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1.
J Endocr Soc ; 8(5): bvae036, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38481602

RESUMO

Context: Moon-like facies (MLF) are a typical side effect of glucocorticoid (GC) therapy; however, its predisposing factors, relationship with GC-induced complications, and effects on body image are not well understood. Objective: This study aimed to determine the predisposing factors for MLF during GC therapy; its association with GC-induced diabetes, hypertension, and dyslipidemia; and its effects on body image. Methods: This prospective observational study spanned 24 weeks and targeted patients who received GC therapy at the University of Yamanashi Hospital from June 2020 to August 2022. The MLF was defined based on the following 3 factors: (1) an increase in facial measurement lengths, (2) subjective facial changes by patients' self-assessment using a visual analog scale; (3) objective and qualitative facial changes assessed by physicians. We examined the predisposing factors for MLF and the association of MLF with GC-induced diabetes, hypertension, dyslipidemia, and body image. Results: The cumulative incidence rate of MLF at 24 weeks was 37.6%. Predisposing factors for MLF were an initial oral prednisolone dosage of ≥ 30 mg/day [odds ratio (OR) 63.91, 95% confidence interval (CI) 5.82-701.81] and female (OR 6.66, 95% CI 1.35-32.79). MLF showed a significant association with the onset of GC-induced diabetes (OR 6.58, 95% CI 1.25-34.74). MLF was also an independent factor contributing to body image disturbance (ß = -18.94, P = .01). Conclusion: MLF contributes to body image disturbance and is associated with the development of GC-induced diabetes; therefore, it is clinically important as a physical manifestation of GC therapy.

2.
Sci Rep ; 13(1): 9086, 2023 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-37277555

RESUMO

Prostasin (PRSS8) is a serine protease that metabolizes and moderates the effect of specific substrates. Epidermal growth factor receptor (EGFR), which modulates insulin secretion and pancreatic ß-cell proliferation, is regulated via proteolytic shedding by PRSS8. We first detected PRSS8 expression in ß-cells of pancreatic islets of mice. To better understand the molecular processes involved in PRSS8-associated insulin secretion, pancreatic ß-cell-specific PRSS8 knockout (ßKO) and PRSS8-overexpressing (ßTG) male mice were generated. We found that glucose intolerance and reduction in glucose-stimulated insulin secretion developed in ßKO mice compared with the control subjects. A higher response to glucose was noted in islets retrieved from ßTG mice. Erlotinib, a specific blocker of EGFR, blocks EGF- and glucose-stimulated secretion of insulin among MIN6 cells, and glucose improves EGF release from ß-cells. After silencing PRSS8 in MIN6 cells, glucose-stimulated insulin secretion decreased, and EGFR signaling was impaired. Conversely, overexpression of PRSS8 in MIN6 cells induced higher concentrations of both basal and glucose-stimulated insulin secretion and increased phospho-EGFR concentrations. Furthermore, short-term exposure to glucose improved the concentration of endogenous PRSS8 in MIN6 cells through inhibition of intracellular degradation. These findings suggest that PRSS8 is involved in glucose-dependent physiological regulation of insulin secretion via the EGF-EGFR signaling pathway in pancreatic ß-cells.


Assuntos
Células Secretoras de Insulina , Peptídeo Hidrolases , Masculino , Animais , Camundongos , Secreção de Insulina , Peptídeo Hidrolases/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Glucose/metabolismo , Receptores ErbB/metabolismo
3.
Endocr J ; 69(3): 263-272, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-34629337

RESUMO

Thyroid hormones are critical regulators of vertebrate development and metabolism. Under hyperthyroid conditions, excess thyroid hormones induce expression of several enzymes and activities via activation of ligand-bound thyroid hormone receptors (TRs). Arginase (ARG) is downstream of a ligand-bound TR and overexpression of ARG2 induces the production of reactive oxygen species and subsequent exacerbation of kidney ischemia/reperfusion (I/R) injury. To clarify the association between I/R-induced kidney injury and hyperthyroidism, mice were pretreated with L-thyroxine (LT4) or vehicle alone, then subjected to I/R. Proximal tubular cell-specific conditional knockout of thyroid hormone receptor ß (TRßcKO) mice was generated and the effects of I/R were analyzed. Hyperthyroidism enhanced tubular damage and fibrosis in the kidneys of mice after I/R. Hyperthyroidism induced tubular cell necroptosis following inflammatory cell accumulation in the kidney after I/R. ARG2 expressions and reactive oxygen species accumulated in the kidneys of hyperthyroid mice after I/R, but these changes were ameliorated in the kidneys of TRßcKO mice. Hyperthyroidism-enhanced kidney injury was ameliorated in the kidney of TRßcKO mice after I/R. These results suggest that excess thyroid hormones are disadvantageous for the kidney under ischemic stress. Overt hypothyroidism represents a severe thyroid hormone deficiency disease that requires LT4 treatment, while overreplacement or iatrogenic thyrotoxicosis might cause kidney injury.


Assuntos
Hipertireoidismo , Hipotireoidismo , Traumatismo por Reperfusão , Animais , Hipertireoidismo/complicações , Hipertireoidismo/genética , Hipotireoidismo/metabolismo , Rim/metabolismo , Camundongos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Hormônios Tireóideos/metabolismo
4.
Endocr J ; 69(5): 539-546, 2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34866068

RESUMO

Inteletin1 (Itln1) is an adipokine that is abundantly expressed in intestine, ovary, and lung. The expression levels of ITLN1 are decreased in the presence of diabetes or obesity, but the mechanisms of its production and function are still controversial. The aim of this study is to elucidate the mechanisms of ITLN1 synthesis and ITLN1-associated macrophage activation. To analyze the effects of high fat and high-carbohydrate diet (HFHCD) on the expression of ITLN1 in the intestine, the mice were fed a HFHCD for 8 weeks. HFHCD feeding enhanced the endoplasmic reticulum (ER)-stress in the intestine and inhibited the expression of Itln1 in the intestinal endocrine cells and lowered circulating ITLN1 levels. In contrast, treatment with a chemical chaperone and reduction of ER-stress restored the expression of Itln1 in the intestine of HFHCD-fed mice. Furthermore, in vitro studies indicated that ITLN1 physically interacts with adiponectin receptor 1 and suppresses lipopolysaccharide-induced mRNA expressions of pro-inflammatory cytokines and phagocytosis activities via inhibition of the nuclear factor kappa B-signaling pathway in macrophages. These results suggest that diet-induced ER-stress decreases circulating ITLN1 via inhibition of its synthesis in the intestine, and a reduction of circulating ITLN1 might enhanced the expression of proinflammatory cytokines and macrophage activation, following exacerbate the chronic inflammation of metabolic syndrome.


Assuntos
Citocinas/metabolismo , Proteínas Ligadas por GPI/metabolismo , Lectinas/metabolismo , Ativação de Macrófagos , NF-kappa B , Animais , Estresse do Retículo Endoplasmático , Feminino , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais
5.
Endocr J ; 68(11): 1309-1320, 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34108302

RESUMO

Hypoxia occurs in the kidneys of chronic kidney disease (CKD) patients, inducing interstitial fibrosis and tubule cell death. Renal tubule cell death is an important determinant of mortality in CKD. We focused on the regulation of cell-cycle-mediated protein expression to prevent cell death under chronic hypoxia in the kidneys of CKD patients. Paraffin-embedded kidney sections from patients with CKD (diabetes nephropathy, nephrosclerosis, or IgA nephropathy) were analyzed for the expression of hypoxia-inducible factor (HIF), thyroid hormone receptor (TR) ß, or p21 and levels of interstitial fibrosis. Human renal proximal tubule cells were exposed to hypoxia and analyzed for the expression of HIF, TRß, or p21 and the cell-cycle stage. TRß expression was enhanced early on when fibrosis was not fully developed in the tubule cells of CKD patients. HIF1α bound to the TRß promoter and directly induced its transcription. Further, HIF1α expression induced the expression of TRß and inhibited cell-cycle progression. In the early stage of kidney injury, TRß might act as a guardian to prepare and organize cell-cycle proliferation and prevent cell death. While the molecular mechanism that regulates the expression of cell-cycle regulators in renal tubule cells remains controversial, TRß has strong potential as a new therapeutic target.


Assuntos
Ciclo Celular/fisiologia , Células Epiteliais/metabolismo , Hipóxia/metabolismo , Túbulos Renais Proximais/patologia , Receptores dos Hormônios Tireóideos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Proliferação de Células , Células Epiteliais/patologia , Feminino , Humanos , Hipóxia/genética , Hipóxia/patologia , Túbulos Renais Proximais/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores dos Hormônios Tireóideos/genética , Adulto Jovem
6.
Blood Purif ; 47 Suppl 2: 25-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943475

RESUMO

BACKGROUND: Peripheral arterial disease (PAD) has increased in association with the increase in the numbers of patients with kidney disease or diabetes. The aim of this study was to assess the prevalence of PAD in hemodialysis patients with diabetes. METHODS: To examine the usefulness of the cardio-ankle vascular index (CAVI) to screen for the presence of PAD, cross-sectional studies of 100 patients undergoing chronic hemodialysis were performed. The CAVI and other inflammatory markers were evaluated. RESULTS: The CAVI was markedly elevated in patients with a history of PAD or cardiovascular disease. When dialysis patients were classified on the basis of CAVI quartiles, increased CAVI was associated with other risk factors for PAD. CONCLUSION: The prevalence of PAD is high in elderly diabetic patients on hemodialysis. The present findings suggest that the CAVI can be a useful index that predicts the occurrence of macrovascular complications in dialysis patients with diabetes.


Assuntos
Complicações do Diabetes/etiologia , Nefropatias/complicações , Doença Arterial Periférica/etiologia , Diálise Renal , Idoso , Índice Tornozelo-Braço , Estudos Transversais , Complicações do Diabetes/diagnóstico , Feminino , Humanos , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Prevalência , Fatores de Risco , Rigidez Vascular
7.
Contrib Nephrol ; 198: 33-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30991405

RESUMO

BACKGROUND: From a global perspective, diabetic kidney disease (DKD) is the leading cause of not only chronic kidney disease and end-stage renal disease but also cardiovascular disease (CVD). SUMMARY: In the early stages of diabetes, patients have a high risk of developing microvascular complications, loss of kidney function, CVD, infection, and death. Hyperglycemia, free fatty acids, and insulin resistance induce metabolic imbalance and DKD initiation. Inflammation is recognized to play a role in DKD pathogenesis. Our recent study indicated that angiopoietin-like protein 2, which is a circulating proinflammatory protein, might be a strong mediator for the development of DKD and a good predictive biomarker of its progression. The need for effective and safe treatment options for complications such as DKD or CVD becomes ever more urgent. Key Messages: Inflammatory mediators have emerged as potential biomarkers and therapeutic targets for DKD.


Assuntos
Nefropatias Diabéticas/patologia , Progressão da Doença , Inflamação , Proteínas Semelhantes a Angiopoietina/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Nefropatias Diabéticas/complicações , Humanos , Mediadores da Inflamação/sangue , Falência Renal Crônica/etiologia , Prognóstico
8.
J Clin Endocrinol Metab ; 104(1): 172-180, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137449

RESUMO

Context: Angiopoietin-like protein 2 (ANGPTL2) is a circulating, proinflammatory protein. Objective: To examine the role of ANGPTL2 in the pathogenesis of diabetic kidney disease (DKD), we studied the epigenetic regulation of angptl2 expression in patients with diabetes. Design, Setting, Participants, and Intervention: We determined the relationship between serum ANGPTL2 levels and the progression of DKD in cross-sectional (220 patients) and cohort (145 patients, 7-year follow-up) studies. Furthermore, we investigated the direct effect of ANGPTL2 on podocyte function. Main Outcomes: The main outcome was progression of DKD. Results: We found that the expression of angptl2 was decreased by the methylation of its promoter region. Multivariate logistic regression analyses revealed that the baseline level of serum ANGPTL2 was an independent risk factor for the progression of DKD during follow-up periods. In cultured podocytes, ANGPTL2 directly increased albumin permeability through the translocation of zonula occludens-1 from the membrane to the cytosol via activation of focal adhesion kinase. Conclusions: ANGPTL2 might be directly involved in podocyte dysfunction and independently associated with the progression of DKD stages.


Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína 2 Semelhante a Angiopoietina , Células Cultivadas , Estudos de Coortes , Estudos Transversais , Nefropatias Diabéticas/patologia , Epigênese Genética , Feminino , Quinase 1 de Adesão Focal/metabolismo , Seguimentos , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Podócitos/patologia , Regiões Promotoras Genéticas , Estudos Retrospectivos , Proteína da Zônula de Oclusão-1/metabolismo
9.
Sci Rep ; 7: 43960, 2017 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-28272516

RESUMO

In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1ß levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.


Assuntos
Macrófagos/metabolismo , NF-kappa B/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Animais , Modelos Animais de Doenças , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Ligantes , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Receptores alfa dos Hormônios Tireóideos/genética , Tri-Iodotironina/farmacologia , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia
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