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1.
Artigo em Inglês | MEDLINE | ID: mdl-38320316

RESUMO

Summary: Approximately 80% of adrenal incidentalomas are benign, and development into adrenal cortical cancer is extremely rare. This is a major reason behind clinical guidelines recommending surveillance of incidentalomas for a relatively short duration of up to 5 years. Surveillance of lesions less than 1 cm is not routinely recommended. A 70-year-old lady was diagnosed with a non-hyperfunctioning 8 mm right adrenal lesion. She underwent annual biochemical and radiological assessment for 5 years before surveillance was extended to 2-yearly intervals. The lesion was stable in size, and radiological characteristics were consistent with a benign adenoma. Seven years after the initial detection of the adrenal lesion, she developed acute abdominal pain. Imaging revealed a 7 cm right adrenal lesion, which was surgically resected and histologically confirmed to be adrenal cortical cancer. She died 1 year later. Clinical guidelines have moved towards a shortened duration of surveillance of incidentalomas. Even though malignant transformation is a rare event, it is possible that this will result in a delayed diagnosis of adrenal cortical cancer, a highly aggressive malignancy with a poor prognosis. To our knowledge, this is the first published case of an adrenal lesion of less than 1 cm developing into adrenal cortical cancer. Learning points: Adrenal incidentalomas are increasingly common. Clinical practice guidelines exist to aid in differentiating benign and malignant lesions and assessing functional status. Transformation of adrenal incidentalomas to adrenal cortical carcinomas is a rare but recognised event.

2.
J Diabetes Complications ; 37(8): 108525, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37301062

RESUMO

AIMS: To investigate whether soluble CD163 (sCD163) is altered in those with diabetes and various subtypes of complications and non-alcoholic fatty liver disease (NAFLD), and whether it can assess disease complications and severity in people with diabetes. METHODS: Adults with diabetes (n = 101) were recruited and assessed for the presence of any complications (D+Comps). Liver steatosis presence was determined by ultrasound and liver stiffness measurement (LSM) by transient elastography. Liver pathology other than non-alcoholic steatohepatitis (NASH) was excluded. Plasma sCD163 was measured by ELISA. RESULTS: sCD163 was higher in D+Comps (n = 59) compared to D-comps (n = 42) in those with microvascular complications (n = 56; 1.3-fold), including a 1.4-fold increase in chronic kidney disease (CKD) (n = 42). sCD163 correlated positively with HbA1c and urinary albumin-creatinine ratio and negatively with HDL-c in D+Comps. sCD163 was increased 1.7-fold in those with advanced NASH fibrosis (LSM ≥ 10.3 kPa, n = 19) compared to those without (LSM < 10.3 kPa, n = 80). The AUC-ROC-curve was 0.64 for sCD163 to detect CKD and 0.74 to detect advanced NASH fibrosis. CONCLUSIONS: In this study, the elevated circulating sCD163 occurred in people with diabetes who had microvascular complications or advanced NASH fibrosis, suggesting sCD163 may have clinical utility as a biomarker in certain diabetes complications and disease severity in NAFLD.


Assuntos
Complicações do Diabetes , Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Fígado/patologia , Biomarcadores , Diabetes Mellitus/patologia , Fibrose , Complicações do Diabetes/complicações , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia
3.
J Cell Commun Signal ; 16(3): 447-460, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35038159

RESUMO

Type 2 diabetes is an independent risk factor for non-alcoholic steatohepatitis (NASH) progression and its mediators have not been resolved. In this study, a pathogenic role of cellular communication network factor 2 (CCN2) protein in NASH pathology, was investigated in an established preclinical NASH model. Male wild type C57BL/6 mice received either Chow or high fat diet (HFD) for 26 weeks, with some mice in each group randomly selected to receive low dose streptozotocin (STZ: 3 i.p. injections, 65 mg/kg) at 15 weeks to induce type 2 diabetes. In the final 10 of the 26 weeks mice from each group were administered i.p. either rabbit anti-CCN2 neutralizing antibody (CCN2Ab) or as control normal rabbit IgG, at a dose of 150 µg per mouse twice/week. NASH developed in the HFD plus diabetes (HFD+DM) group. Administration of CCN2Ab significantly downregulated collagen I and collagen III mRNA induction and prevented pro-inflammatory MCP-1 mRNA induction in HFD+DM mice. At the protein level, CCN2Ab significantly attenuated collagen accumulation by PSR stain and collagen I protein induction in HFD+DM. Phosphorylation of the pro-fibrotic ERK signalling pathway in liver in HFD+DM was attenuated by CCN2Ab treatment. Intrahepatic CCN1 mRNA was induced, whereas CCN3 was downregulated at both the mRNA and protein levels in HFD+DM. CCN3 down-regulation was prevented by CCN2Ab treatment. This in vivo study indicates that CCN2 is a molecular target in NASH with high fat diet and diabetes, and that regulation of ERK signalling is implicated in this process.

4.
Acta Diabetol ; 50(4): 645-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22183926

RESUMO

Diabetes mellitus is associated with oxidative injury to the vasculature. Here, the link between oxidative stress and ultrastructural changes in the hepatic microcirculation was investigated as well as the effects of a synthetic antioxidant, tert-butyl bisphenol (tBP). The study focused on the impact of experimental diabetes on liver sinusoidal endothelial cell (LSEC) fenestrations, which are pores in the liver endothelium that facilitate substrate transfer between blood and hepatocytes. Adult male rats were rendered diabetic using streptozotocin (60 mg/kg) and administered 1-2 IU insulin daily. After 8 weeks, animals received either 100 mg/kg tBP or vehicle alone, on 2 consecutive days. Livers were harvested 24 h later under isofluorane anaesthesia (5% v/v in O2(g) by inhalation) and fixed for scanning electron microscopy to evaluate fenestrations or for immuno-histochemical assessment of nitrotyrosine, a marker of nitrosative stress. Median fenestration diameter increased significantly following 8 weeks of diabetes (80 nm vs. 70 nm controls; P < 0.001). LSEC porosity increased by ~50% (P < 0.001). Treatment with tBP reversed these changes completely. Periportal nitrotyrosine staining was increased in diabetic livers, and this was abrogated by tBP, indicating that tBP reduced nitrosative stress in the liver. Early diabetes caused an increase in fenestration diameter and porosity. This was reversed by acute treatment with tBP, suggesting a link between nitrosative stress and regulation of liver endothelial fenestrations, and indicates that antioxidant therapy may protect the liver microvasculature against the effects of diabetes mellitus.


Assuntos
Antioxidantes/administração & dosagem , Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Fígado/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Fenóis/administração & dosagem , Animais , Antioxidantes/síntese química , Compostos Benzidrílicos/síntese química , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fenóis/síntese química , Ratos , Ratos Wistar , Tirosina/análogos & derivados , Tirosina/metabolismo
5.
Free Radic Res ; 45(9): 1000-12, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21726176

RESUMO

Rhabdomyolysis (RM) caused by severe burn releases extracellular myoglobin (Mb) that accumulates in the kidney. Extracellular Mb is a pro-oxidant. This study tested whether supplementation with tert-butyl-bisphenol (BP) or vitamin E (Vit E, as α-tocopherol) at 0.12% w/w in the diet inhibits acute renal failure (ARF) in an animal model of RM. After RM-induction in rats, creatinine clearance decreased (p < 0.01), proteinuria increased (p < 0.001) and renal-tubule damage was detected. Accompanying ARF, biomarkers of oxidative stress (lipid oxidation and hemeoxygenase-1 (HO-1) gene and protein activity) increased in the kidney (p < 0.05). Supplemented BP or Vit E decreased lipid oxidation (p < 0.05) and HO-1 gene/activity and restored aortic cyclic guanylyl monophosphate in control animals (p < 0.001), yet ARF was unaffected. Antioxidant supplementation inhibited oxidative stress, yet was unable to ameliorate ARF in this animal model indicating that oxidative stress in kidney and vascular cells may not be causally related to renal dysfunction elicited by RM.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Antioxidantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fenóis/uso terapêutico , Rabdomiólise/tratamento farmacológico , alfa-Tocoferol/uso terapêutico , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/genética , Animais , Creatinina/sangue , Modelos Animais de Doenças , Heme Oxigenase-1/sangue , Peroxidação de Lipídeos , Masculino , Mioglobina/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/sangue , Espécies Reativas de Oxigênio/metabolismo , Rabdomiólise/complicações
6.
Free Radic Biol Med ; 51(7): 1390-8, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21784147

RESUMO

The acute-phase protein serum amyloid A (SAA) is elevated during inflammation and may be deposited in atheroma where it promotes atherosclerosis. We investigated the proatherogenic effects of SAA on the vascular endothelium and their regulation by high-density lipoprotein (HDL). Exposure of human aortic endothelial cells (HAEC) to SAA (0.25-25µg/ml) decreased nitric oxide ((•)NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10µg/ml) stimulated a Ca(2+) influx linked to apocynin-sensitive superoxide radical anion (O(2)(•-)) production. Gene expression for arginase-1, nuclear factor κB (NF-κB), interleukin-8, and tissue factor (TF) increased within 4h of SAA stimulation. Enzymatically active Arg-1/2 was detected in HAEC cultured with SAA for 24h. Therefore, in addition to modulating (•)NO bioavailability by stimulating O(2)(•-) production in the endothelium, SAA modulated vascular l-Arg bioavailability. SAA also diminished relaxation of preconstricted aortic rings induced by acetylcholine, and added superoxide dismutase restored the vascular response. Preincubation of HAEC with HDL (100 or 200, but not 50, µg/ml) before (not after) SAA treatment ameliorated the Ca(2+) influx and O(2)(•-) production; decreased TF, NF-κB, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating (•)NO and l-Arg bioavailability, and HDL pretreatment may be protective. The relative HDL to SAA concentrations may regulate the proatherogenic properties of SAA on the vascular endothelium.


Assuntos
Aorta/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Lipoproteínas HDL/uso terapêutico , Proteína Amiloide A Sérica/efeitos adversos , Superóxidos/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/patologia , Arginase/genética , Arginase/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Western Blotting , Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/farmacologia , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Tromboplastina/genética , Tromboplastina/metabolismo
7.
Free Radic Res ; 44(8): 843-53, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20528578

RESUMO

Abstract Rhabdomyolysis caused by severe burn releases extracellular myoglobin (Mb) that accumulates in the kidney and urine (maximum [Mb] approximately 50 microM) (termed myoglobinuria). Extracellular Mb can be a pro-oxidant. This study cultured Madin-Darby-canine-kidney-Type-II (MDCK II) cells in the presence of Mb and tested whether supplementation with a synthetic tert-butyl-polyphenol (tert-butyl-bisphenol; t-BP) protects these renal cells from dysfunction. In the absence of t-BP, cells exposed to 0-100 microM Mb for 24 h showed a dose-dependent decrease in ATP and the total thiol (TSH) redox status without loss of viability. Gene expression of superoxide dismutases-1/2, haemoxygenase-1 and tumour necrosis factor increased and receptor-mediated endocytosis of transferrin and monolayer permeability decreased significantly. Supplementation with t-BP before Mb-insult maintained ATP and the TSH redox status, diminished antioxidant/pro-inflammatory gene responses, enhanced monolayer permissiveness and restored transferrin uptake. Overall, bolstering the total antioxidant capacity of the kidney may protect against oxidative stress induced by experimental myoglobinuria.


Assuntos
Antioxidantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Flavonoides/farmacologia , Rim/citologia , Mioglobina/farmacologia , Fenóis/farmacologia , Trifosfato de Adenosina/análise , Antioxidantes/síntese química , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Epiteliais/patologia , Flavonoides/síntese química , Flavonoides/química , Humanos , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/síntese química , Fenóis/química , Polifenóis , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
8.
Kidney Blood Press Res ; 31(1): 16-28, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18182776

RESUMO

BACKGROUND: Muscle degradation caused by severe burn releases myoglobin (Mb), which accumulates in the kidney (termed myoglobinuria). Mb is a pro-oxidant. AIM: To demonstrate that Mb promotes oxidative stress and dysfunction in cultured Madin-Darby canine kidney type II (MDCK II) cells. METHODS: The glutathione redox ratio was used to monitor oxidative stress. Regulation of antioxidant response genes was determined with RT-PCR. Propidium iodide and annexin V staining were markers of necrosis and apoptosis, respectively. Mitochondrial function was assessed by monitoring mitochondrial depolarisation. Endocytosis was determined with immune fluorescence microscopy, and monolayer permeability was monitored with labelled inulin. RESULTS: Kidney epithelial cells exposed to (0-100 muM) Mb showed a dose-dependent decrease in the glutathione redox ratio indicative of enhanced oxidative stress. In parallel, the expression of antioxidant genes for superoxide dismutase (SOD)-1/2, inducible haemoxygenase (HO-1) and catalase (CAT) increased in MDCK II cells, coupled with increases in corresponding activity. Notably, apoptosis and necrosis remained unaffected. However, transferrin endocytosis and monolayer permeability decreased significantly, while clathrin distribution and mitochondrial function were unaffected. CONCLUSION: Low concentrations of Mb promote oxidative stress in kidney epithelial cells that manifest as subtle changes to function without decreasing viability. Whether this impairs kidney function in burns patients is not clear.


Assuntos
Endocitose/fisiologia , Células Epiteliais/metabolismo , Rim/metabolismo , Mioglobina/fisiologia , Estresse Oxidativo/fisiologia , Animais , Linhagem Celular , Sobrevivência Celular/fisiologia , Células Cultivadas , Cães , Células Epiteliais/citologia , Rim/citologia , Mioglobina/metabolismo
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