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The main pathogenic features of immunoglobulin A vasculitis (IgAV) are overactive B cells and elevated production of IgA, which requires help from T follicular helper 17 (Tfh17) cells. To evaluate the pathological role of Tfh17 cells in IgAV, we investigated the mechanism responsible for Tfh17 differentiation and explored how to ameliorate IgAV by modulating Tfh17 generation. Peripheral blood mononuclear cells from IgAV patients were analyzed by flow cytometry. In vitro culture was performed to assess the modulation of cytokine-induced phenotypes. IgAV rats were used to explore the therapeutic effects of IL-6 blockade and the regulatory functions of IL-6 in Tfh17 cells. Serum cytokine and IgA levels were measured by ELISA while histopathological changes were evaluated by H&E,PAS or immunofluorescence staining. Frequency of CD4+CXCR5+CCR6+ Tfh17 cells were increased in IgAV patients and associated with disease severity. There was also a significant infiltration of Tfh17 cells in the kidney of human IgAV nephritis patients. IL-6 promoted the dendritic cell production of TGF-ß and Tfh17 differentiation. In IgAV rats, the in vivo blockade of IL-6 signaling inhibited Tfh17 differentiation, resulting in reduction of the germinal center and IgA production. Suppression of Tfh17 cells using IL-6 blockade greatly ameliorated clinical symptoms such as hemorrhagic rash and bloody stool and decreased IgA deposition and mesangial proliferation in the kidney in IgAV rats. Our findings suggest that suppression of Tfh17 differentiation can alleviate IgA-mediated vasculitis and may permit the development of tailored medicines for treating IgAV.
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Owing to the mature technology, natural abundance of raw materials, high recycling efficiency, cost-effectiveness, and high safety of lead-acid batteries (LABs) have received much more attention from large to medium energy storage systems for many years. Lead carbon batteries (LCBs) offer exceptional performance at the high-rate partial state of charge (HRPSoC) and higher charge acceptance than LAB, making them promising for hybrid electric vehicles and stationary energy storage applications. Despite that, adding carbon to the negative active electrode considerably enhances the electrochemical performance. However, carbon brings some adverse effects, such as the severe hydrogen evolution reaction (HER) in the NAM due to the low overpotential of carbon material, promoting severe water loss in LCBs. From a practical application point of view, the irreversible sulfation of the negative active material (NAM) and extreme shedding and softening of the positive active material (PAM) are the main obstacles for next-generation LCBs. Recently, a lead-carbon composite additive delayed the parasitic hydrogen evolution and eliminated the sulfation problem, ensuring a long life of LCBs for practical aspects. This comprehensive review outlines a brief developmental historical background of LAB, its shifting towards LCB, the failure mode of LAB, and possible potential solutions to tackle the failure problems. The detailed LCB's development towards long life was discussed in light of the reported literature to guide the researcher to date progress. More emphasis was directed toward the new applications of LCBs for stationary energy storage applications. Finally, state-of-the-art progress and further research gaps were pointed out for future work in this exciting era.
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OBJECTIVES: T peripheral helper (Tph) cells have major roles in pathological processes in SLE. We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. METHOD: Phenotypes and functions of Tph cell-related markers in human CD4+ T cells purified from volunteers or patients were analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. RESULTS: Among multiple cytokines, transforming growth factor (TGF)-ß3 characteristically induced programmed cell death protein 1 (PD-1)hi musculoaponeurotic fibrosarcoma (MAF)+, IL-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4 and CXCL13. The induction of Tph-like cells by TGF-ß3 was suppressed by the neutralization of TGF-ß type II receptor (TGF-ßR2). TGF-ß3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-ß3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. CONCLUSION: The induction of Tph-like cells by TGF-ß3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B-cell differentiation in patients with SLE.
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Lúpus Eritematoso Sistêmico , Receptor de Morte Celular Programada 1 , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Fator de Crescimento Transformador beta3 , Linfócitos T Auxiliares-Indutores , Diferenciação Celular , Fatores de Transcrição SOXC/metabolismoRESUMO
BACKGROUND: Chronic kidney disease (CKD) is characterized by high morbidity and mortality and is difficult to cure. Renal interstitial fibrosis (RIF) is a major determinant of, and commonly occurs within, CKD progression. Epithelial mesenchymal transition (EMT) has been identified as a crucial process in triggering renal interstitial fibrosis (RIF). Interleukin-like EMT inducer (ILEI) is an important promotor of EMT; this study aims to elucidate the mechanisms involved. METHODS: Male C57BL6/J mouse were randomly divided into 6 groups: sham (n = 10), sham with negative control (NC) shRNA (sham + NC, n = 10), sham with ILEI shRNA (sham + shILEI, n = 10), unilateral ureteral obstruction (UUO, n = 10), UUO with NC (UUO + NC, n = 10) and UUO with ILEI shRNA (UUO + shILEI, n = 10). Hematoxylin and eosin (H&E), Masson, and immunohistochemical (IHC) staining and western blotting (WB) were performed on murine kidney tissue to identify the function and mechanism of ILEI in RIF. In vitro, ILEI was overexpressed to induce EMT in HK2 cells and analyzed via transwell, WB, real-time PCR, and co-immunoprecipitation. Finally, tissue from 12 pediatric CKD patients (seven with RIF and five without RIF) were studied with H&E, Masson, and IHC staining. RESULTS: Our in vitro model revealed that ILEI facilitates RIF in the UUO model via the Akt and ERK pathways. Further experiments in vivo and in vitro revealed that ILEI promotes renal tubular EMT by binding and activating leukemia inhibitory factor receptor (LIFR), in which phosphorylation of Akt and ERK is involved. We further find markedly increased expression levels of ILEI and LIFR in kidneys from pediatric CKD patients with RIF. CONCLUSION: Our results indicate that ILEI may be a useful biomarker for renal fibrosis and a potential therapeutic target for modulating RIF.
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Nefropatias , Insuficiência Renal Crônica , Animais , Criança , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Fibrose , Humanos , Nefropatias/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de OSM-LIF/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Renal interstitial fibrosis is the most common process by which chronic kidney diseases progress to end-stage renal failure. Epithelial-to-mesenchymal transitions (EMTs) play a crucial role in the progression of renal interstitial fibrosis. A newly identified cytokine, interleukin-like EMT inducer (ILEI), has been linked to EMT in some diseases. However, the effects of ILEI on renal tubular EMT have not yet been well established. Here, we characterize the expression of ILEI in tubular EMT and describe the role and mechanism of ILEI in transforming growth factor beta 1 (TGF-ß1)-induced renal tubular EMT. The results indicate that ILEI is involved in renal tubular EMT induced by TGF-ß1, as overexpression of ILEI not only induces EMT of HK-2 cells independently but also profoundly enhances EMT in response to TGF-ß1. Supporting this finding, ILEI small interfering RNA was found to block the EMT of HK-2 cells induced by TGF-ß1. This work additionally suggests ILEI mediates TGF-ß1-dependent EMT via the extracellular regulated protein kinases (ERKs) and protein kinase B (Akt) signalling pathways. In conclusion, ILEI appears to play a crucial role in mediating TGF-ß1-induced EMT through the Akt and ERK pathways, which may provide a therapeutic target for the treatment of fibrotic kidney diseases. SIGNIFICANCE OF THE STUDY: There is no study reporting the effect of ILEI in renal EMTs. In this research, we examined the role and mechanism of ILEI in EMT using tubular epithelial cell; we found that ILEI participated in renal tubular EMT, and overexpression of ILEI can not only induce EMT of HK-2 cells independently but also enhance EMT in response to TGF-ß1. Meanwhile, we found ILEI small interfering RNA blocked the EMT induced by TGF-ß1, and ILEI participates in the EMT caused by TGF-ß1 via ERK and Akt signalling pathways. We hoped to provide new ideas in further study on the prevention and treatment of fibrotic kidney diseases.
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Citocinas/metabolismo , Transição Epitelial-Mesenquimal , Túbulos Renais/metabolismo , Proteínas de Neoplasias/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células Cultivadas , HumanosRESUMO
OBJECTIVE: To study feasibility of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) and British Isles Lupus Assessment Group 2004 (BILAG-2004) scoring systems for assessing renal disease activity in children with lupus nephritis (LN). METHODS: The clinical data of 159 children with systemic lupus erythematosus (SLE) and LN were collected, and disease activity was assessed by SLEDAI-2000 and BILAG-2004 scoring systems. The correlations between SLEDAI-2000 and BILAG-2004 scores and 24-hour urinary protein excretion and renal pathology index were analyzed. The SLEDAI-2000 and BILAG-2004 scoring systems were evaluated using ROC curve. RESULTS: Approximately one third (31.5%) of the 159 children had a moderate level of 24-hour urinary protein excretion. Among the 37 patients undergoing renal biopsy, 46.0% had diffuse LN (type â £). 24-hour urinary protein excretion was positively correlated with both SLEDAI-2000 (r=0.36, P<0.05) and BILAG-2004 scores (r= 0.39, P<0.05). Children with types â , â ¡, â ¢, and â £ LN had pathology activity index (AI) which positively correlated with SLEDAI-2000 scores (r=0.86, 0.88, 0.84, 0.77 respectively; P<0.05) and BILAG-2004 scores (r= 0.88, 0.98, 0.86, 0.89 respectively; P<0.05). SLEDAI-2000 score showed the best correlation with AI in patients with type â ¡ LN, followed by those with type â LN. BIILAG-2004 score showed the best correlation with AI in patients with type â ¡ LN, followed by those with type â £ LN. The BILAG-2004 scoring system had an area under the ROC curve (AUC) of 0.93, and the SLEDAI-2000 scoring system had an AUC of 0.88. CONCLUSIONS: BILAG-2004 and SLEDAI-2000 scoring systems can be used to assess renal disease activity of patients with LN. The BILAG-2004 scoring system can provide more reliable and comprehensive assessment.
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Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Adolescente , Criança , Estudos de Viabilidade , Feminino , Humanos , Rim/patologia , Masculino , Proteinúria/classificação , Curva ROCRESUMO
BACKGROUND: The incidence of ischemic cerebrovascular disease (ICVD) has been increasing, leading to disability and deaths among middle-aged and elderly people. Digital subtraction angiography (DSA) is the gold standard for diagnosing ICVD, but it is invasive, expensive, and complex to operate. Transcranial Doppler (TCD) ultrasound is characterized by high accuracy, simplicity, and low cost, and thus became the focus of this study. METHODS: The databases of PubMed, Web of Science, Embase, and The Cochrane Library were searched from January 2000 to September 2020, for literature involving the use of TCD to diagnose ICVD. The software RevMan 5.3 was used for quality assessment, and forest plots and summary receiver operating characteristic (SROC) curves were drawn. The software STATA12.0 was adopted for publication bias analysis. RESULTS: A total of 11 references were included, and the combined sensitivity, specificity, and 95% confidence interval (CI) of TCD were 0.93 (0.75 to 1.00) and 0.95 (0.78 to 1.00), respectively. The area under the curve (AUC) of SROC was 0.887. DISCUSSION: Superb capabilities in diagnosing ICVD have been demonstrated by TCD, and it should therefore be applied in the clinic. The results are important to realize early diagnosis of ICVD and improve the prognosis of patients.
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Transtornos Cerebrovasculares , Ultrassonografia Doppler Transcraniana , Idoso , Transtornos Cerebrovasculares/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Renal interstitial fibrosis is accepted as a crucial component of chronic kidney diseases (CKD). Epithelial-mesenchymal transition (EMT) is an important factor contributing to renal interstitial fibrosis. Livin, due to its ability to induce EMT, is an important regulator of many types of tumors and might also be involved in human renal tubular EMT. METHODS: We confirmed that Livin and lncRNA-ATB could aggravate EMT in vivo and in vitro, lncRNA-ATB could be suppressed by the silencing of Livin whereas Livin expression was nearly stable when lncRNA-ATB was overexpressed or knocked out. RESULTS: Livin was upregulated in vivo and in vitro at the similar rate as the occurrence of EMT, which could be relieved when Livin was silenced. LncRNA-ATB, which is another important regulator of EMT, was also found highly expressed during this process. The silencing of lncRNA-ATB could lessen the severity of EMT, and the overexpression of lncRNA-ATB could aggravate EMT without affecting the expression of Livin. CONCLUSIONS: Livin promotes EMT through the regulation of lncRNA-ATB. The silencing of Livin might be an effective targeted therapy for renal fibrosis.
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BACKGROUND: Henoch-Schonlein purpura nephritis (HSPN) is a very common secondary kidney disease of childhood. Its pathogenesis and the treatment mechanism of glucocorticoid have not been fully elucidated. The aim of this study was to determine the relationship between p300 and the pathogenesis, glucocorticoid therapy in mice with HSPN, respectively. METHODS: Forty-eight C57BL/6N male mice, weighing 18 to 20âg, were selected (3-4 weeks old, nâ=â8 per group). The mice in the normal control group (Group I) were given normal solvent and the HSPN model group (Group II) were given sensitizing drugs. The mice in Group III were injected intraperitoneally with dexamethasone after being given sensitizing drugs. Meanwhile, mice in Groups IV, V and VI with conditional knockout of p300 were also given normal solvent, sensitizing drugs and dexamethasone.The levels of serum IgA, creatinine, and circulating immune complex (CIC) concentrations, 24âh urinary protein and urinary erythrocyte in C57 wild mice, and p300 conditional knockout mice in each group were measured. The expression of p300 in renal tissues and the expression of glucocorticoid receptor (GR) α and ß, transforming growth factor (TGF)-ß1, and activator protein (AP)-1 after dexamethasone treatment were determined by real-time polymerase chain reaction and Western blotting. RESULTS: Compared with the normal solvent control group (Group I), the expression of p300 mRNA in the model group (Group II) was significantly up-regulated. Western blotting further confirmed the result. Urinary erythrocyte count, 24âh urinary protein quantification, serum IgA, CIC, and renal pathologic score in Group V were distinctly decreased compared with non-knockout mice in Group II (9.7â±â3.8 per high-power field [/HP] vs. 18.7â±â6.2/HP, tâ=â1.828, Pâ=â0.043; 0.18â±â0.06âg/24âh vs. 0.36â±â0.08âg/24âh, tâ=â1.837, Pâ=â0.042; 18.78â±â0.85âmg/mL vs. 38.46â±â0.46âmg/mL, tâ=â1.925, Pâ=â0.038; 0.80â±â0.27âµg/mL vs. 1.64â±â0.47âµg/mL, tâ=â1.892, Pâ=â0.041; 7.0â±â0.5 vs. 18.0â±â0.5, tâ=â1.908, Pâ=â0.039). Compared with non-knockout mice (Group III), the level of urinary erythrocyte count and serum IgA in knockout mice (Group VI) increased significantly after treatment with dexamethasone (3.7â±â0.6/HP vs. 9.2â±â3.5/HP, tâ=â2.186, Pâ=â0.024; 12.38â±â0.26âmg/mL vs. 27.85â±â0.65âmg/mL, tâ=â1.852, Pâ=â0.041). The expression level of GRα was considerably increased in the knockout group after dexamethasone treatment compared with non-knockout mice in mRNA and protein level (tâ=â2.085, Pâ=â0.026; tâ=â1.928, Pâ=â0.035), but there was no statistically significant difference in the expression level of GRß between condition knockout and non-knockout mice (tâ=â0.059, Pâ=â0.087; tâ=â0.038, Pâ=â1.12). Furthermore, the expression levels of glucocorticoid resistance genes (AP-1 and TGF-ß1) were notably increased after p300 knockout compared with non-knockout mice in mRNA and protein level (TGF-ß1: tâ=â1.945, Pâ=â0.034; tâ=â1.902, Pâ=â0.039; AP-1: tâ=â1.914, Pâ=â0.038; tâ=â1.802, Pâ=â0.041). CONCLUSIONS: p300 plays a crucial role in the pathogenesis of HSPN. p300 can down-regulate the expression of resistance genes (AP-1 and TGF-ß1) by binding with GRα to prevent further renal injury and glucocorticoid resistance. Therefore, p300 is a promising new target in glucocorticoid therapy in HSPN.
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Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Vasculite por IgA/tratamento farmacológico , Vasculite por IgA/metabolismo , Nefrite/tratamento farmacológico , Nefrite/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Creatinina/sangue , Humanos , Vasculite por IgA/sangue , Vasculite por IgA/genética , Imunoglobulina A/sangue , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite/sangue , Nefrite/genética , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fatores de Crescimento Transformadores/genética , Fatores de Crescimento Transformadores/metabolismo , Fatores de Transcrição de p300-CBP/genéticaRESUMO
Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to development and progression of renal interstitial fibrosis in CKD. p21-activated kinase 4 (PAK4) is a member of serine/threonine protein kinases but the role of PAK4 in renal fibrosis remains unknown. In this study, we investigated the effects of PAK4 on transforming growth factor-ß1 (TGF-ß1)-treated human renal tubular epithelial cells (HK-2 cells) and aimed to elucidate probable mechanisms for its fibrogenic effects. Our results revealed that PAK4 was highly expressed in TGF-ß1-treated HK-2 cells. Overexpressing PAK4 could further decrease TGF-ß1-induced E-cadherin expression and increase TGF-ß1-induced fibronectin and vimentin expression in HK-2 cells. In addition, overexpressing PAK4 could promote the translocation of ß-catenin from cell membranes into the nucleus in TGF-ß1-treated HK-2 cells. These results indicate that PAK4 could enhance TGF-ß1-induced EMT in renal tubular epithelial cells. Our findings indicate that PAK4 may promote renal interstitial fibrosis by activating ß-catenin signaling pathway. Thus, we suggest that PAK4 might be a potential therapeutic target for ameliorating renal interstitial fibrosis.