scholarly journals Pharmic Activation of PKG2 Alleviates Diabetes-Induced Osteoblast Dysfunction by Suppressing PLCβ1-Ca2+-Mediated Endoplasmic Reticulum Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Tingting Jia ◽  
Ya-nan Wang ◽  
Yao Feng ◽  
Chenchen Wang ◽  
Dongjiao Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Proteomic Analysis ◽  
Underlying Mechanism ◽  
Favorable Effect ◽  
Promote Cell Proliferation ◽  
Dependent Protein ◽  
Rat Osteoblast

As reported in our previous study, cinaciguat can improve implant osseointegration in type 2 diabetes mellitus (T2DM) rats by reactivating type 2 cGMP-dependent protein kinase (PKG2), but the downstream mechanisms remain unclear. In the present study, we investigated the favorable effect of cinaciguat on primary rat osteoblast, which was cultivated on titanium disc under vitro T2DM conditions (25 mM glucose and 200 μM palmitate), and clarified the therapeutic mechanism by proteomic analysis. The results demonstrated that T2DM medium caused significant downregulation of PKG2 and induced obvious osteoblast dysfunction. And overexpression of PKG2 by lentivirus and cinaciguat could promote cell proliferation, adhesion, and differentiation, leading to decreased osteoblasts injury. Besides, proteomic analysis revealed the interaction between PKG2 and phospholipase Cβ1 (PLCβ1) in the cinaciguat addition group, and we further verified that upregulated PKG2 by cinaciguat could inhibit the activation of PLCβ1, then relieve intracellular calcium overload, and suppress endoplasmic reticulum (ER) stress to ameliorate osteoblast functions under T2DM condition. Collectively, these findings provided the first detailed mechanisms responsible for cinaciguat provided a favorable effect on promoting osseointegration in T2DM and demonstrated a new insight that diabetes mellitus-induced the aberrations in PKG2-PLCβ1-Ca2+-ER stress pathway was one underlying mechanism for poor osseointegration.

scholarly journals Interaction between Mitochondria and the Endoplasmic Reticulum: Implications for the Pathogenesis of Type 2 Diabetes Mellitus

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Jaechan Leem ◽  
Eun Hee Koh
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Type 2 Diabetes Mellitus ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Apoptotic Cell ◽  
Peripheral Insulin Resistance ◽  
Type 2 Dm

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated withβ-cell dysfunction and peripheral insulin resistance. Thus, each of these factors contributes to the development of type 2 diabetes mellitus (DM). The accumulated evidence reveals structural and functional communications between mitochondria and the ER. It is now well established that ER stress causes apoptotic cell death by disturbing mitochondrial Ca2+homeostasis. In addition, recent studies have shown that mitochondrial dysfunction causes ER stress. In this paper, we summarize the roles that mitochondrial dysfunction and ER stress play in the pathogenesis of type 2 DM. Structural and functional communications between mitochondria and the ER are also discussed. Finally, we focus on recent findings supporting the hypothesis that mitochondrial dysfunction and the subsequent induction of ER stress play important roles in the pathogenesis of type 2 DM.

scholarly journals Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Basma Basha ◽  
Samson Mathews Samuel ◽  
Chris R. Triggle ◽  
Hong Ding
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Clinical Trials ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Therapeutic Agents ◽  
Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

scholarly journals 1α,25-dihydroxyvitamin D3 promotes osseointegration of titanium implant via downregulating AGEs/RAGE pathway in T2DM

2018 ◽  
Vol 7 (11) ◽  
pp. 1186-1195 ◽  
Author(s):  
Tingting Jia ◽  
Ya-nan Wang ◽  
Dongjiao Zhang ◽  
Xin Xu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Bone Microarchitecture ◽  
Titanium Implant ◽  
Underlying Mechanism ◽  
High Rate ◽  
Alizarin Red

Diabetes-induced advanced glycation end products (AGEs) overproduction would result in compromised osseointegration of titanium implant and high rate of implantation failure. 1α,25-dihydroxyvitamin D3 (1,25VD3) plays a vital role in osteogenesis, whereas its effects on the osseointegration and the underlying mechanism are unclear. The purpose of this study was to investigate that 1,25VD3 might promote the defensive ability of osseointegration through suppressing AGEs/RAGE in type 2 diabetes mellitus. In animal study, streptozotocin-induced diabetic rats accepted implant surgery, with or without 1,25VD3 intervention for 12 weeks. After killing, the serum AGEs level, bone microarchitecture and biomechanical index of rats were measured systematically. In vitro study, osteoblasts differentiation capacity was analyzed by alizarin red staining, alkaline phosphatase assay and Western blotting, after treatment with BSA, AGEs, AGEs with RAGE inhibitor and AGEs with 1,25VD3. And the expression of RAGE protein was detected to explore the mechanism. Results showed that 1,25VD3 could reverse the impaired osseointegration and mechanical strength, which possibly resulted from the increased AGEs. Moreover, 1,25VD3 could ameliorate AGEs-induced damage of cell osteogenic differentiation, as well as downregulating the RAGE expression. These data may provide a theoretical basis that 1,25VD3 could work as an adjuvant treatment against poor osseointegration in patients with type 2 diabetes mellitus.

scholarly journals Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells

2021 ◽  
Vol 22 (20) ◽  
pp. 10951
Author(s):  
Chong-Sun Khoi ◽  
Yu-Wen Lin ◽  
Jia-Huang Chen ◽  
Biing-Hui Liu ◽  
Tzu-Yu Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Ochratoxin A ◽  
Reactive Oxygen ◽  
Underlying Mechanism ◽  
Oxygen Species ◽  
Food And Feed ◽  
Renal Proximal Tubular Cells ◽  
Induced Apoptosis

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

Abstract 393: Reticulon-4B Protects Against Endoplasmic Reticulum Stress Induced Platelet Apoptosis and Hyperactivation in Diabetes

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yan Wang ◽  
Wai Ho Tang ◽  
Xinbo Zhang ◽  
Jing Du ◽  
John Hwa ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Trafficking ◽  
Surface Expression ◽  
Diabetic Mouse ◽  
Mitochondrial Damage ◽  
Ros Production ◽  
Mitochondria Membrane Potential ◽  
Platelet Apoptosis

Background: Hyperglycemia triggered endoplasmic reticulum (ER) stress is one of the major causes for platelet hyperactivation and apoptosis in diabetes mellitus (DM). Reticulon-4B (aka Nogo-B) mainly localizes to the ER, and has been shown to influence the ER morphology, ER-Golgi trafficking, apoptotic balance, vesicle formation and protein trafficking in cells. The present study is aimed to investigate the role of Nogo-B on platelet function in DM. Methods and Results: Nogo-B is highly expressed in platelets from healthy individual. Platelets from DM patients and diabetic mice have decreased Nogo-B level. Using Streptozotocin (STZ) induced diabetic mouse model, we show that loss of Nogo (Nogo-/- mice) decreased platelet number, increased mean platelet volume and prolonged bleeding time compared to wild-type (WT) mice. Platelets from Nogo-/- mice were hyperactive with higher JONA and P-selectin surface expression compared to WT mice. Loss of Nogo increased thrombin and collagen induced platelet aggregation. Furthermore, platelets from diabetic Nogo-/- mice show elevated reactive oxygen species (ROS) production, decreased mitochondria membrane potential and increased apoptosis, which can be rescued by antioxidant N-acetyl-L-cysteine. Mechanistically, we show Nogo-B prevented sequestration of antiapoptotic proteins Bcl-xL and Bcl-2 induced by hyperglycemia, subsequently protected against platelet mitochondrial damage, ROS production, caspase-3 activation and apoptosis. Conclusion: These findings demonstrate that Nogo-B protects against ER stress induced platelet apoptosis and hyperactivation in DM by regulating Bcl-xL and Bcl-2 sequestration and mitochondrial damage. This novel pathway may provide therapeutic targets for thrombotic complications in diabetes mellitus.

scholarly journals Ly6C + Inflammatory Monocyte Differentiation Partially Mediates Hyperhomocysteinemia-Induced Vascular Dysfunction in Type 2 Diabetic db/db Mice

2019 ◽  
Vol 39 (10) ◽  
pp. 2097-2119 ◽  
Author(s):  
Pu Fang (方璞) ◽  
Xinyuan Li (李欣源) ◽  
Huimin Shan (单慧敏) ◽  
Jason J. Saredy ◽  
Ramon Cueto ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Bone Marrow Cells ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Underlying Mechanism ◽  
Monocyte Subset ◽  
Monocyte Differentiation ◽  
Inflammatory Monocyte ◽  
M1 Macrophage

Objective: Hyperhomocysteinemia (HHcy) is a potent risk factor for diabetic cardiovascular diseases. We have previously reported that hyperhomocysteinemia potentiates type 1 diabetes mellitus-induced inflammatory monocyte differentiation, vascular dysfunction, and atherosclerosis. However, the effects of hyperhomocysteinemia on vascular inflammation in type 2 diabetes mellitus (T2DM) and the underlying mechanism are unknown. Approach and Results: Here, we demonstrate that hyperhomocysteinemia was induced by a high methionine diet in control mice (homocysteine 129 µmol/L), which was further worsened in T2DM db/db mice (homocysteine 180 µmol/L) with aggravated insulin intolerance. Hyperhomocysteinemia potentiated T2DM-induced mononuclear cell, monocyte, inflammatory monocyte (CD11b + Ly6C + ), and M1 macrophage differentiation in periphery and aorta, which were rescued by folic acid-based homocysteine-lowering therapy. Moreover, hyperhomocysteinemia exacerbated T2DM-impaired endothelial-dependent aortic relaxation to acetylcholine. Finally, transfusion of bone marrow cells depleted for Ly6C by Ly6c shRNA transduction improved insulin intolerance and endothelial-dependent aortic relaxation in hyperhomocysteinemia+T2DM mice. Conclusions: Hyperhomocysteinemia potentiated systemic and vessel wall inflammation and vascular dysfunction partially via inflammatory monocyte subset induction in T2DM. Inflammatory monocyte may be a novel therapeutic target for insulin resistance, inflammation, and cardiovascular complications in hyperhomocysteinemia+T2DM.

scholarly journals Proanthocyanidins Ameliorated Deficits of Lipid Metabolism in Type 2 Diabetes Mellitus Via Inhibiting Adipogenesis and Improving Mitochondrial Function

2020 ◽  
Vol 21 (6) ◽  
pp. 2029
Author(s):  
Fangfang Tie ◽  
Jifei Wang ◽  
Yuexin Liang ◽  
Shujun Zhu ◽  
Zhenhua Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Lipid Metabolism ◽  
Mitochondrial Function ◽  
Underlying Mechanism ◽  
Mitochondrial Dysfunctions ◽  
Mitochondrial Mass

Proanthocyanidins are the major active compounds extracted from Iris lactea Pall. var. Chinensis (Fisch.) Koidz (I. lactea). Proanthocyanidins exhibit a variety of pharmacological activities such as anti-oxidation, anti-inflammation, anti-tumor, and lowering blood lipids. However, the underlying mechanism of its regulating effect on lipid metabolism in diabetic conditions remains unclear. The present study investigated the effects of I. lactea-derived proanthocyanidins on lipid metabolism in mice of type 2 diabetes mellitus (T2DM). Results demonstrated a beneficial effect of total proanthocyanidins on dysregulated lipid metabolism and hepatic steatosis in high-fat-diet/streptozocin (STZ)-induced T2DM. To identify the mechanisms, six flavan-3-ols were isolated from proanthocyanidins of I. lacteal and their effects on adipogenesis and dexamethasone (Dex)-induced mitochondrial dysfunctions in 3T3-L1 adipocytes were determined. In vitro studies showed flavan-3-ols inhibited adipogenesis and restored mitochondrial function after Dex-induced insulin resistance, being suggested by increased mitochondrial membrane potential, intracellular ATP contents, mitochondrial mass and mitochondrial biogenesis, and reduced reactive oxygen species. Among the six flavan-3-ols, procyanidin B3 and procyanidin B1 exhibited the strongest effects. Our study suggests potential of proanthocyanidins as therapeutic target for diabetes.

scholarly journals Hepatic Transcriptome Analysis Revealing the Molecular Pathogenesis of Type 2 Diabetes Mellitus in Zucker Diabetic Fatty Rats

2020 ◽  
Vol 11 ◽  
Author(s):  
Chengdong Xia ◽  
Xiuli Zhang ◽  
Tianshu Cao ◽  
Jiannong Wang ◽  
Cuidan Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Liver Injury ◽  
Er Stress ◽  
Molecular Pathogenesis ◽  
Clinical Indices ◽  
Zdf Rats ◽  
Hepatic Transcriptome

Around 9% of the adult population in the world (463 million) suffer from diabetes mellitus. Most of them (~90%) belong to type 2 diabetes mellitus (T2DM), which is a common chronic metabolic disorder, and the number of cases has been reported to increase each year. Zucker diabetic fatty (ZDF) rat provides a successful animal model to study the pathogenesis of T2DM. Although previous hepatic transcriptome studies revealed some novel genes associated with the occurrence and development of T2DM, there still lacks the comprehensive transcriptomic analysis for the liver tissues of ZDF rats. We performed comparative transcriptome analyses between the liver tissues of ZDF rats and healthy ZCL rats and also evaluated several clinical indices. We could identify 214 and 104 differentially expressed genes (DEGs) and lncRNAs in ZDF rats, respectively. Pathway and biofunction analyses showed a synergistic effect between mRNAs and lncRNAs. By comprehensively analyzing transcriptomic data and clinical indices, we detected some typical features of T2DM in ZDF rats, such as upregulated metabolism (significant increased lipid absorption/transport/utilization, gluconeogenesis, and protein hydrolysis), increased inflammation, liver injury and increased endoplasmic reticulum (ER) stress. In addition, of the 214 DEGs, 114 were known and 100 were putative T2DM-related genes, most of which have been associated with substance metabolism (particularly degradation), inflammation, liver injury and ER stress biofunctions. Our study provides an important reference and improves understanding of molecular pathogenesis of obesity-associated T2DM. Our data can also be used to identify potential diagnostic markers and therapeutic targets, which should strengthen the prevention and treatment of T2DM.

scholarly journals Effects of ubiquitin C-terminal hydrolase L1 deficiency on mouse ova

Reproduction ◽  
2012 ◽  
Vol 143 (3) ◽  
pp. 271-279 ◽  
Author(s):  
Sayaka Koyanagi ◽  
Hiroko Hamasaki ◽  
Satoshi Sekiguchi ◽  
Kenshiro Hara ◽  
Yoshiyuki Ishii ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Endoplasmic Reticulum ◽  
Proteomic Analysis ◽  
Ubiquitin Proteasome System ◽  
Underlying Mechanism ◽  
Wild Type ◽  
Transmission Electron ◽  
Ubiquitin Proteasome

Maternal proteins are rapidly degraded by the ubiquitin–proteasome system during oocyte maturation in mice. Ubiquitin C-terminal hydrolase L1 (UCHL1) is highly and specifically expressed in mouse ova and is involved in the polyspermy block. However, the role of UCHL1 in the underlying mechanism of polyspermy block is poorly understood. To address this issue, we performed a comprehensive proteomic analysis to identify maternal proteins that were relevant to the role of UCHL1 in mouse ova using UCHL1-deficientgad. Furthermore, we assessed morphological features ingadmouse ova using transmission electron microscopy. NACHT, LRR, and PYD domain-containing (NALP) family proteins and endoplasmic reticulum (ER) chaperones were identified by proteomic analysis. We also found that the ‘maternal antigen that embryos require’ (NLRP5 (MATER)) protein level increased significantly ingadmouse ova compared with that in wild-type mice. In an ultrastructural study,gadmouse ova contained less ER in the cortex than in wild-type mice. These results provide new insights into the role of UCHL1 in the mechanism of polyspermy block in mouse ova.

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