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Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
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BACKGROUND: Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown. METHODS: We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-ß, a marker of beta cell function. RESULTS: Median (IQR) arsenic concentration was 0.45 (0.67) µg/g in toenails and 2.0 (6.5) µg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (- 3.13, 3.37) higher and HOMA-ß was 0.96% (- 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null. CONCLUSIONS: Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function.
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Arsénico , Diabetes Gestacional , Arsénico/análisis , Bangladesh/epidemiología , Glucemia , Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/epidemiología , Femenino , Glucosa , Humanos , Periodo Posparto , EmbarazoRESUMEN
The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)-repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine376 and Serine389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially co-localized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2S4-S8 and CHK1S345 phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE-/-), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis.
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Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Reparación del ADN , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Animales , Núcleo Celular/enzimología , Núcleo Celular/metabolismo , Senescencia Celular , ADN/metabolismo , Roturas del ADN de Doble Cadena , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Homeostasis , Pulmón/fisiopatología , Proteína Homóloga de MRE11 , Ratones Endogámicos C57BL , Ratones Noqueados , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/fisiopatología , Receptor para Productos Finales de Glicación Avanzada/genética , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Transducción de SeñalRESUMEN
Neutrophil elastase and myeloperoxidase enzymes have been implicated in high-fat diet-induced obesity, insulin resistance (IR) and atherosclerosis in animal models. The aim of the present study was to explore neutrophil elastase and myeloperoxidase mRNA expressions in the peripheral blood leukocytes (PBL) in overweight and obese subjects, and to correlate those mRNA expressions with BMI, IR and cardiovascular biomarkers. In this cross-sectional study, 74 apparently healthy subjects including 22 lean, 27 overweight and 25 obese subjects were recruited. Cardiovascular and metabolic biomarkers were evaluated from fasting blood samples. The mRNA levels of neutrophil elastase and myeloperoxidase genes in the PBL were quantified by real-time PCR. Compared to lean group, the overweight and obese groups showed significant upregulation of both neutrophil elastase (p < 0.001) and myeloperoxidase (p < 0.03) mRNA expressions in the PBL. But no difference was found between overweight and obese groups. The neutrophil elastase and myeloperoxidase mRNA levels showed significant positive correlation with BMI, serum triglyceride, atherogenic index of plasma and 10-year risk of developing cardiovascular disease. But no correlation was found with glucose, insulin or IR. It was concluded that the neutrophil elastase and myeloperoxidase genes are up-regulated in both overweight and obese subjects and are associated with BMI and markers of cardiovascular disease.
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Elastasa de Leucocito/genética , Obesidad/genética , Sobrepeso/genética , Peroxidasa/genética , Regulación hacia Arriba , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Resistencia a la Insulina/genética , Masculino , Obesidad/sangre , Sobrepeso/sangre , Triglicéridos/sangreAsunto(s)
Fumar Cigarrillos , Enfermedad Pulmonar Obstructiva Crónica , Biomarcadores , Humanos , Fumar , Fumar TabacoRESUMEN
PURPOSE: To establish the key insulin receptor substrate 1 (IRS-1) structural elements required in this insulin regulatory pathway, we investigated the effects of substituting alanine for serine 307 in IRS-1 on the ability of tumor necrosis factor-α (TNF-α) and a related mediator, suppressor of cytokine signaling 3 (SOCS3), to phosphorylate IRS-1 and regulate insulin signaling in the rat retinal Müller cell (rMC-1) cell line. METHODS: rMC-1 cells were grown in normal (5 mM) or high (25 mM) glucose medium and transfected with either normal IRS-1(Ser307)plasmid or a mutated IRS-1(Ser307Ala) plasmid. Cells were also treated with recombinant TNF-α or SOCS3 to induce increased levels of these proteins. RESULTS: In cells with IRS-1(Ser307Ala), TNF-α and SOCS3 failed to phosphorylate IRS-1. Likewise, resulting downstream effects, including changes in phosphorylation of insulin receptor(Tyr960), antiapoptotic Akt phosphorylation, and proapoptotic cleavage of caspase 3 were also blocked. We also report for the first time that SOCS3 and TNF-α are reciprocally stimulatory leading to a mutual enhancement of levels of both factors, thus forming a potential positive feedback loop that contributes to insulin receptor resistance. CONCLUSIONS: Increases in TNF-α and SOCS3 are triggered by high glucose and through reciprocal stimulation of expression of these two factors, which in turn could be major drivers of insulin resistance and related cell death. The demonstration that a single phosphorylation site is key for these pathways suggests that drugs targeted to this site might be effective in protecting against diabetic damage to the retina.
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Células Ependimogliales/metabolismo , Glucosa/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Alanina/genética , Alanina/metabolismo , Sustitución de Aminoácidos , Animales , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Células Ependimogliales/citología , Células Ependimogliales/efectos de los fármacos , Retroalimentación Fisiológica , Regulación de la Expresión Génica , Glucosa/farmacología , Proteínas Sustrato del Receptor de Insulina/química , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Serina/genética , Serina/metabolismo , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/farmacología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The severity of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), greatly varies from patient to patient. In the present study, we explored and compared mutation profiles of SARS-CoV-2 isolated from mildly affected and severely affected COVID-19 patients in order to explore any relationship between mutation profile and disease severity. Genomic sequences of SARS-CoV-2 were downloaded from Global Initiative on Sharing Avian Influenza Data (GISAID) database. With the help of Genome Detective Coronavirus Typing Tool, genomic sequences were aligned with the Wuhan seafood market pneumonia virus reference sequence and all the mutations were identified. Distribution of mutant variants was then compared between mildly and severely affected groups. Among the numerous mutations detected, 14,408C>T and 23,403A>G mutations resulting in RNA-dependent RNA polymerase (RdRp) P323L and spike protein D614G mutations, respectively, were found predominantly in severely affected group (>82%) compared with mildly affected group (<46%, p < 0.001). The 241C>T mutation in the non-coding region of the genome was also found predominantly in severely affected group (p < 0.001). The 3,037C>T, a silent mutation, also appeared in relatively high frequency in severely affected group compared with mildly affected group, but the difference was not statistically significant (p = 0.06). We concluded that spike protein D614G and RdRp P323L mutations in SARS-CoV-2 are associated with severity of COVID-19. Further studies will be required to explore whether these mutations have any impact on the severity of disease.
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BACKGROUND AND AIMS: Neutrophil elastase and myeloperoxidase enzymes protect us from infection by killing pathogens. However, exaggerated activities of these enzymes can induce tissue damage, inflammation and oxidative stress. The present study was aimed to explore the expressions of neutrophil elastase and myeloperoxidase mRNA in the peripheral blood leukocytes (PBL) in patients with newly diagnosed type 2 diabetes mellitus. METHODS: In this cross-sectional study, 104 participants including 65 normoglycemic control subjects and 39 newly diagnosed type 2 diabetes patients were recruited. Glycemic and metabolic markers were evaluated from fasting blood samples. The mRNA levels of neutrophil elastase and myeloperoxidase genes in the PBL were quantified by real-time quantitative PCR. RESULTS: Compared to control subjects, diabetes patients showed a significant down regulation of both neutrophil elastase (p = 0.039) and myeloperoxidase (p = 0.023) mRNA expressions in the PBL. The neutrophil elastase and myeloperoxidase mRNA levels showed a negative trend with fasting glucose levels but did not show any significant correlations with HbA1c, insulin level, insulin resistance or sensitivity status. CONCLUSIONS: It was concluded that type 2 diabetes mellitus is associated with a decrease in neutrophil elastase and myeloperoxidase gene expression in the PBL.
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Diabetes Mellitus Tipo 2/enzimología , Elastasa de Leucocito/metabolismo , Peroxidasa/metabolismo , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Leucocitos/enzimología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The objective of this pharmacogenetic study was to investigate the relationship of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with methotrexate (MTX)-induced toxicities and plasma homocysteine level in patients with acute lymphoblastic leukemia (ALL) from Bangladesh. Several polymorphisms result in reduced MTHFR activity that causes impaired remethylation of homocysteine to methionine and abnormal MTX metabolism, especially in tissues with high turnover. Therefore, the risk of elevated plasma homocysteine as well as MTX-induced toxicities become higher with MTHFR polymorphisms. PATIENTS AND METHODS: We recruited 160 patients with ALL receiving MTX containing chemotherapeutic protocol, and they were genotyped for MTHFR C677T and A1298C polymorphisms with polymerase chain reaction-restriction fragment length polymorphism. We also measured the plasma homocysteine level of 51 patients by the AxSYM homocysteine assay method. RESULTS: We found 68.1% CC, 26.3% CT, and 5.6% TT genotype for MTHFR C677T polymorphism and 39.3% AA, 46.9% AC, and 13.8% CC genotype for MTHFR A1298C polymorphism in patients with ALL. Our study suggested that MTX-induced mucositis and diarrhea are significantly associated with MTHFR C677T as well as MTHFR A1298C polymorphisms (P < .05). CONCLUSION: The risk of elevated plasma homocysteine level was 5 to 6 times higher for both polymorphisms. This study may help to identify the patients who are at higher risk for MTX-related toxicities.
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Metotrexato/efectos adversos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Bangladesh , Niño , Preescolar , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Persona de Mediana Edad , Variantes Farmacogenómicas , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Adulto JovenRESUMEN
Green tea (GT), through its antioxidant properties, may be useful to treat or prevent human diseases. Because several lines of evidence suggest that oxidative stress contributes to the pathogenesis of diabetic nephropathy, we tested the hypothesis that GT prevents diabetes and hypertension-related renal oxidative stress, attenuating renal injury. Spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes and nondiabetic SHR were treated daily with tap water or freshly prepared GT (13.3 g/L). After 12 wk, the systolic blood pressure did not differ between treated and untreated nondiabetic or diabetic rats. However, body weight was less (P < 0.05) and glycemia was greater in diabetic SHR rats than in nondiabetic rats. Renal oxidative stress variables such as 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine expression, NADPH oxidase-dependent superoxide generation, and the expression of renal cortex Nox4 were greater (P < 0.05) in diabetic rats that received water (DW) than in nondiabetic rats that received water (CW). The 8-OHdG and NADPH oxidase-dependent superoxide generation were significantly less in rats treated with GT. Nitrotyrosine and Nox4 expression were significantly less in diabetic rats that received GT (DGT) than in DW. Likewise, the indices of renal injury, albuminuria, and renal expression of collagen IV were significantly greater in DW than in CW. These differences were significantly less in DGT than in DW. GT reestablished the redox state and reduced the indicators of nephropathy without altering glycemia and blood pressure levels in diabetic SHR. These findings suggest that the consumption of GT may ameliorate nephropathy in diabetic hypertensive patients.
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Camellia sinensis/química , Diabetes Mellitus Experimental/complicaciones , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Enfermedades Renales/prevención & control , NADPH Oxidasas/metabolismo , Extractos Vegetales/farmacología , Animales , Biomarcadores , Regulación hacia Abajo , Enfermedades Renales/complicaciones , NADPH Oxidasa 4 , NADPH Oxidasas/genética , Estrés Oxidativo , Extractos Vegetales/química , Ratas , Ratas Endogámicas SHR , Superóxidos/metabolismoRESUMEN
AIMS: The presence of hypertension increases renal oxidative stress by increasing NADPH oxidase-dependent superoxide production and by decreasing antioxidant defense in the early stage of experimental diabetes mellitus (DM). In the present study, we investigated whether the administration of an antioxidant mimetic of the superoxide dismutase (SOD) (tempol) corrects the oxidative imbalance and oxidative stress-induced renal injury in the presence of DM and hypertension. METHODS: DM was induced in spontaneously hypertensive rats (SHR) by streptozotocin at 4 weeks of age. The diabetic rats either did or did not receive tempol for 20 days. Oxidative-stress parameters and indices of renal injury were evaluated. RESULTS: Tempol reestablished the imbalance in redox status induced by DM. It elevated the expression of renal antioxidant extracellular SOD, p < 0.0001; decreased (p = 0.049) the production of renal NADPH-dependent superoxide production, and diminished (p = 0.016) a marker of oxidative stress-induced DNA damage, 8-hydroxy-2'-deoxyguanosine. Reduction of oxidative stress markers was associated with reduction in renal damage parameters associated with DN. DM-induced albuminuria and elevation in renal expression of collagen IV were reduced to the level observed in control rats. CONCLUSION: We conclude that an imbalance in renal redox status is associated with markers of renal injury in the early stage of DM and hypertension. Antioxidant treatment reestablished the redox status and prevented oxidative stress-induced renal damage.
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Antioxidantes/farmacología , Óxidos N-Cíclicos/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Hipertensión Renal/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Colágeno Tipo IV/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Hipertensión Renal/metabolismo , Hipertensión Renal/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Imitación Molecular , NADPH Oxidasas/metabolismo , Ratas , Ratas Endogámicas SHR , Marcadores de Spin , Superóxido Dismutasa/metabolismoRESUMEN
AIMS: The combination of hypertension and diabetes exacerbates renal oxidative stress. The aim of the present study was therefore to evaluate the pro-oxidant and antioxidant mechanisms responsible for the induction of renal oxidative stress in the presence of hypertension and diabetes mellitus. METHODS: Diabetes was induced in spontaneously hypertensive rats (SHR) and their genetically normotensive control Wistar-Kyoto (WKY) rats by streptozotocin at 12 weeks of age. After 10 days, pro-oxidant, antioxidant and oxidative stress parameters were evaluated in the renal tissue. RESULTS: NADPH oxidase-dependent superoxide generation in the renal cortex was significantly elevated in WKY and SHR diabetic (D) groups compared to the respective control (C) groups (p < 0.005, n = 5). However, the highest level of superoxide generation was observed in the SHR-D group compared to all other groups. The expression of the gp91phox subunit of NADPH oxidase was significantly elevated in the SHR-D (p < 0.05, n = 5), but not in the WKY-D group, compared to the respective control groups. The renal cortical extracellular-superoxide dismutase level was found to be markedly decreased in the SHR groups compared to the WKY groups (p < 0.05, n = 5). The antioxidant glutathione level was found to be lower in the SHR-D (p = 0.03, n = 15), but not in the WKY-D group, compared to the respective control groups. Finally, nitrotyrosine and 8-hydroxy-2'-deoxyguanosine, markers of oxidative stress, were found to be similar in the kidneys of WKY-C and WKY-D, but were elevated in the SHR-D compared to the SHR-C group. CONCLUSION: We therefore conclude that hypertension increases pro-oxidant generation and decreases antioxidant defense, and thereby induces renal oxidative stress in early diabetes.
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Antioxidantes/metabolismo , Nefropatías Diabéticas/metabolismo , Hipertensión Renal/metabolismo , Oxidantes/biosíntesis , Animales , Presión Sanguínea/fisiología , Nefropatías Diabéticas/patología , Femenino , Glutatión/metabolismo , Hipertensión Renal/patología , Masculino , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Estrés Oxidativo/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Superóxidos/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
The present study was undertaken to identify whether inflammation or oxidative stress is the primary abnormality in the kidney in spontaneously hypertensive rats (SHR). Renal inflammation and oxidative stress were evaluated in 2- and 3-week-old prehypertensive SHR and age-matched genetically normotensive control Wistar-Kyoto (WKY) rats. Blood pressure was similar in WKY and SHR rats at 2 and 3 weeks, of age. Renal inflammation (macrophage and nuclear factor-kappaB) was elevated in SHR at 3 weeks, but not at 2 weeks, of age compared with age-matched WKY rats. Renal oxidative stress (nitrotyrosine, 8-hydroxy-2'-deoxyguanosine and p47phox) was also clearly elevated in 3-week-old SHR compared with age-matched WKY rats. Additionally, NADPH oxidase subunit p47phox was found elevated in 2-week-old SHR compared to age-matched WKY rats. Moreover, antioxidant (N-acetyl-L-cysteine and Tempol) treatment reduced renal inflammation in prehypertensive SHR. We therefore conclude that the oxidative stress appears before inflammation as a primary abnormality in the kidney in prehypertensive SHR.
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Nefritis/metabolismo , Estrés Oxidativo , Ratas Endogámicas SHR/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina , Acetilcisteína/uso terapéutico , Factores de Edad , Animales , Antioxidantes/uso terapéutico , Presión Sanguínea , Óxidos N-Cíclicos/uso terapéutico , Daño del ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análisis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Glutatión/análisis , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Hipertensión/genética , Hipertensión/metabolismo , Corteza Renal/metabolismo , Masculino , NADPH Oxidasas/análisis , Nefritis/tratamiento farmacológico , Nefritis/genética , Nefritis/prevención & control , Ratas , Ratas Endogámicas WKY , Marcadores de Spin , Tirosina/análogos & derivados , Tirosina/análisisRESUMEN
The present study was undertaken to investigate the redox status in the retina of an experimental model that combines hypertension and diabetes. Spontaneously hypertensive rats (SHR) and their control Wystar Kyoto (WKY) rats were rendered diabetic and, after 20 days, the rats were sacrificed and the retinas collected. The superoxide production was higher in diabetic than in control WKY (p < 0.03) and SHR rats showed elevated superoxide production compared with WKY groups (p < 0.009). The glutathione antioxidant system was diminished only in diabetic SHR (p < 0.04). Tirosyne nitration was higher in diabetic WKY and control SHR compared with control WKY (p < 0.03), and further increment was observed in diabetic SHR (p < 0.02). The DNA damage estimated by immunohystochemistry for 8-OHdG was higher in control SHR than in WKY, mainly in diabetic SHR (p < 0.0001). Hypertension aggravates oxidative-induced cytotoxicity in diabetic retina due to increasing of superoxide production and impairment of antioxidative system.
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Retinopatía Diabética/complicaciones , Retinopatía Diabética/patología , Hipertensión/complicaciones , Hipertensión/patología , Estrés Oxidativo , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Antioxidantes/metabolismo , Daño del ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Glutatión/química , Glutatión/metabolismo , Masculino , Nitrógeno/química , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Superóxido Dismutasa/química , Tirosina/metabolismoRESUMEN
BACKGROUND/AIMS: Previous partial hepatectomy (HPTX) can attenuate glycerol-induced acute kidney injury (Gly-AKI). The aim of this study was to explore the pathophysiological mechanisms and the role of hepatocyte growth factor (HGF) in kidney protection. METHODS: Rats were subjected to HPTX 24 h before glycerol administration. Renal function, acute tubular necrosis, apoptosis, leukocyte infiltration, and the expression of HGF, c-met, monocyte chemoattractant protein-1, interleukin-1beta, and heme oxygenase-1 were evaluated 24 h after glycerol injection. The regenerative response was analyzed from 6 to 72 h after glycerol injection (BrdU incorporation). In a separate series of experiments, Gly-AKI+HPTX rats were treated with anti-HGF antibody. RESULTS: Gly-AKI+HPTX rats showed an increased expression of renal HGF and c-met as well as an improved creatinine clearance and reduced acute tubular necrosis and apoptosis, cytokine expression, and leukocyte infiltration. The regenerative response was less intense 24 and 72 h after glycerol administration in this group. The anti-HGF treatment disclosed an important role of HGF in the reduction of tubular injury, particularly apoptosis. Overexpression of heme oxygenase-1 was observed in Gly-AKI+HPTX rats, but was not associated with HPTX-induced renal protection. CONCLUSION: We conclude that Gly-AKI+HPTX rats have a reduced susceptibility to renal injury instead of an increased regenerative response and that endogenous HGF overexpression is responsible for suppression of tubular apoptosis.
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Glicerol/toxicidad , Hepatectomía , Factor de Crecimiento de Hepatocito/fisiología , Necrosis Tubular Aguda/prevención & control , Proteínas Proto-Oncogénicas c-met/fisiología , Animales , Apoptosis/efectos de los fármacos , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Creatinina/sangre , Regulación de la Expresión Génica , Hemo Oxigenasa (Desciclizante)/biosíntesis , Hemo Oxigenasa (Desciclizante)/genética , Factor de Crecimiento de Hepatocito/biosíntesis , Factor de Crecimiento de Hepatocito/genética , Interleucina-1/biosíntesis , Interleucina-1/genética , Riñón/metabolismo , Riñón/fisiopatología , Necrosis Tubular Aguda/inducido químicamente , Necrosis Tubular Aguda/metabolismo , Necrosis Tubular Aguda/patología , Necrosis Tubular Aguda/cirugía , Macrófagos/patología , Proteínas Proto-Oncogénicas c-met/biosíntesis , Proteínas Proto-Oncogénicas c-met/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Regeneración , Linfocitos T/patologíaRESUMEN
Inflammation is pivotal to the pathogenesis of diabetic retinopathy (DR). Hypertension is the main secondary risk factor associated with DR. The mechanisms by which hypertension increases the risk for DR are poorly understood. The aim of the current study was to investigate the contribution of genetic hypertension to early retinal inflammation in experimental diabetes. Diabetes was induced in 4-week-old (developing hypertension) and 12-week-old (fully hypertensive) spontaneously hypertensive rats (SHR) and age-matched control normotensive Wistar Kyoto (WKY) rats by administration of streptozotocin (50 mg/kg, i.v); after 20 days the rats were sacrificed and the retinas were collected. ED1 positive cells, ICAM-1 and VEGF levels were significantly higher in diabetic SHR in both prehypertensive and hypertensive ages (p < 0.005). NF-kappaB p65 levels were higher in prehypertensive SHR and in hypertensive diabetic SHR (p < 0.05). Induction of diabetes in normotensive WKY rats did not show any alteration in retinal expression of inflammatory parameters. Therefore, we conclude that the developing hypertension and also the fully developed hypertension lead to earlier development of inflammation in diabetic retina. Aggravation of the inflammatory process may be involved in the mechanism by which essential hypertension exacerbates retinopathy in the presence of diabetes.
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Diabetes Mellitus Experimental/complicaciones , Retinopatía Diabética/etiología , Hipertensión/complicaciones , Retinitis/etiología , Animales , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/metabolismo , Ectodisplasinas/metabolismo , Hipertensión/metabolismo , Técnicas para Inmunoenzimas , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Retinitis/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BackgroundAegle marmelos is a popular fruit plant in the Indian subcontinent, various parts of which are traditionally used against various illnesses including diabetes mellitus (DM). However, the underlying mechanisms of the antidiabetic effects of the plant are not clear, especially in type 2 DM. The present study was undertaken to investigate the effect of aqueous extracts of A. marmelos fruits (AMFE) and leaves (AMLE) on glycemic, lipidemic, insulinemic, insulin resistance and ß-cell functional status of type 2 diabetic model rats. Methods An interventional study was designed using 20 type 2 diabetic rats. Type 2 DM was induced in Long Evans rats by a single intra-peritoneal injection of streptozotocin (90 mg/kg body weight) to 48 h old pups. Three months after induction of diabetes, the rats were divided into three independent groups: water-treated control group (n=6), AMLE-treated group (n=7) and AMFE-treated group (n=7). The rats were fed with extracts or water for 21 consecutive days and blood samples were collected at days 0 and 21 after an overnight fast. Data were expressed as mean±SD and analyzed by paired t-test or ANOVA as appropriate. Results There were significantly lower blood glucose values in AMLE and AMFE groups at Endpoint compared to Baseline (mmol/l, mean±SD, Baseline vs. Endpoint, 7.04±1.0 vs. 6.06±0.92; p=0.032 and 7.04±0.97 vs. 5.87±0.93; p=0.047). There were also significantly lower serum insulin levels in AMLE and AMFE groups at Endpoint compared to Baseline (µIU/mL, mean±SD, Baseline vs. Endpoint, 14.02±5.48 vs. 7.57±2.90; p=0.026 and 11.54±4.83 vs. 6.58±4.36; p=0.008). Insulin resistance (HOMA-IR) was significantly improved both in AMLE and AMFE groups at Endpoint compared to Baseline (mean±SD, Baseline vs. Endpoint, 4.22±1.68 vs. 2.05±0.90; p=0.021 and 3.69±1.79 vs. 1.69±1.61; p=0.013). However, ß-cell function or lipid profile did not show any significant alteration at Endpoint compared to Baseline in AMLE and AMFE groups. Conclusions Aqueous extracts of A. marmelos leaf and fruit have hypoglycemic property which seem to be mediated by lowering of insulin resistance. These findings highlight the therapeutic potential of the extracts of A. marmelos in human type 2 DM and provides strong impetus for further studies.
Asunto(s)
Aegle , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Hipoglucemiantes/farmacología , Insulina/sangre , Lípidos/sangre , Extractos Vegetales/farmacología , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Frutas , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Células Secretoras de Insulina/efectos de los fármacos , Masculino , Fitoterapia , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Ratas Long-EvansRESUMEN
PURPOSE: Successful repair and regeneration in bone tissue engineering vastly depends on proper interaction between the tissue-engineered construct and the recipient's immune system. In clinical application, adverse responses to bioartificial implants may result in chronic inflammation and loss of the implant. It is known that prolonged inflammation linked to NF-κB inflammatory pathways inhibits bone-forming activity of osteoblast cells. Contributing to orchestrate inflammatory processes, the ligand-activated transcription factor peroxisome proliferator-activated receptor alpha (PPARα) holds inhibitory effects on NF-κB and CEBß activity. Sp1, a widely expressed transcription factor, has been linked to PPAR pathways, cellular homeostasis, and responsiveness to environmental perturbation. Formerly not being characterized, the role of PPARα in inflammatory-mediated bone loss requires further investigation. The aim of the present study was to identify regulatory transcription factor binding sites (TFBS) on the PPAR alpha promoter and to assess the role of Sp1 and associated proteins in its regulation. MATERIALS AND METHODS: In a first set of experiments, polymerase chain reaction assessed the presence of PPARα gene expression in isolated murine bone tissue. Deletion mutagenesis was performed on the human PPARα (hPPARα) promoter gene, and the deletion constructs were transiently transfected to murine osteoblasts to identify important TFBS. PPARα promoter-driven reporter gene expression was monitored in response to overexpression and repression of Sp1 to analyze functional transcription factor recruitment to the PPARα promoter. RESULTS: This study could demonstrate that the full-length hPPARα promoter contains inhibiting promoter regions and that hPPARα basal expression can be significantly increased by deletion mutagensis. Sp1 TFBS proved functional in the regulation of PPARα promoter activity, and the first five Sp1 motifs on the PPARα promoter were sufficient to significantly increase PPARα expression. Additional transient co-transfection experiments could not detect any direct effect of NF-κB/IκB downstream pathway on the regulation of PPARα promoter activity. Taken together, we could demonstrate that Sp1 plays a key role in transcriptional regulation of PPARα promoter activity and gene expression. CONCLUSION: This study provides further insight on Sp1-dependent PPARα regulatory mechanisms and suggests that Sp1-regulated PPARα expression plays a key role in inflammatory mediated bone loss.