RESUMO
Hematopoietic stem and progenitor cells generate all the lineages of blood cells throughout the lifespan of vertebrates. The emergence of hematopoietic stem and progenitor cells is finely tuned by a variety of signaling pathways. Previous studies have revealed the roles of pattern-recognition receptors such as Toll-like receptors and RIG-I-like receptors in hematopoiesis. In this study, we find that Nlrc3, a nucleotide-binding domain leucine-rich repeat containing family gene, is highly expressed in hematopoietic differentiation stages in vivo and vitro and is required in hematopoiesis in zebrafish. Mechanistically, nlrc3 activates the Notch pathway and the downstream gene of Notch hey1. Furthermore, NF-kB signaling acts upstream of nlrc3 to enhance its transcriptional activity. Finally, we find that Nlrc3 signaling is conserved in the regulation of murine embryonic hematopoiesis. Taken together, our findings uncover an indispensable role of Nlrc3 signaling in hematopoietic stem and progenitor cell emergence and provide insights into inflammation-related hematopoietic ontogeny and the in vitro expansion of hematopoietic stem and progenitor cells.
Assuntos
Células-Tronco Hematopoéticas , Peixe-Zebra , Animais , Camundongos , Diferenciação Celular/genética , Células-Tronco Hematopoéticas/metabolismo , Hematopoese/genética , Transdução de Sinais , Receptores Notch/metabolismoRESUMO
Growing evidence suggests that highly intestinal microbiota diversity modulates host inflammation and promotes immune tolerance. Several studies have reported that patients undergoing allo-HSCT have experienced microbiota disruption that is characterized by expansion of potentially pathogenic bacteria and loss of microbiota diversity. Thus, the primary aim of this meta-analysis was to determine the association of intestinal microbiota diversity and outcomes after allo-HSCT, and the secondary aim was to analyze the associations of some specific microbiota abundances with the outcomes of allo-HSCT. Electronic databases of Pubmed, Embase, Web of Science, and Cochrane Library were searched from inception to August 2023, and 17 studies were found eligible. The pooled estimate suggested that higher intestinal microbiota diversity was significantly associated with overall survival (OS) benefit (HR = 0.66, 95% CI: 0.55-0.78), as well as decreased risk of transplant-related mortality (HR = 0.56, 95% CI: 0.41-0.76), and lower incidence of grade II-IV aGVHD (HR = 0.41, 95% CI: 0.27-0.63). Furthermore, higher abundance of Clostridiales was associated with a superior OS (HR = 0.40, 95% CI: 0.18-0.87), while higher abundance of Enterococcus (HR = 2.03, 95% CI: 1.55-2.65), γ-proteobacteria (HR = 2.82, 95% CI: 1.53-5.20), and Candida (HR = 3.80, 95% CI: 1.32-10.94) was an adverse prognostic factor for OS. Overall, this meta-analysis highlights the protective role of higher intestinal microbiota diversity on outcomes after allo-HSCT during both pre-transplant and post-transplant periods. Some specific microbiota can be useful in the identification of patients at risk of mortality, offering new tools for individualized pre-emptive or therapeutic strategies to improve allo-HSCT outcomes.
Assuntos
Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microbiota , Humanos , Recidiva Local de Neoplasia/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Bactérias , Doença Enxerto-Hospedeiro/etiologiaRESUMO
The pathogenesis of donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear and likely multifactorial. Leukemic transformation of healthy donor HSCs in recipient's bone marrow microenvironment provides a useful in vivo model for investigating the mechanisms involved in leukemogenesis. Here, we report a rare case of late-onset DCL developing in a recipient. Whole-genome sequencing indicates that donor-derived cells harboring clonal hematopoiesis of indeterminate potential (CHIP)-associated genetic alterations expand and eventually transform to full-blown AML via acquisition of additional somatic mutations within the recipient's bone marrow microenvironment. The 10× single-cell RNA sequencing reveals the abundance of GMP-like cells with a specific transcriptional signature in DCL. Moreover, impaired immune surveillance, including dysfunction of cytotoxic T lymphocytes (CTLs) and decreased number of canonical NK cells, is discovered in DCL. Our data add valuable information to the current understanding of the mechanisms of DCL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia/genética , Genômica , Evolução Clonal/genética , Perfilação da Expressão Gênica , Microambiente TumoralRESUMO
Foreign body ingestion is a common problem among elderly patients and can pose a serious health risk, particularly for those with communication barriers, cognitive impairments, or obscure medical histories. This report presents the case of a 67-year-old female inpatient who had a language communication barrier and accidentally ingested a blister pack. Effective communication was facilitated through an interpreter, and prompt endoscopic intervention was conducted to remove the foreign body safely. The patient was discharged with no further symptoms during follow-up. This case highlights the importance of prompt evaluation and intervention for foreign body ingestion in elderly patients, particularly those with communication barriers.
RESUMO
YPEL5 is a member of the Yippee-like (YPEL) gene family that is evolutionarily conserved in eukaryotic species. To date, the physiological function of YPEL5 has not been assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line. Disruption of ypel5 expression leads to liver enlargement associated with hepatic cell proliferation. Meanwhile, hepatic metabolism and function are dysregulated in ypel5-/- mutant zebrafish, as revealed by metabolomic and transcriptomic analyses. Mechanistically, Hnf4a is identified as a crucial downstream mediator that is positively regulated by Ypel5. Zebrafish hnf4a overexpression could largely rescue ypel5 deficiency-induced hepatic defects. Furthermore, PPARα signaling mediates the regulation of Hnf4a by Ypel5 through directly binding to the transcriptional enhancer of the Hnf4a gene. Herein, this work demonstrates an essential role of Ypel5 in hepatocyte proliferation and function and provides the first in vivo evidence for a physiological role of the ypel5 gene in vertebrates.
RESUMO
The human ζ-globin gene (HBZ) is transcribed in primitive erythroid cells only during the embryonic stages of development. Reactivation of this embryonic globin synthesis would likely alleviate symptoms both in α-thalassemia and sickle-cell disease. However, the molecular mechanisms controlling ζ-globin expression have remained largely undefined. Moreover, the pharmacologic agent capable of inducing ζ-globin production is currently unavailable. Here, we show that TRIAC, a bioactive thyroid hormone metabolite, significantly induced ζ-globin gene expression during zebrafish embryogenesis. The induction of ζ-globin expression by TRIAC was also observed in human K562 erythroleukemia cell line and primary erythroid cells. Thyroid hormone receptor α (THRA) deficiency abolished the ζ-globin-inducing effect of TRIAC. Furthermore, THRA could directly bind to the distal enhancer regulatory element to regulate ζ-globin expression. Our study provides the first evidence that TRIAC acts as a potent inducer of ζ-globin expression, which might serve as a new potential therapeutic option for patients with severe α-thalassemia or sickle-cell disease.
Assuntos
Expressão Gênica/efeitos dos fármacos , Receptores alfa dos Hormônios Tireóideos/genética , Tri-Iodotironina/análogos & derivados , Regulação para Cima/efeitos dos fármacos , Globinas zeta/genética , Animais , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Células K562 , Receptores alfa dos Hormônios Tireóideos/deficiência , Tri-Iodotironina/farmacologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Acute lung injury (ALI) is a life-threatening medical condition with higher mortality and morbidity in elderly patients. Recently, metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, has been shown to be an effective anti-inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In our study, we found that epithelial cell senescence was elevated after lipopolysaccharide (LPS) exposure in vivo and in vitro, accompanied by decreased expression of ATG5 and impaired autophagy activity. To further discover the molecular regulation mechanism between cellular senescence and autophagy in LPS-treated MLE-12 cells, we demonstrated that inhibition of ATG5 could decrease autophagy levels and promote the senescence of MLE-12 cells. On the contrary, elevating the expression of ATG5 could effectively suppress LPS-induced cellular senescence via enhancing autophagy activity. In addition, we demonstrated that metformin could protect MLE-12 cells from LPS-induced senescence via increasing the expression of ATG5 and augmenting autophagy activity. Our data implicate that activation of autophagy by metformin may provide a preventive and therapeutic strategy for ALI.
Assuntos
Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Metformina/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Autofagia/fisiologia , Proteína 5 Relacionada à Autofagia/antagonistas & inibidores , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular , Senescência Celular/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Masculino , Metformina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Kawasaki disease (KD) is the leading cause of acquired heart disease in children, and is steadily increasing in prevalence in East Asia. KD is often complicated by coronary artery damage, including dilatation and/or aneurysms. Aspirin is used with intravenous immunoglobulin (IVIG) to prevent coronary artery abnormalities in KD. However, the role and optimal dose of aspirin remain controversial. Identifying the dose of aspirin in the acute phase will facilitate development of a more appropriate treatment strategy in improving the outcome of KD. METHODS: A total of 2369 patients with KD were retrospectively analyzed and divided into three groups according to the aspirin dose: 510 in group 1 (20-29 mg/kg/day), 1487 in group 2 (30-39 mg/kg/day), and 372 in group 3 (40-50 mg/kg/day). The differences in laboratory data, rate of IVIG resistance and coronary artery damage were compared among the groups. RESULTS: There was no difference in the incidence of coronary artery aneurysms (CAAs) in group 1 compared with groups 2 and 3 (2 weeks of illness: 2.94% vs. 1.90% vs. 3.36%; 3-4 weeks of illness: 1.94% vs. 2.32% vs. 2.65%). The risk for developing CAA was not reduced at 2 weeks of illness onset in groups 2 and 3 compared with group 1 (adjusted OR = 1.05, 95% confidence interval: 0.34-3.18; aOR = 1.81, 95% CI: 0.42-7.83). Furthermore, the risk for developing CAA was not reduced at 3-4 weeks of illness onset in groups 2 and 3 (aOR = 2.63, 95% CI: 0.61-11.28; aOR = 0.52, 95% CI: 0.03-9.54). There was no significant difference in the rate of IVIG resistance among the groups. Platelet levels after IVIG treatment in group 1 were significantly lower than those in groups 2 and 3 (522.29 × 109/L, 544.69 × 109/L, and 557.77 × 109/L, p = 0.013). C reactive protein of the 30-40 mg/kg*day group was slightly higher than the other two groups. (7.76, 8.00, and 7.01 mg/L, p = 0.028). CONCLUSIONS: Aspirin at the dose of 20-29 mg/kg/day dose not increase the risk of coronary artery damage and IVIG resistance compared with the dose of 30-50 mg/kg/day. This low dose may have a lower risk for a potential effect on liver function.
Assuntos
Aspirina/administração & dosagem , Aneurisma Coronário , Relação Dose-Resposta a Droga , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Aspirina/efeitos adversos , Pré-Escolar , China/epidemiologia , Aneurisma Coronário/diagnóstico , Aneurisma Coronário/epidemiologia , Aneurisma Coronário/etiologia , Aneurisma Coronário/prevenção & controle , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Our goal was to compare the clinical results and quality-of-life (QoL) in tongue cancer patients undergoing submental island pedicled (SIP) flap and radial forearm free (RFF) flap reconstruction. MATERIALS AND METHODS: Patients undergoing SIP or RFF flap reconstruction for primary tongue squamous cell carcinoma were prospectively enrolled and were asked to complete the University of Washington Quality-of-Life (UW-QOL) questionnaire, version 4, at 12 months after the operation. The study's main interest was QoL as well as locoregional recurrence control. RESULTS: A total of 190 patients were enrolled for analysis, and the SIP and RFF groups showed significant differences in patient age, American Society of Anesthesiologists classification, and hospital cost. In the survival analysis, locoregional recurrence occurred in 35 patients in the SIP group and 48 patients in the RFF group; the difference was not significant (P = .440). In the QoL analysis, compared with patients in the SIP group, those in the RFF group had higher scores in the domains of activity and recreation. No significant differences were found with respect to the other domains. CONCLUSIONS: The SIP flap and RFF flap have comparable survival control in tongue squamous cell carcinoma patients. The RFF flap might lead to better QoL, but the SIP flap imposes fewer limitations on patients' health status and is associated with lower hospital cost.
Assuntos
Retalhos de Tecido Biológico , Procedimentos de Cirurgia Plástica , Neoplasias da Língua , Antebraço/cirurgia , Humanos , Recidiva Local de Neoplasia , Qualidade de Vida , Neoplasias da Língua/cirurgiaRESUMO
SUMOylation, covalent conjugation of small ubiquitin-related modifier (SUMO), has been emerging as a critical posttranslational modification of developmental transcription factors, as well as key regulators in the adult heart. Identifying the SUMOylated targets within cardiac transcription factors will facilitate to unravel the roles of SUMOylation in heart development and disease. Here, we show that Gata6, an essential cardiac transcription factor, can be modified by SUMO in vivo. Mutation of potential SUMOylation sites reveals that a lysine residue at amino acid position 12 of Gata6 serves as the major attachment site for SUMO. Pias1, as an E3 SUMO ligase, preferentially enhances the conjugation of SUMO1 to Gata6 through its RING finger domain. Functional analyses with SUMOylation-deficient mutant indicate that SUMOylation does not affect the subcellular localization but instead represses Gata6 transcriptional activity. Our data suggest that posttranslational modification of Gata6 by SUMO conjugation provides a novel mechanism to regulate Gata6 activity.
Assuntos
Fator de Transcrição GATA6/metabolismo , Regulação da Expressão Gênica , Lisina/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação , Sequência de Aminoácidos , Animais , Fator de Transcrição GATA6/genética , Humanos , Lisina/genética , Homologia de Sequência , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Peixe-ZebraRESUMO
Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1ß, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1ß was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1ß and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.
Assuntos
Antígenos de Neoplasias/genética , Proteína HMGB1/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Síndrome de Linfonodos Mucocutâneos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/genética , Animais , Candida albicans/patogenicidade , Caspase 1/genética , Catepsinas/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Síndrome de Linfonodos Mucocutâneos/microbiologia , Síndrome de Linfonodos Mucocutâneos/patologia , Proteínas de Ligação a Fosfato/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genéticaRESUMO
Neuroinflammation is associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder characterized by a progressive loss of dopaminergic (DAergic) neurons within the substantia nigra. Transforming growth factor (TGF)-ß1 exerts anti-inflammatory and neuroprotective properties. However, it is unclear if microglia are required for TGF-ß1 neuroprotection in PD. Here we used both shRNA and pharmacologic inhibition to determine the role of microglial TGF-ß receptor (TßR)-I and its downstream signaling pathways in 1-methyl-4-phenylpyridinium (MPP(+))-induced DAergic neuronal toxicity. As expected, MPP(+) reduced the number of tyrosine hydroxylase (TH)-immunoreactive cells in ventral mesencephalic cell cultures. We found that MPP(+) activated microglia as determined by an upregulation in expression of CD11b and inducible nitric oxide synthase (iNOS), an increase in expression and secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, and a decrease in expression and secretion of the neurotrophic factor, insulin-like growth factor (IGF)-1. Pretreatment with TGF-ß1 significantly inhibited all these changes caused by MPP(+). Expression of microglial TßR-I was upregulated by TGF-ß1. Silencing of the TßR-I gene in microglia abolished both the neuroprotective and anti-inflammatory properties of TGF-ß1. TGF-ß1 increased microglial p38 MAPK and Akt phosphorylation, both of which were blocked by the p38 inhibitor SB203580 and the PI3K inhibitor LY294002, respectively. Pretreatment of microglia with either SB203580 or LY294002 impaired the ability of TGF-ß1 to inhibit MPP(+)-induced DAergic neuronal loss and microglial activation. These findings establish that TGF-ß1 activates TßR-I and its downstream p38 MAPK and PI3K-Akt signaling pathways in microglia to protect against DAergic neuronal loss that characterizes in PD.