carotid arteries of the rats was determined via immunoblotting. Moreover, an in vitro model of type 1 diabetes was induced by incubation of primary vascular smooth muscle cells (VSMCs) with glucose and/or insulin. Cellular proliferation and signaling protein expression levels in VSMCs were determined by measuring the incorporation of tritiated thymidine and performing immunoblotting, respectively. The results demonstrated that compared with that in control rats, neointimal hyperplasia and expression of p­Akt in uncontrolled type 1 diabetic rats were significantly decreased. This decrease was recovered in controlled type 1 diabetes with insulin therapy. Furthermore, the difference in the expression of p­ERK between groups was not significant. Additionally, the results of the cell experiments were consistent with those from the animal studies. In conclusion, the preferential signaling along the phosphatidylinositol 3­kinase/Akt pathway of insulin action in response to insulin restoration may contribute to neointimal hyperplasia. The present study provides a novel approach for the further treatment of neointimal hyperplasia in type 1 diabetes.


Assuntos
Insulina/metabolismo , Neointima/patologia , Túnica Íntima/metabolismo , Animais , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/patologia , Proliferação de Células/efeitos dos fármacos , China , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucose/farmacologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Insulina/farmacologia , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Túnica Íntima/patologia
17.
Food Funct ; 11(12): 10617-10634, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33210684

RESUMO

Type 2 diabetes has a series of metabolic aberrations accompanied by chronic hyperglycemia, along with various comorbidities. In recent reports, punicalagin from pomegranate has been reported to exert hypoglycemic effects against diabetes. The goal of the current research was to investigate the therapeutic effectiveness and elucidate the mechanisms of punicalagin underlying type 2 diabetes. Type 2 diabetes was induced by a high-fat diet (HFD) combined with streptozotocin (STZ) injection in C57BL/6J mice. Punicalagin was administered daily by oral gavage for 4 weeks. The results indicated that high FBG (fasting blood glucose), dyslipidemia and associated islet, liver and kidney injury were observed in the model group mice. Through metabolomics analysis, it was found that the administration of punicalagin could regulate 24 potential biomarkers and their related metabolic pathways. Moreover, the pathological changes in the liver and kidney were mainly mediated by reducing gluconeogenesis and increasing glycogenesis via stimulation of the PI3K/AKT signaling pathway and regulation of the HMGB-1/TLR4/NF-κB signaling pathway, which simultaneously interrelated to ten main pathological pathways. In addition, we confirmed the positive role of punicalagin in glucosamine-induced HepG2 cells and HG-induced HK-2 cells through related mechanistic studies in vitro. In conclusion, these findings suggested that the multi-effect and multi-target action mode of punicalagin had a significant hypoglycemic effect and a protective effect on diabetes mellitus. Punicalagin might serve as an alternative functional food or as a clinical supplemental therapy for the diabetic population to ameliorate metabolic syndrome.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Taninos Hidrolisáveis/farmacologia , Hipoglicemiantes/farmacologia , Estreptozocina/efeitos adversos , Animais , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/tratamento farmacológico , Células Hep G2 , Humanos , Hiperglicemia/tratamento farmacológico , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Síndrome Metabólica , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Biosci Biotechnol Biochem ; 84(12): 2533-2544, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32892714

RESUMO

The objective of present investigation was to appraise the effects of piperine on STZ-induced diabetic cardiomyopathy in rats. Diabetes was induced in Sprague-Dawley rats with intraperitoneal STZ injection, and the rats were assigned to seven groups. Electrocardiograph, hemodynamic, various biochemical, molecular, and histological parameters were examined. Treatment with piperine significantly (p < 0.05) restored altered myocardial functions, inhibited cardiac marker, and restored electrocardiogram and hemodynamic alterations. The elevated level of cardiac oxido-nitrosative stress and decreased cardiac Na-K-ATPase concentration, after STZ administration, were significantly (p < 0.05) attenuated by piperine treatment. Piperine also considerably (p < 0.05) increased myocardial mitochondrial enzyme activity. STZ-induced alteration in heart ANP, BNP, cTn-I, Bcl2, Bax/Bcl2, and caspase3 mRNA expression was significantly (p < 0.05) restored by piperine treatment. Piperine administration reduced histopathological aberrations induced by STZ. In conclusion, the present investigation suggests that piperine ameliorates STZ-induced diabetic cardiomyopathy via modulation of caspase-3, Bcl2, Bax/Bcl2 pathways. Abbreviations: ACE: Angiotensin-Converting Enzyme; ANOVA: Analysis of Variance; ANP: Atrial Natriuretic Peptide; APAF: Apoptotic Protease-Activating Factor; ARB: Angiotensin Receptor Blockers; ATP: Adenosine Triphosphate; Bax: Bcl-2-associated X protein; Bcl2: B-cell lymphoma 2; BPM: Beats Per Minute; BNP: brain natriuretic peptide; CAD: Caspase-3-Activated DNase; cDNA: Complementary DNA; CK-MB: Creatine Kinase-MB; CPCSEA: Committee for the Purpose of Control And Supervision of Experiments on Animals; cTn-I: cardiac troponin I; DBP: Diastolic Blood Pressure; DCM: Diabetic Cardiomyopathy; DNA: Deoxyribonucleic Acid; DPX: DisterenePhthalate Xylene; ECG: Electrocardiogram; ETC: Electron Transport Chain; GOD-POD: Glucose Oxidase Peroxidase; GSH: Glutathione; IAEC: Institutional Animal Ethics Committee; IL-6: Interleukin-6; IL-1b: Interleukin-1b; LDH: Lactate Dehydrogenase; LV: Left Ventricle; LVEDP: left ventricular end-diastolic Pressure; MABP: Mean Arterial Blood Pressure; MDA: Malondialdehyde; mRNA: Messenger Ribonucleic Acid; MTT: 3- (4,5-Dimethylthiazol-2-yl)-2,5-DiphenyltetrazoliumBromide; NADH: Nicotinamide Adenine Dinucleotide Phosphate; NADPH: Nicotinamide Adenine Dinucleotide Phosphate Hydrogen; NO: nitric oxide; NP: Natriuretic Peptides; OXPHOS: Oxidative Phosphorylation; p.o.: per os; PCR: Polymerase Chain Reaction; RT-PCR: Reverse Transcriptionpolymerase Chain Reaction; PPAR: Peroxisome Proliferator-Activated Receptor Gamma; RAS: Renin-Angiotensin System; RNA: Ribonucleic Acid; ROS: Reactive Oxygen Species; SBP: Systolic Blood Pressure; SDH: Succinate Dehydrogenase; SEM: Standard Error Means; SOD: superoxide dismutase: STZ: Streptozotocin; TNF: Tumor Necrosis Factor Alpha; TnI: Troponin I.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Estreptozocina/efeitos adversos , Proteína X Associada a bcl-2/metabolismo , Alcaloides/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Benzodioxóis/uso terapêutico , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glutationa/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Urina/química
19.
Cell Tissue Res ; 382(3): 477-486, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32783101

RESUMO

Diabetic retinopathy (DR) is a serious neurodegenerative disease that is induced by hyperglycaemia. Oxidative stress, inflammation and endoplasmic reticulum (ER) stress are involved in the development of DR. Sulforaphane (SF) is widely found in cruciferous plants and has a protective effect against retinal neurodegeneration in diabetes, but the mechanism is unclear. In this study, we investigated the mechanism by which SF protects against photoreceptor degeneration in diabetes. In vivo, a mouse model of diabetes was established by streptozotocin (STZ) injection, and the mice were treated with/without SF. Electroretinography (ERG) and H&E staining were used to evaluate retinal function and morphology. In vitro, 661w cells were treated with AGEs with/without SF. Cell viability and apoptosis were analysed by CCK-8 assay and flow cytometry. The expression of proteins and genes was assessed by western blot and qRT-PCR. The amplitude of the a-wave was decreased and the morphology was changed in the diabetic mice, and these changes were delayed by SF treatment. The percentage of apoptotic cells was increased and the cell viability was decreased after the treatment of 661w cells with AGEs. Moreover, the expression of GRP78, Txnip and TNFα was increased, however, this increased expression was reversed by SF treatment via AMPK pathway activation. Taken together, these data show that SF can delay photoreceptor degeneration in diabetes, and the underlying mechanism is related to the inhibition of ER stress, inflammation and Txnip expression through the activation of the AMPK pathway.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Produtos Finais de Glicação Avançada/metabolismo , Isotiocianatos/uso terapêutico , Doenças Neurodegenerativas/complicações , Degeneração Retiniana/tratamento farmacológico , Sulfóxidos/uso terapêutico , Animais , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Isotiocianatos/farmacologia , Masculino , Camundongos , Doenças Neurodegenerativas/patologia , Estreptozocina/efeitos adversos , Sulfóxidos/farmacologia
20.
Cells ; 9(8)2020 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-32824296

RESUMO

Lysophosphatidic acid (LPA) signaling is known to play key roles in the initiation and maintenance of various chronic pain models. Here we examined whether LPA signaling is also involved in diabetes-induced abnormal pain behaviors. The high-fat diet (HFD) showing elevation of blood glucose levels and body weight caused thermal, mechanical hyperalgesia, hypersensitivity to 2000 or 250 Hz electrical-stimulation and hyposensitivity to 5 Hz stimulation to the paw in wild-type (WT) mice. These HFD-induced abnormal pain behaviors and body weight increase, but not elevated glucose levels were abolished in LPA1-/- and LPA3-/- mice. Repeated daily intrathecal (i.t.) treatments with LPA1/3 antagonist AM966 reversed these abnormal pain behaviors. Similar abnormal pain behaviors and their blockade by daily AM966 (i.t.) or twice daily Ki16425, another LPA1/3 antagonist was also observed in db/db mice which show high glucose levels and body weight. Furthermore, streptozotocin-induced similar abnormal pain behaviors, but not elevated glucose levels or body weight loss were abolished in LPA1-/- and LPA3-/- mice. These results suggest that LPA1 and LPA3 play key roles in the development of both type I and type II diabetic neuropathic pain.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/genética , Animais , Glicemia/análise , Peso Corporal , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Dieta Hiperlipídica/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Fenilacetatos/farmacologia , Fenilacetatos/uso terapêutico , Propionatos/farmacologia , Propionatos/uso terapêutico , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genética , Estreptozocina/efeitos adversos
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