المؤلفون: Zheng, Xiaowei, Narayanan, Sampath, Xu, Cheng, Eliasson Angelstig, Sofie, Grunler, Jacob, Zhao, Allan, Di Toro, Alessandro, Bernardi, Luciano, Mazzone, Massimiliano, Carmeliet, Peter, Del Sole, Marianna, Solaini, Giancarlo, Forsberg, Elisabete A., Zhang, Ao, Brismar, Kerstin, Schiffer, Tomas A., Rajamand Ekberg, Neda, Botusan, Ileana Ruxandra, Palm, Fredrik, 1973, Catrina, Sergiu-Bogdan

المصدر: eLIFE. 11

مصطلحات موضوعية: diabetes, hypoxia, hypoxia-inducible factor-1, reactive oxygen species, mitochondria, diabetic complications, Human, Mouse

الوصف: Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469764Test
https://doi.org/10.7554/eLife.70714Test
https://uu.diva-portal.org/smash/get/diva2:1644536/FULLTEXT01.pdfTest

المؤلفون: Zhao, Allan, Jiang, Hong, Palomares, Arturo Reyes, Larsson, Alice, He, Wenteng, Grünler, Jacob, Zheng, Xiaowei, Rodriguez Wallberg, Kenny A, Catrina, Sergiu-Bogdan, Deng, Qiaolin

المصدر: EMBO Reports; Apr2024, Vol. 25 Issue 4, p1752-1772, 21p

مستخلص: Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes. Synopsis: Appropriate glycemic management in diabetes protects the female germline from hyperglycemia-induced molecular alterations. It is not sufficient though to protect the uterine environment and affects fetal development, suggesting that the uterine environment might be a potential therapeutic target. Improved treatment for patients with type 1 diabetes (T1D) has led to appropriate glycemic management for patients but effects on offspring development persist. Glycemic levels reflecting appropriate glycemic management safeguard the molecular signatures of oocytes from both T1D model mice and human donors. Glycemic levels reflecting appropriate glycemic management fail to protect fetal development from an adverse uterine environment and placental hypoxia. Appropriate glycemic management in diabetes protects the female germline from hyperglycemia-induced molecular alterations. It is not sufficient though to protect the uterine environment and affects fetal development, suggesting that the uterine environment might be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

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المؤلفون: Zhao, Allan Z., Zhao, Hong, Teague, Jeanette, Fujimoto, Wilfred, Beavo, Joseph A.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 1997 Apr 01. 94(7), 3223-3228.

الوصول الحر: https://www.jstor.org/stable/41804Test

المؤلفون: Xiaowei Zheng, Narayanan, Sampath, Sunkari, Vivekananda Gupta, Eliasson, Sofie, Botusan, Ileana Ruxandra, Grünler, Jacob, Catrina, Anca Irinel, Radtke, Freddy, Cheng Xu, Zhao, Allan, Ekberg, Neda Rajamand, Lendahl, Urban, Catrina, Sergiu-Bogdan

المصدر: Proceedings of the National Academy of Sciences of the United States of America; 4/2/2019, Vol. 116 Issue 14, p6985-6994, 10p

مصطلحات موضوعية: DIABETIC foot, WOUND healing, CELL differentiation, NOTCH signaling pathway, GLUCOSE

مستخلص: Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1–4) and ligands (Jagged 1–2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)–Notch1 feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4–Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs. [ABSTRACT FROM AUTHOR]

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المؤلفون: Dong Wei, Li, Jie, Shen, Miaoda, Wei Jia, Nuoqi Chen, Tao Chen, Dongming Su, Haoming Tian, Shusen Zheng, Yifan Dai, Zhao, Allan

المصدر: Diabetes; Feb2010, Vol. 59 Issue 2, p471-478, 8p, 1 Diagram, 1 Chart, 4 Graphs

مصطلحات موضوعية: UNSATURATED fatty acids, PANCREATIC beta cells, ISLANDS of Langerhans, INSULIN, CYTOKINES, APOPTOSIS, TRANSGENIC mice, DIABETES

مستخلص: OBJECTIVE--To evaluate the direct impact of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the functions and viability of pancreatic β-cells. RESEARCH DESIGN AND METHODS--We developed an mfat-1 transgenic mouse model in which endogenous production of n-3 PUFAs was achieved through overexpressing a C. elegans n-3 fatty acid desaturase gene, mfat-1. The islets and INS-1 cells expressing mfat-1 were analyzed for insulin secretion and viability in response to cytokine treatment. RESULTS--The transgenic islets contained much higher levels of n-3 PUFAs and lower levels of n-6 PUFAs than the wild type. Insulin secretion stimulated by glucose, amino acids, and glucagon-like peptide-1 (GLP-1) was significantly elevated in the transgenic islets. When challenged with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and γ-interferon (IFN-γ), the transgenic islets completely resisted cytokine-induced cell death. Adenoviral transduction of mfat-1 gene in wild-type islets and in INS-1 cells led to acute changes in the cellular levels of n-3- and n-6 PUFAs and recapitulated the results in the transgenic islets. The expression of mfat-1 led to decreased production of prostaglandin E[sub 2] (PGE[sub 2]), which in turn contributed to the elevation of insulin secretion. We further found that cytokine-induced activation of NF-κB and extracellular signal-related kinase 1/2 (ERK[sub 1/2]) was significantly attenuated and that the expression of pancreatic duodenal hemeobox-1 (PDX-1), glucokinase, and insulin-1 was increased as a result of n-3 PUFA production. CONCLUSIONS--Stable cellular production of n-3 PUFAs via mfat-1 can enhance insulin secretion and confers strong resistance to cytokine-induced β-cell destruction. The utility of mfat-1 gene in deterring type 1 diabetes should be further explored in vivo. Diabetes 59:471-478, 2010 [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Rao, Poornima, Roccisana, Jennifer, Takane, Karen K., Bottino, Rita, Zhao, Allan, Trucco, Massimo, García-Ocaña, Adolfo, García-Ocaña, Adolfo

المصدر: Diabetes; Jun2005, Vol. 54 Issue 6, p1664-1675, 12p, 3 Color Photographs, 1 Black and White Photograph, 1 Diagram, 6 Graphs

مصطلحات موضوعية: GENETIC transformation, ISLANDS of Langerhans, DIABETES, MICE, HYPERGLYCEMIA, TRANSPLANTATION of organs, tissues, etc.

مستخلص: Akt is an important intracellular mediator of beta-cell growth and survival in rodents. However, whether constitutive activation of Akt in human beta-cells enhances the survival and function of transplanted islets is unknown. In the current study, we examined the efficacy of constitutive activation of Akt in improving human islet transplant outcomes using a marginal mass model in diabetic severe combined immunodeficient (SCID) mice. Human islets transduced with adenoviruses encoding constitutively active Akt1 (Adv-CA-Akt) displayed increased total and phosphorylated Akt and Akt kinase activity compared with control islets. Expression of CA-Akt in human islets induced a significant increase in beta-cell replication and a significant decrease in beta-cell death induced by serum and glucose deprivation or chronic hyperglycemia. Two control groups of islets (1,500 uninfected or adenovirus LacZ [Adv-LacZ]-transduced human islet equivalents [IEQs]) transplanted under the kidney capsule of streptozotocin-induced diabetic SCID mice were insufficient to correct hyperglycemia. Importantly and in marked contrast to these controls, 1,500 Adv-CA-Akt-transduced IEQs were capable of restoring euglycemia in diabetic SCID mice. Moreover, blood glucose normalization persisted for at least 6 months. Human plasma insulin at day 54 after transplant was 10-fold higher in Adv-CA-Akt islet recipients (2.4 +/- 0.4 ng/ml) compared with those receiving Adv-LacZ islets (0.25 +/- 0.08 ng/ml) (P < 0.05). In summary, expression of CA-Akt in human islets improves islet transplant outcomes in a subcapsular renal graft model in SCID mice. Akt is an attractive target for future strategies aimed at reducing the number of islets required for successful islet transplantation in humans. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Schwank-Xu, Cheng, Forsberg, Elisabete, Bentinger, Magnus, Zhao, Allan, Ansurudeen, Ishrath, Dallner, Gustav, Catrina, Sergiu-Bogdan, Brismar, Kerstin, Tekle, Michael, Tiano, Luca, Orlando, Patrick, Silvestri, Sonia, Marcheggiani, Fabio, Cirilli, Ilenia

المصدر: Antioxidants; May2021, Vol. 10 Issue 5, p793, 1p

مصطلحات موضوعية: UBIQUINONES, FATTY liver, TYPE 2 diabetes, MITOCHONDRIA, LABORATORY mice, BIOSYNTHESIS

مستخلص: Mitochondrial dysfunction in type 2 diabetes leads to oxidative stress, which drives disease progression and diabetes complications. L-carnosine, an endogenous dipeptide, improves metabolic control, wound healing and kidney function in animal models of type 2 diabetes. Coenzyme Q (CoQ), a component of the mitochondrial electron transport chain, possesses similar protective effects on diabetes complications. We aimed to study the effect of carnosine on CoQ, and assess any synergistic effects of carnosine and CoQ on improved mitochondrial function in a mouse model of type 2 diabetes. Carnosine enhanced CoQ gene expression and increased hepatic CoQ biosynthesis in db/db mice, a type 2 diabetes model. Co-administration of Carnosine and CoQ improved mitochondrial function, lowered ROS formation and reduced signs of oxidative stress. Our work suggests that carnosine exerts beneficial effects on hepatic CoQ synthesis and when combined with CoQ, improves mitochondrial function and cellular redox balance in the liver of diabetic mice. (4) Conclusions: L-carnosine has beneficial effects on oxidative stress both alone and in combination with CoQ on hepatic mitochondrial function in an obese type 2 diabetes mouse model. [ABSTRACT FROM AUTHOR]

: Copyright of Antioxidants is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)