Ischemic post-conditioning promotes mitochondrial translocation of DJ-1 and stabilizes binding to Bcl- xL to attenuate myocardial ischemic-reperfusion injury in STZ-induced diabetic rats

Abstract Background Ischemic post-conditioning (IPO) is a strategy in reducing myocardial ischemic-reperfusion (I/R) injury, but its specific molecular mechanism is incompletely understood. Deletions or mutations in the DJ-1 gene are directly linked to the cardiovascular system. DJ-1 plays a critical role in regulating mitochondrial homeostasis in response to stress through translocation of DJ-1 from the cytoplasm into the nucleus. Meanwhile, how the DJ-1 is removed in myocardial I/R injury and regulating apoptosis is needed to further verified. Given the discovery mentioned above, we hypothesize that DJ-1 translocate to mitochondria recover IPO induced cardioprotection in STZ-induced diabetic rats. To evaluate our hypothesis, we overexpressed the DJ-1 protein under high glucose condition, subjected IPO or not. And then measure the expression of DJ-1 in mitochondria and cytoplasm after myocardial I/R. Results We found that DJ-1 translocated to mitochondria combined with Bcl-xL was reduced cardiomyocyte injury and apoptosis in diabetic myocardial I/R heart. Additionally, the binding of DJ-1 and Bcl-xL is dependent on the oxidative state of DJ-1(oxidation of DJ-1 at Cys-106 is important for its protective effect). Conclusions If our hypothesis is correct, promote DJ-1 mitochondrial transfer may be critical with respect to restoring myocardial responsiveness to IPO in diabetes.

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PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02628-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Miao Chen ◽

Dian Jing ◽

Rui Ye ◽

Jianru Yi ◽

Zhihe Zhao

Keyword(s):

Bone Regeneration ◽

Osteogenic Differentiation ◽

Bone Healing ◽

High Glucose ◽

Diabetic Rats ◽

Diabetic Patients ◽

Regulatory Effect ◽

Compound C ◽

High Glucose Condition ◽

Glucose Condition

Abstract Background Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. Methods We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. Results Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. Conclusion In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

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The effects of high glucose condition on rat tenocytesin vitroand rat Achilles tendonin vivo

Bone and Joint Research ◽

10.1302/2046-3758.75.bjr-2017-0126.r2 ◽

2018 ◽

Vol 7 (5) ◽

pp. 362-372 ◽

Cited By ~ 8

Author(s):

Y. Ueda ◽

A. Inui ◽

Y. Mifune ◽

R. Sakata ◽

T. Muto ◽

...

Keyword(s):

Cell Proliferation ◽

Achilles Tendon ◽

High Glucose ◽

Type I Collagen ◽

Diabetic Rats ◽

Type I ◽

High Glucose Condition ◽

Glucose Condition

ObjectivesThe aim of this study was to investigate the effect of hyperglycaemia on oxidative stress markers and inflammatory and matrix gene expression within tendons of normal and diabetic rats and to give insights into the processes involved in tendinopathy.MethodsUsing tenocytes from normal Sprague-Dawley rats, cultured both in control and high glucose conditions, reactive oxygen species (ROS) production, cell proliferation, messenger RNA (mRNA) expression of NADPH oxidase (NOX) 1 and 4, interleukin-6 (IL-6), matrix metalloproteinase (MMP)-2, tissue inhibitors of matrix metalloproteinase (TIMP)-1 and -2 and type I and III collagens were determined after 48 and 72 hours in vitro. In an in vivo study, using diabetic rats and controls, NOX1 and 4 expressions in Achilles tendon were also determined.ResultsIn tenocyte cultures grown under high glucose conditions, gene expressions of NOX1, MMP-2, TIMP-1 and -2 after 48 and 72 hours, NOX4 after 48 hours and IL-6, type III collagen and TIMP-2 after 72 hours were significantly higher than those in control cultures grown under control glucose conditions. Type I collagen expression was significantly lower after 72 hours. ROS accumulation was significantly higher after 48 hours, and cell proliferation after 48 and 72 hours was significantly lower in high glucose than in control glucose conditions. In the diabetic rat model, NOX1 expression within the Achilles tendon was also significantly increased.ConclusionThis study suggests that high glucose conditions upregulate the expression of mRNA for NOX1 and IL-6 and the production of ROS. Moreover, high glucose conditions induce an abnormal tendon matrix expression pattern of type I collagen and a decrease in the proliferation of rat tenocytes. Cite this article: Y. Ueda, A. Inui, Y. Mifune, R. Sakata, T. Muto, Y. Harada, F. Takase, T. Kataoka, T. Kokubu, R. Kuroda. The effects of high glucose condition on rat tenocytes in vitro and rat Achilles tendon in vivo. Bone Joint Res 2018;7:362–372. DOI: 10.1302/2046-3758.75.BJR-2017-0126.R2

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Endurance Training Regulates Expression of Some Angiogenesis-Related Genes in Cardiac Tissue of Experimentally Induced Diabetic Rats

Biomolecules ◽

10.3390/biom11040498 ◽

2021 ◽

Vol 11 (4) ◽

pp. 498

Author(s):

Mojdeh Khajehlandi ◽

Lotfali Bolboli ◽

Marefat Siahkuhian ◽

Mohammad Rami ◽

Mohammadreza Tabandeh ◽

...

Keyword(s):

Gene Expression ◽

Endurance Training ◽

Molecular Mechanisms ◽

Cardiac Tissue ◽

Critical Role ◽

Diabetic Rats ◽

Moderate Intensity ◽

Pcr Analysis ◽

Cardiac Tissues ◽

The Impact

Exercise can ameliorate cardiovascular dysfunctions in the diabetes condition, but its precise molecular mechanisms have not been entirely understood. The aim of the present study was to determine the impact of endurance training on expression of angiogenesis-related genes in cardiac tissue of diabetic rats. Thirty adults male Wistar rats were randomly divided into three groups (N = 10) including diabetic training (DT), sedentary diabetes (SD), and sedentary healthy (SH), in which diabetes was induced by a single dose of streptozotocin (50 mg/kg). Endurance training (ET) with moderate-intensity was performed on a motorized treadmill for six weeks. Training duration and treadmill speed were increased during five weeks, but they were kept constant at the final week, and slope was zero at all stages. Real-time polymerase chain reaction (RT-PCR) analysis was used to measure the expression of myocyte enhancer factor-2C (MEF2C), histone deacetylase-4 (HDAC4) and Calmodulin-dependent protein kinase II (CaMKII) in cardiac tissues of the rats. Our results demonstrated that six weeks of ET increased gene expression of MEF2C significantly (p < 0.05), and caused a significant reduction in HDAC4 and CaMKII gene expression in the DT rats compared to the SD rats (p < 0.05). We concluded that moderate-intensity ET could play a critical role in ameliorating cardiovascular dysfunction in a diabetes condition by regulating the expression of some angiogenesis-related genes in cardiac tissues.

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Abstract 90: Diabetes Impairs Post-stroke Cerebrovascular Plasticity And Long-term Functional Recovery.

Stroke ◽

10.1161/str.44.suppl_1.a90 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Roshini Prakash ◽

Weiguo Li ◽

Zhi Qu ◽

Susan C Fagan ◽

Adviye Ergul

Keyword(s):

Cognitive Decline ◽

Reperfusion Injury ◽

Functional Recovery ◽

Diabetic Rats ◽

Neurological Deficits ◽

Ischemic Reperfusion Injury ◽

Post Stroke ◽

Ischemic Reperfusion ◽

Sensorimotor Recovery ◽

The Impact

Background: Stroke associated with pre-existing diabetes worsens ischemic injury and impairs recovery. We have previously shown that type-2-diabetic rats subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation (HT) and greater neurological deficits. These diabetic rats also exhibit enhanced dysfunctional cerebral neovascularization that increases the risk of bleeding post-stroke. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that post-stroke neovascularization is impaired in diabetes and this is associated with poor sensorimotor and cognitive outcomes. Methods: Reparative neovascularization was assessed in the lesional and non-lesional areas in diabetic rats after 14 days of ischemic reperfusion injury. 3-dimensional reconstruction of the FITC stained vasculature were obtained by confocal microscopy and stereological parameters including vascular volume and surface area were measured. Astrogliosis was also determined by GFAP staining. The relative rates of sensorimotor recovery, cognitive decline and spontaneous activity were assessed. Results: Diabetes impairs reparative neovascularization in the lesional areas compared to control rats. Astroglial swelling and reactivity was pronounced in diabetic stroke compared to control stroke. Rate of sensorimotor recovery was significantly slower in diabetic stroke compared to the controls. Diabetes also exacerbated anxiety-like symptoms and cognitive decline post-stroke relative to control. Conclusion: Diabetes impairs post-stroke reparative neovascularization and impedes functional recovery. The impact of glycemic control on poor recovery in this critical period needs to be tested. N=6-8 * p≤ 0.05, ** p≤ 0.005

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PDGF-β receptor and PKC have no effect on angiotensin II-induced JAK2 and STAT1 phosphorylation in vascular smooth muscle cells under high glucose condition

Journal of Receptors and Signal Transduction ◽

10.3109/10799893.2011.592535 ◽

2011 ◽

Vol 31 (5) ◽

pp. 340-349

Author(s):

Oktay Hasan Öztürk ◽

Arzu Çetin ◽

Alper Tokay ◽

Fatih Uzuner ◽

Gamze Tanrıöver ◽

...

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

High Glucose ◽

Muscle Cells ◽

High Glucose Condition ◽

Β Receptor ◽

Glucose Condition

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β-carotene suppresses Porphyromonas gingivalis lipopolysaccharide-mediated cytokine production in THP-1 monocytes cultured with high glucose condition

Cell Biology International ◽

10.1002/cbin.10873 ◽

2017 ◽

Vol 42 (1) ◽

pp. 105-111 ◽

Cited By ~ 4

Author(s):

Yukari Kajiura ◽

Yasufumi Nishikawa ◽

Jung Hwan Lew ◽

Jun-ichi Kido ◽

Toshihiko Nagata ◽

...

Keyword(s):

Porphyromonas Gingivalis ◽

High Glucose ◽

Cytokine Production ◽

High Glucose Condition ◽

Porphyromonas Gingivalis Lipopolysaccharide ◽

Glucose Condition ◽

Β Carotene

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Effect of metformin and celecoxib on cytotoxicity and release of GDF-15 from human mesenchymal stem cells in high glucose condition

Cell Biochemistry and Function ◽

10.1002/cbf.3289 ◽

2017 ◽

Vol 35 (7) ◽

pp. 407-413 ◽

Cited By ~ 3

Author(s):

Elaheh Zafarvahedian ◽

Azam Roohi ◽

Mohammad Reza Sepand ◽

Seyed Nasser Ostad ◽

Mohammad Hossein Ghahremani

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

High Glucose ◽

Human Mesenchymal Stem Cells ◽

High Glucose Condition ◽

Glucose Condition

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ERM Complex, a Therapeutic Target for Vascular Leakage Induced by Diabetes

Current Medicinal Chemistry ◽

10.2174/0929867328666210526114417 ◽

2021 ◽

Vol 28 ◽

Author(s):

Olga Simó-Servat ◽

Hugo Ramos ◽

Patricia Bogdanov ◽

Marta García-Ramírez ◽

Jordi Huerta ◽

...

Keyword(s):

High Glucose ◽

Therapeutic Target ◽

Vascular Leakage ◽

Cell Permeability ◽

Diabetic Patients ◽

Diabetic Mice ◽

Erm Proteins ◽

High Glucose Condition ◽

Tnf Α ◽

Glucose Condition

Background: Ezrin, radixin, and moesin (the ERM complex) interact directly with membrane proteins regulating their attachment to actin filaments. ERM protein activation modifies cytoskeleton organization and alters the endothelial barrier function, thus favoring vascular leakage. However, little is known regarding the role of ERM proteins in diabetic retinopathy (DR). Objective: This study aimed to examine whether overexpression of the ERM complex exists in db/db mice and its main regulating factors. Methods: 9 male db/db mice and 9 male db/+ aged 14 weeks were analyzed. ERM proteins were assessed by western blot and by immunohistochemistry. Vascular leakage was determined by the Evans blue method. To assess ERM regulation, HRECs were cultured in a medium containing 5.5 mM D-glucose (mimicking physiological conditions) and 25 mM D-glucose (mimicking hyperglycemia that occurs in diabetic patients). Moreover, treatment with TNF-α, IL-1β, or VEGF was added to a high glucose condition. The expression of ERM proteins was quantified by RT-PCR. Cell permeability was evaluated by measuring movements of FITC-dextran. Results: A significant increase of ERM in diabetic mice in comparison with non-diabetic mice was observed. A high glucose condition alone did not have any effect on ERM expression. However, TNF-α and IL-1β induced a significant increase in ERM proteins. Conclusion: The increase of ERM proteins induced by diabetes could be one of the mechanisms involved in vascular leakage and could be considered as a therapeutic target. Moreover, the upregulation of the ERM complex by diabetes is induced by inflammatory mediators rather than by high glucose itself.

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