Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(7): 704-710, 2021 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34382586

RESUMO

OBJECTIVES: To investigate the risk factors for serious infections among hospitalized systemic lupus erythematosus (SLE) patients, and to provide the advice for preventing serious infections in SLE patients. METHODS: Information of SLE patients hospitalized from March 2017 to February 2019 at the Department of Rheumatology and Immunology, Xiangya Hospital, Central South University was obtained. The patients were assigned into a serious infection group and a non-serious infection group. The risk factors for serious infections among SLE inpatients were identified by comparison between the 2 groups and multivariate logistic regression analysis. RESULTS: There were 463 SLE inpatients in total, and 144 were in the serious infection group and 319 in the non-serious infection group. Multivariate logistic regression analysis showed that age ≥54.50 years old (OR=4.958, P<0.001), cardiovascular involvement (OR=6.287, P<0.001), hematologic involvement (OR=2.643, P=0.003), serum albumin <20 g/L (OR=2.340, P=0.036), C-reaction protein (CRP)/erythrocyte sedimentation rate (ESR)≥0.12 (OR=2.430, P=0.002), glucocorticoid dose ≥8.75 mg/d prednisone-equivalent (OR=2.465, P=0.002), and the combined use of immunosuppressive agents (OR=2.847, P=0.037) were the risk factors for serious infections in SLE inpatients. CONCLUSIONS: SLE patients with older age, cardiovascular involvement, hematologic involvement, low serum albumin are prone to suffering serious infections. Increased CRP/ESR ratio indicates serious infections in SLE inpatients. High-dose glucocorticoid and the combined use of immunosuppressive agents can increase the risk of serious infections in SLE inpatients.


Assuntos
Pacientes Internados , Lúpus Eritematoso Sistêmico , Idoso , Glucocorticoides/efeitos adversos , Humanos , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Prednisona , Fatores de Risco
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(7): 780-784, 2021 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34382597

RESUMO

Addison disease is rare, and it is rarer to coexist with systemic lupus erythematosus and antiphospholipid antibody syndrome. We hereby reported a middle-aged female who presented with nausea, vomit, skin and mucosa hyperpigmentation, hypotension, hyponatremia, and pulmonary infection after diagnosis of deep venous thrombosis of the left lower extremity and systemic lupus erythematosus in 2012. The patient was finally diagnosed with antiphospholipid antibody syndrome secondary to systemic lupus erythematosus with Addison disease after the examination, such as blood cortisol, adrenocorticotropic hormone rhythm, and antiphospholipid antibody, who was improved clinically after hormone, anti-infective, and anticoagulant treatment. The patient's condition was stable in the follow-up. In clinic, we should pay attention to adrenal damage in patients with connective tissue diseases such as systemic lupus erythematosus and antiphospholipid antibody syndrome, and be alert to the occurrence of adrenal crisis.


Assuntos
Doença de Addison , Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Doença Aguda , Doença de Addison/complicações , Doença de Addison/diagnóstico , Síndrome Antifosfolipídica/complicações , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade
3.
Neuropsychiatr Dis Treat ; 17: 297-304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33568909

RESUMO

Purpose: Learning impairment after electroconvulsive therapy (ECT) is common. Ketamine, an anesthetic used for ECT, has been demonstrated to attenuate cognitive impairment after ECT. However, the mechanism by which ketamine occurs in this case is still unknown. We aimed to explore the role of ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] in the protection against learning impairment and investigate whether autophagy is involved in the protective effect. Materials and Methods: A rat depression model received electroconvulsive shock (ECS; simulated ECT in animal models) daily for 3 days. The Morris water maze was used to assess the spatial learning function of the rats. Western blotting was used to detect the expression of Beclin-1, light chain (LC)3-II/LC3-I, p62, mammalian target of rapamycin (mTOR), and p-mTOR in the hippocampus. Results: The escape latency for the maze in the ECS group was significantly longer than that in the sham ECS group (P=0.042). Meanwhile, the escape latency in the (2R,6R)-HNK+ECS group was significantly shorter than that in the ECS group (P=0.005). The LC3-II/LC3-I ratio and Beclin-1 expression level significantly increased, and the p62 expression level significantly decreased in the ECS group, compared with those in the sham ECS group (all P<0.001). The (2R,6R)-HNK+ECS group showed lower LC3-II/LC3-I ratio (P<0.001) and Beclin-1 expression level (P<0.001) and higher p62 (P<0.001) and p-mTOR expression levels (P=0.048) than did the ECS group. After small-molecule enhancer of rapamycin 28 (SMER28) administration, the role of (2R,6R)-HNK in protecting against learning impairment and inhibiting autophagy was abrogated, showing no difference in the escape latency; the difference in the LC3-II/LC3-I ratio and p62 expression level between the SMER28+(2R,6R)-HNK+ECS and ECS groups was not as significant as that between the (2R,6R)-HNK+ECS and ECS groups (P<0.05-0.01 vs P<0.001). Conclusion: (2R,6R)-HNK yields cognitive protection by suppressing autophagy through the mTOR signaling pathway in the ECS-treated rat hippocampus.

4.
Am J Med Sci ; 361(1): 63-68, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32988597

RESUMO

BACKGROUND: Specific factors correlated with hypothyroidism in systemic lupus erythematosus (SLE) patients remain unclear. Therefore, we aim to evaluate the prevalence of thyroid dysfunction in Chinese patients with SLE and the relationship between clinical hypothyroidism and SLE. METHODS: We conducted a cross sectional study of the prevalence of thyroid dysfunction in 672 patients with SLE and 605 age- and sex-matched healthy controls. Demographic, clinical, and biochemical data were compared between 58 patients with SLE with hypothyroidism and 197 patients with SLE with euthyroidism. Multivariate analysis was performed using binomial logistic regression analysis. Spearman's rank correlation was used to identify an association between thyroid function and disease activity. RESULTS: The prevalence of thyroid dysfunction was significantly higher in patients with SLE than in controls (70.7% vs 19.7%). SLE was associated with higher rates of hypothyroidism (9.6%, P ≤ 0.001) and euthyroid sick syndrome (49.6%, P ≤ 0.001) compared with control subjects. Further analyses showed that hypothyroidism in patients with SLE was associated with high blood pressure, renal disorder, high serum creatinine, high uric acid, hyperlipidaemia, low C3 and C4, positive anti-dsDNA antibodies, and high SLE disease activity index (SLEDAI) score. In multiple logistic regression models, albumin, platelet count, serum creatinine, and anti-dsDNA antibodies were associated with hypothyroidism. Finally, free tri-iodothyronine was significantly negatively correlated with SLEDAI score. CONCLUSIONS: Hypothyroidism was more prevalent in patients with SLE. There was a relationship between hypothyroidism with renal disorder and lupus activity. Albumin, platelet count, serum creatinine, and anti-dsDNA antibodies were correlated with hypothyroidism.


Assuntos
Hipotireoidismo/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipotireoidismo/complicações , Lúpus Eritematoso Sistêmico/complicações , Masculino , Prevalência
5.
J Immunol ; 206(1): 59-66, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33268481

RESUMO

Friend leukemia virus integration 1 (Fli-1) is an ETS transcription factor and a critical regulator of inflammatory mediators, including MCP-1, CCL5, IL-6, G-CSF, CXCL2, and caspase-1. GM-CSF is a regulator of granulocyte and macrophage lineage differentiation and a key player in the pathogenesis of inflammatory/autoimmune diseases. In this study, we demonstrated that Fli-1 regulates the expression of GM-CSF in both T cells and endothelial cells. The expression of GM-CSF was significantly reduced in T cells and endothelial cells when Fli-1 was reduced. We found that Fli-1 binds directly to the GM-CSF promoter using chromatin immunoprecipitation assay. Transient transfection assays indicated that Fli-1 drives transcription from the GM-CSF promoter in a dose-dependent manner, and mutation of the Fli-1 DNA binding domain resulted in a significant loss of transcriptional activation. Mutation of a known phosphorylation site within the Fli-1 protein led to a significant increase in GM-CSF promoter activation. Thus, direct binding to the promoter and phosphorylation are two important mechanisms behind Fli-1-driven activation of the GM-CSF promoter. In addition, Fli-1 regulates GM-CSF expression in an additive manner with another transcription factor Sp1. Finally, we demonstrated that a low dose of a chemotherapeutic drug, camptothecin, inhibited expression of Fli-1 and reduced GM-CSF production in human T cells. These results demonstrate novel mechanisms for regulating the expression of GM-CSF and suggest that Fli-1 is a critical druggable regulator of inflammation and immunity.


Assuntos
Endotélio/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Linfócitos T/fisiologia , Animais , Camptotecina/farmacologia , Endotélio/patologia , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Células Jurkat , Camundongos , Terapia de Alvo Molecular , Células NIH 3T3 , Regiões Promotoras Genéticas/genética , Proteína Proto-Oncogênica c-fli-1/genética , RNA Interferente Pequeno/genética , Fator de Transcrição Sp1/genética , Linfócitos T/efeitos dos fármacos , Inibidores da Topoisomerase I/farmacologia
6.
Front Neurosci ; 14: 859, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013289

RESUMO

Background: Our previous study in animal models revealed that bilirubin could induce Aß formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aß deposition. Hence, lowering the concentration of the free bilirubin capable of crossing the blood brain-barrier may benefit the treatment of Alzheimer's disease (AD). Objectives: The objectives of this study were to examine the change in the serum bilirubin and albumin concentrations of dementia patients with Aß deposition, and to determine the effects of intravenous administration of albumin in the treatment of AD. Methods: Bilirubin and albumin concentrations in dementia patients with Aß deposition were examined. Cell viability and apoptosis were determined in dopaminergic neuron-like cells MN9D treated with bilirubin in the presence of diverse concentrations of serum. Human albumin at a dose of 10 g every 2 weeks for 24 weeks was administered intravenously to AD patients to examine the effect of albumin on AD symptoms. Results: Significantly higher indirect bilirubin (IBIL) concentrations, lower albumin concentrations, and higher ratio of IBIL to albumin (IBIL/ALB) were observed in dementia patients with Aß deposition, including AD, dementia with Lewy bodies, and general paresis of insane. In vitro assays showed that bilirubin-induced injury in cultured dopaminergic neuron-like cells negatively depends on the concentration of serum in the culture medium. General linear model with repeated measures analysis indicated a main effect of group on the change in albumin concentrations and Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) scores, and the main effect of time and group, and group-by-time interaction on the change of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores. Analysis of the combined data of the entire 28 weeks of assessment period using the area under curve convincingly showed significantly improvements in the change of albumin concentrations, ADCS-ADL scores, and CDR-SB scores. Conclusion: IBIL and the IBIL/ALB ratio are significantly higher in dementia patients with Aß deposition, and intravenous administration of albumin is beneficial to AD treatment. Trial Registration: The intervention study was registered at http://www.chictr.org.cn (ChiCTR-IOR-17011539). Date of registration: June 1, 2017.

7.
J Affect Disord ; 277: 212-217, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32829197

RESUMO

BACKGROUND: Both an elevated homocysteine (Hcy) level and depression are risk factors for cognitive impairment in the general population, but no study has analyzed whether the coexistence of an elevated Hcy level and late-life depression (LLD) is associated with worse cognitive performance. OBJECTIVE: We aimed to investigate the relationship between Hcy levels and cognitive function in individuals with LLD and whether the coexistence of an elevated Hcy level and LLD is associated with worse cognitive performance. METHODS: A total of 113 LLD patients and 89 normal controls underwent a standardized clinical interview and comprehensive neuropsychological assessment battery. Plasma concentrations of Hcy were detected. Factorial analyses were performed to examine the impact of the coexistence of an elevated Hcy level and LLD on cognitive performance. RESULTS: Plasma Hcy levels in patients with LLD were significantly higher than that in normal controls. Only for LLD patients, Hcy level was negatively correlated with global cognition, executive function, attention, and visual space. The factorial analysis showed that there was a significant interactive effect of Hcy level (normal and elevated levels) and LLD (with and without LLD) on global cognition. In post hoc comparisons, the elderly individuals with both elevated Hcy levels and LLD tended to have the worst global cognitive function compared with those with LLD or elevated Hcy levels alone. CONCLUSIONS: The coexistence of an elevated Hcy level and LLD was associated with worse cognitive performance. Early intervention should be initiated to protect cognition in LLD patients with elevated Hcy levels.


Assuntos
Disfunção Cognitiva , Depressão , Idoso , Cognição , Disfunção Cognitiva/etiologia , Homocisteína , Humanos , Testes Neuropsicológicos
8.
J Alzheimers Dis ; 77(1): 313-322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804135

RESUMO

BACKGROUND: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer's disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. OBJECTIVE: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. METHODS: Levels of neurogranin (NGRN) and ß-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-ß 1-40 (Aß40), Aß42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. RESULTS: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. CONCLUSION: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

9.
Front Pharmacol ; 11: 1126, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848745

RESUMO

Intracerebral hemorrhage (ICH) is a disease with a significantly high rate of morbidity, mortality and disability. Inhibition of inflammation is considered a potential strategy for improving the clinical symptoms induced by ICH. The hallmark of neuroinflammation is microglial activation. Microglia can polarize into either the classically activated M1 (proinflammatory) phenotype, exacerbating neuronal damage, or the alternatively activated M2 (antiinflammatory) phenotype, exerting neuroprotection and promoting neuronal recovery. Promoting microglial polarization to the M2 phenotype may be a viable strategy for treating neuroinflammation. Several studies have indicated that promoting blood circulation and removing blood stasis exhibits therapeutic effects on intracerebral hemorrhage. Dahuang Zhechong Pill (DHZCP), a classical recipe that promotes blood circulation and removes blood stasis, has been reported to improve the clinical outcome of ICH. DHZCP has been shown to exert antiinflammatory effects. However, the detailed antiinflammatory mechanism of DHZCP in ICH has rarely been investigated. In this study, DHZCP inhibited lipopolysaccharide (LPS)-induced M1 microglial activation. DHZCP exerted antiinflammatory effects, by inhibiting LPS-induced M1 proinflammatory cytokine (TNF-α and IL-6), and iNOS production and increasing M2 antiinflammatory cytokine (IL-10) production. DHZCP also switched microglial polarization from M1 to M2, as indicated by significantly increased expression of M2 polarization markers (CD209, and CD206) and markedly decreased expression of an M1 polarization marker (CD54). In addition, DHZCP inhibited p38 and TLR4/NF-κB signaling activation, as demonstrated by inhibition of LPS-induced increases in p-p38, TLR4 and nuclear factor kappa B p-65 (NF-κB p-65) protein expression. Taken together, DHZCP modulates microglial M1/M2 polarization via the p38 and TLR4/NF-κB signaling pathways to confer antiinflammatory effects.

10.
BMC Med Res Methodol ; 20(1): 99, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357838

RESUMO

BACKGROUND: Previous studies indicate that the prevalence of hypothyroidism is much higher in patients with lupus nephritis (LN) than in the general population, and is associated with LN's activity. Principal component analysis (PCA) and logistic regression can help determine relevant risk factors and identify LN patients at high risk of hypothyroidism; as such, these tools may prove useful in managing this disease. METHODS: We carried out a cross-sectional study of 143 LN patients diagnosed by renal biopsy, all of whom had been admitted to Xiangya Hospital of Central South University in Changsha, China, between June 2012 and December 2016. The PCA-logistic regression model was used to determine the influential principal components for LN patients who have hypothyroidism. RESULTS: Our PCA-logistic regression analysis results demonstrated that serum creatinine, blood urea nitrogen, blood uric acid, total protein, albumin, and anti-ribonucleoprotein antibody were important clinical variables for LN patients with hypothyroidism. The area under the curve of this model was 0.855. CONCLUSION: The PCA-logistic regression model performed well in identifying important risk factors for certain clinical outcomes, and promoting clinical research on other diseases will be beneficial. Using this model, clinicians can identify at-risk subjects and either implement preventative strategies or manage current treatments.


Assuntos
Hipotireoidismo , Nefrite Lúpica , China/epidemiologia , Estudos Transversais , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Modelos Logísticos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/epidemiologia , Análise de Componente Principal
11.
Circ Res ; 127(3): 360-375, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32284030

RESUMO

RATIONALE: Hypoxia promotes renal damage and progression of chronic kidney disease (CKD). The erythrocyte is the only cell type for oxygen (O2) delivery. Sphingosine 1-phosphate (S1P)-a highly enriched biolipid in erythrocytes-is recently reported to be induced under high altitude in normal humans to enhance O2 delivery. However, nothing is known about erythrocyte S1P in CKD. OBJECTIVE: To investigate the function and metabolic basis of erythrocyte S1P in CKD with a goal to explore potential therapeutics. METHODS AND RESULTS: Using erythrocyte-specific SphK1 (sphingosine kinase 1; the only enzyme to produce S1P in erythrocytes) knockout mice (eSphK1-/-) in an experimental model of hypertensive CKD with Ang II (angiotensin II) infusion, we found severe renal hypoxia, hypertension, proteinuria, and fibrosis in Ang II-infused eSphk1-/- mice compared with controls. Untargeted metabolomics profiling and in vivo U-13C6 isotopically labeled glucose flux analysis revealed that SphK1 is required for channeling glucose metabolism toward glycolysis versus pentose phosphate pathway, resulting in enhanced erythroid-specific Rapoport-Luebering shunt in Ang II-infused mice. Mechanistically, increased erythrocyte S1P functioning intracellularly activates AMPK (AMP-activated protein kinase) 1α and BPGM (bisphosphoglycerate mutase) by reducing ceramide/S1P ratio and inhibiting PP2A (protein phosphatase 2A), leading to increased 2,3-bisphosphoglycerate (an erythrocyte-specific metabolite negatively regulating Hb [hemoglobin]-O2-binding affinity) production and thus more O2 delivery to counteract kidney hypoxia and progression to CKD. Preclinical studies revealed that an AMPK agonist or a PP2A inhibitor rescued the severe CKD phenotype in Ang II-infused eSphK1-/- mice and prevented development of CKD in the control mice by inducing 2,3-bisphosphoglycerate production and thus enhancing renal oxygenation. Translational research validated mouse findings in erythrocytes of hypertensive CKD patients and cultured human erythrocytes. CONCLUSIONS: Our study elucidates the beneficial role of eSphk1-S1P in hypertensive CKD by channeling glucose metabolism toward Rapoport-Luebering shunt and inducing 2,3-bisphosphoglycerate production and O2 delivery via a PP2A-AMPK1α signaling pathway. These findings reveal the metabolic and molecular basis of erythrocyte S1P in CKD and new therapeutic avenues.


Assuntos
Reprogramação Celular , Metabolismo Energético , Eritrócitos/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/sangue , Adulto , Animais , Estudos de Casos e Controles , Hipóxia Celular , Modelos Animais de Doenças , Eritrócitos/enzimologia , Feminino , Fibrose , Humanos , Hipertensão/complicações , Rim/patologia , Masculino , Metaboloma , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia
12.
Exp Cell Res ; 387(1): 111779, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846625

RESUMO

Renal fibrosis is a key pathological feature in chronic kidney diseases (CKDs). Dysregulation of hydrogen sulfide (H2S) homeostasis is implicated in the pathogenesis of CKDs. Here, C57/BL6 mice were allocated to Sham and unilateral ureteral obstruction (UUO) groups, which were treated with NaHS or NLRP3 inflammasome inhibitor 16673-34-0 for 3-14 days. UUO mice displayed downregulation of H2S production and increased macrophage infiltration in obstructed kidneys. H2S donor NaHS treatment attenuated renal damage and fibrosis and inhibited M1 and M2 macrophage infiltration. NLPR3 inflammasome was activated and levels of phosphorylated nuclear factor κB (NF-κB) p65 subunit, phosphorylated signal transducer and activator of transcription 6 (STAT6) and interleukin (IL)-4 protein were increased in the kidneys after UUO. NLRP3 inhibitor inactivated NF-κB and IL-4/STAT6 signaling, suppressed M1 and M2 macrophage infiltration and attenuated renal damage and fibrosis in UUO mice. NaHS treatment also suppressed NLRP3, NF-κB and IL-4/STAT6 activation in the obstructed kidneys. In conclusion, the therapeutic effects of H2S on UUO-induced renal injury and fibrosis are at least in part by inhibition of M1 and M2 macrophage infiltration. H2S suppresses NLRP3 activation and subsequently inactivates NF-κB and IL-4/STAT6 signaling, which may contribute to the anti-inflammatory and anti-fibrotic effects of H2S.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Fibrose/tratamento farmacológico , Sulfeto de Hidrogênio/farmacologia , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Animais , Fibrose/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Obstrução Ureteral/metabolismo
13.
Clin Exp Rheumatol ; 38(4): 680-690, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31694740

RESUMO

OBJECTIVES: Lupus nephritis (LN) is an immune-complex mediated nephritis with complicated pathogenesis. The aims of the present study were to investigate whether inflammasomes are activated in the renal pathology of LN patients and analyse the association of inflammasome activation in different classes of LN renal tissues with the disease activity. METHODS: A total of 86 patients with renal biopsy-proven chronic kidney disease admitted in Xiangya Hospital from January 2015 to August 2018 were enrolled in the present study. Immunofluorescence analysis was applied to examine NLRP1, NLRP3 and AIM3 expression in renal tissues. RESULTS: AIM2 was mainly expressed in glomerular cells of LN class II. No obvious positive staining of AIM2 in renal tissues was found in other LN classes. NLRP1 and NLRP3 were mainly localised in tubular cells. NLRP1 was mainly expressed in tubular cells of LN class II and class IV while NLRP3 was expressed in tubular cells of LN class IV. Moreover, NLRP3 expression level was positive correlated with the activity index (AI) score in patients with LN. CONCLUSIONS: NLRP3, NLRP1 and AIM2 activation are involved in the progress of LN. NLRP3 activation has a positive correlation with the AI score of LN.


Assuntos
Inflamassomos , Nefrite Lúpica , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Proteínas de Ligação a DNA , Humanos , Rim , Glomérulos Renais , Proteína 3 que Contém Domínio de Pirina da Família NLR
14.
Braz J Med Biol Res ; 52(11): e8772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664306

RESUMO

This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Nefropatias/patologia , Piridonas/farmacologia , Obstrução Ureteral/patologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Fator Apoptótico 1 Ativador de Proteases/efeitos dos fármacos , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Nitrogênio da Ureia Sanguínea , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Creatinina/sangue , Modelos Animais de Doenças , Enalapril/metabolismo , Enalapril/farmacologia , Proteína de Domínio de Morte Associada a Fas/efeitos dos fármacos , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibrose , Masculino , Piridonas/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Fator de Transcrição CHOP/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo
15.
J Am Soc Nephrol ; 30(8): 1413-1424, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31278195

RESUMO

BACKGROUND: Oxygen deprivation or hypoxia in the kidney drives CKD and contributes to end organ damage. The erythrocyte's role in delivery of oxygen (O2) is regulated by hypoxia, but the effects of CKD are unknown. METHODS: We screened all of the metabolites in the whole blood of mice infused with angiotensin II (Ang II) at 140 ng/kg per minute up to 14 days to simulate CKD and compared their metabolites with those from untreated mice. Mice lacking a receptor on their erythrocytes called ADORA2B, which increases O2 delivery, and patients with CKD were studied to assess the role of ADORA2B-mediated O2 delivery in CKD. RESULTS: Untargeted metabolomics showed increased production of 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite promoting O2 delivery, in mice given Ang II to induce CKD. Genetic studies in mice revealed that erythrocyte ADORA2B signaling leads to AMPK-stimulated activation of BPG mutase, promoting 2,3-BPG production and O2 delivery to counteract kidney hypoxia, tissue damage, and disease progression in Ang II-induced CKD. Enhancing AMPK activation in mice offset kidney hypoxia by triggering 2,3-BPG production and O2 delivery. Patients with CKD had higher 2,3-BPG levels, AMPK activity, and O2 delivery in their erythrocytes compared with controls. Changes were proportional to disease severity, suggesting a protective effect. CONCLUSIONS: Mouse and human evidence reveals that ADORA2B-AMPK signaling cascade-induced 2,3-BPG production promotes O2 delivery by erythrocytes to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD targeting this pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Eritrócitos/metabolismo , Hipóxia/metabolismo , Falência Renal Crônica/metabolismo , Oxigênio/metabolismo , Receptor A2B de Adenosina/metabolismo , 2,3-Difosfoglicerato/farmacologia , Adulto , Angiotensina II/metabolismo , Animais , Progressão da Doença , Feminino , Humanos , Masculino , Metabolômica , Camundongos , Pessoa de Meia-Idade , Modelos Genéticos , Transdução de Sinais
16.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(6): 614-620, 2019 Jun 28.
Artigo em Chinês | MEDLINE | ID: mdl-31304921

RESUMO

OBJECTIVE: To observe the effect of enalapril on the apoptosis of renal tubular epithelial cells in renal interstitial fibrosis rats and to explore the mechanism of enalapril on renal interstitial fibrosis.
 Methods: Twenty-four SD male rats were randomly divided into a sham operation group, a model group and an enalapril group (n=8 in each group). The rats in the model group and the enalapril group underwent the operation of left urethral obstruction to establish the animal model of unilateral urethral obstruction (UUO). Fourteen days later after the operation, all rats were sacrificed and their obstructed kidneys were collected for HE and Masson staining to observe the pathological change of renal tissues. Terminal deoxynucleotidyl transferase-mediated (dUTP) nick end-labeling (TUNEL) staining was used to detect the apoptosis of renal tubular epithelial cells. Immunohistochemistry and Western blotting were used to detect the protein expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (APAF-1) and C/EBP homologous protein (CHOP).
 Results: Compared with the sham operation group, the renal interstitial injury index and renal interstitial fibrosis index were significantly increased in the model group (P<0.05). Compared with the model group, the renal interstitial injury index and renal interstitial fibrosis index were both significantly decreased in the enalapril group (P<0.05). Compared with the sham group, the apoptosis rate of renal tubular epithelial cells was increased in the model group (P<0.05); compared with the model group, the apoptosis rate of renal tubular epithelial cells was significantly reduced in the enalapril group (P<0.05). The protein levels of FADD, APAF-1 and CHOP in the model group were significantly elevated than those in the sham group (all P<0.05), which were reversed in presence of enalapril (all P<0.05). 
 Conclusion: Enalapril can alleviate renal interstitial fibrosis through inhibiting apoptosis of renal tubular epithelial cells in UUO rats.


Assuntos
Túbulos Renais , Animais , Apoptose , Enalapril , Células Epiteliais , Fibrose , Masculino , Ratos , Obstrução Ureteral
17.
Medicine (Baltimore) ; 98(28): e16397, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305448

RESUMO

RATIONALE: Vasculitis is one of the common pathological hallmarks of systemic lupus erythematosus (SLE). Vascular lesions in SLE commonly involve medium- and small-sized vessels. Rarely, vasculitis in SLE may involve large vessels such as the aorta leading to life-threatening complications. Reported cases of large vessel lesions in SLE included aortic aneurysm and aortic dissection. PATIENT CONCERNS: Here, we report a 52-year-old Chinese woman with SLE, who was stable on oral glucocorticoid, but showed sudden intractable hypertension and heavy proteinuria before we found aorta coarctation in her computed tomography (CT) scan of the aorta. DIAGNOSES: This patient's large vascular lesions were likely secondary and not a primary manifestation of lupus activity. INTERVENTIONS AND OUTCOMES: After endovascular stent graft repair of the abdominal aorta, her hypertension and proteinuria were controlled. LESSONS: In the context of reported cases of large vessel lesions in SLE, our case further supports the significance of having a wide differential for vascular lesions in SLE, especially when an SLE patient presents sudden hypertension and heavy proteinuria. This case also demonstrates that vascular lesions in SLE may lead to serious, potentially fatal consequences.


Assuntos
Coartação Aórtica/etiologia , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/cirurgia , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Pessoa de Meia-Idade
18.
Exp Cell Res ; 383(2): 111507, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356816

RESUMO

Fibrosis is a common pathology in renal disease. Hypertensive nephropathy (HN) is one of the most common secondary nephropathies that often progresses to severe renal fibrosis with limited treatment options beyond hypertension control. Bromodomain-containing protein 4 (Brd4) was recently recognized as a target in signaling pathways that underlie the pathologies of inflammatory diseases and tumors. A recently developed inhibitor of Brd4, JQ1, has been shown to exert antifibrotic effects and is being clinically explored as an anti-inflammatory and antitumor drug. Here, using human kidney biopsies and Angiotensin II-induced mouse fibrotic kidney samples, we show that Brd4 was upregulated in renal tissue from HN patients and hypertensive mouse models. In mice, JQ1 alleviated Angiotensin II-induced kidney fibrosis and blocked epithelial-mesenchymal transition (EMT) by altering the expression of EMT-related proteins. Using an in vitro model of HK2 cells exposed to Angiotensin II, we also demonstrated that JQ1 suppressed the protein expression of fibrotic genes in these cells. These results further implicate Brd4 in the fibrotic response in HN and reveal that Brd4 is a potential antifibrotic target. BET inhibitors are currently being investigated in clinical trials as antitumor agents and show potent pharmacological effects. Our findings suggest that BET inhibitors may also be potential translational therapies for HN.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Transição Epitelial-Mesenquimal/genética , Hipertensão Renal/genética , Rim/patologia , Nefrite/genética , Fatores de Transcrição/fisiologia , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Fibrose/tratamento farmacológico , Fibrose/genética , Fibrose/patologia , Humanos , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/patologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/tratamento farmacológico , Nefrite/patologia , Proteínas Nucleares/fisiologia , Triazóis/farmacologia , Triazóis/uso terapêutico
19.
Braz. j. med. biol. res ; 52(11): e8772, 2019. graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1039259

RESUMO

This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.

20.
Sci Rep ; 8(1): 10231, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29980727

RESUMO

Effective treatment of lupus nephritis and assessment of patient prognosis depend on accurate pathological classification and careful use of acute and chronic pathological indices. Renal biopsy can provide most reliable predicting power. However, clinicians still need auxiliary tools under certain circumstances. Comprehensive statistical analysis of clinical indices may be an effective support and supplementation for biopsy. In this study, 173 patients with lupus nephritis were classified based on histology and scored on acute and chronic indices. These results were compared against machine learning predictions involving multilinear regression and random forest analysis. For three class random forest analysis, total classification accuracy was 51.3% (class II 53.7%, class III&IV 56.2%, class V 40.1%). For two class random forest analysis, class II accuracy reached 56.2%; class III&IV 63.7%; class V 61%. Additionally, machine learning selected out corresponding important variables for each class prediction. Multiple linear regression predicted the index of chronic pathology (CI) (Q2 = 0.746, R2 = 0.771) and the acute index (AI) (Q2 = 0.516, R2 = 0.576), and each variable's importance was calculated in AI and CI models. Evaluation of lupus nephritis by machine learning showed potential for assessment of lupus nephritis.


Assuntos
Nefrite Lúpica/classificação , Nefrite Lúpica/patologia , Aprendizado de Máquina , Modelos Estatísticos , Adulto , Biópsia , Feminino , Humanos , Nefrite Lúpica/cirurgia , Masculino , Prognóstico , Proteinúria/epidemiologia , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...