RESUMO
Age-related macular degeneration (AMD) causes severe blindness in the elderly due to choroidal neovascularization (CNV), which results from the dysfunction of the retinal pigment epithelium (RPE). While normal RPE depends exclusively on mitochondrial oxidative phosphorylation for energy production, the inflammatory conditions associated with metabolic reprogramming of the RPE play a pivotal role in CNV. Although mitochondrial pyruvate dehydrogenase kinase (PDK) is a central node of energy metabolism, its role in the development of CNV in neovascular AMD has not been investigated. In the present study, we used a laser-induced CNV mouse model to evaluate the effects of Pdk4 gene ablation and treatment with pan-PDK or specific PDK4 inhibitors on fluorescein angiography and CNV lesion area. Among PDK isoforms, only PDK4 was upregulated in the RPE of laser-induced CNV mice, and Pdk4 gene ablation attenuated CNV. Next, we evaluated mitochondrial changes mediated by PDK1-4 inhibition using siRNA or PDK inhibitors in inflammatory cytokine mixture (ICM)-treated primary human RPE (hRPE) cells. PDK4 silencing only in ICM-treated hRPE cells restored mitochondrial respiration and reduced inflammatory cytokine secretion. Likewise, GM10395, a specific PDK4 inhibitor, restored oxidative phosphorylation and decreased ICM-induced upregulation of inflammatory cytokine secretion. In a laser-induced CNV mouse model, GM10395 significantly alleviated CNV. Taken together, we demonstrate that specific PDK4 inhibition could be a therapeutic strategy for neovascular AMD by preventing mitochondrial metabolic reprogramming in the RPE under inflammatory conditions.
Assuntos
Neovascularização de Coroide , Modelos Animais de Doenças , Degeneração Macular , Piruvato Desidrogenase Quinase de Transferência de Acetil , Epitélio Pigmentado da Retina , Animais , Humanos , Camundongos , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Neovascularização de Coroide/tratamento farmacológico , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Reprogramação MetabólicaRESUMO
This study investigated facial skin color differences before and after makeup. Toward this goal, a photo gauge, devised with a pair of color checkers as a reference, collected face images. In addition, color calibration and a deep-learning method extracted the color values of representative areas of facial skin. The photo gauge photographed 516 Chinese females before and after applying makeup. Then, the collected images were calibrated by referencing skin color patches, and the lower cheek regions' pixel colors were extracted using open-source computer vision libraries. Following the visible color spectrum of humans, the color values were computed in L*, a*, and b* of CIE1976L*a*b*. The results showed that the facial colors of the Chinese females changed to become brighter, less reddish, and less yellowish after applying the makeup, resulting in a paler skin tone. During the experiment, subjects were given five varieties of liquid foundation to choose one sample that best fits their skin. However, we failed to find any noticeable relationship between the individual's facial skin color characteristics and the liquid foundation selected. In addition, 55 subjects were identified according to their makeup use frequency and skill, but their color changes did not differ from the other subjects. This study provided quantitative evidence of makeup trends in the Shanghai region in China, and the method proposes a novel approach toward remote skin color research.
Assuntos
Cor , Cosméticos , Face , Pigmentação da Pele , Feminino , Humanos , Povo Asiático , China , Pele , Fotografação , Comportamento de EscolhaRESUMO
Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.
Assuntos
Hepatopatias , Triptofano Hidroxilase , Animais , Barreira Hematoencefálica/metabolismo , Mamíferos/metabolismo , Obesidade/tratamento farmacológico , Serotonina , Triptofano Hidroxilase/metabolismoRESUMO
BACKGROUND: Chronic exposure to low-dose persistent organic pollutants (POPs) can induce mitochondrial dysfunction. This study evaluated the association between serum POP concentrations and oxygen consumption rate (OCR) as a marker of mitochondrial function in humans and in vitro cells. METHODS: Serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in 323 adults. The OCRs of platelets and peripheral blood mononuclear cells (PBMCs) were assessed in 20 mL of fresh blood using a Seahorse XF analyzer. Additionally, the in vitro effects of Arochlor-1254, ß-hexachlorocyclohexane, and p,p´-dichlorodiphenyltrichloroethane at concentrations of 0.1 pM to 100 nM were evaluated in human platelets, human PBMCs, and Jurkat T-cells. RESULTS: The association between serum POP concentrations and OCR differed depending on the cell type. As serum OCP concentrations increased, basal platelet OCR levels decreased significantly; according to the OCP quintiles of summary measure, they were 8.6, 9.6, 8.2, 8.0, and 7.1 pmol/min/µg (P trend=0.005). Notably, the basal PBMC OCR levels decreased remarkably as the serum PCB concentration increased. PBMC OCR levels were 46.5, 34.3, 29.1, 16.5, and 13.1 pmol/min/µg according to the PCB quintiles of summary measure (P trend <0.001), and this inverse association was consistently observed in all subgroups stratified by age, sex, obesity, type 2 diabetes mellitus, and hypertension, respectively. In vitro experimental studies have also demonstrated that chronic exposure to low-dose POPs could decrease OCR levels. CONCLUSION: The findings from human and in vitro studies suggest that chronic exposure to low-dose POPs can induce mitochondrial dysfunction by impairing oxidative phosphorylation.
Assuntos
Diabetes Mellitus Tipo 2 , Bifenilos Policlorados , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Exposição Ambiental/efeitos adversos , Humanos , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Poluentes Orgânicos Persistentes , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/toxicidadeRESUMO
Cancer cells predominantly generate energy via glycolysis, even in the presence of oxygen, to support abnormal cell proliferation. Suppression of PDHA1 by PDK1 prevents the conversion of cytoplasmic pyruvate into Acetyl-CoA. Several PDK inhibitors have been identified, but their clinical applications have not been successful for unclear reasons. In this study, endogenous PDHA1 in A549 cells was silenced by the CRISPR/Cas9 system, and PDHA1WT and PDHA13SD were transduced. Since PDHA13SD cannot be phosphorylated by PDKs, it was used to evaluate the specific activity of PDK inhibitors. This study highlights that PDHA1WT and PDHA13SD A549 cells can be used as a cell-based PDK inhibitor-distinction system to examine the relationship between PDH activity and cell death by established PDK inhibitors. Leelamine, huzhangoside A and otobaphenol induced PDH activity-dependent apoptosis, whereas AZD7545, VER-246608 and DCA effectively enhanced PDHA1 activity but little toxic to cancer cells. Furthermore, the activity of phosphomimetic PDHA1 revealed the complexity of its regulation, which requires further in-depth investigation. [BMB Reports 2021; 54(11): 563-568].
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Avaliação de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/patologia , Piruvato Desidrogenase (Lipoamida)/antagonistas & inibidores , Células A549 , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Inibidores Enzimáticos/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , FosforilaçãoRESUMO
Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity.
Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , Dieta Hiperlipídica/efeitos adversos , Obesidade/etiologia , Obesidade/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/deficiência , Células 3T3-L1 , Adipócitos/citologia , Adiposidade/genética , Animais , Biomarcadores , Expressão Gênica , Glicólise , Resistência à Insulina , Ácido Láctico/metabolismo , Camundongos , Camundongos Knockout , Obesidade/patologia , Tamanho do ÓrgãoRESUMO
Purpose: To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE). Methods: The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine. Results: In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells. Conclusions: Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.
Assuntos
Neovascularização de Coroide/prevenção & controle , Corioidite/tratamento farmacológico , Fursultiamina/uso terapêutico , Inflamação/tratamento farmacológico , Epitélio Pigmentado da Retina/efeitos dos fármacos , Complexo Vitamínico B/uso terapêutico , Animais , Western Blotting , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Técnicas de Reprogramação Celular , Quimiocina CCL2/metabolismo , Neovascularização de Coroide/metabolismo , Corioidite/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Inflamação/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Epitélio Pigmentado da Retina/metabolismoRESUMO
Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE-/- mice fed a western diet (WD) has not yet been investigated. WD-fed ApoE-/- mice developed atherosclerotic plaques and hyperlipidemia along with obesity, which were significantly ameliorated by DCA administration. Increased oxygen consumption was associated with heat production in the DCA-treated group, with no change in food intake or physical activity compared with those of the control. These processes were correlated with the increased gene expression of Dio2 and Ucp-1, which represents brown adipose tissue (BAT) activation, in both WD-induced atherosclerosis and high-fat-induced obesity models. In addition, we found that DCA stimulated hepatic fibroblast growth factor 21 (Fgf21) mRNA expression, which might be important for lowering lipid levels and insulin sensitization via BAT activation, in a dose- and time-dependent manner associated with serum FGF21 levels. Interestingly, Fgf21 mRNA expression was mediated in an AMP-activated protein kinase (AMPK)-dependent manner within several minutes after DCA treatment independent of peroxisome proliferator-activated receptor alpha (PPARα). Taken together, the results suggest that enhanced glucose oxidation by DCA protects against atherosclerosis by inducing hepatic FGF21 expression and BAT activation, resulting in augmented energy expenditure for heat generation.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Aterosclerose/tratamento farmacológico , Fármacos Cardiovasculares/farmacologia , Ácido Dicloroacético/farmacologia , Inibidores Enzimáticos/farmacologia , Fatores de Crescimento de Fibroblastos/genética , Placa Aterosclerótica/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Ocidental/efeitos adversos , Dislipidemias/tratamento farmacológico , Dislipidemias/etiologia , Dislipidemias/genética , Dislipidemias/patologia , Metabolismo Energético/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/agonistas , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Consumo de Oxigênio/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Iodotironina Desiodinase Tipo IIRESUMO
Pyruvate dehydrogenase kinases (PDHKs) promote abnormal respiration in cancer cells. Studies with novel resorcinol amide derivatives based on VER-246608 (6) led to the identification of 19n and 19t containing five-membered heteroaromatic rings as unique structural features. These substances possess single-digit nanomolar activities against PDHKs. 19t exhibits higher potencies against PDHK1/2/4 than does 6 and inhibits only PDHKs among 366 kinases. Moreover, 19g, 19l, and 19s were found to be isotype-selective PDHK inhibitors. Molecular dynamics simulations provide a better understanding of how the heteroaromatic rings affect the activities of 19n and 19t on PDHK1/2/3/4. Moreover, 19n possesses a much higher antiproliferative activity against cancer cells than does 6. We demonstrated that the results of PDH assays better correlate with cellular activities than do those of PDHK kinase assays. Furthermore, 19n induces apoptosis of cancer cells via mitochondrial dysfunction, suppresses tumorigenesis, and displays a synergistic effect on satraplatin suppression of cancer cell proliferation.
Assuntos
Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Piruvato Desidrogenase Quinase de Transferência de Acetil/química , Resorcinóis/farmacologia , Amidas/química , Apoptose , Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células , Inibidores Enzimáticos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Peptídeos/química , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Resorcinóis/químicaRESUMO
Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.
Assuntos
Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/imunologia , Complexo Piruvato Desidrogenase/imunologia , Acetilcoenzima A/imunologia , Acetilcoenzima A/metabolismo , Animais , Citosol/imunologia , Citosol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Macrófagos/classificação , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/imunologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/deficiência , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Complexo Piruvato Desidrogenase/metabolismo , Ácido Pirúvico/imunologia , Ácido Pirúvico/metabolismoRESUMO
Millions of people worldwide have diabetes, which is diagnosed by fasting blood glucose levels exceeding 126 mg/dL. Regardless of the type of diabetes, prolonged hyperglycemia is damaging to several organs including eyes, kidneys, nerve, and/or heart. The damages are associated with a high risk of morbidity and mortality. Diabetes has been implicated in ischemia in the microvasculature of the target tissues, which occurs due to the insufficient perfusion of tissues. The resulting occlusion and pain affect the quality of life. Multiple therapeutic approaches have been proposed for a long time to overcome these vascular complications. Apart from systemically controlling high glucose levels, other therapeutic strategies are not well understood. In this review, we summarize the recent literature for biochemical/cellular targets that are being utilized for the treatment of diabetic microvascular diseases. These targets, which are closely associated with mitochondrial dysfunction, include the polyol and diacylglycerol-protein kinase C pathways, oxidative stress, non-enzymatic glycation and the formation of advanced glycation end products, and immune dysregulation/inflammation.
Assuntos
Angiopatias Diabéticas/patologia , Animais , Angiopatias Diabéticas/metabolismo , Humanos , Mitocôndrias/metabolismoRESUMO
Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.
Assuntos
Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Administração Oral , Animais , Antraquinonas/química , Antraquinonas/metabolismo , Antraquinonas/uso terapêutico , Sítios de Ligação , Linhagem Celular , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Masculino , Doenças Metabólicas/patologia , Doenças Metabólicas/veterinária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/patologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Atherosclerosis is a major cause of morbidity and mortality due to cardiovascular diseases, such as coronary artery disease, stroke, and peripheral vascular disease, that are associated with thrombosis-induced organ infarction. In Westernized countries, the high prevalence of obesity-induced insulin resistance is predicted to be a major factor leading to atherosclerotic vascular disease. Both genetic and environmental factors interfere with immune responses in atherosclerosis development with chronic and non-resolving states. The most known autoimmune disease therapy is cytokine-targeted therapy, which targets tumor necrosis factor-α and interleukin (IL)-17 antagonists. Recently, a clinical trial with the anti-IL-1ß antibody (canakinumab) had shown that the anti-inflammatory effects in canakinumab-treated subjects play a critical role in reducing cardiovascular disease prevalence. Recent emerging data have suggested effective therapeutics involving anti-obesity and anti-diabetic agents, as well as statin and anti-platelet drugs, for atherothrombosis prevention. It is well-known that specialized immune differentiation and activation completely depends on metabolic reprogramming mediated by mitochondrial dynamics in distinct immune cells. Therefore, there is a strong mechanistic link between metabolism and immune function mediated by mitochondrial function. In this review, we describe that cellular metabolism in immune cells is strongly interconnected with systemic metabolism in terms of diverse phenotypes and activation.
RESUMO
The objective of this study was to clarify the lifestyle characteristics of patients with alcoholic liver disease (ALD) who were readmitted to the hospital, and to identify the background factors associated with these characteristics. This was a prospective observational study. Over a period of 3 months following hospital discharge, we conducted structured interviews to investigate the following five lifestyle characteristics based on our previous research: dietary intake, alcohol consumption or abstinence, psycho-emotional status, regularity of life habits, adherence to treatment. We also collected data on background factors from medical records and questionnaires. The analysis was performed using conceptual cluster matrices, with participants divided into two groups (at-home recovery and readmission). Lifestyle, health status, and background factors were compared between the two groups. Of the 34 patients with ALD recruited, 21 completed the one-month follow-up and were included in the analysis-14 patients were in the at-home recovery group and 7 in the readmission group. The at-home group's lifestyle was characterized by controlled alcohol consumption, but with maintenance of regular life and eating habits and adherence to treatment. In contrast, irregular eating habits (p=0.006) and the development of irregular life habits or the discontinuation of treatment very quickly after hospital discharge characterized the readmission group's lifestyle. Experiences of loss were a lifestyle-related background factor that was associated with readmission (p=0.017). Based on these findings, supporting patients with ALD in maintaining regular eating habits and taking experiences of loss into consideration would be important in avoiding readmission over the short-term.
Assuntos
Estilo de Vida , Hepatopatias Alcoólicas/fisiopatologia , Hepatopatias Alcoólicas/psicologia , Readmissão do Paciente , Adulto , Idoso , Consumo de Bebidas Alcoólicas , Dieta , Emoções , Comportamento Alimentar , Seguimentos , Nível de Saúde , Humanos , Hepatopatias Alcoólicas/terapia , Pessoa de Meia-Idade , Cooperação do Paciente , Readmissão do Paciente/estatística & dados numéricos , Estudos Prospectivos , PsicologiaRESUMO
Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.
RESUMO
We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation was functionally determined in kidneys of wild-type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood-perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, Nω-nitro-l-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N5-(1-imino-3-butenyl)-l-ornithine (VNIO). Acetylcholine (0.1 mM) produced a significant vasoconstriction in afferent arterioles of AT1A/AT1B mice (-10.9 ± 5.1%) and no changes in afferent arteriolar diameters of AT1A knockout mice. NLA (0.01-1 mM) or VNIO (0.01-1 µM) induced significant dose-dependent vasoconstrictions (-19.8 ± 4.0% 1 mM NLA; -7.8 ± 3.5% 1 µM VNIO) in afferent arterioles of kidneys of wild-type mice. VNIO had no effect on afferent arteriole diameters of AT1A knockout or AT1A/AT1B knockout mice, suggesting nonfunctional neuronal nitric oxide synthase. These data indicate that acetylcholine produces a significant renal afferent arteriole vasodilation independently of nitric oxide synthases in wild-type mice. AT1A receptors are essential for the manifestation of renal afferent arteriole responses to neuronal nitric oxide synthase-mediated nitric oxide release.
Assuntos
Acetilcolina/farmacologia , Arteríolas/efeitos dos fármacos , Agonistas Colinérgicos/farmacologia , Sistema Justaglomerular/irrigação sanguínea , Óxido Nítrico Sintase/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Arteríolas/enzimologia , Inibidores Enzimáticos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Low-dose persistent organic pollutants (POPs), especially organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), have emerged as a new risk factor for type 2 diabetes. We evaluated whether chronic exposure to low-dose POPs affects insulin secretory function of ß-cells in humans and in vitro cells. Serum concentrations of OCPs and PCBs were measured in 200 adults without diabetes. Mathematical model-based insulin secretion indices were estimated by using a 2-h seven-sample oral glucose tolerance test. Insulin secretion by INS-1E ß-cells was measured after 48 h of treatment with three OCPs or one PCB mixture. Static second-phase insulin secretion significantly decreased with increasing serum concentrations of OCPs. Adjusted means were 63.2, 39.3, 44.1, 39.3, 39.7, and 22.3 across six categories of a summary measure of OCPs (Ptrend = 0.02). Dynamic first-phase insulin secretion remarkably decreased with increasing concentrations of OCPs among only insulin-sensitive individuals (Ptrend = 0.02); the insulin levels among individuals with high OCPs were â¼30% of those with low OCPs. Compared with OCPs, PCBs showed weaker associations. The decreased insulin secretion by INS-1E ß-cells was observed for even 1 pmol/L OCP. The data from human and in vitro cell experiments suggest that chronic exposure to low-dose POPs, especially OCPs, can induce pancreatic ß-cell dysfunction.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Poluentes Ambientais/toxicidade , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adulto , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Poluentes Ambientais/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Hidrocarbonetos Clorados/sangue , Hidrocarbonetos Clorados/toxicidade , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Bifenilos Policlorados/sangue , Bifenilos Policlorados/toxicidade , RatosRESUMO
Clinical prescription of cisplatin, one of the most widely used chemotherapeutic agents, is limited by its side effects, particularly tubular injury-associated nephrotoxicity. Since details of the underlying mechanisms are not fully understood, we investigated the role of pyruvate dehydrogenase kinase (PDK) in cisplatin-induced acute kidney injury. Among the PDK isoforms, PDK4 mRNA and protein levels were markedly increased in the kidneys of mice treated with cisplatin, and c-Jun N-terminal kinase activation was involved in cisplatin-induced renal PDK4 expression. Treatment with the PDK inhibitor sodium dichloroacetate (DCA) or genetic knockout of PDK4 attenuated the signs of cisplatin-induced acute kidney injury, including apoptotic morphology of the kidney tubules along with numbers of TUNEL-positive cells, cleaved caspase-3, and renal tubular injury markers. Cisplatin-induced suppression of the mitochondrial membrane potential, oxygen consumption rate, expression of electron transport chain components, cytochrome c oxidase activity, and disruption of mitochondrial morphology were noticeably improved in the kidneys of DCA-treated or PDK4 knockout mice. Additionally, levels of the oxidative stress marker 4-hydroxynonenal and mitochondrial reactive oxygen species were attenuated, whereas superoxide dismutase 2 and catalase expression and glutathione synthetase and glutathione levels were recovered in DCA-treated or PDK4 knockout mice. Interestingly, lipid accumulation was considerably attenuated in DCA-treated or PDK4 knockout mice via recovered expression of peroxisome proliferator-activated receptor-α and coactivator PGC-1α, which was accompanied by recovery of mitochondrial biogenesis. Thus, PDK4 mediates cisplatin-induced acute kidney injury, suggesting that PDK4 might be a therapeutic target for attenuating cisplatin-induced acute kidney injury.
Assuntos
Injúria Renal Aguda/prevenção & controle , Cisplatino , Túbulos Renais/enzimologia , Proteínas Serina-Treonina Quinases/deficiência , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Animais , Apoptose , Caspase 3/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Metabolismo Energético , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/ultraestrutura , Masculino , Potencial da Membrana Mitocondrial , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Biogênese de Organelas , Estresse Oxidativo , Fenótipo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used antihyperglycemic agents for type 2 diabetes mellitus. Recently, increasing attention has been focused on the pleiotropic actions of DPP-4 inhibitors. The aim of the present study was to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could ameliorate features of metabolic syndrome. Mice were fed a Western diet (WD) for 12 weeks and were subsequently divided into 2 groups: mice fed a WD diet alone or mice fed a WD diet supplemented with gemigliptin for an additional 4 weeks. Gemigliptin treatment attenuated WD-induced body mass gain, hypercholesterolemia, adipocyte hypertrophy, and macrophage infiltration into adipose tissue, which were accompanied by an increased expression of uncoupling protein 1 in subcutaneous fat. These events contributed to improved insulin sensitivity, as assessed by the homeostasis model assessment of insulin resistance and intraperitoneal insulin tolerance test. Furthermore, gemigliptin reduced WD-induced hepatic triglyceride accumulation via inhibition of de novo lipogenesis and activation of fatty acid oxidation, which was accompanied by AMP-dependent protein kinase activation. Gemigliptin ameliorated WD-induced hepatic inflammation and fibrosis through suppression of oxidative stress. These results suggest that DPP-4 inhibitors may represent promising therapeutic agents for metabolic syndrome beyond their current role as antihyperglycemic agents.