eIF5A inhibition influences T cell dynamics in the pancreatic microenvironment of the humanized mouse model of Type 1 Diabetes

Imam, Shahnawaz; Prathibha, R.; Dar, Pervaiz Ahmad; Almotah, Khalil; Al-Khudhair, Ahmed; Hasan, Syed Abdul Moiz; Salim, Nancy; Jilani, Talha N.; Mirmira, Raghavendra G.; Jaume, Juan Carlos

doi:10.1038/s41598-018-38341-5

Cited by 21 publications

(28 citation statements)

References 78 publications

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“…It is known that dhps deficiency (the gene encoding DHS) or chronic treatment with DHS inhibitors, as GC7, ameliorate glucose tolerance and glycaemia in various mouse models of diabetes (HFD 30 , 31 , STZ 9 , 32 , humanized mouse model of T1D 33 , db/db 29 ; NOD 34 ). All these exciting studies relied hypusination inhibition effect to beta cell mass protection and decreased pancreas inflammation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

et al. 2021

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Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.

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Section: Discussionmentioning

confidence: 99%

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

et al. 2021

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“…T1DM is considered to be an inflammatory and autoimmune disorder that results from the infiltration of autoreactive T lymphocytes and the consequent generation of proinflammatory cytokines and the appearance of excessive reactive oxygen species (ROS). As a consequence, increased pancreatic β cell death results in hyperglycemia, which is dependent on exogenous insulin administration, concomitantly with evident glucagon secretion imbalance [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of resistance training and turmeric supplementation on reactive species marker stress in diabetic rats

Júnior

Aidar

Santos

et al. 2020

BMC Sports Sci Med Rehabil

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Background: Type 1 diabetes mellitus (T1DM) is a metabolic disease characterized by hyperglycemia and excessive generation of reactive oxygen species caused by autoimmune destruction of beta-cells in the pancreas. Among the antioxidant compounds, Curcuma longa (CL) has potential antioxidant effects and may improve hyperglycemia in uncontrolled T1DM/TD1, as well as prevent its complications (higher costs for the maintenance of health per patient, functional disability, cardiovascular disease, and metabolic damage). In addition to the use of compounds to attenuate the effects triggered by diabetes, physical exercise is also essential for glycemic control and the maintenance of skeletal muscles. Our objective is to evaluate the effects of CL supplementation associated with moderate-to high-intensity resistance training on the parameters of body weight recovery, glycemic control, reactive species markers, and tissue damage in rats with T1DM/TD1. Methods: Forty male 3-month-old Wistar rats (200-250 g) with alloxan-induced T1DM were divided into 4 groups (n = 7-10): sedentary diabetics (DC); diabetic rats that underwent a 4-week resistance training protocol (TD); CLsupplemented diabetic rats (200 mg/kg body weight, 3x a week) (SD); and supplemented diabetic rats under the same conditions as above and submitted to training (TSD). Body weight, blood glucose, and the following biochemical markers were analyzed: lipid profile, aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid, creatine kinase (CK), lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances (TBARS). Results: Compared to the DC group, the TD group showed body weight gain (↑7.99%, p = 0.0153) and attenuated glycemia (↓23.14%, p = 0.0008) and total cholesterol (↓31.72%, p ≤ 0.0041) associated with diminished reactive species markers in pancreatic (↓45.53%, p < 0.0001) and cardiac tissues (↓51.85%, p < 0.0001). In addition, compared to DC, TSD promoted body weight recovery (↑15.44%, p ≤ 0.0001); attenuated glycemia (↓42.40%, p ≤ 0.0001), triglycerides (↓39.96%, p ≤ 0.001), and total cholesterol (↓28.61%, p ≤ 0.05); and attenuated the reactive species markers in the serum (↓26.92%, p ≤ 0.01), pancreas (↓46.22%, p ≤ 0.0001), cardiac (↓55.33%, p ≤ 0.001), and skeletal muscle (↓42.27%, p ≤ 0.001) tissues caused by T1DM.

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“…The specificity of immunosuppression executed by engineered T reg cells towards autologous pathogenic T eff cells can be enhanced by the expression of either the antigen-specific T-cell receptor (TCR) or the chimeric antigen receptor (CAR) on the surface of the T reg cells ( 203 , 204 ). Studies using mouse models of autoimmune diabetes have demonstrated that therapy with antigen-specific T reg cells can improve the targeting of the adoptively transferred cells to specific tissues, and allow the specific recognition of common antigens in autoimmune diseases ( 195 , 205 , 206 ). Therefore, the antigen-specificity of T reg cells can improve their suppressive potency as well as the safety and efficacy of T reg cell-based therapies ( 201 , 207 ).…”

Section: Type 1 Diabetes Mellitusmentioning

confidence: 99%

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children

et al. 2021

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The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.

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eIF5A inhibition influences T cell dynamics in the pancreatic microenvironment of the humanized mouse model of Type 1 Diabetes

Cited by 21 publications

References 78 publications

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Effects of resistance training and turmeric supplementation on reactive species marker stress in diabetic rats

Intestinal Microbiota in Common Chronic Inflammatory Disorders Affecting Children

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