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1.
Biomed Pharmacother ; 153: 113411, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076481

RESUMO

Myocardial disorders are the most common cause of renal failure and mortality in diabetic patients, but the molecular mechanism of this process is not yet clear. The reduction of nuclear Erythroid2-related factor-2 (Nrf-2) and positive regulators of Nrf-2 proteins, such as DJ-1 and microRNA-126 (miR-126), after hypoxia and the promotion of reactive oxygen species, might be an intervention indicator in renal failure after myocardial ischemia-reperfusion. Therefore, this study evaluates the renoprotective effect of exercise training and Crataegus persica extract (CE) on myocardial ischemia-reperfusion-induced kidney injury in diabetic rats. Fifty rats were divided into five groups: healthy sedentary control (Con), sedentary diabetic (D), interval trained diabetic (TD), diabetic plus Crataegus persica extract treatment (CD), and interval trained diabetic plus Crataegus persica extract treatment (TCD) groups. The rats in the exercise groups were subjected to moderate-intensity interval training five days per week for ten weeks. The rats in CD and TCD groups received 300 mg/kg of Crataegus persica through gavage for ten weeks. Then, the subjects underwent 30 min of myocardial ischemia and subsequently reperfusion for 24 h. At the end of the experiment, insulin sensitivity, oxidative stress, renal function, histopathology of the kidney, Nrf-2, miR-126, and DJ-1 gene expression levels were evaluated. The results show that the treatments decreased elevated levels of renal oxidative stress, glomerular filtration rate, insulin sensitivity, and pathological score in diabetic rats. Also, the expression of Nrf-2 and miR-126, unlike DJ-1, decreased in diabetic rats due to interval training. Due to the results, diabetes aggravates acute myocardial ischemia-reperfusion-induced kidney injury, while moderate-intensity interval training and Crataegus persica treatment simultaneously ameliorate myocardial ischemia-reperfusion-induced renal injury via miR-126/Nrf-2 pathway and improve insulin sensitivity and renal function in type 1 diabetic rats.


Assuntos
Crataegus , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Resistência à Insulina , MicroRNAs , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Insuficiência Renal , Traumatismo por Reperfusão , Animais , Diabetes Mellitus Experimental/patologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Extratos Vegetais/efeitos adversos , Ratos , Traumatismo por Reperfusão/metabolismo
2.
Biomed Res Int ; 2022: 1129297, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36124067

RESUMO

This study investigated the healing effects of topical application of zerumbone, a well-known anti-inflammatory compounds loaded on nanostructured lipid carrier gel (Carbopol 940) (ZER-NLCG) on excisional wounds in streptozotocin-induced diabetic rats. Diabetic rats with inflicted superficial skin wound were topically treated with ZER-NLCG, empty NLCG, and silver sulfadiazine cream (SSDC) once daily for 21 days. Wound tissue samples were analyzed for proinflammatory cytokines, namely, interleukin-6 (IL-6), interleukin-1 ß (IL-1ß), and tumor necrosis factor-α (TNF-α), hydroxyproline contents, catalase, superoxide dismutase activities, and lipid peroxidation level, and were subjected to histopathological analysis, respectively. Among the treated groups, ZER-NLCG was the most effective at decreasing proinflammatory cytokine level and inflammatory cell infiltration while increasing antioxidant enzyme activities, hydroxyproline content, and granulation of wound tissues of diabetic rats. ZER-NLCG is a potent formulation for the enhancement of wound healing in diabetic rats through its anti-inflammatory, antioxidant, and tissue repair activities.


Assuntos
Diabetes Mellitus Experimental , Fator de Necrose Tumoral alfa , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catalase , Citocinas/farmacologia , Diabetes Mellitus Experimental/patologia , Hidroxiprolina , Interleucina-1beta/farmacologia , Interleucina-6 , Lipídeos/farmacologia , Ratos , Ratos Wistar , Sesquiterpenos , Sulfadiazina de Prata/farmacologia , Estreptozocina/farmacologia , Superóxido Dismutase , Fator de Necrose Tumoral alfa/farmacologia , Cicatrização
3.
Molecules ; 27(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36080332

RESUMO

Oxidative stress and inflammation play a crucial role in the pathogenesis and progression of diabetes. Currently, there is a growing need to exploit plant-derived bioactive compounds to support conventional therapies. The purpose of this study was to explore allyl isothiocyanate (AITC) potency in reducing oxidative and inflammatory stress along with its profitable modulation trace element status in pathological conditions such as diabetes. Two weeks of oral AITC treatments (2.5, 5, and 25 mg/kg body weight per day) were evaluated in Wistar rats with diabetes induced by a high-fat diet and streptozotocin. The study included AITC influence on antioxidant factors (SOD, CAT, GST, Nrf2), stress and inflammatory markers (cortisol, CRP, IL-1ß, IL-6, TNFα, NF-κB), lipid peroxidation indices (TBARS, -SH groups), and trace element status (Fe, Zn, and Cu) in the detoxification and lymphoid organs. Independently of dose, AITC increased cortisol levels in rat blood serum and decreased total thiol groups (T-SH) and protein-bound thiol groups (PB-SH) collaterally with raised thiobarbituric acid reactive substances (TBARS) in diabetic rat liver. The inflammation and oxidative effects were enhanced by an AITC dose increase. The highest dose of AITC, 25 mg/kg b.w., strongly affected the inflammation process by increasing IL-6, IL-1ß, and TNFα in the blood serum, and it upregulated Nrf2 transcription factor with increased SOD, GPx, and GST activities in the liver. AITC showed an equivocal effect on profitable modulation of disturbances in mineral homeostasis in the liver, kidney, and spleen. Our findings revealed that two-week AITC treatment exacerbated oxidative and inflammation status in diabetic rats.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Oligoelementos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hidrocortisona , Inflamação/tratamento farmacológico , Interleucina-6/farmacologia , Isotiocianatos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ratos , Ratos Wistar , Compostos de Sulfidrila/farmacologia , Superóxido Dismutase/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico , Fator de Necrose Tumoral alfa/farmacologia
4.
Stem Cell Res Ther ; 13(1): 418, 2022 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-35964109

RESUMO

BACKGROUND: Autologous stem cell therapy is a promising strategy for cardiovascular diseases including diabetic cardiomyopathy (DCM), but conclusions from clinical trials were compromised. We assumed that diabetes might induce the dysfunction of stem cells and thus limit its therapeutic effect. This study aimed to compare the effect of diabetes and nondiabetes-derived bone marrow mesenchymal stem cells (BMSCs) transplantation on DCM and explored the potential mechanism. METHODS: Rats with diabetes were induced using high-fat diets and streptozotocin (STZ) injection. BMSCs harvested from diabetic and nondiabetic rats were infused into DCM rats, and the effects on the heart were identified by echocardiography and histopathology. The inhibition or overexpression of SAHH in nondiabetic and diabetic BMSCs was used to confirm its key role in stem cell activity and cardiac therapy. RESULTS: Compared with normal BMSCs, the therapeutic effects of diabetic rat-derived stem cells on improving cardiac function and adverse remodeling were significantly attenuated. In vitro, diabetic BMSCs had lower cell viability and paracrine function than nondiabetic BMSCs. It was further found that diabetic BMSCs had obvious mitochondrial oxidative stress damage and S-adenosylhomocysteine (SAH) accumulation due to S-adenosylhomocysteine hydrolase (SAHH) deficiency. SAHH inhibition by adenosine dialdehyde (ADA) or shSAHH plasmid in normal BMSCs significantly reduced the favorable effects on endothelial cell proliferation and tube-forming capacity. In contrast, SAHH overexpression in diabetic BMSCs significantly improved cellular activity and paracrine function. Transplantation of BMSCs with SAHH overexpression improved cardiac adverse remodeling and angiogenesis. Activation of the Nrf2 signaling pathway may be one of the key mechanisms of SAHH-mediated improvement of stem cell viability and cardiac repair. CONCLUSIONS: Diabetes leads to compromised bioactivity and repair capacity of BMSCs. Our study suggests that SAHH activation may improve the cardioprotective effect of autologous transplantation of diabetes-derived BMSCs on patients with DCM. Diabetes induced the inhibition of S-adenosylhomocysteine (SAH) expression and aging phenotype in BMSCs and thus decreased the cell viability and paracrine function. Compared with normal BMSCs, the therapeutic effects of diabetic rat-derived BMSCs on improving cardiac function and adverse remodeling were significantly attenuated. SAHH overexpression in diabetic BMSCs significantly rescued cellular function partly via activating Nrf2/HO-1 signal. Transplantation of diabetic BMSCs with SAHH overexpression improved angiogenesis and cardiac adverse remodeling in rats.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Células-Tronco Mesenquimais , Adenosil-Homocisteinase/metabolismo , Adenosil-Homocisteinase/farmacologia , Animais , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/terapia , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , S-Adenosil-Homocisteína/metabolismo , S-Adenosil-Homocisteína/farmacologia
5.
Exp Mol Med ; 54(8): 1086-1097, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35918533

RESUMO

Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Estresse do Retículo Endoplasmático , Fibrose , Humanos , Rim/patologia , Losartan , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Ratos , Quinases da Família src/metabolismo
6.
BMC Med Imaging ; 22(1): 136, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927630

RESUMO

BACKGROUND: Altered neural activity based on the fractional amplitude of low-frequency fluctuations (fALFF) has been reported in patients with diabetes. However, whether fALFF can differentiate healthy controls from diabetic animals under anesthesia remains unclear. The study aimed to elucidate the changes in fALFF in a rat model of diabetes under isoflurane anesthesia. METHODS: The first group of rats (n = 5) received a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to cause the development of diabetes. The second group of rats (n = 7) received a single intraperitoneal injection of the same volume of solvent. Resting-state functional magnetic resonance imaging was used to assess brain activity at 4 weeks after STZ or solvent administration. RESULTS: Compared to the healthy control animals, rats with diabetes showed significantly decreased fALFF in various brain regions, including the cingulate cortex, somatosensory cortex, insula, and striatum (all P < 0.05). The decreased fALFF suggests the aberrant neural activities in the diabetic rats. No regions were detected in which the control group had a lower fALFF than that in the diabetes group. CONCLUSIONS: The results of this study demonstrated that the fALFF could be used to differentiate healthy controls from diabetic animals, providing meaningful information regarding the neurological pathophysiology of diabetes in animal models.


Assuntos
Anestesia , Diabetes Mellitus Experimental , Isoflurano , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/patologia , Isoflurano/farmacologia , Imageamento por Ressonância Magnética/métodos , Ratos , Solventes
7.
Int J Mol Sci ; 23(16)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36012625

RESUMO

Despite the worldwide prevalence and severe complications of type 2 diabetes mellitus (T2DM), the pathophysiological mechanisms underlying the development of diabetic polyneuropathy (DPN) are poorly understood. Beyond strict control of glucose levels, clinical trials for reversing DPN have largely failed. Therefore, understanding the pathophysiological and molecular mechanisms underlying DPN is crucial. Accordingly, this study explored biochemical and neuropathological deficits in a rat model of T2DM induced through high-fat diet (HFD) feeding along with two low-dose streptozotocin (STZ) injections; the deficits were explored through serum lipid, neurobehavioral, neurophysiology, neuropathology, and immunohistochemistry examinations. Our HFD/STZ protocol induced (1) mechanical hyperalgesia and depression-like behaviors, (2) loss of intraepidermal nerve fibers (IENFs) and reduced axonal diameters in sural nerves, and (3) decreased compound muscle action potential. In addition to hyperglycemia, which was correlated with the degree of mechanical hyperalgesia and loss of IENFs, we observed that hypertriglyceridemia was the most dominant deficit in the lipid profiles of the diabetic rats. In particular, SEPT9, the fourth component of the cytoskeleton, increased in the satellite glial cells (SGCs) of the dorsal root ganglia (DRG) in the T2DM-like rats. The number of SEPT9(+) SGCs/DRG was correlated with serum glucose levels and mechanical thresholds. Our findings indicate the putative molecular mechanism underlying DPN, which presumably involves the interaction of SGCs and DRG neurons; nevertheless, further functional research is warranted to clarify the role of SEPT9 in DPN.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Neuralgia , Septinas , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Neuropatias Diabéticas/patologia , Gânglios Espinais/patologia , Glucose/uso terapêutico , Hiperalgesia , Lipídeos/uso terapêutico , NAD , Neuralgia/patologia , Neuroglia/patologia , Ratos , Ratos Sprague-Dawley , Septinas/genética , Estreptozocina , Regulação para Cima
8.
Cardiovasc Diabetol ; 21(1): 165, 2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36030201

RESUMO

BACKGROUND: Cardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes. METHODS: Type 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed. RESULTS: We showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes. CONCLUSIONS: We have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cardiomiopatias Diabéticas , Necroptose , Proteínas Quinases , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Glucose , Camundongos , Proteínas Quinases/metabolismo , RNA Interferente Pequeno , Troponina I
9.
Cell Mol Biol (Noisy-le-grand) ; 67(4): 42-55, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35809303

RESUMO

In view of many complications of diabetes, kidney failure is considered as one of the main complications. The oxidative stress-induced due to persistent hyperglycemic conditions is the major cause of kidney disease. The present study was designed to explore the nephroprotective efficacy of polyherbal (PH) extract in a diabetic model induced by streptozotocin (STZ). STZ (55 mg/kg body weight, intraperitoneal) was injected in overnight fasting rats to develop the diabetic experimental model. Effect on kidney injury was evaluated by investigating biochemical and histological evidences in renal tissue after 56 days of treatment of PH extract. Results showed the high glucose level in STZ treated rats that suggested hyperglycemia persistence along with the successful establishment of nephropathy in diabetic rats with altered renal function, inflammatory cytokines level as well as oxidative and nitrosative stress. Administration of PH extract significantly improved the glycemic condition, glomerular function and proximal reabsorptive markers. Further, elevated pro-inflammatory cytokines levels and disturbed redox status were restored. Moreover, findings were fostered and substantiated by histopathological examinations. Our work strongly proposes that the nephroprotective effect of the PH extract on renal damage could be attributed due to its anti-inflammatory and antioxidant properties. Thus, PH extract could have potential as a pharmaceutical drug for diabetes mellitus (DM). Additional long-term study or clinical trial is required for further investigations.


Assuntos
Diabetes Mellitus Experimental , Insuficiência Renal , Animais , Glicemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Rim/metabolismo , Modelos Teóricos , Estresse Oxidativo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Insuficiência Renal/complicações , Estreptozocina/farmacologia
10.
Stem Cell Res Ther ; 13(1): 293, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35841055

RESUMO

BACKGROUND: As a leading cause of vision decline and severe blindness in adults, diabetic retinopathy (DR) is characterized by the aggravation of retinal oxidative stress and apoptosis in the early stage. Emerging studies reveal that mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) treatment represents a promising cell-free approach to alleviate ocular disorders. However, the repairing effects of MSC-sEV in DR remain largely unclear. This study aimed at exploring the role and the underlying mechanism of MSC-sEV in hyperglycemia-induced retinal degeneration. METHODS: In vivo, we used streptozotocin (STZ) to establish diabetic rat model, followed by the intravitreal injection of MSC-sEV to determine the curative effect. The cell viability and antioxidant capacity of retinal pigment epithelium (RPE) cells stimulated with high-glucose (HG) medium after MSC-sEV treatment were analyzed in vitro. By detecting the response of cell signaling pathways in MSC-sEV-treated RPE cells, we explored the functional mechanism of MSC-sEV. Mass spectrometry was performed to reveal the bioactive protein which mediated the role of MSC-sEV. RESULTS: The intravitreal injection of MSC-sEV elicited antioxidant effects and counteracted retinal apoptosis in STZ-induced DR rat model. MSC-sEV treatment also reduced the oxidative level and enhanced the proliferation ability of RPE cells cultured in HG conditions in vitro. Further studies showed that the increased level of phosphatase and tensin homolog (PTEN) inhibited AKT phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2) expression in RPE cells stimulated with HG medium, which could be reversed by MSC-sEV intervention. Through mass spectrometry, we illustrated that MSC-sEV-delivered neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) could cause PTEN ubiquitination and degradation, activate AKT signaling and upregulate NRF2 level to prevent DR progress. Moreover, NEDD4 knockdown impaired MSC-sEV-mediated retinal therapeutic effects. CONCLUSIONS: Our findings indicated that MSC-sEV ameliorated DR through NEDD4-induced regulation on PTEN/AKT/NRF2 signaling pathway, thus revealing the efficiency and mechanism of MSC-sEV-based retinal protection and providing new insights into the treatment of DR.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Vesículas Extracelulares , Células-Tronco Mesenquimais , Ubiquitina-Proteína Ligases Nedd4 , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Retinopatia Diabética/terapia , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ubiquitina-Proteína Ligases Nedd4/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
11.
Dis Markers ; 2022: 9696303, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35845136

RESUMO

Objective: To determine the expression profiling and mechanism of thioredoxin-interacting protein (TXNIP)/nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome pathway in sciatic nerve (SN) of type 2 diabetes mellitus (T2DM) rats. Methods: Ten out of the 35 healthy SD rats (specific pathogen free) purchased were randomized into the control group, while the others were established a T2DM model by feeding a high-fat and high-sugar diet plus laparoscopic injection of 1% streptozotocin (STZ). The successfully modeled rats were subgrouped into two arms: a DM group with 10 rats and a resveratrol- (RES-) treated DM intervention group with 11 rats. Normal saline to control and DM groups. Alterations in fasting blood glucose (FBG) and body weight (BW) at different time points after administration were observed. Sciatic nerve conduction velocity (SNCV) and mechanical pain threshold (MPT) were measured. TXNIP, NLRP3, caspase-1, and interleukin- (IL-) 1ß levels in rat SN tissue were determined. Results: DM group rats showed higher FBG and lower BW than control rats at different time points (P < 0.05). The FBG of DM intervention group at 2, 4, and 6 weeks after administration was lower, and the BW at 4 and 6 weeks after dosing was higher than DM group. Higher MPT and SNCV were determined in DM intervention group versus DM group (P < 0.05). DM group rats had disordered, swollen, and dissolved SN myelin sheath structure; TXNIP inhibition led to a small amount of nerve myelin fragments and mild pathological changes. Lower TXNIP, NLRP3, caspase-1, and IL-1ß protein levels were found in DM intervention group versus DM group (P < 0.05). Conclusion: The pathogenesis of peripheral neuropathy in T2DM rats may be linked to TXNIP/NLRP3 inflammasome pathway activation, indicating the potential of this pathway as a therapeutic target for diabetic peripheral neuropathy (DPN).


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Caspases , Proteínas de Ciclo Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Inflamassomos/metabolismo , Inflamassomos/uso terapêutico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
12.
Commun Biol ; 5(1): 734, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869269

RESUMO

Podocyte injury is involved in the onset and progression of various kidney diseases. We previously demonstrated that the transcription factor, old astrocyte specifically induced substance (OASIS) in myofibroblasts, contributes to kidney fibrosis, as a novel role of OASIS in the kidneys. Importantly, we found that OASIS is also expressed in podocytes; however, the pathophysiological significance of OASIS in podocytes remains unknown. Upon lipopolysaccharide (LPS) treatment, there is an increase in OASIS in murine podocytes. Enhanced serum creatinine levels and tubular injury, but not albuminuria and podocyte injury, are attenuated upon podocyte-restricted OASIS knockout in LPS-treated mice, as well as diabetic mice. The protective effects of podocyte-specific OASIS deficiency on tubular injury are mediated by protein kinase C iota (PRKCI/PKCι), which is negatively regulated by OASIS in podocytes. Furthermore, podocyte-restricted OASIS transgenic mice show tubular injury and tubulointerstitial fibrosis, with severe albuminuria and podocyte degeneration. Finally, there is an increase in OASIS-positive podocytes in the glomeruli of patients with minimal change nephrotic syndrome and diabetic nephropathy. Taken together, OASIS in podocytes contributes to podocyte and/or tubular injury, in part through decreased PRKCI. The induction of OASIS in podocytes is a critical event for the disturbance of kidney homeostasis.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Podócitos , Albuminúria/genética , Albuminúria/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Fibrose , Homeostase , Rim/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Pirróis , Regulação para Cima , Compostos de Vinila
13.
Cell Death Dis ; 13(7): 663, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35908070

RESUMO

Sestrin2 is identified as a stress-induced protein and could functionate in many aspects. In our study, we investigated the latent impact of Sestrin2 on podocyte injury and its molecular mechanism in vivo and in vitro in diabetic kidney disease (DKD). Sestrin2 was low-expressed in renal biopsies from individuals with DKD, the glomeruli from diabetic mice, and mouse podocytes exposed to high glucose (HG). Sestrin2 overexpression ameliorated HG-induced phenotypic alterations, apoptosis, and oxidative stress in conditionally immortalized mouse podocytes and modulated the activity of Thrombospondin-1 (TSP-1)/transforming growth factor (TGF-ß1)/Smad3 pathway in podocytes. Moreover, TSP-1 inhibitor LSKL or TGF-ß blocker Pirfenidone arrested podocyte injury induced by HG. Streptozotocin (STZ) was employed to render equivalent diabetes in B6-TgN (CMV-Sestrin2) (TgN) and wild-type (WT) control mice. Sestrin2 alleviated increased levels of 24-h urinary protein, blood urea nitrogen, serum creatinine and triglyceride, and urine 8-OHdG in diabetic mice. Podocyte phenotypic alterations, increased expression of apoptosis-associated proteins and podocyte loss were observed in WT but not in diabetic TgN mice, as well as oxidative stress. Additionally, TSP-1/TGF-ß1/Smad3 signaling pathway was also suppressed in glomeruli of diabetic TgN mice. Thus, Sestrin2 mitigates podocyte injury in DKD via orchestrating TSP-1/TGF-ß1/Smad3 pathway, underlining Sestrin2 as a promising therapeutic target for DKD.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Podócitos , Sestrinas/metabolismo , Animais , Apoptose , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Camundongos , Podócitos/metabolismo , Proteína Smad3/metabolismo , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
FASEB J ; 36(8): e22440, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35815932

RESUMO

4-hydroxy-2-nonenal (4HNE), an oxidative stress byproduct, is elevated in diabetes which decreases coronary angiogenesis, and this was rescued by the 4HNE detoxifying enzyme, aldehyde dehydrogenase 2 (ALDH2). Adiponectin (APN), an adipocytokine, has pro-angiogenic properties and its loss of function is critical in diabetes and its complications. Coronary endothelial cell (CEC) damage is the initiating step of diabetes-mediated heart failure with preserved ejection fraction (HFpEF) pathogenesis. Thus, we hypothesize that ALDH2 restores 4HNE-induced downregulation of APN signaling in CECs and subsequent coronary angiogenesis in diabetic HFpEF. Treatment with disulfiram, an ALDH2 inhibitor, exacerbated 4HNE-mediated decreases in APN-induced increased coronary angiogenesis and APN-signaling cascades, whereas pretreatment with alda1, an ALDH2 activator, rescued the effect of 4HNE. We employed control mice (db/m), spontaneous type-2 diabetic mice (db/db), ALDH2*2 knock-in mutant mice with intrinsic low ALDH2 activity (AL), and diabetic mice with intrinsic low ALDH2 activity (AF) mice that were created by crossing db/db and AL mice to test our hypothesis in vivo. AF mice exhibited heart failure with preserved ejection fraction (HFpEF)/severe diastolic dysfunction at 6 months with a preserved systolic function compared with db/db mice as well as 3 months of their age. Decreased APN-mediated coronary angiogenesis, along with increased circulatory APN levels and decreased cardiac APN signaling (index of APN resistance) were higher in AF mice relative to db/db mice. Alda1 treatment improved APN-mediated angiogenesis in AF and db/db mice. In summary, 4HNE-induces APN resistance and a subsequent decrease in coronary angiogenesis in diabetic mouse heart which was rescued by ALDH2.


Assuntos
Diabetes Mellitus Experimental , Insuficiência Cardíaca , Adiponectina , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Diabetes Mellitus Experimental/patologia , Camundongos , Volume Sistólico
15.
J Immunol ; 209(3): 465-475, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35725270

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic ß cells, inflammatory lesions within islets (insulitis), and ß cell loss. We previously showed that Ag-specific tolerance targeting single ß cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD.scid mice. However, tolerance induction to individual diabetogenic proteins, for example, GAD65 (glutamic acid decarboxylase 65) or insulin, has failed to ameliorate T1D both in wild-type NOD mice and in the clinic. Initiation and progression of T1D is likely due to activation of T cells specific for multiple diabetogenic epitopes. To test this hypothesis, recombinant insulin, GAD65, and chromogranin A proteins were encapsulated within poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (COUR CNPs) to assess regulatory T cell induction, inhibition of Ag-specific T cell responses, and blockade of T1D induction/progression in NOD mice. Whereas treatment of NOD mice with CNPs containing a single protein inhibited the corresponding Ag-specific T cell response, inhibition of overt T1D development only occurred when all three diabetogenic proteins were included within the CNPs (CNP-T1D). Blockade of T1D following CNP-T1D tolerization was characterized by regulatory T cell induction and a significant decrease in both peri-insulitis and immune cell infiltration into pancreatic islets. As we have recently published that CNP treatment is both safe and induced Ag-specific tolerance in a phase 1/2a celiac disease clinical trial, Ag-specific tolerance induced by nanoparticles encapsulating multiple diabetogenic proteins is a promising approach to T1D treatment.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Nanopartículas , Animais , Diabetes Mellitus Experimental/patologia , Epitopos , Insulina , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas
16.
Anal Chem ; 94(25): 8909-8918, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35699514

RESUMO

Unresolved inflammation compromises diabetic wound healing. Recently, we reported that inadequate RNA packaging in murine wound-edge keratinocyte-originated exosomes (Exoκ) leads to persistent inflammation [Zhou, X. ACS Nano 2020, 14(10), 12732-12748]. Herein, we use charge detection mass spectrometry (CDMS) to analyze intact Exoκ isolated from a 5 day old wound-edge tissue of diabetic mice and a heterozygous nondiabetic littermate control group. In CDMS, the charge (z) and mass-to-charge ratio (m/z) of individual exosome particles are measured simultaneously, enabling the direct analysis of masses in the 1-200 MDa range anticipated for exosomes. These measurements reveal a broad mass range for Exoκ from ∼10 to >100 MDa. The m and z values for these exosomes appear to fall into families (subpopulations); a statistical modeling analysis partially resolves ∼10-20 Exoκ subpopulations. Complementary proteomics, immunofluorescence, and electron microscopy studies support the CDMS results that Exoκ from diabetic and nondiabetic mice vary substantially. Subpopulations having high z (>650) and high m (>44 MDa) are more abundant in nondiabetic animals. We propose that these high m and z particles may arise from differences in cargo packaging. The veracity of this idea is discussed in light of other recent CDMS results involving genome packaging in vaccines, as well as exosome imaging experiments. Characterization of intact exosome particles based on the physical properties of m and z provides a new means of investigating wound healing and suggests that CDMS may be useful for other pathologies.


Assuntos
Diabetes Mellitus Experimental , Exossomos , Animais , Diabetes Mellitus Experimental/patologia , Exossomos/patologia , Inflamação , Queratinócitos , Espectrometria de Massas , Camundongos
17.
Drug Deliv ; 29(1): 1776-1784, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35642489

RESUMO

The current work aims to design thioctic acid (TA) and glatiramer acetate (GA) nanoconjugate (thioctamer) loaded hydrogel formula as well as evaluation of thioctamer preclinical efficacy in expediting wound healing in a rat model of the diabetic wound. Thioctamer was prepared by conjugation of GA and TA in a 1:1 molar ratio. Particle size, zeta potential, and thermodynamic stability of the prepared thioctamer were assessed. Thioctamer was loaded in hydroxypropyl methylcellulose-based hydrogel and in vitro release study was investigated. The ability of thioctamer to enhance the process of wound healing in diabetic rats was investigated by assessing wound contraction and immunohistochemical assessment of the inflammation markers IL-6 and TNF-α. The results demonstrated that thioctamer showed particle size of 137 ± 21.4 nm, polydispersity index (PDI) of 0.235, and positive zeta potential value of 7.43 ± 4.95 mV. On day 7 of making a skin excision, diabetic rat wounds administered thioctamer preparation showed almost complete healing (95.6 ± 8.6%). Meanwhile, % of wound contraction in animals treated with TA or GA groups exhibited values amounting to 56.5 ± 5.8% and 62.6 ± 7.1%, respectively. Histological investigation showed that the highest healing rate was noted in the thioctamer group animals, as the surface of the wound was nearly fully protected by regenerated epithelium with keratinization, with few inflammatory cells noticed. Thioctamer significantly (p<.05) inhibited IL-6 and TNF-α expression as compared with sections obtained from the negative control, TA, GA, or positive control group animals on day 7. The evidence of the ability of thioctamer to significantly expedite wound healing in the diabetic rats is presented.


Assuntos
Diabetes Mellitus Experimental , Ácido Tióctico , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Acetato de Glatiramer , Hidrogéis , Interleucina-6 , Nanoconjugados , Ratos , Fator de Necrose Tumoral alfa , Cicatrização
18.
Nat Commun ; 13(1): 3545, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35729232

RESUMO

Pancreatic ß cell dysfunction contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic ß cell function remains largely elusive. In the current study, we identify the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their ß cells (miR-21ßKO). We find that miR-21ßKO mice develop glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies reveal that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets results in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrate that delivery of miR-21 into the pancreas of type 2 diabetic db/db male mice is able to promote Glut2 expression and reduce blood glucose level. Taking together, our results reveal that miR-21 in islet ß cell promotes insulin secretion and support a role for miR-21 in the regulation of pancreatic ß cell function in type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Glucose , Células Secretoras de Insulina , MicroRNAs , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
19.
BMC Musculoskelet Disord ; 23(1): 563, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35689230

RESUMO

BACKGROUND: Quercetin, a flavonoid abundantly in vegetables and fruits, exerts antioxidant and anti-inflammatory effects. We investigated the protective effects of quercetin against oxidative stress in the Achilles tendons of diabetic rats. METHODS: Cells were collected from the Achilles tendons of Sprague-Dawley rats and cultured under four conditions: regular glucose (RG) without quercetin (Quer-), RG with quercetin (Quer +), high-glucose (HG) Quer-, and HG Quer + . The expression of genes related to NADPH oxidase (NOX) and inflammation, reactive oxygen species accumulation, and apoptosis rates was analyzed. Additionally, diabetic rats were divided into two groups and subjected to quercetin (group Q) or no quercetin (group C) treatment. Histological evaluation and expression analysis of relevant genes in the Achilles tendon were performed. RESULTS: In rat tendon-derived cells, the expression of Nox1, Nox4, and Il6; reactive oxygen species accumulation; and apoptosis rates were significantly decreased by quercetin treatment in the HG group. The collagen fiber arrangement was significantly disorganized in the diabetic rat Achilles tendons in group C compared with that in group Q. The mRNA and protein expression levels of NOX1 and NOX4 were significantly decreased upon quercetin treatment. Furthermore, the expression of Il6, type III collagen, Mmp2, and Timp2 was significantly decreased, whereas that of type I collagen was significantly increased in group Q compared with that in group C. CONCLUSIONS: Quercetin treatment decreases NOX expression and thus exerts antioxidant and anti-inflammatory effects in the Achilles tendons of diabetic rats. Quercetin treatment may be effective against diabetic tendinopathy.


Assuntos
Tendão do Calcâneo , Diabetes Mellitus Experimental , Hiperglicemia , Tendão do Calcâneo/patologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Interleucina-6/metabolismo , NADPH Oxidases/metabolismo , Estresse Oxidativo , Quercetina/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
20.
Front Immunol ; 13: 930397, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757735

RESUMO

Metabolic disorders (i.e., hyperglycemia, hyperlipidemia, and hyperinsulinemia) cause increased secretion of inflammatory cytokines/chemokines, leading to gradual loss of cardiac resident macrophage population and increased accumulation of inflammatory monocytes/macrophages in the heart. Such self-perpetuating effect may contribute to the development of cardiomyopathy during diabetes. Recent meta-analysis data reveal that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue of patients with heart failure but is increased in the blood of septic patients. However, the functional role of Lcn10 in cardiac inflammation triggered by metabolic disorders has never been investigated. In this study, we demonstrate that the expression of Lcn10 in macrophages was significantly decreased under multiple metabolic stress conditions. Furthermore, Lcn10-null macrophages exhibited pro-inflammatory phenotype in response to inflammation stimuli. Next, using a global Lcn10-knockout (KO) mouse model to induce type-2 diabetes (T2D), we observed that loss of Lcn10 promoted more pro-inflammatory macrophage infiltration into the heart, compared to controls, leading to aggravated insulin resistance and impaired cardiac function. Similarly, adoptive transfer of Lcn10-KO bone marrow cells into X-ray irradiated mice displayed higher ratio of pro-/anti-inflammatory macrophages in the heart and worsened cardiac function than those mice received wild-type (WT) bone marrows upon T2D conditions. Mechanistically, RNA-sequencing analysis showed that Nr4a1, a nuclear receptor known to have potent anti-inflammatory effects, is involved in Lcn10-mediated macrophage activation. Indeed, we found that nuclear translocation of Nr4a1 was disrupted in Lcn10-KO macrophages upon stimulation with LPS + IFNγ. Accordingly, treatment with Cytosporone B (CsnB), an agonist of Nr4a1, attenuated the pro-inflammatory response in Lcn10-null macrophages and partially improved cardiac function in Lcn10-KO diabetic mice. Together, these findings indicate that loss of Lcn10 skews macrophage polarization to pro-inflammatory phenotype and aggravates cardiac dysfunction during type-2 diabetes through the disruption of Nr4a1-mediated anti-inflammatory signaling pathway in macrophages. Therefore, reduction of Lcn10 expression observed in diabetic macrophages may be responsible for the pathogenesis of diabetes-induced cardiac dysfunction. It suggests that Lcn10 might be a potential therapeutic factor for diabetic heart failure.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Lipocalinas , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lipocalinas/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética
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