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In 1902, Ralph Larrabee provided intriguing evidence suggesting parallels between the changes in white blood cell counts observed in Boston Marathon runners and those seen in specific disease states. Notably he also noted a considerable leukocytosis of the inflammatory type, suggesting a potential link between extreme exercise and inflammatory responses. This early observation laid the groundwork for further investigations into the complex relationship between exercise intensity, immune system activation, and health outcomes, igniting an ongoing debate about the impact of exercise on the immune system.

Today we know exercise shows quantifiable and observable benefits to human health across multiple scales, but the specific genetic and biological processes and pathways underlying these benefits remain unclear. This is primarily caused by individuals exhibiting significant physiological variations in their response to exercise training, coupled with the diverse methods, subjects and timelines used in studying this phenomenon, which impacts the potential for clear and reproducible analysis. A deeper grasp of the metabolic and cellular impacts of exercise could lead to more targeted exercise approaches. Additionally, unraveling the molecular shifts induced by various exercise methods may hasten the identification of pharmaceutical targets for improving metabolic well-being. To combat the global pandemic of physical inactivity and its associated toll of 5.3 million deaths annually, we must gain a better understanding of the fundamental principles governing physical activity’s benefits.

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Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes

Ammar A. Abdelrahman, Porsche V. Sandow, Jing Wang, Zhimin Xu, ... Robert W. Caldwell

Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes

 

Objective

Chronic inflammation and oxidative stress mediate the pathological progression of diabetic complications, like diabetic retinopathy (DR), peripheral neuropathy (DPN) and impaired wound healing. Studies have shown that treatment with a stable form of arginase 1 that reduces l-arginine levels and increases ornithine and urea limits retinal injury and improves visual function in DR. We tested the therapeutic efficacy of PEGylated arginine deiminase (ADI-PEG20) that depletes l-arginine and elevates l-citrulline on diabetic complications in the db/db mouse model of type 2 diabetes (T2D).

Methods

Mice received intraperitoneal (IP), intramuscular (IM), or intravitreal (IVT) injections of ADI-PEG20 or PEG20 as control. Effects on body weight, fasting blood glucose levels, blood-retinal-barrier (BRB) function, visual acuity, contrast sensitivity, thermal sensitivity, and wound healing were determined. Studies using bone marrow-derived macrophages (BMDM) examined the underlying signaling pathway.

Results

Systemic injections of ADI-PEG20 reduced body weight and blood glucose and decreased oxidative stress and inflammation in db/db retinas. These changes were associated with improved BRB and visual function along with thermal sensitivity and wound healing. IVT injections of either ADI-PEG20, anti-VEGF antibody or their combination also improved BRB and visual function. ADI-PEG20 treatment also prevented LPS/IFNℽ-induced activation of BMDM in vitro as did depletion of l-arginine and elevation of l-citrulline.

Conclusions/interpretation

ADI-PEG20 treatment limited signs of DR and DPN and enhanced wound healing in db/db mice. Studies using BMDM suggest that the anti-inflammatory effects of ADI-PEG20 involve blockade of the JAK2-STAT1 signaling pathway via l-arginine depletion and l-citrulline production.

 

Articles in Press

Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes

Ammar A. Abdelrahman, Porsche V. Sandow, Jing Wang, Zhimin Xu, ... Robert W. Caldwell

Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes

 

Objective

Chronic inflammation and oxidative stress mediate the pathological progression of diabetic complications, like diabetic retinopathy (DR), peripheral neuropathy (DPN) and impaired wound healing. Studies have shown that treatment with a stable form of arginase 1 that reduces l-arginine levels and increases ornithine and urea limits retinal injury and improves visual function in DR. We tested the therapeutic efficacy of PEGylated arginine deiminase (ADI-PEG20) that depletes l-arginine and elevates l-citrulline on diabetic complications in the db/db mouse model of type 2 diabetes (T2D).

Methods

Mice received intraperitoneal (IP), intramuscular (IM), or intravitreal (IVT) injections of ADI-PEG20 or PEG20 as control. Effects on body weight, fasting blood glucose levels, blood-retinal-barrier (BRB) function, visual acuity, contrast sensitivity, thermal sensitivity, and wound healing were determined. Studies using bone marrow-derived macrophages (BMDM) examined the underlying signaling pathway.

Results

Systemic injections of ADI-PEG20 reduced body weight and blood glucose and decreased oxidative stress and inflammation in db/db retinas. These changes were associated with improved BRB and visual function along with thermal sensitivity and wound healing. IVT injections of either ADI-PEG20, anti-VEGF antibody or their combination also improved BRB and visual function. ADI-PEG20 treatment also prevented LPS/IFNℽ-induced activation of BMDM in vitro as did depletion of l-arginine and elevation of l-citrulline.

Conclusions/interpretation

ADI-PEG20 treatment limited signs of DR and DPN and enhanced wound healing in db/db mice. Studies using BMDM suggest that the anti-inflammatory effects of ADI-PEG20 involve blockade of the JAK2-STAT1 signaling pathway via l-arginine depletion and l-citrulline production.

 

You are what you eat

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