The Dual Specificity Role of Transcription Factor FOXO in Type 2-diabetes and Cancer

Fatima, Kaneez; Mathew, Shilu; Faheem, Muhammed; Mehmood, Tahir; Yassine, Hadi M.; Thani, Asmaa A. Al; Abdel-Hafiz, Hany A.; Ghamdy, Khalid Al; Qadri, Ishtiaq

doi:10.2174/1381612824666180911114210

Cited by 7 publications

(6 citation statements)

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“…13 Gluconeogenesis is classically regulated by hepatocyte nuclear factor 4 a (HNF4a), 18,19 PPARa, 20 and FOXO1. 21 PT cells are the only cell type able to perform this process in the cortical kidney area, harboring the expression of rate-limiting enzymes such as fructose-1,6-bisphosphatase (FBP1), phosphoenolpyruvate carboxykinase 1 (PCK1), or glucose-6-phosphatase (G6PC) and using lactate as the main substrate. 22 Renal gluconeogenesis appears particularly relevant in acute conditions, because it is also regulated by pH and stress hormones, and provides 40% of systemic gluconeogenesis in fasting conditions.…”

Section: Discussionmentioning

confidence: 99%

“…, 16 , 17 Gluconeogenesis encompasses a series of enzymatic reactions that are usually regulated in opposition to glycolysis 13 . Gluconeogenesis is classically regulated by hepatocyte nuclear factor 4 α (HNF4 α ), 18 , 19 PPAR α , 20 and FOXO1 21 . PT cells are the only cell type able to perform this process in the cortical kidney area, harboring the expression of rate-limiting enzymes such as fructose-1,6-bisphosphatase (FBP1), phosphoenolpyruvate carboxykinase 1 (PCK1), or glucose-6-phosphatase (G6PC) and using lactate as the main substrate 22 …”

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confidence: 99%

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Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease

Verissimo¹,

Faivre²,

Rinaldi³

et al. 2022

JASN

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IntroductionCKD is associated with alterations of tubular function. Renal gluconeogenesis is responsible for 40% of systemic gluconeogenesis during fasting, but how and why CKD affects this process and the repercussions of such regulation are unknown.MethodsWe used data on the renal gluconeogenic pathway from more than 200 renal biopsies performed on CKD patients and from 43 kidney allograft patients, and studied three mouse models, of proteinuric CKD (POD-ATTAC), of ischemic CKD, and of unilateral urinary tract obstruction. We analyzed a cohort of patients who benefitted from renal catheterization and a retrospective cohort of patients hospitalized in the intensive care unit.ResultsRenal biopsies of CKD and kidney allograft patients revealed a stage-dependent decrease in the renal gluconeogenic pathway. Two animal models of CKD and one model of kidney fibrosis confirm gluconeogenic downregulation in injured proximal tubule cells. This shift resulted in an alteration of renal glucose production and lactate clearance during an exogenous lactate load. The isolated perfused kidney technique in animal models and renal venous catheterization in CKD patients confirmed decreased renal glucose production and lactate clearance. In CKD patients hospitalized in the intensive care unit, systemic alterations of glucose and lactate levels were more prevalent and associated with increased mortality and a worse renal prognosis at follow-up. Decreased expression of the gluconeogenesis pathway and its regulators predicted faster histologic progression of kidney disease in kidney allograft biopsies.ConclusionRenal gluconeogenic function is impaired in CKD. Altered renal gluconeogenesis leads to systemic metabolic changes with a decrease in glucose and increase in lactate level, and is associated with a worse renal prognosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease

Verissimo¹,

Faivre²,

Rinaldi³

et al. 2022

JASN

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“…Insulin on the other hand downregulates renal gluconeogenesis (66), which could be due to PCK1/G6Pc regulation through phosphorylation (66,67) but also to the reduction of substrates availability (glycerol and glutamine) (68,69) or their redirection to the oxidative pathways (13,68). Gluconeogenesis is regulated by factors implicated in global metabolic regulation, such as peroxisome proliferator-activated receptor alpha (PPARα) (70), Forkhead Box O1(FOXO1) (71) and hepatocyte nuclear factor 4 alpha (HNF4α) but also by glucose levels, through the modification of the NAD + /NADH ratio which causes an indirect downregulation of PCK1 at mRNA level (66). Acidosis also seems to play a role, with the induction of PCK1 at the mRNA and enzymatic activity level (72,73) and hence increased renal glucose production.…”

Section: Glucose Metabolism During Kidney Diseasementioning

confidence: 99%

Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries

et al. 2021

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Acute and chronic kidney disease are responsible for large healthcare costs worldwide. During injury, kidney metabolism undergoes profound modifications in order to adapt to oxygen and nutrient shortage. Several studies highlighted recently the importance of these metabolic adaptations in acute as well as in chronic phases of renal disease, with a potential deleterious effect on fibrosis progression. Until recently, glucose metabolism in the kidney has been poorly studied, even though the kidney has the capacity to use and produce glucose, depending on the segment of the nephron. During physiology, renal proximal tubular cells use the beta-oxidation of fatty acid to generate large amounts of energy, and can also produce glucose through gluconeogenesis. In acute kidney injury, proximal tubular cells metabolism undergo a metabolic shift, shifting away from beta-oxidation of fatty acids and gluconeogenesis toward glycolysis. In chronic kidney disease, the loss of fatty acid oxidation is also well-described, and data about glucose metabolism are emerging. We here review the modifications of proximal tubular cells glucose metabolism during acute and chronic kidney disease and their potential consequences, as well as the potential therapeutic implications.

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“…The same results were also obtained when we tested the effect of BKM120 on the apoptotic effect of pioglitazone (Figure 4). The results of the previous studies indicated that PPARγ, as a nuclear receptor, has a tight interplay with different nuclear proteins, foremost nuclear factor (NF)‐κB and forkhead transcription factors (FOXO) (Fatima et al, 2018; Kunicka et al, 2019). In agreement with the results of Annexin‐PI staining, the qRT‐PCR analysis also revealed that in the presence of CAL‐101, pioglitazone might have more ability to increase the expression of FOXO3a and PUMA, while reducing the expression level of anti‐apoptotic genes, such as Bcl‐2, MCL‐1, and SVV (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

Synergistic effects of PI3K inhibition and pioglitazone against acute promyelocytic leukemia cells

Esmaeili

Yousefi

Delshad

et al. 2022

Molec Gen & Gen Med

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Background Although pioglitazone, a well‐known anti‐diabetic agent, has recently established itself as a pillar of cancer treatment, its therapeutic value could be attenuated by the aberrant activation of the PI3K/Akt pathway. Aim To evaluate whether the PI3K/Akt suppression in leukemic cells could potentiate the anti‐leukemic effects of pioglitazone. Methods To assess the anti‐leukemic effects of PI3K/Akt inhibitors on anti‐leukemic effects of pioglitazone, we used MTT and trypan blue assays. Flow cytometric analysis and qRT‐PCR were also applied to evaluate cell cycle and apoptosis. Result The resulting data revealed that upon PPARγ stimulation in different leukemic cell lines using pioglitazone, the survival and the proliferative capacity of the cells were significantly halted. Then, we evaluated the impact of the PI3K/Akt axis on the effectiveness of the drug in the most sensitive leukemic cell line; NB4 cells. Our results showed that treatment of NB4 cells with the PI3K inhibitors increased the sensitivity of leukemic cells to pioglitazone to the degree that even lower concentrations of the agent succeeded to induce apoptotic as well as the anti‐proliferative effects. Moreover, it seems that PI3K inhibition could potentiate the anti‐leukemic effect of pioglitazone through induction of p21‐mediated sub‐G1 cell cycle arrest and altering the balance between the pro‐and anti‐apoptotic genes. Conclusion This study sheds light on the significance of the PI3K/Akt pathway in APL cell sensitivity to pioglitazone and proposed that the presence of the PI3K inhibitor in the therapeutic regimen containing pioglitazone could be promising in the treatment of this malignancy.

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The Dual Specificity Role of Transcription Factor FOXO in Type 2-diabetes and Cancer

Cited by 7 publications

References 0 publications

Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease

Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease

Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries

Synergistic effects of PI3K inhibition and pioglitazone against acute promyelocytic leukemia cells

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