Nuclear Factor Erythroid 2-Related Factor 2 Deletion Impairs Glucose Tolerance and Exacerbates Hyperglycemia in Type 1 Diabetic Mice

The present study tested whether MG132 increases vascular nuclear factor E2-related factor-2 (Nrf2) expression and transcription to provide a therapeutic effect on diabetes-induced pathogenic changes in the aorta. To this end, three-month-old OVE26 diabetic and age-matched control mice were intraperitoneally injected with MG-132, 10 μg/kg daily for 3 months. OVE26 transgenic type 1 diabetic mice develop hyperglycemia at 2-3 weeks of age and exhibit albuminuria at 3 months of age with mild increases in TNF-αexpression and 3-NT accumulation in the aorta. Diabetes-induced significant increases in the wall thickness and structural derangement of aorta were found in OVE26 mice with significant increases in aortic oxidative and nitrosative damage, inflammation, and remodeling at 6 months of diabetes, but not at 3 months of diabetes. However, these pathological changes seen at the 6 months of diabetes were abolished in OVE26 mice treated with MG-132 for 3 months that were also associated with a significant increase in Nrf2 expression in the aorta as well as transcription of downstream genes. These results suggest that chronic treatment with low-dose MG132 can afford an effective therapy for diabetes-induced pathogenic changes in the aorta, which is associated with the increased Nrf2 expression and transcription.

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Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice

Molecules ◽

10.3390/molecules25194381 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4381

Author(s):

Zakiyatul Faizah ◽

Bella Amanda ◽

Faisal Yusuf Ashari ◽

Efta Triastuti ◽

Rebecca Oxtoby ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glucose Tolerance ◽

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

In Vivo Models ◽

Type 2 Dm ◽

Type 1 Dm

Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM—type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated using anti-hyperglycemic agents. Despite its effectiveness in controlling blood glucose level, this therapeutic approach is not able to reduce the decline in the number of functional pancreatic β cells. MST1 is a strong pro-apoptotic kinase that is expressed in pancreatic β cells. It induces β cell death and impairs insulin secretion. Recently, a potent and specific inhibitor for MST1, called XMU-MP-1, was identified and characterized. We hypothesized that treatment with XMU-MP-1 would produce beneficial effects by improving the survival and function of the pancreatic β cells. We used INS-1 cells and STZ-induced diabetic mice as in vitro and in vivo models to test the effect of XMU-MP-1 treatment. We found that XMU-MP-1 inhibited MST1/2 activity in INS-1 cells. Moreover, treatment with XMU-MP-1 produced a beneficial effect in improving glucose tolerance in the STZ-induced diabetic mouse model. Histological analysis indicated that XMU-MP-1 increased the number of pancreatic β cells and enhanced Langerhans islet area in the severe diabetic mice. Overall, this study showed that MST1 could become a promising therapeutic target for diabetes mellitus.

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Reversal of New-Onset Type 1 Diabetes in Mice and Induction of FoxP3+ Regulatory T Cells by Syngeneic Bone Marrow Transplantation.

Blood ◽

10.1182/blood.v110.11.4857.4857 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4857-4857

Author(s):

Jian Ouyang ◽

Yanting Wen ◽

Junhao Chen ◽

Yong Liu ◽

De Pei Wu

Keyword(s):

Bone Marrow ◽

Type 1 Diabetes ◽

Blood Glucose ◽

Bone Marrow Transplantation ◽

Glucose Tolerance ◽

Marrow Transplantation ◽

Diabetic Mice ◽

Insulin Levels ◽

New Onset

Abstract Objective: Autologous bone marrow transplantation (ABMT) was introduced as a novel strategy to treat new-onset type 1 diabetes (T1D). Induction of CD4+CD25+ FoxP3+T regulatory lymphocytes (Tregs) helps maintain self-tolerance in autoimmune diabetes. Here, we were tying to investigate the effects of syngeneic bone marrow transplantation (syn-BMT) in T1D mice models and to investigate the role of Tregs in this context. Research design and methods: Syn-BMT was used to mimic the ABMT to T1D patients in human. Fraternal inbred multiple low doses of streptozotocin (mld-SZ) induced diabetic mice were used as both donors (n = 7) and recipients (n = 20). And normal fraternal inbred mice were also used as donors (n=13). After total body irritation to recipient mice, syn-BMT was given either on day 10 or on day 40 of T1D. Blood and urine glucose was observed. On day120 after syn-BMT, glucose tolerance was tested and then mice were killed. Insulin levels in sera were tested by ELISA and pancreata histological and morphometry were analyzed by HE staining. Tregs in spleens were tested by Flow cytometry analysis, FoxP3 protein was tested by western blot, and FoxP3 mRNA was tested by real time PCR. Results: Syn-BMT, if applied when T1D is new-onset (10 d), can reverse blood glucose to close to normoglycemia without farther relapse, maintain blood insulin levels, improve glucose tolerance and ameliorate pancreata destruction. Syn-BMT leading to recovery of T1D results in the induction of Tregs, increased Foxp3 protein and mRNA expression in both the groups of diabetic mice receiving syn-BMT with either diabetic or normal donors. However, if given on a later disease stage (40 d), although syn-BMT helped reduce blood glucose for about 66 d and improved pancreata histological and morphometry, it showed relapse of diabetes further and decrement of insulin levels. Interestingly, this group did not show the increment of Tregs, Foxp3 protein or mRNA expression. Conclusions: This study provided a rationale to treat human new-onset T1D with autologous HSC. Syn-BMT, if given when T1D is new-onset, is safe and is able to reverse the diabetic status. The induction of Tregs and Foxp3 in both mRNA and protein levels as the results of syn-BMT, may contribute to the immune tolerance after syn-BMT, and the observed improvement of new-onset T1D.

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HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00465.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E150-E162 ◽

Cited By ~ 11

Author(s):

Jian Zhang ◽

Zheng Xu ◽

Junlian Gu ◽

Saizhi Jiang ◽

Quan Liu ◽

...

Keyword(s):

Nuclear Translocation ◽

Hdac Inhibitors ◽

Vascular Complications ◽

Specific Inhibitor ◽

Histone Deacetylation ◽

Fibroblast Growth Factor 21 ◽

Related Factor ◽

Diabetic Mice ◽

Protein Levels

Vascular complications are common pathologies associated with type 1 diabetes. In recent years, histone deacetylation enzyme (HDAC) inhibitors have been shown to be successful in preventing atherosclerosis. To investigate the mechanism for HDAC3 inhibition in preventing diabetic aortic pathologies, male OVE26 type 1 diabetic mice and age-matched wild-type (FVB) mice were given the HDAC3-specific inhibitor RGFP-966 or vehicle for 3 mo. These mice were then euthanized immediately or maintained for an additional 3 mo without treatment. Levels of aortic inflammation and fibrosis and plasma and fibroblast growth factor 21 (FGF21) levels were determined. Because the liver is the major organ for FGF21 synthesis in diabetic animals, the effects of HDAC3 inhibition on hepatic FGF21 synthesis were examined. Additionally, hepatic miR-200a and kelch-like ECH-associated protein 1 (Keap1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation were measured. HDAC3 inhibition significantly reduced aortic fibrosis and inflammation in OVE26 mice at both 3 and 6 mo. Plasma FGF21 levels were significantly higher in RGFP-966-treated OVE26 mice compared with vehicle-treated mice at both time points. It also significantly reduced hepatic pathologies associated with diabetes, accompanied by increased FGF21 mRNA and protein expression. HDAC3 inhibition also increased miR-200a expression, reduced Keap1 protein levels, and increased Nrf2 nuclear translocation with an upregulation of antioxidant gene and FGF21 transcription. Our results support a model where HDAC3 inhibition may promote Nrf2 activity by increasing miR-200a expression with a concomitant decrease in Keap1 to preserve hepatic FGF21 synthesis. The preservation of hepatic FGF21 synthesis ultimately leads to a reduction in diabetes-induced aorta pathologies.

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Effects of Lespedeza Bicolor Extract on Regulation of AMPK Associated Hepatic Lipid Metabolism in Type 2 Diabetic Mice

Antioxidants ◽

10.3390/antiox8120599 ◽

2019 ◽

Vol 8 (12) ◽

pp. 599 ◽

Cited By ~ 3

Author(s):

Younmi Kim ◽

Heaji Lee ◽

Sun Yeou Kim ◽

Yunsook Lim

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Smooth Muscle Actin ◽

Lipid Synthesis ◽

Hepatic Damage ◽

Related Factor ◽

Nuclear Factor ◽

Diabetic Mice ◽

Lespedeza Bicolor

Lespedeza bicolor (LB) is one of the ornamental plants used for the treatment of inflammation caused by oxidative damage. However, its beneficial effects on hyperglycemia-induced hepatic damage and the related molecular mechanisms remain unclear. We hypothesized that Lespedeza bicolor extract (LBE) would attenuate hyperglycemia-induced liver injury in type 2 diabetes mellitus (T2DM). Diabetes was induced by a low dosage of streptozotocin (STZ) injection (30 mg/kg) with a high fat diet in male C57BL/6J mice. LBE was administered orally at 100 mg/kg or 250 mg/kg for 12 weeks. LBE supplementation regardless of dosage ameliorated plasma levels of hemoglobin A1c (HbA1c) in diabetic mice. Moreover, both LBE supplementations upregulated AMP-activation kinase (AMPK), which may activate sirtuin1 (SIRT) associated pathway accompanied by decreased lipid synthesis at low dose of LBE supplementation. These changes were in part explained by reduced protein levels of oxidative stress (nuclear factor erythroid 2-related factor 2 (Nrf2) and catalase), inflammation (nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide synthases (iNOS)), and fibrosis (α-smooth muscle actin (α-SMA) and protein kinase C (PKC)) in diabetic liver. Taken together, LBE might be a potential nutraceutical to ameliorate hepatic damage by regulation of AMPK associated pathway via oxidative stress, inflammation, and fibrosis in T2DM.

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Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections

Open Heart ◽

10.1136/openhrt-2020-001568 ◽

2021 ◽

Vol 8 (1) ◽

pp. e001568

Author(s):

James J DiNicolantonio ◽

Mark McCarty ◽

Jorge Barroso-Aranda

Keyword(s):

Viral Infections ◽

Rna Virus ◽

High Mobility ◽

Related Factor ◽

Nuclear Factor ◽

Virus Infections ◽

Nuclear Retention ◽

General Utility ◽

Type 1 Interferons

A recent retrospective study has provided evidence that COVID-19 infection may be notably less common in those using supplemental melatonin. It is suggested that this phenomenon may reflect the fact that, via induction of silent information regulator 1 (Sirt1), melatonin can upregulate K63 polyubiquitination of the mitochondrial antiviral-signalling protein, thereby boosting virally mediated induction of type 1 interferons. Moreover, Sirt1 may enhance the antiviral efficacy of type 1 interferons by preventing hyperacetylation of high mobility group box 1 (HMGB1), enabling its retention in the nucleus, where it promotes transcription of interferon-inducible genes. This nuclear retention of HMGB1 may also be a mediator of the anti-inflammatory effect of melatonin therapy in COVID-19—complementing melatonin’s suppression of nuclear factor kappa B activity and upregulation of nuclear factor erythroid 2-related factor 2. If these speculations are correct, a nutraceutical regimen including vitamin D, zinc and melatonin supplementation may have general utility for the prevention and treatment of RNA virus infections, such as COVID-19 and influenza.

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