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1.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500601

RESUMO

Kahweol is a diterpene molecule found in coffee that exhibits a wide range of biological activity, including anti-inflammatory and anticancer properties. However, the impact of kahweol on pancreatic ß-cells is not known. Herein, by using clonal rat INS-1 (832/13) cells, we performed several functional experiments including; cell viability, apoptosis analysis, insulin secretion and glucose uptake measurements, reactive oxygen species (ROS) production, as well as western blotting analysis to investigate the potential role of kahweol pre-treatment on damage induced by streptozotocin (STZ) treatment. INS-1 cells pre-incubated with different concentrations of kahweol (2.5 and 5 µM) for 24 h, then exposed to STZ (3 mmol/L) for 3 h reversed the STZ-induced effect on cell viability, apoptosis, insulin content, and secretion in addition to glucose uptake and ROS production. Furthermore, Western blot analysis showed that kahweol downregulated STZ-induced nuclear factor kappa B (NF-κB), and the antioxidant proteins, Heme Oxygenase-1 (HMOX-1), and Inhibitor of DNA binding and cell differentiation (Id) proteins (ID1, ID3) while upregulated protein expression of insulin (INS), p-AKT and B-cell lymphoma 2 (BCL-2). In conclusion, our study suggested that kahweol has anti-diabetic properties on pancreatic ß-cells by suppressing STZ induced apoptosis, increasing insulin secretion and glucose uptake. Targeting NF-κB, p-AKT, and BCL-2 in addition to antioxidant proteins ID1, ID3, and HMOX-1 are possible implicated mechanisms.


Assuntos
Café/química , Diterpenos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Antioxidantes , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
2.
Life Sci ; 283: 119857, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34339715

RESUMO

AIM: Diabetic cardiomyopathy (DCM) accomodates a spectrum of cardiac abnormalities. This study aims to investigate whether DCM is associated with changes in cyclic adenosine 3'-5' monophosphate (cAMP) signaling, particularly cyclic nucleotide phosphodiesterases (PDEs). MAIN METHODS: Type 1 diabetes (T1D) was induced in rats by streptozotocin (STZ, 65 mg/kg) injection. Myocardial remodeling, structure and function were evaluated by histology and echocardiography, respectively. We delineated the sequential changes affecting cAMP signaling and characterized the expression pattern of the predominant cardiac PDE isoforms (PDE 1-5) and ß-adrenergic (ß-AR) receptors at 4, 8 and 12 weeks following diabetes induction, by real-time quantitative PCR and Western blot. cAMP levels were measured by immunoassays. KEY FINDINGS: T1D-induced DCM was associated with cardiac remodeling, steatosis and fibrosis. Upregulation of ß1-AR receptor transcripts was noted in diabetic hearts at 4 weeks along with an increase in cAMP levels and an upregulation in the ejection fraction and fraction shortening. However, ß2-AR receptors expression remained unchanged regardless of the disease stage. Moreover, we noted an early and specific upregulation of cardiac PDE1A, PDE2A, PDE4B, PDE4D and PDE5A expression at week 4, followed by increases in PDE3A levels in diabetic hearts at week 8. However, DCM was not associated with changes in PDE4A gene expression irrespective of the disease stage. SIGNIFICANCE: We show for the first time differential and time-specific regulations in cardiac PDEs, data that may prove useful in proposing new therapeutic approaches in T1D-induced DCM.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diester Fosfórico Hidrolases/metabolismo , Animais , AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/metabolismo , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Diester Fosfórico Hidrolases/fisiologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Estreptozocina/farmacologia
3.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445689

RESUMO

The purpose of our study was to evaluate the role of macrophage migration inhibitory factor (MIF) in the differentiation of tendon-derived stem cells (TdSCs) under hyperglycemic conditions. In the in vivo experiment, rats were classified into diabetic (DM) and non-DM groups depending on the intraperitoneal streptozotocin (STZ) or saline injection. Twelve-week after STZ injection, the supraspinatus tendon was harvested and prepared for histological evaluation and real-time reverse transcription polymerase chain reaction for osteochondrogenic (aggrecan, BMP-2, and Sox9) and tenogenic (Egr1, Mkx, scleraxis, type 1 collagen, and Tnmd) markers. For the in vitro experiment, TdSCs were isolated from healthy rat Achilles tendons. Cultured TdSCs were treated with methylglyoxal and recombinant MIF or MIF gene knockdown to determine the effect of hyperglycemic conditions and MIF on the differentiation function of TdSCs. These conditions were classified into four groups: hyperglycemic-control group, hyperglycemic-recombinant-MIF group, hyperglycemic-knockdown-MIF group, and normal-control group. The mRNA expression of osteochondrogenic and tenogenic markers was compared among the groups. In the in vivo experiment, the mRNA expression of all osteochondrogenic and tenogenic differentiation markers in the DM group was significantly higher and lower than that in the non-DM group, respectively. Similarly, in the in vitro experiments, the expression of all osteochondrogenic and tenogenic differentiation markers was significantly upregulated and downregulated, respectively, in the hyperglycemic-control group compared to that in the normal-control group. The hyperglycemic-knockdown-MIF group demonstrated significantly decreased expression of all osteochondrogenic differentiation markers and increased expression of only some tenogenic differentiation markers compared with the hyperglycemic-control group. In contrast, the hyperglycemic-recombinant-MIF group showed significantly increased expression of all osteochondrogenic differentiation markers, but no significant difference in any tenogenic marker level, compared to the hyperglycemic-control group. These results suggest that tendon homeostasis could be affected by hyperglycemic conditions, and MIF appears to alter the differentiation of TdSCs via enhancement of the osteochondrogenic differentiation in hyperglycemic conditions. These are preliminary findings, and must be confirmed in a further study.


Assuntos
Fatores Inibidores da Migração de Macrófagos/metabolismo , Células-Tronco/metabolismo , Tendões/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Expressão Gênica/genética , Fatores Inibidores da Migração de Macrófagos/farmacologia , Fatores Inibidores da Migração de Macrófagos/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia , Tendões/fisiologia
4.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328201

RESUMO

Diabetes­associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2­deoxy­2­(3­methy1­3­nitrosoureido) D­glucopyranose; STZ] is one of the most well­established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8­B4 microglia transformed by the stimulus of repetitive low­dose lipopolysaccharide (LPSx3­microglia) prevent STZ­induced Neuro­2a neuronal cell death in vitro. The ELISA results showed that neurotrophin­4/5 (NT­4/5) secretion was promoted in LPSx3­microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3­microglia prevented STZ­induced neuronal cell death. In addition, reverse transcription­quantitative PCR showed that neurons treated with the culture supernatant of LPSx3­microglia promoted the gene expression of B­cell lymphoma­extra large and glucose­dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT­4/5, suppressed the neuroprotective effect of LPSx3­microglia. Taken together, the present study demonstrated that LPSx3­microglia prevent STZ­induced neuronal death and that NT­4/5 may be involved in the neuroprotective mechanism of LPSx3­microglia.


Assuntos
Morte Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Neurônios/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores dos Hormônios Gastrointestinais/genética , Estreptozocina/farmacologia , Proteína bcl-X/genética
5.
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
6.
Biomolecules ; 11(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208360

RESUMO

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.


Assuntos
Proteína Forkhead Box O1/metabolismo , Glucose/metabolismo , Metformina/farmacologia , Animais , Aspirina/metabolismo , Aspirina/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Proteína Forkhead Box O1/farmacologia , Gluconeogênese/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Resistência à Insulina/fisiologia , Fígado/metabolismo , Masculino , Metformina/metabolismo , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosforilação , Transdução de Sinais , Estreptozocina/farmacologia
7.
Biomed Pharmacother ; 139: 111683, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243631

RESUMO

Diabetes mellitus causes changes in metabolism of extracellular nucleotides acting through P2 receptors (P2Rs). This affects renal function and may lead to glomerular and tubular disturbances. We measured urinary excretion of nucleotides (ATP, ADP, AMP, UTP, UDP, UMP) in streptozotocin-induced diabetic rats (65 mg/kg, i.p., day 0) and the effects of P2Rs' blockade by suramin (10 mg/kg, i.p., days +7, +14) on glomerular P2×7R expression and urinary excretion of glomerular (albumin, nephrin) and tubular (KIM-1, NGAL) injury markers, electrolytes, and oxidative stress markers (TBARS, 8-OHdG). Concentrations of nucleotides, specific proteins, electrolytes, and oxidative stress markers in 24-h urine samples collected in metabolic cages at days -1, +6 and +20 were measured using ion-paired reversed-phase HPLC, immunoenzymatic and fluorometric methods, and flame photometry, respectively. Expression of KIM-1 and P2×7R was examined by immunohistochemistry or immunoblotting. Diabetes was associated with increased urinary excretion of ATP, ADP, UTP, UDP and glomerular P2×7R expression. Suramin attenuated P2×7R expression but did not affect urinary excretion of nucleotides. Urinary excretion of albumin, nephrin, NGAL, and 8-OHdG were increased in diabetic rats and were not affected by suramin. TBARS was higher in diabetic rats and suramin attenuated the excretion dynamics in this group. KIM-1 excretion was higher in diabetic rats and suramin further increased excretion of KIM-1 in both diabetic and non-diabetic rats. Furthermore, suramin attenuated the diabetes-induced natriuresis and kaliuresis. It is possible that suramin affects both glomerular and tubular functions in diabetic rats.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/urina , Glomérulos Renais/efeitos dos fármacos , Suramina/farmacologia , Animais , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Glomérulos Renais/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina/farmacologia
8.
Chem Biol Interact ; 345: 109563, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34166651

RESUMO

Streptozotocin exhibits tropism to insulin-producing beta-cells in mammals and has been used to model diabetes-like phenotypes in insects. We have previously shown increased brain glucose levels and oxidative stress in STZ-treated nymphs of Nauphoeta cinerea. Here, we validate Nauphoeta cinerea as an experimental organism for studying STZ-induced metabolic disruptions by investigating the potential changes in the expression of inflammation and antioxidant related genes. Cockroaches were injected with 0.8% NaCl, 74 and 740 nmol of STZ. mRNA extracted from the head of cockroaches was used to estimate the RT-qPCR expression of inflammation and antioxidant genes. STZ-treatment upregulated the target genes of the JNK pathway (early growth factor response factor and reaper) but had no effect on PDGF-and VEGF-related factor 1. TOLL 1, the target gene of TOLL/NF-kB pathway was up regulated, while both the activator and target gene of the UPD3/JAK/STAT pathway [unpaired 3 and Suppressor of cytokine signalling at 36E] were upregulated. mRNA levels of primary antioxidants (superoxide dismutase and catalase) were increased in STZ treated nymphs but there was no effect on thioredoxins and Peroxiredoxin 4. Likewise, STZ treatment did not affect the expression of the delta class of the glutathione S-transferase gene family, but the sigma and theta classes of the GST family were upregulated. The STZ-induced N. cinerea gene expression modification demonstrates the involvement of primary antioxidants and the GST detoxification system in the cockroach oxidative stress response and buttresses the proposed crosstalk between inflammatory and redox pathways.


Assuntos
Antioxidantes/metabolismo , Baratas , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia , Animais , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , NF-kappa B/metabolismo , RNA Mensageiro/genética , Regulação para Cima/efeitos dos fármacos
9.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846768

RESUMO

Diabetic liver injury is a serious complication of type 2 diabetes mellitus (T2DM), which is often irreversible in the later stage, and affects the quality of life. Autophagy serves an important role in the occurrence and development of diabetic liver injury. For example, it can improve insulin resistance (IR), dyslipidaemia, oxidative stress and inflammation. Astragaloside IV (AS­IV) is a natural saponin isolated from the plant Astragalus membranaceus, which has comprehensive pharmacological effects, such as anti­oxidation, anti­inflammation and anti­apoptosis properties, as well as can enhance immunity. However, whether AS­IV can alleviate diabetic liver injury in T2DM and its underlying mechanisms remain unknown. The present study used high­fat diets combined with low­dose streptozotocin to induce a diabetic liver injury model in T2DM rats to investigate whether AS­IV could alleviate diabetic liver injury and to identify its underlying mechanisms. The results demonstrated that AS­IV treatment could restore changes in food intake, water intake, urine volume and body weight, as well as improve liver function and glucose homeostasis in T2DM rats. Moreover, AS­IV treatment promoted suppressed autophagy in the liver of T2DM rats and improved IR, dyslipidaemia, oxidative stress and inflammation. In addition, AS­IV activated adenosine monophosphate­activated protein kinase (AMPK), which inhibited mTOR. Taken together, the present study suggested that AS­IV alleviated diabetic liver injury in T2DM rats, and its mechanism may be associated with the promotion of AMPK/mTOR­mediated autophagy, which further improved IR, dyslipidaemia, oxidative stress and inflammation. Thus, the regulation of autophagy may be an effective strategy to treat diabetic liver injury in T2DM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Fígado/lesões , Fígado/metabolismo , Saponinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/farmacologia , Animais , Astragalus propinquus , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Glucose/metabolismo , Homeostase , Resistência à Insulina , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Qualidade de Vida , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia
10.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805770

RESUMO

Pre-mRNA splicing plays an important role in muscle function and diseases. The RNA binding motif 20 (RBM20) is a splicing factor that is predominantly expressed in muscle tissues and primarily regulates pre-mRNA splicing of Ttn, encoding a giant muscle protein titin that is responsible for muscle function and diseases. RBM20-mediated Ttn splicing has been mostly studied in heart muscle, but not in skeletal muscle. In this study, we investigated splicing specificity in different muscle types in Rbm20 knockout rats and hormonal effects on RBM20-mediated splicing both in cellulo and in vivo studies. The results revealed that RBM20 is differentially expressed across muscles and RBM20-mediated splicing is muscle-type specific. In the presence of RBM20, Ttn splicing responds to hormones in a muscle-type dependent manner, while in the absence of RBM20, Ttn splicing is not affected by hormones. In differentiated and undifferentiated C2C12 cells, RBM20-mediated splicing in response to hormonal effects is mainly through genomic signaling pathway. The knowledge gained from this study may help further understand muscle-specific gene splicing in response to hormone stimuli in different muscle types.


Assuntos
Conectina/genética , Músculo Esquelético/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Precursores de RNA/genética , Splicing de RNA , Proteínas de Ligação a RNA/genética , Animais , Antitireóideos/farmacologia , Linhagem Celular , Conectina/metabolismo , Cruzamentos Genéticos , Feminino , Humanos , Masculino , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/citologia , Mioblastos/metabolismo , Especificidade de Órgãos , Propiltiouracila/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Estreptozocina/farmacologia , Tri-Iodotironina/farmacologia
11.
Aging (Albany NY) ; 13(7): 9719-9731, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33744845

RESUMO

The present study assessed the body composition trajectory of rats (N = 96) placed into 5 groups according to lifespan, using dual-energy x-ray absorptiometry every 6 months until end-of-life. A striking linearity between lifespan and bone mass percentage (not absolute bone mass) was observed. Long-lived rats show a higher bone mass percentage with a delayed insulin rise to a similar peak level as short-lived counterparts, followed by insulin declines and bone mass loss. Decreasing insulin after streptozotocin (STZ) injection caused a rapid bone mass loss (-10.5%) with a decreased 5-day survival rate to 35% in old rats (20 months). Insulin replacement to STZ-injected rats completely blocked bone mass loss and increased the survival rate to 71%. Normal old rats (20 months) had faster lean mass loss despite greater myofiber regeneration (centronucleation) compared with the young rats (4 months). Increased CD68+ and CD163+ cell infiltration into insulin-depleted muscle suggests a bone marrow cell exhaustion by aging muscle. Bone produces stem cells and phagocytes to continuously rejuvenate peripheral tissues. Our data suggests that aging and unsustainable life is associated with development of disproportionality between bone and the growing body size, partly due to insulin reversal from hyperinsulinemia during late life.


Assuntos
Envelhecimento/fisiologia , Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Insulina/sangue , Longevidade/fisiologia , Absorciometria de Fóton , Tecido Adiposo/diagnóstico por imagem , Animais , Glicemia/metabolismo , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina/farmacologia
12.
Life Sci ; 272: 119246, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607156

RESUMO

AIMS: Memory impairment is determined to be the most well-known symptom of Alzheimer's disease (AD). Although cell therapy seems is an efficient therapeutic strategy to attenuate the AD-related memory impairment, transplanted cells have a short lifespan and do not survive long term in the recipient animals. Herein, we investigated whether the combination therapy of Selenium nanoparticles (SeNPs) and stem cells attenuates the neurotoxicity in an AD animal model. MATERIAL AND METHODS: The adipose-derived mesenchymal stem cells (AMSCs) were transplanted in the AD model. In addition to cell injections, the animals also received oral administration of SeNPs (0.4 mg/kg) for one month. Recognition memory, cell survival, and BDNF concentration were assessed using the novel object recognition task, immunofluorescence, and ELISA methods. KEY FINDINGS: Our results showed that the combined therapy was more effective in increasing the discrimination index than the administering SeNPs or AMSCs alone. Moreover, SeNPs and stem cells together had the greatest effects in reducing the deposition of Aß and increasing the concentration of BDNF. Ultimately, the survival and proliferation of transplanted cells were more in the group that received stem cells besides SeNPs. SIGNIFICANCE: Taken together, it seems that the transplantation of MSCs combined with SeNPs could achieve better results in the neuroprotection in the AD model than a conventional treatment of SeNPs or stem cells alone.


Assuntos
Transtornos da Memória/terapia , Células-Tronco Mesenquimais/metabolismo , Selênio/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanopartículas Metálicas/uso terapêutico , Neuroproteção/efeitos dos fármacos , Ratos , Ratos Wistar , Células-Tronco/efeitos dos fármacos , Estreptozocina/farmacologia
13.
Life Sci ; 272: 119250, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631174

RESUMO

AIM: Despite CXC chemokine ligand 16 (CXCL16) contributes to the pathogenesis of many inflammatory disorders, the mechanism by which CXCL16 is involved in T1DM remains unclear. In this study, we examined the role of the CXCL16/NF-κΒ p65 signaling pathway in the progression of this disease and the possible protective effect of resveratrol (RES) on streptozotocin (STZ)-induced T1DM. MAIN METHODS: Mice were classified into four groups of 10 animals each. The control group received citrate buffer. The RES group received 50 mg/kg i.p. RES for 12 days beginning on day 4 of citrate buffer. The STZ group received 55 mg/kg i.p. STZ once a day for 5 consecutive days. The fourth group injected with RES (50 mg/kg) for 12 days starting on day 4 of STZ injection. Biochemical, physical and oxidative stress parameters were measured in all groups. Moreover, expression of CXCL16 and CD45 was measured in pancreatic islets and spleen. Additionally, NF-κΒ p65 was investigated in isolated islets. KEY FINDINGS: Our results showed a significant elevation of CXCL16, NF-κΒ p65 and CD45 in islets of diabetic (DM) mice. Intriguingly, RES significantly restored distorted biochemical, physical and oxidative stress parameters after STZ treatment as well as inhibited the expression of CXCL16/NF-κΒ p65 in pancreatic islets. Moreover, RES normalized CXCL16 and CD45 expression in islets and spleen. SIGNIFICANCE: This study demonstrates first evidence that CXCL16/NF-κΒ p65 signaling pathway is associated with macrophage infiltration to pancreatic islet in T1DM and that RES successfully improved T1DM may be at least via inhibiting this pathway.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Ilhotas Pancreáticas/metabolismo , Resveratrol/farmacologia , Animais , Quimiocina CXCL16/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Modelos Animais de Doenças , Ilhotas Pancreáticas/efeitos dos fármacos , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Resveratrol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia , Fator de Transcrição RelA/metabolismo
14.
Diabetes ; 70(4): 1006-1018, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500254

RESUMO

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse ß-cells, its precise role in human ß-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired ß-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human ß-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of ß-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human ß-cell function and demonstrate the crucial role of MANF in this process.


Assuntos
Estresse do Retículo Endoplasmático/genética , Fatores de Crescimento Neural/metabolismo , Western Blotting , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Edição de Genes/métodos , Teste de Tolerância a Glucose , Humanos , Imuno-Histoquímica , Masculino , Mutação/genética , Fatores de Crescimento Neural/genética , Reação em Cadeia da Polimerase em Tempo Real , Estreptozocina/farmacologia
15.
Gene ; 768: 145288, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33181259

RESUMO

The present study was carried out to explore a novel strategy with the hypothesis that the combined treatment with standard antidiabetic drug metformin (MET) and chitosan stabilized nanoparticles (CTS-Se-NPs) may have a potential role on insulin level, hepatic damage and apoptosis, and cardiac injury markers of type 2 diabetes mellitus (T2DM) in rat model. T2DM was induced by a high fat diet (HFD) for 8 weeks and a single injection of a low dose streptozotocin (STZ) (35 mg/kg) in Sprague Dawley rats. A total number of one hundred rats were divided into five groups; the first served as a control (non-diabetic) group and the other four groups served as diabetic rats. The treatments were even mono or combined therapy by CTS-Se-NPs and/or MET for 8 weeks. A group was given only MET (500 mg/kg bw/day), another was administered only CTS-Se-NPs at a dose of 2 mg se/kg/day, while the last group was given both of them (co-treated group). Biochemical, molecular and histopathological analyses were conducted to figure out the efficiency of the treatment by the monotherapeutic mode or combination therapy on the insulin level, oxidants/antioxidants status, inflammatory mediators, hepatic and cardiac injury biomarkers and apoptotic/anti-apoptotic gene expressions. Our results indicated that HFD/STZ-induced toxic effects on the serum, hepatic and cardiac tissues including a remarkable elevation of the oxidative and inflammatory mediators, and up-regulation of the apoptotic genes (Bax, Caspase-3, Fas, Fas-L) expression. Histologically, the heart tissue revealed various degenerative, vascular and inflammatory alterations characteristic to murine cardiomyopathy. Besides, livers from HFD-STZ-treated rats showed numerous cytotoxic, circulatory and inflammatory alterations. Combined therapy with MET and CTS-Se-NPs resulted in a better remarkable anti-diabetic effect demonstrated by substantial decreases in fasting blood glucose and insulin levels, and elevated with up-regulation of anti-apoptotic gene (BCL-2) and down-regulation of apoptotic genes after 8 weeks of treatment than that revealed in the monotherapeutic strategy. In addition, it ameliorated the damage of cardiac and hepatic tissues and reduced lipid accumulation, and pro-inflammatory cytokines levels and restored the antioxidant capacity. It could be concluded that, the combined strategy applied in the current study have a potential role to limit the diabetic complications and restore insulin resistance to a higher extent than monotherapeutic strategy and could be considered a promising therapeutic alternative in T2DM rat model.


Assuntos
Quitosana/química , Diabetes Mellitus Tipo 2/metabolismo , Cardiopatias/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Nanopartículas/química , Selênio/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Caspases/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Dieta Hiperlipídica/efeitos adversos , Proteína Ligante Fas/metabolismo , Cardiopatias/etiologia , Cardiopatias/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Selênio/química , Estreptozocina/farmacologia , Proteína X Associada a bcl-2/metabolismo , Receptor fas/metabolismo
16.
Phytomedicine ; 86: 153066, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31447278

RESUMO

BACKGROUND: Diabetic complications-coronary atherosclerosis is closely related to the increased reactive oxygen species (ROS) induced by hyperglycemia. ROS are reported to induce the abnormal proliferation of vascular smooth muscle cells (VSMCs) under high glucose conditions. Leaf and seed extracts from Moringa oleifera are found to exhibit antioxidant activity. However, few studies are evaluating the antioxidant activities of chemical compounds isolated from the M. oleifera especially in cardiovascular field. PURPOSE: The aim of this study is to explore the antioxidative effect during hyperglycemia of niazirin from M. oleifera. STUDY DESIGN: A cell model was applied. METHODS: After the taking the in vitro antioxidant experiment including ferric reducing antioxidant power (FRAP), 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) assay and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Cell viability was carried out using high glucose-induced VSMCs model. ROS production was tested by 2',7'-dichlorofluorescein diacetate (DCF-DA) assay. The protein kinase C zeta (PKCζ) and NADPH oxidase 4 (Nox 4) expression in vitro and in vivo were measured by western blot analysis. RESULTS: Niazirin showed good free radical scavenging activity. Niazirin significantly attenuated the proliferation of high glucose-induced VSMCs. Furthermore, it could decrease the ROS and malondialdehyde (MDA) productions, while increased total antioxidant capacity (T-AOC), superoxide dismutase (SOD) as well as glutathione peroxidase (GPx) levels in high glucose-induced VSMCs and streptozotocin-induced mice. In addition, niazirin could eliminate the high glucose-induced PKCζ activation, indicated by Thr410 phosphorylation and inhibition of the Nox4 protein expression in vitro and in vivo. CONCLUSION: Niazirin from M. oleifera exhibited notably antioxidant activities and could be utilized as a potential natural antioxidant in preventing diabetic atherosclerosis.


Assuntos
Acetonitrilas/farmacologia , Antioxidantes/farmacologia , Moringa oleifera/química , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína Quinase C/metabolismo , Acetonitrilas/isolamento & purificação , Animais , Glucose/farmacologia , Glutationa Peroxidase/metabolismo , Malondialdeído/metabolismo , Camundongos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Sementes/química , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo
17.
Gene ; 766: 145155, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950634

RESUMO

Expression of browning genes are lower in both humans and animals with type 2 diabetes (T2D). This study aims at determining effects of long-term nitrate administration on protein and mRNA levels of uncoupling protein 1 (UCP1), peroxisome proliferator activated receptor gamma (PPAR-γ), and PPAR-γ coactivator 1 alpha (PGC1-α) in epididymal adipose tissue (eAT) of rats with T2D. Male Wistar rats were divided into 4 groups (n = 6/group): Control, diabetes, control + nitrate (CN), and diabetes + nitrate (DN). T2D was induced using high fat diet combined with a low-dose of streptozotocin (30 mg/kg body weight). Sodium nitrate was administrated at a dose of 100 mg/L for 6 months in nitrate-treated rats. Fasting serum glucose and insulin concentrations were measured at months 0 (i.e. at start of the protocol), 3, and 6. At month 6, protein and mRNA levels of UCP1, PPAR-γ, and PGC1-α were measured in eAT samples. In addition, tissue concentration of cyclic guanosine monophosphate (cGMP) was measured and histological analyses were done at month 6. In rats with T2D, 6-month administration of nitrate decreased serum glucose and insulin concentrations by 13% and 23%, respectively and increased cGMP level by 85%. Rats with T2D had lower mRNA and protein levels of PPAR-γ (62%, P < 0.0001 and 18%, P = 0.0472), PGC1-α (49%, P = 0.0019 and 21%, P = 0.0482), and UCP1 (35%, P = 0.0613 and 30%, P = 0.0031) in eAT; 6-month nitrate administration restored these decreased levels to near control values. In addition, nitrate increased adipocyte density by 193% and decreased adipocyte area by 53% in rats with T2D. In conclusion, long-term low-dose nitrate administration increased mRNA and protein expressions of browning genes in white adipose tissue of male rats with T2D; these findings partly explain favorable metabolic effects of nitrate administration in diabetes.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Epididimo/efeitos dos fármacos , Nitratos/administração & dosagem , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epididimo/metabolismo , Glucose/metabolismo , Insulina/sangue , Masculino , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Wistar , Estreptozocina/farmacologia
18.
Int J Nanomedicine ; 15: 9265-9282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262587

RESUMO

Background: Diabetic foot ulcer is an intractable complication of diabetes, characterized by the disturbed inflammatory and proliferative phases of wound healing. Sesamol, a phenolic compound, has been known for its powerful antioxidant, anti-inflammatory, anti-hyperglycaemic and wound healing properties. The aim of the present study was to develop a sesamol nano formulation and to study its effect on the various phases of the wound healing process in diabetic foot condition. Methods: Sesamol-PLGA (SM-PLGA) nanosuspension was developed  using nanoprecipitation method. TEM, in vitro drug release assay and in vivo pharmacokinetic studies were performed for the optimised formulation. Diabetic foot ulcer (DFU) in high fat diet (HFD)-fed streptozotocin-induced type-II diabetic animal model was used to assess the SM-PLGA nanosuspension efficacy. SM-PLGA nanosuspension was administered by oral route. TNF-α levels were estimated using ELISA and Western blot analysis was performed to assess the effect on the expression of HSP-27, ERK, PDGF-B and VEGF in wound tissue. Wound re-epithelization, fibroblast migration, collagen deposition and inflammatory cell infiltration were assessed by H&E and Masson's trichrome staining. Effect on angiogenesis was assessed by CD-31 IHC staining in wound sections. Results: The optimized SM-PLGA nanosuspension had an average particle size of <300 nm, PDI<0.200 with spherical shaped particles. Approximately 80% of the drug was released over a period of 60 h in in vitro assay. Half-life of the formulation was found to be 13.947 ± 0.596 h. SM-PLGA nanosuspension treatment decreased TNF-α levels in wound tissue and accelerated the collagen deposition. Whereas, HSP-27, ERK, PDGF-B and VEGF expression increased and improved new blood vessels' development. Rapid re-epithelization, fibroblast migration, collagen deposition and reduced inflammatory cell infiltration at the wound site were also observed. Conclusion: Results indicate that sesamol-PLGA nanosuspension significantly promotes the acceleration of wound healing in diabetic foot ulcers by restoring the altered wound healing process in diabetic condition.


Assuntos
Benzodioxóis/uso terapêutico , Pé Diabético/tratamento farmacológico , Nanopartículas/química , Fenóis/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cicatrização/efeitos dos fármacos , Animais , Benzodioxóis/sangue , Benzodioxóis/farmacocinética , Benzodioxóis/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Pé Diabético/sangue , Pé Diabético/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Liberação Controlada de Fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Teste de Tolerância a Glucose , Proteínas de Choque Térmico HSP27/metabolismo , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Fenóis/sangue , Fenóis/farmacocinética , Fenóis/farmacologia , Fator de Crescimento Derivado de Plaquetas , Álcool de Polivinil/química , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Estreptozocina/farmacologia , Suspensões , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Sci Rep ; 10(1): 20708, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244056

RESUMO

Vascular calcification (VC) is a common complication in patients with chronic kidney disease (CKD). Particularly, CKD patients with diabetes mellitus (DM) develop severe VC. Specific mechanisms of VC remain unclear; this study aimed to investigate them in the context of coexisting CKD and DM, mainly regarding oxidative stress. Sprague Dawley rats were randomly divided into six groups as follows: control rats (Control), 5/6 nephrectomized rats (CKD), streptozotocin-injected rats (DM), 5/6 nephrectomized and streptozotocin-injected rats (CKD + DM), CKD + DM rats treated with insulin (CKD + DM + INS), and CKD + DM rats treated with antioxidant apocynin (CKD + DM + APO). At 18 weeks old, the rats were sacrificed for analysis. Compared to the control, DM and CKD groups, calcification of aortas significantly increased in the CKD + DM group. Oxidative stress and osteoblast differentiation-related markers considerably increased in the CKD + DM group compared with the other groups. Moreover, apocynin considerably reduced oxidative stress, osteoblast differentiation-related markers, and aortic calcification despite high blood glucose levels. Our data indicate that coexisting CKD and DM hasten VC primarily through an increase in oxidative stress; anti-oxidative therapy may prevent the VC progression.


Assuntos
Diabetes Mellitus/patologia , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica/patologia , Calcificação Vascular/patologia , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Glicemia/metabolismo , Diferenciação Celular/fisiologia , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/metabolismo , Progressão da Doença , Masculino , Osteoblastos/metabolismo , Osteoblastos/patologia , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Estreptozocina/farmacologia , Calcificação Vascular/metabolismo
20.
PLoS One ; 15(9): e0238727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941450

RESUMO

PURPOSE: Female mice have been found to be resistant to streptozotocin (STZ)-induced diabetes, and pre-clinical research related to diabetic complications commonly omits females. The purpose of this study was to develop a method to induce diabetes in female mice, and to determine if retinas of diabetic female mice develop molecular changes and histopathological abnormalities comparable to those which develop in male diabetic mice. METHODS: To induce diabetes, animals of both sexes received daily intraperitoneal (i.p.) injection of STZ for 5 consecutive days at 55 mg/kg BW (a dose that is known to induce diabetes in male mice) or for females, 75 mg/kg BW of STZ. Retinal abnormalities that have been implicated in the development of the retinopathy (superoxide generation and expression of inflammatory proteins, iNOS and ICAM-1) were evaluated at 2 months of diabetes, and retinal capillary degeneration was evaluated at 8 months of diabetes. RESULTS: Daily i.p. injection of STZ for 5 consecutive days at a concentration of 55 mg/kg BW was sufficient to induce diabetes in 100% of male mice, but only 33% of female mice. However, females did become hyperglycemic when the dose of STZ administered was increased to 75 mg/kg BW. The resulting STZ-induced hyperglycemia in female and male mice was sustained for at least 8 months. After induction of the diabetes, both sexes responded similarly with respect to the oxidative stress, expression of iNOS, and degeneration of retinal capillaries, but differed in the limited population evaluated with respect to expression of ICAM-1. CONCLUSIONS: The resistance of female mice to STZ-induced diabetes can be overcome by increasing the dose of STZ used. Female mice can, and should, be included in pre-clinical studies of diabetes and its complications.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Retinopatia Diabética/patologia , Retinopatia Diabética/fisiopatologia , Modelos Animais de Doenças , Caracteres Sexuais , Animais , Capilares/efeitos dos fármacos , Capilares/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Retina/efeitos dos fármacos , Retina/patologia , Estreptozocina/farmacologia
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