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1.
Gastroenterology ; 167(4): 733-749.e3, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38810839

RESUMO

BACKGROUND & AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.


Assuntos
Butiratos , Epigênese Genética , Microbioma Gastrointestinal , Cirrose Hepática Biliar , Reprogramação Metabólica , Células Supressoras Mieloides , Animais , Feminino , Humanos , Masculino , Camundongos , Butiratos/metabolismo , Reprogramação Celular , Modelos Animais de Doenças , Disbiose/metabolismo , Disbiose/microbiologia , Fezes/microbiologia , Fezes/química , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/microbiologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
2.
Hepatology ; 79(1): 25-38, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37505225

RESUMO

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8 + T cells (T RM ). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T RM . APPROACH AND RESULTS: The numbers of intrahepatic CD103 + T RM were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic T RM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103 + T RM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103 + T RM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103 + T RM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8 + T cells. Moreover, 4-OI reduced intrahepatic CD103 + T RM and ameliorated liver injury in murine models of PSC. CONCLUSIONS: Itaconate exerted immunomodulatory activity on CD103 + T RM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103 + T RM with itaconate has therapeutic potential in PSC.


Assuntos
Colangite Esclerosante , Hepatopatias , Animais , Camundongos , Colangite Esclerosante/patologia , Cromatografia Líquida , Espectrometria de Massas em Tandem , Inflamação
3.
Hepatology ; 78(1): 10-25, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36799463

RESUMO

BACKGROUNDS: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. METHODS: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. RESULTS: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. CONCLUSIONS: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.


Assuntos
Colangite Esclerosante , Colestase , Hepatopatias , Animais , Humanos , Camundongos , Colangite Esclerosante/patologia , Colestase/metabolismo , Modelos Animais de Doenças , Fibrose , Fígado/patologia , Cirrose Hepática/patologia , Hepatopatias/patologia , Camundongos Knockout , Pró-Colágeno-Prolina Dioxigenase/metabolismo
4.
J Hepatol ; 79(6): 1478-1490, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37659731

RESUMO

BACKGROUND & AIMS: Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown. METHODS: Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice and established three cholestatic murine models. The transcriptome was analyzed by RNA-seq. A specific inhibitor of the Mertk receptor was used in vitro and in vivo. Promoter activity was determined by chromatin immunoprecipitation-seq against Arid3a and a luciferase reporter assay. RESULTS: In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury (accompanied by decreased accumulation of macrophages). Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor of the efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages via upregulation of Mertk. Arid3a negatively regulated Mertk transcription by directly binding to its promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages. Arid3a was upregulated in hepatic macrophages and circulating monocytes in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC. Mertk+ cells were located in close proximity to cholangiocytes, while Arid3a+ cells were scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC. CONCLUSIONS: Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases. IMPACT AND IMPLICATIONS: Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm to explain how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.


Assuntos
Colestase , Proteínas de Ligação a DNA , Hepatopatias , Fatores de Transcrição , c-Mer Tirosina Quinase , Animais , Camundongos , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo , Colestase/metabolismo , Hepatopatias/metabolismo , Macrófagos/metabolismo , Camundongos Knockout , Fagocitose/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Gut ; 71(5): 899-909, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34035120

RESUMO

OBJECTIVE: Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. DESIGN: We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. RESULTS: Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. CONCLUSIONS: Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.


Assuntos
Colangite Esclerosante , Colestase , Microbioma Gastrointestinal , Colangite Esclerosante/microbiologia , Humanos , Imunoglobulina G , Metaboloma , RNA Ribossômico 16S/genética
6.
J Hepatol ; 77(5): 1311-1324, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35753523

RESUMO

BACKGROUND & AIMS: Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC. METHODS: Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model. RESULTS: Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFßR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFß-Smad signaling. CONCLUSIONS: CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC. LAY SUMMARY: Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.


Assuntos
Linfócitos T CD8-Positivos , Cirrose Hepática Biliar , Animais , Camundongos , Autoantígenos , Epitopos Imunodominantes , Cirrose Hepática Biliar/genética , Oxirredutases , Piruvatos , Fator de Crescimento Transformador beta , Ácido Ursodesoxicólico/farmacologia
7.
Hepatology ; 74(2): 847-863, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33554350

RESUMO

BACKGROUND AND AIMS: The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. APPROACH AND RESULTS: We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-ß on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-ß and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. CONCLUSIONS: Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.


Assuntos
Hepatite Autoimune/imunologia , Fígado/patologia , Células T de Memória/imunologia , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biópsia , Antígenos CD8/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Voluntários Saudáveis , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/patologia , Humanos , Cadeias alfa de Integrinas/metabolismo , Lectinas Tipo C/metabolismo , Fígado/imunologia , Masculino , Células T de Memória/efeitos dos fármacos , Células T de Memória/metabolismo , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/antagonistas & inibidores , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Índice de Gravidade de Doença
8.
J Immunol ; 202(7): 2027-2034, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30745458

RESUMO

Methicillin-resistant Staphylococcus aureus has emerged as a significant contributor to morbidity and mortality associated with influenza infection. In this study, we show in a mouse model that preceding influenza infection promotes S. aureus resistance to killing by antibiotics. This resistance coincides with influenza-induced accumulation of inflammatory monocytes in the lung. CCR type 2 (CCR2) is responsible for pulmonary monocyte recruitment after influenza infection. We found that antibiotic-treated Ccr2-deficient (Ccr2-/-) mice exhibit significantly improved bacterial control and survival from influenza and methicillin-resistant S. aureus coinfection, despite a delay in viral clearance. Mechanistically, our results from in vivo studies indicate that influenza-induced monocytes serve as reservoirs for intracellular S. aureus survival, thereby promoting bacterial resistance to antibiotic treatment. Blocking CCR2 with a small molecular inhibitor (PF-04178903), in conjunction with antibiotic treatment, enhanced lung bacterial clearance and significantly improved animal survival. Collectively, our study demonstrates that inflammatory monocytes constitute an important and hitherto underappreciated mechanism of the conflicting immune requirements for viral and bacterial clearance by hosts, which subsequently leads to exacerbated outcomes of influenza and S. aureus coinfection.


Assuntos
Coinfecção/imunologia , Staphylococcus aureus Resistente à Meticilina/imunologia , Monócitos/imunologia , Monócitos/microbiologia , Infecções por Orthomyxoviridae/complicações , Animais , Farmacorresistência Bacteriana/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Receptores CCR2/imunologia
9.
J Cell Mol Med ; 23(4): 2280-2292, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30724027

RESUMO

Although the application of multiple chemotherapy brought revolutionary changes to improve overall survival of osteosarcoma patients, the existence of multidrug resistance (MDR) has become a great challenge for successful osteosarcoma treatment in recent decades. Substantial studies have revealed various underlying mechanisms of MDR in cancers. As for osteosarcoma, evidence has highlighted that microRNAs (miRNAs) can mediate in the processes of DNA damage response, apoptosis avoidance, autophagy induction, activation of cancer stem cells, and signal transduction. Besides, these drug resistance-related miRNAs showed much promise for serving as candidates for predictive biomarkers of poor outcomes and shorter survival time, and therapeutic targets to reverse drug resistance and overcome treatment refractoriness. This review aims to demonstrate the potential molecular mechanisms of miRNAs-regulated drug resistance in osteosarcoma, and provide insight in translating basic evidence into therapeutic strategies.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Osteossarcoma/tratamento farmacológico , Pesquisa Translacional Biomédica , Apoptose/genética , Autofagia/genética , Dano ao DNA/efeitos dos fármacos , Humanos , MicroRNAs/uso terapêutico , Osteossarcoma/genética , Osteossarcoma/patologia
11.
Biomed Chromatogr ; 31(8)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28139829

RESUMO

Vancomycin (VCM) is clinically used in treating patients with postoperative intracranial infections. The cerebrospinal fluid (CSF) concentration of VCM varies greatly among patients. To guide the dosage regimens, monitoring of VCM in CSF is needed. However a method for analysis of VCM in human CSF is lacking. An ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for analysis of VCM in human CSF, and the agreement of UPLC-MS/MS and chemiluminescence immunoassay (CLIA) in the analysis of CSF VCM was evaluated. The ion transitions were m/z 725.5 > 144.1 for VCM and m/z 455.2 > 308.2 for methotrexate (internal standard). The agreement between UPLC-MS/MS and CLIA was evaluated by Bland-Altman plot in 179 samples. The calibration range of the UPLC-MS/MS method was 1-400 mg/L. The inaccuracy and imprecision were -0.69-10.80% and <4.95%. The internal standard normalized recovery and matrix factor were 86.14-99.31 and 85.84-92.07%, respectively. The measurements of CLIA and UPLC-MS/MS were strongly correlated (r > 0.98). The 95% limit of agreement of the ratio of CLIA to UPLC-MS/MS was 61.66-107.40%. Further studies are warranted to confirm the results.


Assuntos
Antibacterianos/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Vancomicina/líquido cefalorraquidiano , Monitoramento de Medicamentos/métodos , Humanos , Imunoensaio
12.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 44(5): 584-8, 2015 09.
Artigo em Zh | MEDLINE | ID: mdl-26713536

RESUMO

Kidney dendritic cells(DC) play important roles in the pathogenesis of kidney diseases. Kidney DC presents anti-inflammatory effects in certain kidney diseases, sometimes presents pro-inflammation in other diseases, and sometimes their effects are changing in different stages of the disease, suggesting that the differentiation and function of kidney DC may be influenced by microenvironment. This article reviews the origin and distribution of kidney DC subsets and their roles in the pathogenesis of kidney diseases such as lupus nephritis and pyelonephritis, and the functional regulation of kidney DC by proximal tubule epithelial cells.


Assuntos
Células Dendríticas/citologia , Nefropatias/imunologia , Rim/citologia , Diferenciação Celular , Células Dendríticas/imunologia , Células Epiteliais/citologia , Humanos , Inflamação/imunologia , Nefrite Lúpica/imunologia , Pielonefrite/imunologia
13.
Front Psychol ; 15: 1372005, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38784622

RESUMO

This research focuses on the Chinese learning strategies employed by learners from Central Asian countries, specifically examining the effects of gender, age, and learning duration. The study aims to identify and analyze the demographic factors that influence the learning approaches of these learners, providing insights for more effective teaching and learning of Chinese as a foreign language. Data are collected through questionnaires and interviews, and statistical analysis is conducted to explore the correlations between gender, age, learning duration, and learning strategies. The learning strategy model adopted in this study provides a comprehensive classification of language learning strategies. The results underscore the significance of incorporating these factors into language education programs, providing valuable insights into the unique needs and challenges encountered by learners from Central Asian countries. The findings indicate that students from Central Asian countries predominantly utilize social strategies, metacognitive strategies, and affective strategies in their Chinese language learning. These are followed by compensatory strategies, cognitive strategies, and memory strategies. While gender does not exert a significant impact on the utilization of Chinese learning strategies, there are discernible variations in memory and affective strategies between males and females. Age does not significantly affect overall learning strategies, but there are notable disparities in compensatory strategies among different age groups. Learning duration has a significant effect on compensation and metacognitive strategies. The correlation between learning duration and overall strategies is significant indicating that learners with different learning durations exhibit notable differences in compensation and metacognitive strategies.

14.
RSC Adv ; 14(38): 28210-28214, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39234524

RESUMO

A strategy for the efficient metal-free C-O bond cleavage of ester using amines for the synthesis of substituted oxazoles was developed for the first time. The synthesis proceeded smoothly under metal-free conditions, combining C-O bond cleavage as well as C-N and C-O bond formation in one pot to yield desired products in moderate to excellent yields, and accommodated a wide range of functional groups and substrates.

15.
Med ; 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39305900

RESUMO

BACKGROUND: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC. METHODS: We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts. FINDINGS: PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridialow microbiomes, Clostridiahigh microbiomes were more similar to healthy controls. Notably, patients in the Clostridialow subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridiahigh subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridialow subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridiahigh group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts. CONCLUSIONS: Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies. FUNDING: This research was mainly supported by the National Natural Science Foundation of China.

16.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 42(5): 492-7, 2013 Sep.
Artigo em Zh | MEDLINE | ID: mdl-24167128

RESUMO

OBJECTIVE: To investigate the effects of TcpC on human umbilical vascular endothelial cells (HUVECs) and its mechanisms. METHODS: HUVECs were co-cultured with TcpC secreting wild-type E. coli strain CFT073 (TcpC(wt)) or tcpc gene-deleted CFT073 mutant strain (TcpC(mut)) in transwell system,respectively. Apoptosis of HUVECs was analyzed by Annexin-V/PI double staining. Mitochondrial membrane depolarization was detected by JC-1 staining. Expression of apoptosis-related proteins in HUVECs was determined by Western blot. RESULTS: HUVECs showed morphological changes after co-cultured with TcpC(wt) for 24 h: the cells became detached and cell debris increased,and cell number was also decreased when compared to HUVECs co-cultured with TcpC(mut). The apoptosis of HUVEC cells co-cultured with TcpC(wt) for 24 h significantly increased,compared to that of control group and TcpC(mut) group (60.1% 9.7% compared with 9.0% 1.3% and 16.9% 0.4%,respectively, P<0.05); meanwhile the mitochondrial depolarization of HUVECs co-cultured with TcpC(wt) was significantly increased,compared to that in control and TcpC(mut) groups (64.5% 0.9% compared with 14.5% 2.1% and 15.6% 3.3%, respectively,P<0.05). Cleavage of PARP and inhibition of Mcl-1 and XIAP expression were seen in HUVECs co-cultured with TcpC(wt),but not in groups of control and TcpC(mut). CONCLUSION: TcpC secreted from CFT073 can induce apoptosis of HUVECs through mitochondrial pathway, in which PARP is cleaved and Mcl-1 and XIAP expressions are inhibited.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Escherichia coli/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/patologia , Fatores de Virulência/farmacologia , Células Cultivadas , Escherichia coli/metabolismo , Humanos , Potencial da Membrana Mitocondrial , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
17.
Nat Commun ; 14(1): 1732, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36977669

RESUMO

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.


Assuntos
Predisposição Genética para Doença , Cirrose Hepática Biliar , Humanos , Estudo de Associação Genômica Ampla , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/patologia , Genótipo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética
18.
Clin Liver Dis ; 26(4): 583-611, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36270718

RESUMO

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.


Assuntos
Colangite , Cirrose Hepática Biliar , Feminino , Humanos , Cirrose Hepática Biliar/metabolismo , Ductos Biliares , Bicarbonatos/metabolismo , Anticorpos Antinucleares , Ácidos e Sais Biliares/metabolismo , Proteínas de Membrana Transportadoras/metabolismo
19.
Front Immunol ; 13: 1076594, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36591302

RESUMO

Background and aims: Tetraspanin proteins are closely related to the functional changes of B cells, including antigen presentation, production of cytokines, and transduction. We aim to explore the potential role of Tetraspanin 1 (TSPAN1) in the biological activities of B cells in AIH. Methods and results: Herein, this study found that numbers of cells expressing TSPAN1 were significantly increased in AIH patients compared to PBC, chronic hepatitis B, and healthy control (P < 0.0001). Moreover, there was a positive correlation between numbers of TSPAN1+ cells and AIH disease severity (P < 0.0001). Immunofluorescence staining further confirmed that TSPAN1 was primarily expressed on CD19+ B cells. Flow-cytometric analysis showed that TSPAN1+ B cells secreted more inflammatory cytokines and expressed higher level of CD86 than TSPAN1- B cells. Furthermore, compared with TSAPN1- cells, the expression of CXCR3 on TSPAN1+ cells was also higher. Meanwhile, CXCL10, the ligand of CXCR3, was significantly elevated in the liver of AIH (P < 0.01) and had positive correlation with the quantities of TSPAN1 (P < 0.05). Interestingly, the numbers of TSPAN1+ B cells were decreased in AIH patients after immunosuppressive therapy. Conclusions: TSPAN1+ B cells in the liver may promote the progression of AIH via secreting cytokines and presenting antigens. The chemotactic movement of TSPAN1+ B cells toward the liver of AIH was possibly due to CXCR3 - CXCL10 interaction.


Assuntos
Linfócitos B , Hepatite Autoimune , Humanos , Linfócitos B/imunologia , Citocinas , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Tetraspaninas/genética , Tetraspaninas/imunologia
20.
Hepatol Commun ; 6(5): 1016-1031, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34894107

RESUMO

Autoimmune hepatitis (AIH) is an inflammatory liver disease driven by the hyperactivation of various intrahepatic antigen-specific T cells due to a breach of immune tolerance. Studies in immunometabolism demonstrate that activated T cells harbor increased levels of reactive oxygen species that cause oxidative DNA damage. In this study, we assessed the potential of DNA damage repair enzyme MutT homolog 1 (MTH1) as a therapeutic target in AIH and karonudib as a novel drug for patients with AIH. We report herein that MTH1 expression was significantly increased in liver samples from patients with AIH compared to patients with chronic hepatitis B and nonalcoholic fatty liver disease and from healthy controls. In addition, the expression of MTH1 was positively correlated with AIH disease severity. We further found abundant T cells that expressed MTH1 in AIH. Next, we found that karonudib significantly altered T-cell receptor signaling in human T cells and robustly inhibited proliferation of human T cells in vitro. Interestingly, our data reflected a preferential inhibition of DNA damage repair in activated T cells by karonudib. Moreover, MTH1 was required to develop liver inflammation and damage because specific deletion of MTH1 in T cells ameliorated liver injury in the concanavalin A (Con A)-induced hepatitis model by inhibiting T-cell activation and proliferation. Lastly, we validated the protective effect of karonudib on the Con A-induced hepatitis model. Conclusion: MTH1 functions as a critical regulator in the development of AIH, and its inhibition in activated T cells reduces liver inflammation and damage.


Assuntos
Hepatite Autoimune , Concanavalina A/farmacologia , Dano ao DNA , Reparo do DNA , Hepatite Autoimune/tratamento farmacológico , Humanos , Inflamação/induzido quimicamente , Monoéster Fosfórico Hidrolases , Pirimidinas , Linfócitos T/metabolismo
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