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1.
Chem Biol Interact ; 347: 109603, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34352274

RESUMO

AIMS: Major depressive disorder (MDD) affects approximately 322 million people worldwide and is a common comorbidity in patients with diabetes mellitus (DM). A possible pathophysiological mechanism correlating both diseases is the increased oxidative stress in brain regions due to hyperglycemia. Myrsine coriacea (Primulaceae) is popularly known as "capororoca" and studies have been shown that this plant exhibits several pharmacological properties attributed to myrsinoic acid A (MAA) and B (MAB). Indeed, previous results have been shown its effects on the central nervous system, leading us to explore possible psychotropic effects. MAIN METHODS: The effects of treatment with hydroalcoholic extract of the barks from Myrsine coriacea (HEBMC, 150 mg/kg, o.g.), MAA (5 mg/kg, o.g.), and MAB (3 mg/kg, o.g.) were evaluated in streptozotocin (75 mg/kg, i.p.)-induced diabetic female rats. After 28 days of treatments, rats were submitted to the forced swim test (FST) and open field test (OFT). Also, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and lipid hydroperoxides (LOOH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of these rats. KEY FINDINGS: The treatment with MAA or MAB increased the latency of first immobility in diabetic rats, and the HEBMC administration decreased the immobility time, and increase the climbing in FST. However, only MAB treatment reduces the immobility time, increases the climbing, and swimming in FST, and increases the crossing of diabetic animals in the OFT. Besides, this behavioral improvement promoted by MAB administration was accompanied by reducing in oxidative stress in the HIP and PFC, but not reducing hyperglycemia in diabetic rats. SIGNIFICANCE: The results suggest that MAB's antioxidant effect in the HIP of diabetic animals may be essential to its antidepressant-like effect.


Assuntos
Alcenos/uso terapêutico , Antidepressivos/uso terapêutico , Benzofuranos/uso terapêutico , Depressão/prevenção & controle , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Catalase/metabolismo , Depressão/etiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Feminino , Myrsine/química , Teste de Campo Aberto/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Caules de Planta/química , Ratos Wistar , Estreptozocina
2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445504

RESUMO

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.


Assuntos
Diabetes Mellitus Experimental/complicações , Perda Auditiva/fisiopatologia , Mitocôndrias/ultraestrutura , Receptores para Leptina/genética , Animais , Apoptose , Biomarcadores/metabolismo , Cóclea/irrigação sanguínea , Cóclea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Regulação para Baixo , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/metabolismo , Humanos , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445586

RESUMO

Remote ischemic preconditioning (RIPC) protects hearts from ischemia-reperfusion (I/R) injury in experimental studies; however, clinical RIPC trials were unsatisfactory. This discrepancy could be caused by a loss of cardioprotection due to comorbidities in patients, including diabetes mellitus (DM) and hyperglycemia (HG). RIPC is discussed to confer protective properties by release of different humoral factors activating cardioprotective signaling cascades. Therefore, we investigated whether DM type 1 and/or HG (1) inhibit the release of humoral factors after RIPC and/or (2) block the cardioprotective effect directly at the myocardium. Experiments were performed on male Wistar rats. Animals in part 1 of the study were either healthy normoglycemic (NG), type 1 diabetic (DM1), or hyperglycemic (HG). RIPC was implemented by four cycles of 5 min bilateral hind-limb ischemia/reperfusion. Control (Con) animals were not treated. Blood plasma taken in vivo was further investigated in isolated rat hearts in vitro. Plasma from diseased animals (DM1 or HG) was administered onto healthy (NG) hearts for 10 min before 33 min of global ischemia and 60 min of reperfusion. Part 2 of the study was performed vice versa-plasma taken in vivo, with or without RIPC, from healthy rats was transferred to DM1 and HG hearts in vitro. Infarct size was determined by TTC staining. Part 1: RIPC plasma from NG (NG Con: 49 ± 8% vs. NG RIPC 29 ± 6%; p < 0.05) and DM1 animals (DM1 Con: 47 ± 7% vs. DM1 RIPC: 38 ± 7%; p < 0.05) reduced infarct size. Interestingly, transfer of HG plasma showed comparable infarct sizes independent of prior treatment (HG Con: 34 ± 9% vs. HG RIPC 35 ± 9%; ns). Part 2: No infarct size reduction was detectable when transferring RIPC plasma from healthy rats to DM1 (DM1 Con: 54 ± 13% vs. DM1 RIPC 53 ± 10%; ns) or HG hearts (HG Con: 60 ± 16% vs. HG RIPC 53 ± 14%; ns). These results suggest that: (1) RIPC under NG and DM1 induces the release of humoral factors with cardioprotective impact, (2) HG plasma might own cardioprotective properties, and (3) RIPC does not confer cardioprotection in DM1 and HG myocardium.


Assuntos
Cardiotônicos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Hiperglicemia/complicações , Imunidade Humoral , Precondicionamento Isquêmico Miocárdico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Wistar , Transdução de Sinais
4.
Acta Cir Bras ; 36(7): e360702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34431921

RESUMO

PURPOSE: To develop a model of induction of type-2 diabetes (DM2) by combining low doses of streptozotocin (STZ) and a cafeteria diet. METHODS: Forty male Wistar rats (200 g) were allocated into four groups: control (non-diabetic, n = 10); STZ 30 mg/kg (diabetic, n = 10); STZ 35 mg/kg (diabetic,n = 10); and STZ 40 mg/kg (diabetic, n = 10). DM2 was induced with a single intraperitoneal injection of STZ after four weeks of cafeteria diet in the three diabetic groups. All animals were evaluated as for anthropometric, and biochemical analyses, as well as liver, kidney and pancreas histological analyses. RESULTS: Lower weight gain, higher water intake, higher Lee index, hyperglycemia and modified total protein, urea, alpha-amylase, as well as insulin resistance, hepatic steatosis, pancreas, and kidney injury were observed in animals treated with 35 and 40 mg/kg of STZ. CONCLUSIONS: The results show that the experimental model using cafeteria diet associated with 35 mg/kg of STZ is a low-cost model and efficient in order to develop DM2, confirmed by the presence of polydipsia, hyperglycemia, altered biochemical tests, insulin resistance and damages to the liver, pancreas and kidney, which is similar to the disease found in humans.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/etiologia , Dieta , Masculino , Ratos , Ratos Wistar , Estreptozocina
5.
Chem Biol Interact ; 347: 109617, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34391751

RESUMO

PURPOSE: This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells. METHODS AND RESULTS: DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters. CONCLUSION: The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Eletrocardiografia/efeitos dos fármacos , Eritropoetina/sangue , Eritropoetina/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Wistar , Estreptozocina
6.
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
7.
Nat Commun ; 12(1): 4452, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294713

RESUMO

Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Cultivadas , Cisteína/química , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/química , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Knockout , Mutagênese Sítio-Dirigida , Óxido Nítrico Sintase Tipo II/metabolismo , Compostos Nitrosos/química , Compostos Nitrosos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores CXCR5/deficiência , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Fatores de Transcrição/metabolismo
8.
Free Radic Biol Med ; 173: 70-80, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298092

RESUMO

Accumulating studies have demonstrated the protective roles of mesenchymal stem cells against several disorders. However, one of their crucial limitations is reduced viability under stress conditions, including the hyperglycemia induced by diabetes. The molecular mechanisms involved in diabetes-induced kidney injuries are not fully elucidated. In this study, we found that high glucose (HG) reduced human proximal tubular epithelial cell viability. Further, hyperglycemia induced oxidative stress-mediated apoptosis and fibrosis in HK-2 cells via activation of the mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal kinase JNK and p38 kinase. Carboxyl terminus of HSP70 interacting protein (CHIP) overactivation considerably rescued cell viability under HG stress. Moreover, Western blot analysis, flow cytometry, and MitoSOX staining revealed that hyperglycemia-induced mitochondrial oxidative stress production and apoptosis were attenuated in CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Co-culture with CHIP-expressing WJMSCs maintained HK-2 cell viability, and inhibited apoptosis and fibrosis by attenuating HG-induced ROS-mediated MAPK activation. CHIP-overexpressing WJMSCs also rescued the decreased kidney weight and hyperglycemia-induced kidney damage observed in streptozotocin-induced diabetic rats. Cumulatively, the current research findings demonstrate that CHIP suppresses hyperglycemia-induced oxidative stress and confers resistance to MAPK-induced apoptosis and fibrosis, and suggests that CHIP protects WJMSCs and the high quality WJMSCs have therapeutic effects against diabetes-induced kidney injuries.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Células-Tronco Mesenquimais , Geleia de Wharton , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/metabolismo , Rim/metabolismo , Estresse Oxidativo , Ratos
9.
J Transl Med ; 19(1): 294, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233716

RESUMO

OBJECTIVE: Diabetic retinopathy, a common complication of diabetes mellitus and a major cause of blindness. circRNAs spongs target miRNA and thus influencing mRNA expression in DR. We investigated the mechanism of circ_001209 in regulating diabetic retinal vascular dysfunction. METHODS: QRT-PCR analysis was performed to detect the expression of miR-15b-5p, COL12A1 and circ_001209 in human retinal vascular endothelial cells (HRVECs) under high glucose conditions. Western blot assay, wound healing assay, transwell assay and tube formation were used to explore the roles of circ_001209/miR-15b-5p/COL12A1 in retinal vascular dysfunction. Bioinformatics analysis and luciferase reporter, RNA-FISH, and overexpression assays were performed to reveal the mechanisms of the circ_001209/miR-15b-5p/COL12A1 interaction. TUNEL staining and H&E staining were used to evaluate the pathological changes in streptozotocin (STZ)-induced DR in rats. RESULTS: Downregulation of miR-15b-5p under HG conditions promoted proliferation, migration, and tube formation of HRVECs. QRT-PCR and western blot results revealed that miR-15b-5p affected the HRVECs function through targeting COL12A1. Under HG conditions, circ_001209, which acts as a sponge of miR-15b-5p, is upregulated. Besides, overexpression of circ_001209 can affect HRVEC function and aggravate retinal injury in diabetic rats. CONCLUSION: Upregulation of circ_001209 contributes to vascular dysfunction in diabetic retinas through regulating miR-15b-5p and COL12A1, providing a potential treatment strategy for diabetic retinopathy.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , MicroRNAs , Animais , Proliferação de Células , Colágeno Tipo XII , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Retinopatia Diabética/genética , Células Endoteliais , MicroRNAs/genética , Ratos
10.
Anticancer Res ; 41(8): 4053-4059, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281874

RESUMO

BACKGROUND/AIM: Diabetes is a risk factor for dementia. However, no radical preventive method for diabetes-associated dementia has yet been developed. Our previous study revealed that oral administration of lipopolysaccharide (LPS) prevents high-fat diet-induced cognitive impairment. Therefore, we investigated here whether oral administration of LPS (OAL) could also prevent diabetes-associated dementia. MATERIALS AND METHODS: Diabetic mice were produced by intraperitoneal administration of streptozotocin (STZ), and then mice were orally administered LPS. Cognitive ability was evaluated using the Morris water maze, and gene expression was analyzed in isolated microglia. RESULTS: OAL prevented STZ-induced diabetic cognitive impairment, but did not affect blood glucose levels. Moreover, OAL promoted the expression of neuroprotective genes in microglia, such as heat shock protein family 40 (HSP40) and chemokine CCL7. CONCLUSION: OAL prevents diabetes-associated dementia, potentially via promotion of HSP40 and CCL7 expression in microglia.


Assuntos
Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Quimiocina CCL7/genética , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Proteínas de Choque Térmico HSP40/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia
11.
Front Immunol ; 12: 633540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295325

RESUMO

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. 21 days after diabetes induction by intravenous injection of alloxan, we induced moderate sepsis in Swiss-Webster mice through cecum ligation and puncture (CLP). The glucagon receptor (GcgR) antagonist des-his1-[Glu9]-glucagon amide was injected intraperitoneally 24h and 1h before CLP. We also tested the effect of glucagon on CXCL1/KC-induced neutrophil migration to the peritoneal cavity in mice. Neutrophil chemotaxis in vitro was tested using transwell plates, and the expression of total PKA and phospho-PKA was evaluated by western blot. GcgR antagonist restored neutrophil migration, reduced CFU numbers in the peritoneal cavity and improved survival rate of diabetic mice after CLP procedure, however, the treatment did no alter hyperglycemia, CXCL1/KC plasma levels and blood neutrophilia. In addition, glucagon inhibited CXCL1/KC-induced neutrophil migration to the peritoneal cavity of non-diabetic mice. Glucagon also decreased the chemotaxis of neutrophils triggered by CXCL1/KC, PAF, or fMLP in vitro. The inhibitory action of glucagon occurred in parallel with the reduction of CXCL1/KC-induced actin polymerization in neutrophils in vitro, but not CD11a and CD11b translocation to cell surface. The suppressor effect of glucagon on CXCL1/KC-induced neutrophil chemotaxis in vitro was reversed by pre-treatment with GcgR antagonist and adenylyl cyclase or PKA inhibitors. Glucagon also increased PKA phosphorylation directly in neutrophils in vitro. Furthermore, glucagon impaired zymosan-A-induced ROS production by neutrophils in vitro. Human neutrophil chemotaxis and adherence to endothelial cells in vitro were inhibited by glucagon treatment. According to our results, this inhibition was independent of CD11a and CD11b translocation to neutrophil surface or neutrophil release of CXCL8/IL-8. Altogether, our results suggest that glucagon may be involved in the reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice. This work collaborates with better understanding of the increased susceptibility and worsening of sepsis in diabetics, which can contribute to the development of new effective therapeutic strategies for diabetic septic patients.


Assuntos
Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Suscetibilidade a Doenças/etiologia , Glucagon/administração & dosagem , Neutrófilos/efeitos dos fármacos , Sepse/etiologia , Sepse/imunologia , Adulto , Animais , Movimento Celular/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Feminino , Glucagon/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Neutrófilos/imunologia
12.
Molecules ; 26(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299486

RESUMO

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.


Assuntos
Berberina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Berberina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/metabolismo
13.
ACS Appl Mater Interfaces ; 13(23): 26770-26781, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34096258

RESUMO

Diabetic foot ulcers (DFUs) are hard-healing chronic wounds and susceptible to bacterial infection. Conventional hydrogel dressings easily lose water at high temperature or freeze at low temperature, making them unsuitable for long-term use or in extreme environments. Herein, a temperature-tolerant (-20 to 60 °C) antibacterial hydrogel dressing is fabricated by the assembly of polyacrylamide, gelatin, and ε-polylysine. Owing to the water/glycerin (Gly) binary solvent system, the resultant hydrogel (G-PAGL) displayed good heat resistance and antifreezing properties. Within the wide temperature range (-20 to 60 °C), all the desirable features of the hydrogel, including superstretchability (>1400%), enduring water retention, adhesiveness, and persistent antibacterial property, are quite stable. Remarkably, the hydrogel wound dressing displayed lasting and broad antibacterial activity against Gram-positive and Gram-negative bacteria. Satisfactorily, the double-network (DN) G-PAGL hydrogel dressing could effectively promote the healing of DFUs by accelerating collagen deposition, promoting angiogenesis, and inhibiting bacterial breed. As far as we know, this is the first time that the extensive temperature-tolerant DN hydrogel with antibacterial ability is developed to use as DFU wound dressing. The G-PAGL hydrogel provides more choices for DFU wound dressings that could be used in extreme environments.


Assuntos
Antibacterianos/administração & dosagem , Diabetes Mellitus Experimental/complicações , Pé Diabético/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hidrogéis/administração & dosagem , Cicatrização/efeitos dos fármacos , Adesivos , Animais , Antibacterianos/química , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Bandagens , Pé Diabético/etiologia , Pé Diabético/patologia , Hidrogéis/química , Ratos , Temperatura
14.
Life Sci ; 279: 119674, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081992

RESUMO

One of the global alarming prevalent metabolic diseases is Type 2 diabetes mellitus (T2DM) than other diabetes and sustains a substantial burden on public and healthcare systems. This study attempts to endeavor the beneficial effect of chitosan stabilized nanoparticles Ch-SeNPs on combating diabetic nephropathy (DN) after induction of T2DM in rats (DN.STZ-induced T2D). High-fat diet (HFD) and STZ were used for the induction of T2DM in rats, and then they were treated with either metformin alone (MEF) (500 mg/kg b.wt.) or combined with (Ch-SeNPs) (2 mg Se/kg b.wt.) for eight weeks. The microvascular complications in renal tissue of diabetic rats were pronounced by the prevalence of microalbuminuria and elevated levels of urea, creatinine, and BUN. Pronounced oxidative stress with enhanced inflammatory response. In the urine of diabetic rats, a marked increase in Kim 1, ß2-microglobulin, and urinary albumin. Renal morphological alterations were observed in all groups upon induction of T2DM, except for the Ch-SeNPs/MEF group showed noticeable improvements. The expression levels of Aldo-keto reductase AKr1B1, profibrotic protein transforming growth factor-ß1 (TGF-ß1), nestin, desmin, and vimentin, were up-regulated in the diabetic group. Significant down-regulation of their expression and restored antioxidant capacity was observed in the combined-treated group than single treated ones. Ch-SeNPs helped limit the prevalence of TNF-α, IL-6, and IL-1ß while used after T2DM induction by STZ and HFD. Ch-SeNPs/MEF co-therapy could effectively guard the kidneys and reduce the renal tissue injury via inhibiting oxidative stress and restoring glucose hemostasis, which indicates a promising line for treating T2DM nephropathy.


Assuntos
Aldeído Redutase/metabolismo , Quitosana/química , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , Nanopartículas/administração & dosagem , Selênio/química , Aldeído Redutase/genética , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Rim/lesões , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Masculino , Nanopartículas/química , Ratos , Ratos Sprague-Dawley
15.
Life Sci ; 279: 119676, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087285

RESUMO

AIMS: The effects of three types of bariatric interventions on myocardial infarct size were tested in the rat model of type 2 diabetes mellitus (T2DM). We also evaluated the effects of bariatric surgery on no-reflow phenomenon and vascular dysfunction caused by T2DM. MAIN METHODS: Rats with T2DM were assigned into groups: without surgery, sham-operated, ileal transposition, Roux-en-Y gastric bypass, and sleeve gastrectomy. Oral glucose tolerance, glucagon-like peptide-1, and insulin levels were measured. Six weeks after surgery, the animals were subjected to myocardial ischemia-reperfusion followed by histochemical determination of infarct size (IS), no-reflow zone, and blood stasis area size. Vascular dysfunction was characterized using wire myography. KEY FINDINGS: All bariatric surgery types caused significant reductions in animal body weight and resulted in T2DM compensation. All bariatric interventions partially normalized glucagon-like peptide-1 responses attenuated by T2DM. IS was significantly smaller in animals with T2DM. Bariatric surgery provided no additional IS limitation compared with T2DM alone. Bariatric surgeries reversed T2DM-induced enhanced contractile responses of the mesenteric artery to 5-hydroxytryptamine. Sleeve gastrectomy normalized decreased nitric oxide synthase contribution to the endothelium-dependent vasodilatation in T2DM. SIGNIFICANCE: T2DM resulted in a reduction of infarct size and no-reflow zone size. Bariatric surgery provided no additional infarct-limiting effect, but it normalized T2DM-induced augmented vascular contractility and reversed decreased contribution of nitric oxide to endothelium-dependent vasodilatation typical of T2DM. All taken together, we suggest that this type of surgery may have a beneficial effect on T2DM-induced cardiovascular diseases.


Assuntos
Cirurgia Bariátrica/métodos , Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Angiopatias Diabéticas/prevenção & controle , Derivação Gástrica/métodos , Infarto do Miocárdio/prevenção & controle , Animais , Glicemia/análise , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/patologia , Peptídeo 1 Semelhante ao Glucagon/análise , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar
16.
Life Sci ; 279: 119697, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102194

RESUMO

AIMS: Vitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model. MAIN METHODS: Diabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/ß-catenin, and TGF-ß/Smad-7 pathways. KEY FINDINGS: Two-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, ß-catenin, and TGF-ß; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function. SIGNIFICANCE: Vitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/ß-catenin; modulating TGF-ß/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Rosuvastatina Cálcica/farmacologia , Vitamina D/administração & dosagem , Animais , Anticolesterolemiantes/farmacologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Quimioterapia Combinada , Masculino , Fator 1 Relacionado a NF-E2/genética , Fator 1 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Vitaminas/administração & dosagem , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
17.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072974

RESUMO

This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/- mice, and diabetic Opa1+/- mice were used in this study. 16 weeks after diabetes onset, retinas were assessed for Opa1 and Bax levels by Western blot analysis, and retinal networks were examined for acellular capillaries (AC) and pericyte loss (PL). Apoptotic cells were detected in retinal capillaries using TUNEL assay, and caspase-3 activity was assessed using fluorometric analysis. Opa1 expression was significantly downregulated in retinas of diabetic and Opa1+/- mice compared with those of WT mice. Inducing diabetes further decreased Opa1 expression in retinas of Opa1+/- mice. Increased cytochrome c release concomitant with increased level of pro-apoptotic Bax and elevated caspase-3 activity were observed in retinas of diabetic and Opa1+/- mice; the number of TUNEL-positive cells and AC/PL was also significantly increased. An additional decrease in the Opa1 level in retinas of diabetic Opa1+/- mice exacerbated the development of apoptotic cells and AC/PL compared with those of diabetic mice. Diabetes-induced Opa1 downregulation contributes, at least in part, to the development of retinal vascular lesions characteristic of DR.


Assuntos
Capilares , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , GTP Fosfo-Hidrolases/fisiologia , Vasos Retinianos , Animais , Apoptose , Capilares/metabolismo , Capilares/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia
18.
Andrologia ; 53(8): e14138, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34137064

RESUMO

Diabetes mellitus (DM), which is closely related to microvascular dysfunction, is a risk factor for erectile dysfunction (ED). Furthermore, the upregulation of inducible nitric oxide synthase (iNOS) is associated with systemic vascular dysfunction in rats with diabetes. The purpose of this study was to investigate the role of iNOS in diabetes mellitus erectile dysfunction (DMED). First, we developed a type 1 DM rat model using streptozotocin and selected those that developed DMED. Then, we injected these rats with the 1400W, an iNOS inhibitor, for 10 weeks and subsequently assessed their ED. Lastly, we performed various molecular studies and histopathological analyses of penile tissues collected from these rats after the experiments. Through the histopathological studies, we also found that the treatment restored the ratios of the smooth muscle to collagen fibres, delayed the development of microvascular injury and alleviated the oxidative stress caused by hyperglycaemia. Based on these results, we confirmed that upregulation of iNOS leads to microvascular dysfunction in patients with ED. Overall, we found that inhibition of iNOS displayed beneficial effects in the treatment of ED, suggesting that its mechanism should be further explored.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Disfunção Erétil , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Masculino , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Ereção Peniana , Pênis/metabolismo , Ratos
19.
J Periodontal Res ; 56(5): 991-1005, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34190354

RESUMO

BACKGROUND AND OBJECTIVE: Periodontitis in diabetic patients is characterized by enhanced inflammation and aggravated tissue damage in comparison with that in non-diabetic counterparts. The progression of periodontal damage under diabetic condition can be partly ascribed to hyperglycemia-induced disturbance between immune activation and inflammation resolution, where macrophages are capable of participating given their plasticity in response to different stimuli. Herein, we aimed to investigate the changes of macrophage polarization in periodontitis under diabetic condition and the underlying mechanism. MATERIALS AND METHODS: Type-1 diabetes was induced by the injection of streptozotocin (STZ, 60 mg/kg) in Sprague-Dawley rats. Rats in N-acetyl cysteine (NAC)-treated groups received NAC dissolved in drinking water (200 mg/kg/day). Experimental periodontitis was induced by ligating 3-0 silk around left maxillary second molars for 4 weeks. Alveolar bone destruction was tested by micro-computed tomography and tartrate-resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization in periodontal tissue was detected by immunohistochemistry staining. RAW264.7 were cultured in normal glucose (5.5 mM) or high glucose environment (25 mM) with or without NAC (8 mmol/L). LPS (100 ng/ml) and IL-4 (20 ng/ml) were used to induce M1 macrophages and M2 macrophages, respectively. M1/M2 macrophage polarization was detected by qRT-PCR, immunofluorescent staining, and flow cytometry. Reactive oxygen species (ROS) accumulation was detected by fluorogenic probes. RANKL (100 ng/ml) were applied to induce osteoclastogenic differentiation of RAW264.7, and osteoclast formation was examined by TRAP staining. RESULTS: Rats with diabetes displayed enhanced macrophages infiltration and M1 macrophage polarization in periodontal lesions compared with vehicle-treated rats. Under LPS or IL-4 stimulation, high glucose culture of RAW264.7 elevated ROS level and increased the expression of M1 macrophage markers (iNOS, TNF-α, and IL-6) whereas decreased the expression of M2 macrophage markers (Arg-1 and CD206). Supernatants of high glucose-treated M1/M2 macrophages enhanced osteoclast formation compared to normal glucose-cultured cells. Decreasing ROS level via NAC partially reversed the effect of high glucose on M1/M2 macrophage polarization. Meanwhile, daily intake of NAC in rodent models inhibited M1 macrophage polarization, which subsequently ameliorated alveolar bone loss and decreased osteoclast numbers in periodontitis in diabetic rats. CONCLUSION: These findings demonstrated that hyperglycemia could polarize macrophage toward M1 macrophages via overproducing ROS under inflammatory condition, which might take responsibility for aggravated periodontal damage in periodontitis under diabetic condition. Inhibiting M1 macrophages and restoring M2 macrophages by ROS scavenger is hopefully a potential adjunct treatment strategy for diabetic periodontitis.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Periodontite , Animais , Diabetes Mellitus Experimental/complicações , Humanos , Hiperglicemia/complicações , Macrófagos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Microtomografia por Raio-X
20.
Aging (Albany NY) ; 13(12): 16105-16123, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34118791

RESUMO

Diabetic patients are more vulnerable to cerebral ischemia-reperfusion (CIR) injury and have a worse prognosis and higher mortality after ischemic stroke than non-diabetic counterparts. Melatonin can exert neuroprotective effects against CIR injury in nondiabetic animal models. However, its effects on diabetic CIR injury and the underlying mechanisms remain unclarified. Herein, we found that melatonin administration improved neurological deficit, cerebral infarct volume, brain edema, and cell viability, reduced mitochondrial swelling, reactive oxygen species generation, and cytoplasmic cytochrome C release, and increased mitochondrial antioxidant enzymes activities, adenosine triphosphate production, and mitochondrial membrane potential in both streptozotocin-induced diabetic mice and high glucose-treated HT22 cells. Importantly, melatonin also activated protein kinase B (Akt) and sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) signaling and upregulated mitochondrial biogenesis-related transcription factors. However, these effects were largely attenuated by LY294002 (a specific Akt signaling blocker) administration. Additionally, 3-TYP (a selective SIRT3 inhibitor) and SIRT3 siRNA inhibited the above protective effects of melatonin as well as the upregulation of SIRT3 and the decrease of SOD2 acetylation but did not affect the p-Akt/Akt ratio. Overall, we demonstrate that melatonin can alleviate CIR injury in diabetic mice by activating Akt-SIRT3-SOD2 signaling and subsequently improving mitochondrial damage.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Melatonina/uso terapêutico , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Edema Encefálico/complicações , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Isquemia Encefálica/complicações , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Diabetes Mellitus Experimental/complicações , Glucose/toxicidade , Masculino , Melatonina/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Morfolinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos
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