RESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by heterogeneous variants in the PKD1 and PKD2 genes. Genetic analysis of PKD1 has been challenging due to homology with 6 PKD1 pseudogenes and high GC content. METHODS: A single-tube multiplex long-range-PCR and long-read sequencing-based assay termed "comprehensive analysis of ADPKD" (CAPKD) was developed and evaluated in 170 unrelated patients by comparing to control methods including next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification. RESULTS: CAPKD achieved highly specific analysis of PKD1 with a residual noise ratio of 0.05% for the 6 pseudogenes combined. CAPKD identified PKD1 and PKD2 variants (ranging from variants of uncertain significance to pathogenic) in 160 out of the 170 patients, including 151 single-nucleotide variants (SNVs) and insertion-deletion variants (indels), 6 large deletions, and one large duplication. Compared to NGS, CAPKD additionally identified 2 PKD1 variants (c.78_96dup and c.10729_10732dup). Overall, CAPKD increased the rate of variant detection from 92.9% (158/170) to 94.1% (160/170), and the rate of diagnosis with pathogenic or likely pathogenic variants from 82.4% (140/170) to 83.5% (142/170). CAPKD also directly determined the cis-/trans-configurations in 11 samples with 2 or 3 SNVs/indels, and the breakpoints of 6 large deletions and one large duplication, including 2 breakpoints in the intron 21 AG-repeat of PKD1, which could only be correctly characterized by aligning to T2T-CHM13. CONCLUSIONS: CAPKD represents a comprehensive and specific assay toward full characterization of PKD1 and PKD2 variants, and improves the genetic diagnosis for ADPKD.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Rim Policístico Autossômico Dominante , Canais de Cátion TRPP , Humanos , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/diagnóstico , Canais de Cátion TRPP/genética , Reação em Cadeia da Polimerase Multiplex/métodos , FemininoRESUMO
Anti-glomerular basement membrane (GBM) disease is a rare autoimmune condition characterized by the presence of positive anti-GBM autoantibodies, linear deposition of immunoglobulin G (IgG) along the GBM and severe kidney injury. In a limited number of cases, the association of anti-GBM disease with other glomerulonephritis has been reported. Herein, we present the case of a 66-year-old female patient with progressive worsen kidney function and decreased urine output. A renal biopsy revealed crescent glomerulonephritis with lineal IgG deposition along the GBM and mesangial IgA deposition, which supported the diagnosis of concurrent anti-GBM disease and IgA nephropathy (IgAN). In an extensive literature review, we identified a total of thirty-nine patients were reported anti-GBM disease combined with IgAN. The clinical characteristics of these patients demonstrate that the anti-GBM disease combined with IgAN tends to be milder with a more indolent course and a better prognosis than the classic anti-GBM disease, and its potential pathogenesis deserves to be further explored.
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Doença Antimembrana Basal Glomerular , Glomerulonefrite por IGA , Glomerulonefrite , Feminino , Humanos , Idoso , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Doença Antimembrana Basal Glomerular/complicações , Doença Antimembrana Basal Glomerular/diagnóstico , Autoanticorpos , Imunoglobulina GRESUMO
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by uncontrolled renal cyst formation, and few treatment options are available. There are many parallels between ADPKD and clear-cell renal cell carcinoma (ccRCC); however, few studies have addressed the mechanisms linking them. In this study, we aimed to investigate their convergences and divergences based on bioinformatics and explore the potential of compounds commonly used in cancer research to be repurposed for ADPKD. We analysed gene expression datasets of ADPKD and ccRCC to identify the common and disease-specific differentially expressed genes (DEGs). We then mapped them to the Connectivity Map database to identify small molecular compounds with therapeutic potential. A total of 117 significant DEGs were identified, and enrichment analyses results revealed that they are mainly enriched in arachidonic acid metabolism, p53 signalling pathway and metabolic pathways. In addition, 127 ccRCC-specific up-regulated genes were identified as related to the survival of patients with cancer. We focused on the compound NS398 as it targeted DEGs and found that it inhibited the proliferation of Pkd1-/- and 786-0 cells. Furthermore, its administration curbed cystogenesis in Pkd2 zebrafish and early-onset Pkd1-deficient mouse models. In conclusion, NS398 is a potential therapeutic agent for ADPKD.
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Nitrobenzenos/farmacologia , Rim Policístico Autossômico Dominante/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Biópsia , Biologia Computacional/métodos , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Bases de Dados Genéticas , Gerenciamento Clínico , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Redes e Vias Metabólicas , Camundongos , Mutação , Nitrobenzenos/uso terapêutico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Mapeamento de Interação de Proteínas/métodos , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Sulfonamidas/uso terapêuticoRESUMO
PKD2 gene variants account for 4.5% to 20% of patients with autosomal dominant polycystic kidney disease (ADPKD). Little is known about the clinical characteristics of PKD2 variants in Chinese patients with ADPKD. Herein, we performed a comprehensive search for variants of PKD2 gene in 44 Chinese ADPKD pedigrees and a total of 37 variants were identified. Of these 37 variants, 18 were nonsense variants, 10 frameshift variants, 4 missense variants, and 5 splice site variants. 11/37 variants were detected for the first time. The median age at diagnosis was 30.5 years, and positive family history was detected in 77.27% patients, liver cysts in 68.18%, hypertension in 45.45%, nephrolithiasis in 31.82%, macro-hematuria in 22.73%, and proteinuria in 13.63%. The level of estimated glomerular filtration rate in 8/39 patients were blow 60 ml/min/1.73m2 . 11/17 patients were classified as rapid progression by Mayo Clinic classification. The end stage renal disease (ESRD) events were reported in 9/22 pedigrees, and the presence of nephrolithiasis and macro-hematuria were significantly associated with ESRD in the pedigrees with PKD2 variants. The identified variants and clinical features will facilitate the early diagnosis and prognosis prediction in Chinese ADPKD patients with PKD2 variants.
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Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Adolescente , Adulto , Povo Asiático/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Rim Policístico Autossômico Dominante/enzimologia , Rim Policístico Autossômico Dominante/fisiopatologia , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Bilateral carotid artery occlusion (CAO) is a rare condition and the collateral circulation is more complicated than in unilateral CAO. The circle of Willis (CoW) is the most important collateral circulation compensation pathway in CAO. However, the specific role of CoW in the collateral circulation compensation pathway of CAO has not been fully elucidated. The purpose of this study is to investigate the role of CoW in the collateral circulation compensation pathway of CAO. MATERIALS AND METHODS: Clinical, imaging, and hemodynamic data of 30 patients with bilateral CAO were collected to analyze the collateral blood flow compensation pathway and its characteristics, and to examine the correlation between the structure of the CoW and the collateral circulation of bilateral CAO. RESULTS: This paper summarized 30 patients with bilateral CAO. There were 0 cases of the CoW complete type, 18 cases of the partially complete type (60%), and 12 cases of the incomplete type (40%). For the partially complete type cases, there were 14 complete anterior circulation cases (46.7%). The collateral circulation collateral circulation pathway included 14 cases with anterior communicating artery(ACoA), 7 cases with posterior cerebral artery (PCA)-middle cerebral artery (MCA) leptomeningeal anastomosis (LMA), 5 cases with ophthalmic artery(OA), 3 cases with lateral posterior communicating artery(PCoA), 1 case with internal carotid artery (ICA) stealing, 1 case with new Moyamoya vessels, and 4 cases of other types. There were four cases (13.3%) with complete posterior circulation, including four cases with bilateral PCoA, three cases with PCA-MCA LMA, and two cases with OA. There were 12 cases (40%) with incomplete CoW, including 8 cases with PCA-MCA LMA, 3 cases with lateral PCoA, 1 case with anterior cerebral artery (ACA)-MCA LMA, 4 cases with OA, and 1 other case. CONCLUSION: The collateral circulation pathway differs among patients with different CoW structure types. When the CoW is partially complete, it mainly provides blood flow compensation to the ischemic area through primary collateral circulation. When the CoW is incomplete, it mainly provides blood flow compensation to the ischemic area through secondary collateral circulation.
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Estenose das Carótidas , Círculo Arterial do Cérebro , Adulto , Artéria Carótida Interna/diagnóstico por imagem , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Circulação Cerebrovascular , Criança , Círculo Arterial do Cérebro/diagnóstico por imagem , Circulação Colateral , HumanosRESUMO
Polycystic kidney disease (PKD) is a group of hereditary kidney diseases caused by genetic mutations. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the two main forms of PKD. The pathological features of PKD include progressive enlargement of renal cysts and destruction of kidney structure, which may eventually lead to end-stage renal disease (ESRD). As a result, the lives of PKD patients can only be sustained by dialysis or kidney transplantation. On the basis of basic research, clinical studies and guidelines issued for PKD at home and abroad, and by combining with the reality of Chinese PKD patients, this guideline has summarized the key points for the genetic counseling and clinical treatment of PKD, with an aim to improve the understanding and standardized diagnosis and treatment for such disorders.
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Doenças Renais Policísticas/diagnóstico , Doenças Renais Policísticas/terapia , Guias de Prática Clínica como Assunto , China , Humanos , Rim/patologia , Mutação , Rim Policístico Autossômico Dominante , Rim Policístico Autossômico RecessivoRESUMO
Polarity complexes, including the PAR (Partitioning-defective), CRB (Crumbs) and SCRIB (Scribble) complexes, are required for the physiologic establishment, stabilization, and maintenance of a functional apical-basolateral polarity. Inactivation of some of the polarity complexes results in cystic kidneys, and apical-basolateral polarity defects are commonly observed in autosomal-dominant polycystic kidney disease (ADPKD); however, little is known about the role that polarity complexes play in ADPKD. Here, we demonstrate that Scribble, a core protein of the SCRIB complex, is down-regulated in ADPKD cell lines and the zebrafish model of this disease ( pkd2 morphants). Overexpression of Scribble could reduce cyst formation in pkd2 morphants, and loss of scrib led to a dilated pronephric duct in zebrafish. Furthermore, the Hippo signaling pathway was inactivated in scrib mutants and pkd2 morphants in which Yes-associated protein (YAP), which is physiologically located in the cytoplasm, was translocated to the nucleus. Of note, overexpression of cytoplasmic YAP, instead of nuclear YAP, could reduce cyst formation in pkd2 morphants. Consistently, knockout of yap resulted in cystic kidneys in zebrafish, which was rescued by the overexpression of cytoplasmic YAP, but not nuclear YAP. Finally, scrib and yap had a genetic interaction with pkd2 in cyst formation, and the overexpression of Scribble attenuated the down-regulation of cytoplasmic YAP in ADPKD. Altogether, our data indicate that Scribble induces the phosphorylation of YAP and, consequently, influences cyst formation in ADPKD by mediating YAP nucleocytoplasmic shuttling.-Xu, D., Lv, J., He, L., Fu, L., Hu, R., Cao, Y., Mei, C. Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway.
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Cistos/metabolismo , Rim/metabolismo , Rim Policístico Autossômico Dominante/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular , Regulação para Baixo/fisiologia , Células HEK293 , Humanos , Camundongos , Fosforilação/fisiologia , Proteína Quinase D2 , Proteínas Quinases/metabolismo , Peixe-ZebraRESUMO
BACKGROUND/AIMS: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic form of kidney disease. High-throughput microarray analysis has been applied for elucidating key genes and pathways associated with ADPKD. Most genetic profiling data from ADPKD patients have been uploaded to public databases but not thoroughly analyzed. This study integrated 2 human microarray profile datasets to elucidate the potential pathways and protein-protein interactions (PPIs) involved in ADPKD via bioinformatics analysis in order to identify possible therapeutic targets. METHODS: The kidney tissue microarray data of ADPKD patients and normal individuals were searched and obtained from NCBI Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified, and enriched pathways and central node genes were elucidated using related websites and software according to bioinformatics analysis protocols. Seven DEGs were validated between polycystic kidney disease and control kidney samples by quantitative real-time polymerase chain reaction. RESULTS: Two original human microarray datasets, GSE7869 and GSE35831, were integrated and thoroughly analyzed. In total, 6,422 and 1,152 DEGs were extracted from GSE7869 and GSE35831, respectively, and of these, 561 DEGs were consistent between the databases (291 upregulated genes and 270 downregulated genes). From 421 nodes, 34 central node genes were obtained from a PPI network complex of DEGs. Two significant modules were selected from the PPI network complex by using Cytotype MCODE. Most of the identified genes are involved in protein binding, extracellular region or space, platelet degranulation, mitochondrion, and metabolic pathways. CONCLUSIONS: The DEGs and related enriched pathways in ADPKD identified through this integrated bioinformatics analysis provide insights into the molecular mechanisms of ADPKD and potential therapeutic strategies. Specifically, abnormal decorin expression in different stages of ADPKD may represent a new therapeutic target in ADPKD, and regulation of metabolism and mitochondrial function in ADPKD may become a focus of future research.
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Biologia Computacional/métodos , Rim Policístico Autossômico Dominante/genética , Animais , Estudos de Casos e Controles , Conjuntos de Dados como Assunto , Decorina/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Camundongos , Análise em Microsséries , Rim Policístico Autossômico Dominante/metabolismo , Peixe-ZebraRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is a common heritable human disease. Recently, the role of repressed autophagy in ADPKD has drawn increasing attention. Here, we investigate the mechanism underlying the effect of Saikosaponin-d (SSd), a sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA) inhibitor. We show that SSd suppresses proliferation in ADPKD cells by up-regulating autophagy. We found that treatment with SSd results in the accumulation of intracellular calcium, which in turn activates the CaMKKß-AMPK signalling cascade, inhibits mTOR signalling and induces autophagy. Conversely, we also found that treatment with an autophagy inhibitor (3-methyladenine), AMPK inhibitor (Compound C), CaMKKß inhibitor (STO-609) and intracellular calcium chelator (BAPTA/AM) could reduce autophagy puncta formation mediated by SSd. Our results demonstrated that SSd induces autophagy through the CaMKKß-AMPK-mTOR signalling pathway in ADPKD cells, indicating that SSd might be a potential therapy for ADPKD and that SERCA might be a new target for ADPKD treatment.
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Proteínas Quinases Ativadas por AMP/biossíntese , Autofagia/efeitos dos fármacos , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/biossíntese , Proliferação de Células/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/biossíntese , Proteínas Quinases Ativadas por AMP/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Linhagem Celular Transformada , Humanos , Ácido Oleanólico/farmacocinética , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genéticaRESUMO
BACKGROUND/AIMS: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. METHODS: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions. RESULTS: A total of 93 mutations in PKD1 and PKD2 were identified in 98 Chinese families with ADPKD inheritance and the detection rate was 81.7% (98/120). The mutation rates of PKD1 and PKD2 were 91.4% (85/93) and 8.6% (85/93), respectively. Among the 93 mutations, 59.1% (55/93) were reported for the first time. A total of 65 mutations (26 nonsense, 33 frameshift, 2 large deletion, and 4 typical splicing mutations) were identified as definite pathogenic mutations. The remaining 28 mutations (21 missense, 3 in-frame deletion, and 4 atypical splicing mutations) were determined as probable pathogenic mutations. In addition, 9 de novo mutations were found by pedigree analysis. Correlation analysis between genotype and phenotype revealed that patients with PKD1 mutations or truncating mutations exhibited the most severe clinical outcome. CONCLUSION: The newly identified sites for known mutations will facilitate the early diagnosis and prediction of prognosis in patients with ADPKD, and provide fundamental genetic information for clinical intervention to prevent the inheritance of this disease in affected families.
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Análise Mutacional de DNA/métodos , Mutação , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Adulto , Povo Asiático/genética , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Linhagem , Adulto JovemRESUMO
BACKGROUND/AIMS: Angiotensin II (Ang II) has been regarded as an important profibrogenic cytokine in renal fibrosis. Krüppel-like factor 15 (KLF15) has been identified as an important negative transcription factor in renal fibrosis. However, little is known about the role of KLF15 in Ang II-induced renal fibrosis. METHODS: In this study, we randomized mice into a control group, Ang II group or Ang II plus losartan group. KLF15 expression was examined with real-time PCR and immunofluorescence in these groups. In vitro, KLF15 expression was examined by Western blot in rat renal fibroblasts (NRK-49F) stimulated with Ang II, and the effect of altered KLF15 expression on the regulation of the profibrotic factor connective tissue growth factor (CTGF) was further explored with co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) analyses. RESULTS: Compared with the control group, the murine model of Ang II-induced renal fibrosis demonstrated a significant decrease in renal KLF15 expression at 4 weeks and presented with progressive renal fibrosis at 6 weeks. Meanwhile, losartan, an angiotensin type 1 (AT1) receptor antagonist, effectively prevented the down-regulation of KLF15 expression induced by Ang II infusion. In vitro, NRK-49F cells stimulated with Ang II exhibited a significant decrease in KLF15 expression, accompanied by a marked increase in the expression of profibrotic factors and in the production of extracellular matrix. The up-regulation of CTGF expression induced by Ang II stimulation was inhibited by KLF15 overexpression in NRK-49F cells, and losartan treatment prevented the down-regulation of KLF15 expression and the up-regulation of CTGF expression induced by Ang II stimulation. Furthermore, CoIP and ChIP assays revealed that the transcription regulator KLF15 directly bound to the co-activator P/CAF and repressed its recruitment to the CTGF promoter. CONCLUSIONS: Ang II down-regulates KLF15 expression via the AT1 receptor, and KLF15 is likely to inhibit Ang II-induced CTGF expression by repressing the recruitment of the co-activator P/CAF to the CTGF promoter.
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Angiotensina II/efeitos adversos , Fator de Crescimento do Tecido Conjuntivo/genética , Proteínas de Ligação a DNA/fisiologia , Fibrose/congênito , Fibrose/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Proteínas de Ligação a DNA/uso terapêutico , Fibrose/induzido quimicamente , Fatores de Transcrição Kruppel-Like , Losartan/farmacologia , Camundongos , Regiões Promotoras Genéticas , Ratos , Receptor Tipo 1 de Angiotensina , Fatores de Transcrição/uso terapêuticoRESUMO
AIMS: Cyclosporin A (CsA) is considered as an effective treatment option for steroid-resistant or-dependent patients with adult-onset minimal change disease (MCD). However, CsA resistance or dependence is also observed in these patients. Tacrolimus (TAC) is a calcineurin inhibitor that is potent in cytokine suppression. The authors aim to evaluate the efficacy and safety of TAC therapy in CsA-resistant and-dependent adult-onset MCD patients. METHODS: Patients with adult-onset MCD were enrolled in our department from 2008 to 2012. All patients were demonstrated to be resistant to or dependent on CsA therapy. Prednisone (0.5 mg/kg per day) combined with TAC (0.05-0.1 mg/kg per day) were prescribed to these patients for at least 6 months. The primary outcome was complete or partial remission of proteinuria. Secondary outcomes included time required for complete or partial remission, adverse events, number of relapses, and TAC dosages. RESULTS: A total of 11 MCD patients were enrolled in this observational study. The numbers of patients who presented with resistance to or dependence on CsA were 7 and 4, respectively. The total remission rate was 90.9% (10/11) with the complete remission rate 72.7% (8/11). Most remission patients achieved remission during the first 2 months of TAC therapy. Patients who presented with dependence on CsA had achieved complete remission with TAC therapy, while outcomes for CsA-resistant patients were four complete remissions, two partial remissions and one resistance. The adverse events were observed in this study included infection, diarrhoea, and worsened hypertension. Five patients who had remission experienced relapse. CONCLUSIONS: Tacrolimus improves proteinuria remission in adults with CsA-resistant or -dependent MCD.
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Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Nefrose Lipoide/tratamento farmacológico , Proteinúria/tratamento farmacológico , Tacrolimo/uso terapêutico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/complicações , Proteinúria/etiologia , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Inflammation plays an important role in polycystic kidney disease (PKD). The current study aimed to examine the efficacy of the anti-inflammatory compound resveratrol in PKD and to investigate its underlying mechanism of action. METHODS: Male Han:SPRD (Cy/+) rats with PKD were treated with 200 mg/kg/day resveratrol or vehicle by gavage for 5 weeks. Human autosomal dominant (AD) PKD cells, three-dimensional (3D) Madin-Darby canine kidney cells and zebrafish were treated with various concentrations of resveratrol or the nuclear factor κB (NF-κB) inhibitor QNZ. RESULTS: Resveratrol treatment reduced blood urea nitrogen levels and creatinine levels by 20 and 24%, respectively, and decreased two-kidney/total body weight ratio by 15% and cyst volume density by 24% in Cy/+ rats. The proliferation index and the macrophage infiltration index were reduced by 40 and 43%, respectively, in resveratrol-treated cystic kidneys. Resveratrol reduced the levels of the pro-inflammatory factors monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and complement factor B (CFB) in Cy/+ rat kidneys in parallel with the decreased activity of NF-κB (p50/p65). The activation of NF-κB and its correlation with pro-inflammatory factor expression were confirmed in human ADPKD cells and kidney tissues. Resveratrol and QNZ inhibited the expression of MCP-1, TNF-α and CFB and reduced NF-κB activity in ADPKD cells. Moreover, NF-κB blockage minimized the inhibition of inflammatory factor production by resveratrol treatment. Furthermore, resveratrol or QNZ inhibited cyst formation in the 3D cyst and zebrafish models. CONCLUSIONS: The NF-κB signaling pathway is activated and partly responsible for inflammation in polycystic kidney tissues. Targeting inflammation through resveratrol could be a new strategy for PKD treatment in the future.
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Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/prevenção & controle , NF-kappa B/antagonistas & inibidores , Doenças Renais Policísticas/prevenção & controle , Rim Policístico Autossômico Dominante/prevenção & controle , Estilbenos/farmacologia , Animais , Estudos de Casos e Controles , Quimiocina CCL2/metabolismo , Progressão da Doença , Cães , Humanos , Inflamação/metabolismo , Inflamação/patologia , Células Madin Darby de Rim Canino , Masculino , NF-kappa B/metabolismo , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/patologia , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Ratos , Ratos Sprague-Dawley , Resveratrol , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Peixe-ZebraRESUMO
Pd/Y multilayer mirrors operating in the soft X-ray region are characterized by a high theoretical reflectance, reaching 65% at normal incidence in the 8-12 nm wavelength range. However, a severe intermixing of neighboring Pd and Y layers results in an almost total disappearance of the interfaces inside the multilayer structures fabricated by direct current magnetron sputtering and thus a dramatic reflectivity decrease. Based on grazing incidence X-ray reflectometry and X-ray photoelectron spectroscopy, we demonstrate that the stability of the interfaces in Pd/Y multilayer structures can be essentially improved by adding a small amount of nitrogen (4-8%) to the working gas (Ar). High resolution transmission electron microscopy shows that the interlayer width is only 0.9 nm and 0.6 nm for Y(N)-on-Pd(N) and Pd(N)-on-Y(N) interfaces, respectively. A well-defined crystalline texture of YN (200) is observed on the electron diffraction pattern. As a result, the measured reflectance of the Pd(N)/Y(N) multilayer achieves 30% at λ = 9.3 nm. The peak reflectivity value is limited by the remaining interlayers and the formation of the YN compound inside the yttrium layers, resulting in an increased absorption.
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Traditional Chinese medicine (TCM) is an essential part of the Chinese medical system and is recognized by the World Health Organization as an important alternative medicine. As an important part of TCM, TCM diagnosis is a method to understand a patient's illness, analyze its state, and identify syndromes. In the long-term clinical diagnosis practice of TCM, four fundamental and effective diagnostic methods of inspection, auscultation-olfaction, inquiry, and palpation (IAOIP) have been formed. However, the diagnostic information in TCM is diverse, and the diagnostic process depends on doctors' experience, which is subject to a high-level subjectivity. At present, the research on the automated diagnosis of TCM based on machine learning is booming. Machine learning, which includes deep learning, is an essential part of artificial intelligence (AI), which provides new ideas for the objective and AI-related research of TCM. This paper aims to review and summarize the current research status of machine learning in TCM diagnosis. First, we review some key factors for the application of machine learning in TCM diagnosis, including data, data preprocessing, machine learning models, and evaluation metrics. Second, we review and summarize the research and applications of machine learning methods in TCM IAOIP and the synthesis of the four diagnostic methods. Finally, we discuss the challenges and research directions of using machine learning methods for TCM diagnosis.
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Inteligência Artificial , Medicina Tradicional Chinesa , Humanos , Medicina Tradicional Chinesa/métodos , Olfato , Aprendizado de Máquina , PalpaçãoRESUMO
Introduction: This study aimed to determine the utility of different methods to predict rapid progressors (RPs) and their clinical characteristics in Asia-Pacific patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: This was a multinational retrospective observational cohort study of patients with ADPKD in the Asia-Pacific region. Five hospitals from Australia, China, South Korea, Taiwan, and Turkey participated in this study. RP was defined by European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) guidelines and compared to slow progressors (SPs). Results: Among 768 patients, 426 patients were RPs. Three hundred six patients met only 1 criterion and 120 patients satisfied multiple criteria for RP. Historical estimated glomerular filtration rate (eGFR) decline fulfilled the criteria for RP in 210 patients. Five patients met the criteria for a historical increase in height-adjusted total kidney volume (TKV). The 210 patients satisfied the criteria for based on kidney volume. During the follow-up period, cyst infections, cyst hemorrhage, and proteinuria occurred more frequently in RP; and 13.9% and 2.1% of RPs and SPs, respectively, progressed to end-stage kidney disease (ESKD). RP criteria based on historical eGFR decline had the strongest correlation with eGFR change over a 2-year follow-up. Conclusion: Various assessment strategies should be used for identifying RPs among Asian-Pacific patients with ADPKD in real-world clinical practice during the follow-up period, cyst infections, cyst hemorrhage, and proteinuria occurred more frequently; and more patients progressed to ESKD in RPs compared with SPs.
RESUMO
Alzheimer's disease (AD) is recognized as one of the most common types of senile dementia. AD patients first suffer memory loss for recent events (short-term memory impairment). As the disease progresses, they are deprived of self-awareness. This study aims to explore the effects of a probiotic-supplemented diet on the cognitive behaviors and pathological features of mouse models of Alzheimer's disease (AD). Mice in the control group and the 3xTg-AD group were fed a regular diet and a probiotic-supplemented diet, respectively, for 20 weeks. Behavioral experiments like Morris's water maze and Y maze were conducted. Then, feces of mice were collected for 16S sRNA gene sequencing for microorganisms. In the end, soluble and insoluble Aß40 and Aß42 in the hippocampus and cortex of mice in each group were quantitatively analyzed with a double-antibody Sandwich ELISA. The expression levels of tau protein and gliocyte in the hippocampus and cortex were detected using the Western Blot method. The result of the Morris water maze experiment indicated that, in the place navigation test, the mice in the 3xTg-AD group experienced a significant decline in the learning ability and a longer escape latency and in the space exploration test, the swimming time of mice in the 3xTg-AD group in the target quadrant decreased and after being treated with the probiotic diet, mice in the 3xTg-AD group had improved learning and memory ability. The result of Y maze showed that the probiotic diet can improve the spontaneous alternation accuracy of mice in the 3xTg-AD group. The result of 16s rRNA gene sequencing showed that, compared with mice in the WT group, those in the 3xTg-AD group experienced a change in the intestinal flora. The Western Blot result displayed a decreased expression level of tau (pS202) (P < 0.05) and decreased expression levels of Iba-1 and GFAP (P < 0.05). The result of the ELISA experiment showed decreased levels of soluble and insoluble Aß40 and Aß42 in 3xTg-AD mice (P < 0.05). In conclusion, a probiotic diet can prevent and treat AD by improving the intestinal flora of 3xTg-AD.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Probióticos , Doença de Alzheimer/patologia , Animais , Cognição , Dieta , Humanos , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Probióticos/uso terapêutico , RNA Ribossômico 16SRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is considered as a tumor-like disease because there are many biological similarities between ADPKD and cancer. However, the commonalities between them are provocative, particularly under the conditions of recent clinical studies. In this paper, we review clinical studies about the association between cancer and ADPKD, and compare the biological characteristics between them, with focusing on cell proliferation, differentiation, migration, apoptosis, and polarity. With detailed literature reviewing, we believe that ADPKD patients have a higher risk of tumorigenesis and thus highly recommend being aware of tumorigenesis during follow-up in patients with ADPKD.
Assuntos
Carcinogênese/patologia , Fenômenos Fisiológicos Celulares , Neoplasias , Rim Policístico Autossômico Dominante/patologia , Detecção Precoce de Câncer , Humanos , Neoplasias/diagnóstico , Neoplasias/patologiaRESUMO
Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Rim Policístico Autossômico Dominante/patologia , Fator B de Elongação Transcricional Positiva/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/química , Cistos/metabolismo , Cistos/patologia , Modelos Animais de Doenças , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Fosforilação , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/metabolismo , Fator B de Elongação Transcricional Positiva/antagonistas & inibidores , Fator B de Elongação Transcricional Positiva/genética , Ligação Proteica , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas Nucleares Pequenas/química , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Transdução de Sinais , Canais de Cátion TRPP/deficiência , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra/metabolismoRESUMO
The alkaline solubilization of excess mixed sludge was investigated and subsequently the released phosphorus was recovered as magnesium ammonium phosphate (MAP). Considerable and rapid release of glycogen and protein was encountered after alkaline addition into the sludge. Only 45.0% of sludge cells were destructed after 240â¯min treatment in R1 while the corresponding ratio was 96.1% in R3 according to the release of DNA. Non-apatite inorganic phosphorus (NAIP) in the alkaline treated sludge decreased due to the dissolution of Al(OH)3 and AlPO4, which was the dominant reason for phosphorus release. Soluble orthophosphate (SOP) in the supernatant of alkaline treated sludge could be recovered quickly with the recovery efficiency of 84.6% within 5â¯min and about 53-55% of P participated in MAP reaction, producing large amounts of acicular crystals.