Diabetic stress: new triumphs and challenges to maintain vascular longevity
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Cited by 34 publications
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Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor κB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care. KeywordsAlzheimer's disease; Akt; angiogenesis; apoptosis; cancer; cardiac; caspases; diabetes; endothelial; erythropoietin; forkhead; FoxO; GSK-3β; inflammation; mitochondria; NF-κB; renal; STATs; Wnt OXIDATIVE STRESSInitial work in pathways that can lead to oxidative stress by early investigators observed that increased metabolic rates could be detrimental to animals in an elevated oxygen environment. More current studies point to the potential aging mechanisms and accumulated toxic effects for an organism that are tied to oxidative stress (Maiese, et al., 2008a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in organisms, or at least the rate of oxygen consumption in organisms, has intrigued several investigators. Pearl proposed that increased exposure to oxygen through an increased metabolic rate could lead to a shortened life span (Pearl, 1928). Subsequent work by multiple investigators has furthered this hypothesis by demonstrating that increased metabolic rates could be detrimental to animals in an elevated oxygen environment . When one moves to more current work, oxygen free radicals and mitochondrial DNA mutations have become associated with oxidative stress injury, aging mechanisms, and accumulated toxicity for an organism (Yui and Matsuura, 2006).Oxygen free radicals can be generated in elevated quantities during the reduction of oxygen and subsequently lead to cell injury and apoptosis. Oxidative stress occurs as a result of the development of reactive oxygen species that consist of oxygen free radicals and other chemical entities. These agents can involve superoxide free radicals, hydrogen peroxide, sin...
Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor κB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care. KeywordsAlzheimer's disease; Akt; angiogenesis; apoptosis; cancer; cardiac; caspases; diabetes; endothelial; erythropoietin; forkhead; FoxO; GSK-3β; inflammation; mitochondria; NF-κB; renal; STATs; Wnt OXIDATIVE STRESSInitial work in pathways that can lead to oxidative stress by early investigators observed that increased metabolic rates could be detrimental to animals in an elevated oxygen environment. More current studies point to the potential aging mechanisms and accumulated toxic effects for an organism that are tied to oxidative stress (Maiese, et al., 2008a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in organisms, or at least the rate of oxygen consumption in organisms, has intrigued several investigators. Pearl proposed that increased exposure to oxygen through an increased metabolic rate could lead to a shortened life span (Pearl, 1928). Subsequent work by multiple investigators has furthered this hypothesis by demonstrating that increased metabolic rates could be detrimental to animals in an elevated oxygen environment . When one moves to more current work, oxygen free radicals and mitochondrial DNA mutations have become associated with oxidative stress injury, aging mechanisms, and accumulated toxicity for an organism (Yui and Matsuura, 2006).Oxygen free radicals can be generated in elevated quantities during the reduction of oxygen and subsequently lead to cell injury and apoptosis. Oxidative stress occurs as a result of the development of reactive oxygen species that consist of oxygen free radicals and other chemical entities. These agents can involve superoxide free radicals, hydrogen peroxide, sin...
A “FOXO” in sight: Targeting Foxo proteins from conception to cancer
SynopsisThe successful treatment for multiple disease entities can rest heavily upon the ability to elucidate the intricate relationships that govern cellular proliferation, metabolism, survival, and inflammation. Here we discuss the therapeutic potential of the mammalian forkhead transcription factors predominantly in the O class, FoxO1, FoxO3, FoxO4, and FoxO6, which play a significant role during normal cellular function as well as during progressive disease. These transcription factors are integrated with several signal transduction pathways, such as Wnt proteins, that can regulate a broad array of cellular process that include stem cell proliferation, aging, and malignancy. FoxO transcription factors are attractive considerations for strategies directed against human cancer in light of their pro-apoptotic effects and ability to lead to cell cycle arrest. Yet, FoxO proteins can be associated with infertility, cellular degeneration, and unchecked cellular proliferation. As our knowledge continues to develop for this novel family of proteins, potential clinical applications for the FoxO family should heighten our ability to limit disease progression without clinical compromise. Keywordscancer; diabetes; immune system; oxidative stress; stem cells Origin and structure of FoxO transcription factorsMore than 100 forkhead genes and 19 human subgroups that extend from FOXA to FOXS are now known to exist since the initial discovery of the fly Drosophila melanogaster gene fork head 1 , 2. A current nomenclature has replaced prior terms, such as forkhead in rhabdomyosarcoma (FKHR), the Drosophila gene fork head (fkh), and Forkhead RElated NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptACtivator (FREAC)-1 and -2. Within the subclasses of the Fox proteins that are each designated by a letter, an Arabic number is provided such that the actual name of a Fox protein would follow the designation of "Fox", then a subclass or subgroup "Letter" is provided, and finally the member "Number" is listed. In relation to the nomenclature for human Fox proteins, all letters are capitalized, otherwise only the initial letter is listed as uppercase for the mouse, and for all other chordates the initial and subclass letters are in uppercase.Of the mammalian forkhead transcription factors in the O class, FoxO1, FoxO3, FoxO4, and FoxO6 proteins can play a significant role during normal cellular function as well as during progressive disease. The most recently cloned member is FoxO6, but progressive interest in FoxO1, FoxO3, and FoxO4 has shown that these transcription factors can promote cell proliferation as well as cell death 3. For example, FoxO proteins are homologous to the transcription factor DAuer in the worm Caenorhabditis elegans that can determine metabolic insulin signaling and lead to lifespan extension 2 , 4. It is believed that FoxO proteins can influence cellular function in multiple species, since metabolic signaling with FoxO proteins is conserved among Caenorhabditis elegans, Drosophila melan...
Construction and evaluation of a metabolic correlation diagnostic model for diabetes based on machine learning algorithms
BackgroundDiabetes mellitus (DM) is a prevalent chronic disease marked by significant metabolic dysfunctions. Understanding its molecular mechanisms is vital for early diagnosis and treatment strategies.MethodsWe used datasets GSE7014, GSE25724, and GSE156248 from the GEO database to build a diagnostic model for DM using Random Forest (RF) and LASSO regression models. GSE20966 served as a validation cohort. DM patients were classified into two subtypes for functional enrichment analysis. Expression levels of key diagnostic genes were validated using quantitative real‐time PCR (qRT‐PCR) on Peripheral Blood Mononuclear Cells (PBMCs) from DM patients and healthy controls, focusing on CXCL12 and PPP1R12B with GAPDH as the internal control.ResultsAfter de‐batching the datasets, we identified 131 differentially expressed genes (DEGs) between DM and control groups, with 70 up‐regulated and 61 down‐regulated. Enrichment analysis revealed significant down‐regulation in the IL‐12 signaling pathway, JAK signaling post‐IL‐12 stimulation, and the ferroptosis pathway in DM. Five genes (CXCL12, MXRA5, UCHL1, PPP1R12B, and C7) were identified as having diagnostic value. The diagnostic model showed high accuracy in both the training and validation cohorts. The gene set also enabled the subclassification of DM patients into groups with distinct functional traits. qRT‐PCR results confirmed the bioinformatics findings, particularly the up‐regulation of CXCL12 and PPP1R12B in DM patients.ConclusionOur study pinpointed seven energy metabolism‐related genes differentially expressed in DM and controls, with five holding diagnostic value. Our model accurately diagnosed DM and facilitated patient subclassification, offering new insights into DM pathogenesis.
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