The Role of Inflammation in Diabetic Retinopathy

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Nov. 6, 2020

Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome particularly implicates innate immunity development of complications. a primary event Type 1 where infectious (viral) / or autoimmune initiate disease; contrast, chronic inflammation typical 2 considered sequel increasing insulin resistance disturbed glucose metabolism. Diabetic retinopathy (DR) perceived as vascular neurodegenerative disease which occurs after some years poorly controlled diabetes. However, many clinical features DR are late events reflect nature retinal architecture its cellular composition. Retinal microvascular is, fact, an early pathogenetically, induced by low grade, persistent leukocyte activation causes repeated episodes capillary occlusion and, progressive, attritional ischemia. The later, overt signs consequence Metabolic dysregulation involving both lipid metabolism may lead activation. On molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) key regulator it possible PTP1B underlie disease. We also adherent CCR5+CD11b+ monocyte macrophages appear be selectively involved occlusion. In this review, discuss relationship between later DR, common pathogenetic diabetic other retinopathies, mechanisms whereby hyperglycemia dyslipidemia, signaling disease, interventions prevent these retinopathies. address role for adaptive DR. Although significant improvements treatment been made with intravitreal anti-VEGF therapy, sizeable proportion patients, sight-threatening macular edema, fail respond. Alternative therapies targeting inflammatory offer advantage.

Language: Английский

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The anaerobic threshold: 50+ years of controversy

The Journal of Physiology, Journal Year: 2020, Volume and Issue: 599(3), P. 737 - 767

Published: Oct. 28, 2020

Abstract The anaerobic threshold (AT) remains a widely recognized, and contentious, concept in exercise physiology medicine. As conceived by Karlman Wasserman, the AT coalesced increase of blood lactate concentration ([La − ]), during progressive test, with an excess pulmonary carbon dioxide output ( ). Its principal tenets were: limiting oxygen (O 2 ) delivery to exercising muscle→increased glycolysis, La H + production→decreased muscle pH→with increased buffered [HCO 3 ]→increased CO release from blood→increased ventilation. This schema stimulated scientific scrutiny which challenged fundamental premise that anoxia was requisite for [La ]. It is now recognized insufficient O not primary basis lactataemia. Increased production utilization represent response glycolytic flux elicited increasing work rate, determine uptake at accumulates arterial (the threshold; LT). However, sustained non‐oxidative contribution energetics critical power, occurs metabolic rate often far above LT separates heavy very heavy/severe‐intensity exercise. Lactate appreciated as crucial energy source, major gluconeogenic precursor signalling molecule but there no ipso facto evidence dysoxia or anoxia. Non‐invasive estimation using gas exchange (non‐linear versus important training clinic, its conceptual should be understood light shuttle biology. image

Language: Английский

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Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

Cell Reports, Journal Year: 2022, Volume and Issue: 39(12), P. 110986 - 110986

Published: June 1, 2022

Regulatory T (Treg) cells play a vital role in maintaining the immunosuppressive tumor microenvironment. Lactate is crucial metabolite cancer and related to prognosis, metastasis, overall survival. In this study, we focus on effects of lactate Treg cells. vitro, improves cell stability function, whereas degradation reduces induction, increases antitumor immunity, decreases growth mice. Mechanistically, modulates generation through lactylation Lys72 MOESIN, which MOESIN interaction with transforming factor β (TGF-β) receptor I downstream SMAD3 signaling. Cotreatment anti-PD-1 dehydrogenase inhibitor has stronger effect than alone. Individuals hepatocellular carcinoma who responded treatment have lower levels nonresponding individuals. Thus, identify as an essential small molecule that reinforces microenvironment lactylation.

Language: Английский

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Lactylation, a Novel Metabolic Reprogramming Code: Current Status and Prospects

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: June 10, 2021

Lactate is an end product of glycolysis. As a critical energy source for mitochondrial respiration, lactate also acts as precursor gluconeogenesis and signaling molecule. We briefly summarize emerging concepts regarding metabolism, such the shuttle, homeostasis, lactate-microenvironment interaction. Accumulating evidence indicates that lactate-mediated reprogramming immune cells enhancement cellular plasticity contribute to establishing disease-specific immunity status. However, mechanisms by which changes in states influence establishment diverse functional adaptive are largely uncharacterized. Posttranslational histone modifications create code functions key sensor metabolism responsible transducing metabolic into stable gene expression patterns. In this review, we describe recent advances novel lactate-induced modification, lysine lactylation. These observations support idea epigenetic reprogramming-linked input related disease state outputs, cancer progression drug resistance.

Language: Английский

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Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11943 - 11943

Published: Oct. 8, 2022

Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, has long been recognized as a waste product. Lactate the acidification tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, immune escape. Notably, histone lysine lactylation (Kla) was identified novel post-modification (PTM), providing new perspective on mechanism by which functions promising potential therapy for tumors target. Further studies have confirmed that protein is essential to function; it involves important life activities such glycolysis-related cell macrophage polarization. This review systematically elucidates role an immunosuppressive molecule from aspects metabolism effects or non-histone cells; provides ideas further understanding in elucidating regulation function. We explored possibility targeting targets cancer treatment. Finally, propose combined strategy inhibiting glycolytic pathway immunotherapy.

Language: Английский

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Crosstalk between glucose metabolism, lactate production and immune response modulation

Cytokine & Growth Factor Reviews, Journal Year: 2022, Volume and Issue: 68, P. 81 - 92

Published: Nov. 7, 2022

Language: Английский

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Role of Lactate in Inflammatory Processes: Friend or Foe

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 14, 2022

During an inflammatory process, shift in the cellular metabolism associated with increase extracellular acidification are well-known features. This pH drop inflamed tissue is largely attributed to presence of lactate by glycolysis. In recent years, evidence has accumulated describing role processes; however, there differences as whether can currently be considered a pro- or anti-inflammatory mediator. Herein, we review these advances on pleiotropic effects process. Taken together, suggests that could exert differential depending metabolic status, cell type which studied, and pathological process analyzed. Additionally, various targets, including post-translational modifications, G-protein coupled receptor transcription factor activation such NF-κB HIF-1, allow modulate signaling pathways control expression cytokines, chemokines, adhesion molecules, several enzymes immune response metabolism. Altogether, this would explain its varied processes beyond waste product

Language: Английский

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Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(3), P. 2057 - 2170

Published: Nov. 17, 2022

Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training are a potent stimulus for physiological adaptation in many organs. Specifically, muscle, remarkable plasticity is demonstrated by the remodeling structure and function terms muscular size, force, endurance, contractile velocity result functional demands induced various types training. This plasticity, mechanistic basis adaptations to response training, underpinned activation and/or repression molecular pathways processes each individual acute session. These include transduction signals arising from neuronal, mechanical, metabolic, hormonal stimuli through complex signal networks, which linked myriad effector proteins involved regulation pre- posttranscriptional processes, protein translation degradation processes. review therefore describes exercise-induced responses including emerging concepts such epigenetic degradation. A critical appraisal methodological approaches current state knowledge informs series recommendations offered future directions field.

Language: Английский

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Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Language: Английский

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Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

Metabolites, Journal Year: 2022, Volume and Issue: 12(11), P. 1026 - 1026

Published: Oct. 26, 2022

Exercise intolerance is a major manifestation of post-acute sequelae severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). in PASC associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism mitochondrial dysfunction. It remains unclear whether the profound disturbances that have been identified plasma from patients suffering disease 2019 (COVID-19) are also present PASC. To bridge this gap, individuals history previous COVID-19 did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) grouped into those developed (n = 29) fully recovered 16). Plasma samples two groups analyzed via mass spectrometry-based untargeted metabolomics compared against metabolic profiles healthy control 30). Observational demographic clinical data retrospectively abstracted medical record. Compared controls who COVID-19, exhibited significantly free- carnitine-conjugated mono-, poly-, highly unsaturated acids, accompanied by markedly levels di- tricarboxylates (pyruvate, lactate, citrate, succinate, malate), polyamines (spermine) taurine. an intermediary phenotype, milder spermine Of note, depletion tryptophan-a hallmark severity COVID-19-is normalized patients, despite normalization kynurenine levels-a tryptophan metabolite predicts mortality hospitalized patients. In conclusion, metabolites indicative dysfunctional mitochondria-dependent lipid catabolism. These obtained rest consistent previously reported dysfunction exercise, may pave way for therapeutic intervention focused on restoring fat-burning capacity.

Language: Английский

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