Protection of pancreatic β-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3β and STAT3/Cyp-D signaling pathways

Wang, Hongyan; Ai, Jie; Shopit, Abdullah; Niu, Mang; Ahmed, Nisar; Tesfaldet, Tsehaye; Tang, Zhongyuan; Li, Xiaodong; Jamalat, Yazeed; Chu, Peng; Peng, Jinyong; Ma, Xiaodong; Qaed, Eskandar; Hân, Gia; Zhang, Weisheng; Wang, Jun; Tang, Zeyao

doi:10.1007/s10565-021-09644-7

Cited by 14 publications

(6 citation statements)

References 42 publications

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“…However, when GLUT4 was silenced, the improvements were partially reversed. These results suggested that, in addition to its relationship with GLUT4, IRS1 may regulate human pancreatic β cells through interactions with other target proteins, such as phosphoinositide-3-kinase/Akt [36], X-box binding protein-1 [37], free fatty acid receptor 1 [38], and glycogen synthase kinase-3β [39].…”

Section: Discussionmentioning

confidence: 98%

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic β Cells Via the IRS1/GLUT4 Pathway

Zeng,

Tang,

Bai

et al. 2024

Exp Clin Endocrinol Diabetes

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Background Type 2 diabetes mellitus (T2DM) is a commonly observed complication associated with obesity. The effect of fibroblast growth factor 19 (FGF19), a promising therapeutic agent for metabolic disorders, on pancreatic β cells in obesity-associated T2DM remains poorly understood. Methods Human pancreatic β cells were cultured with high glucose (HG) and palmitic acid (PA), followed by treatment with FGF19. The cell proliferation, apoptosis, and insulin secretion were evaluated by CCK-8, qRT-PCR, ELISA, flow cytometry, and western blotting. The expression of the insulin receptor substrate (IRS)/glucose transporter (GLUT) pathway was evaluated. The interaction between FGF19 and IRS1 was predicted using the STRING database and verified by co-immunoprecipitation and immunofluorescence. The regulatory effects of the IRS1/GLUT4 pathway on human pancreatic β cells were assessed by overexpressing IRS1 and silencing IRS1 and GLUT4. Results HG+PA treatment reduced the human pancreatic β cell proliferation and insulin secretion and promoted cell apoptosis. However, FGF19 treatment restored these alterations and significantly increased the expressions of IRS1, GLUT1, and GLUT4 in the IRS/GLUT pathway. Furthermore, FGF19 and IRS1 were found to interact. IRS1 overexpression partially promoted the proliferation of pancreatic β cells and insulin secretion through GLUT4. Additionally, the silencing of IRS1 or GLUT4 attenuated the therapeutic effects of FGF19. Conclusion In conclusion, FGF19 partly promoted the proliferation and insulin secretion of human pancreatic β cells and inhibited apoptosis by upregulating the IRS1/GLUT4 pathway. These findings establish a theoretical framework for the clinical utilization of FGF19 in the treatment of obesity-associated T2DM.

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Section: Discussionmentioning

confidence: 98%

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic β Cells Via the IRS1/GLUT4 Pathway

Zeng,

Tang,

Bai

et al. 2024

Exp Clin Endocrinol Diabetes

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“…Recent research has found that CypD is also a phosphorylation substrate of GSK-3β. The phosphorylation of CypD increases binding with ANT, which increases the sensitivity of mPTP to Ca 2+ and reduces the threshold of mPTP opening ( 42 ). The present study found that in pre-osteoblasts exposed to H 2 O 2 , the total amount of GSK-3β remained unaltered, although the level of p-GSK-3β decreased, accompanied by the opening of the mPTP and increases in Ca 2+ , intracellular ROS and mitochondrial superoxide.…”

Section: Discussionmentioning

confidence: 99%

Metformin reverses oxidative stress‑induced mitochondrial dysfunction in pre‑osteoblasts via the EGFR/GSK‑3β/calcium pathway

et al. 2023

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Oxidative stress is one of the main causes of osteoblast apoptosis induced by post-menopausal osteoporosis. The authors previously found that metformin can reverse the loss of bone mass in post-menopausal osteoporosis. The present study aimed to further clarify the effects and mechanisms of action of metformin in post-menopausal osteoporosis under conditions of oxidative stress. Combined with an in-depth investigation using the transcriptome database, the association between oxidative stress and mitochondrial dysfunction in post-menopausal osteoporosis was confirmed. A pre-osteoblast model of oxidative stress was constructed, and the apoptotic rate following the addition of hydrogen peroxide and metformin was detected using CCK-8 assay and Annexin V-FITC/PI staining. Mitochondrial membrane potential was detected using the JC-1 dye, the intracellular calcium concentration was detected using Fluo-4 AM, the intracellular reactive oxygen species (ROS) level was observed using DCFH-DA, and the mitochondrial superoxide level was observed using MitoSOX Red. Bay K8644 was used to increase the level of intracellular calcium. siRNA was used to interfere with the expression of glycogen synthase kinase (GSK)-3β. Western blot analysis was used to detect the expression of mitochondrial dysfunction-related proteins. The results revealed that oxidative stress decreased mitochondrial membrane potential and increased intracellular ROS, mitochondrial superoxide and cytoplasmic calcium levels in pre-osteoblasts; however, metformin improved mitochondrial dysfunction and reversed oxidative stress-induced injury. Metformin inhibited mitochondrial permeability transition pore opening, suppressed the cytoplasmic calcium influx and reversed pre-osteoblast apoptosis by promoting GSK-3β phosphorylation. Moreover, it was found that EGFR was the cell membrane receptor of metformin in pre-osteoblasts, and the EGFR/GSK-3β/calcium axis played a key role in metformin reversing the oxidative stress response of pre-osteoblasts in post-menopausal osteoporosis. On the whole, these findings provide a pharmacological basis for the use of metformin for the treatment of post-menopausal osteoporosis.

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“…Additionally, mitochondrial antioxidative enzymes such as manganese SOD can detoxify ROS. Although these protections can be overwhelmed by high ROS generation, this can damage the mitochondria [31,34].…”

Section: Discussionmentioning

confidence: 99%

“…Exogenous PCr is essential for energy digestion of apoptotic cells, which is performed by preserving image dependability [35]. PCr can restore mitochondrial function in mitochondria damaged by methylglyoxal (MGO) by enhancing oxidative phosphorylation and electron transport [34]. For cell proliferation, survival, and high-quality articulation, the intracellular system known as the Janus kinase/signal transducer and activator of transcription (JAK/STAT signaling pathway is crucial [17].…”

Section: Introductionmentioning

confidence: 99%

Phosphocreatine protects against diabetic retinopathy via improving mitochondrial functions bioenergetics through JAK2/STAT3 signaling pathway in Vivo and in Vitro

Qaed

Zaky

Chu

et al. 2022

Preprint

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The most prevalent chronic consequence of diabetes mellitus is diabetic retinopathy (DR), a clinically microvascular disease characterized by damage to retinal capillaries with subsequent visual deterioration or blindness. DR is mainly attributed to hyperglycemia-induced retinal microvascular damage, however, emerging research has demonstrated that it is intimately linked to mitochondrial energy shortage and raises the generation of reactive emerging research has demonstrated that it is intimately linked to mitochondrial energy shortage and raises the generation of reactive oxygen species (ROS). This study is aimed to develop and investigate methods to safeguard DR membrane composition, such as regaining methods to safeguard DR membrane composition, such as regaining mitochondrial function. Controlling for hyperglycemia cannot reverse the pathologic changes induced by diabetes in the retinal mitochondria. In mitochondria damaged by hyperglycemia, we proposed that phosphocreatine (PCr) might enhance oxidative phosphorylation and electron transport capability. Similarly, we anticipated estimating PCr's protection against DR via the JAK2/STAT3 signaling pathway. PCr has a crucial metabolic function in DR cells, which includes controlling the intracellular content of ATP. Rat mitochondria and RGC-5 cells were evaluated for capacity using high-resolution respirometry (HRR). The expression of JAK2/STAT3 signaling pathways and apoptotic proteins were detected using western blotting. We assessed ROS production and mitochondrial membrane potential (MMP) in Wistar male rats with streptozotocin induced-diabetes. In this study, we found that PCr had protective effects against DR injury by boosting mitochondrial bioenergetics and preventing DR by easing the symptoms of diabetes and improving biochemical indicators. Additionally, PCr decreased the expression of Bax, cleaved caspase 3, cleaved caspase 9, as well as the JAK2/STAT3 signaling pathway while increasing the expression of Bcl-2, caspase 3, and caspase 9 proteins. In Conclusions when exposed to oxidative stress caused by hyperglycemia, PCr improves mitochondrial activity and has antiapoptotic effects in vivo and in vitro through the JAK2/STAT3 signaling pathway. These findings suggest that PCr is a potentially effective therapeutic approach for diabetic retinopathy.

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Protection of pancreatic β-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3β and STAT3/Cyp-D signaling pathways

Cited by 14 publications

References 42 publications

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic β Cells Via the IRS1/GLUT4 Pathway

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic β Cells Via the IRS1/GLUT4 Pathway

Metformin reverses oxidative stress‑induced mitochondrial dysfunction in pre‑osteoblasts via the EGFR/GSK‑3β/calcium pathway

Phosphocreatine protects against diabetic retinopathy via improving mitochondrial functions bioenergetics through JAK2/STAT3 signaling pathway in Vivo and in Vitro

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