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1.
Cell ; 180(1): 107-121.e17, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31866069

RESUMO

Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-ß signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis.


Assuntos
Células-Tronco Adultas/metabolismo , Fibrose Pulmonar Idiopática/etiologia , Alvéolos Pulmonares/metabolismo , Células-Tronco Adultas/patologia , Idoso , Células Epiteliais Alveolares/patologia , Animais , Fenômenos Biomecânicos/fisiologia , Feminino , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Alvéolos Pulmonares/patologia , Regeneração , Transdução de Sinais , Células-Tronco/patologia , Estresse Mecânico , Estresse Fisiológico/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo
3.
J Neurosci ; 44(37)2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39134421

RESUMO

Although the locus ceruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (LC-NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential and single-unit activity in multiple cortical regions associated with auditory-motor processing, including the auditory cortex, posterior parietal cortex, secondary motor cortex, anterior cingulate cortex, prefrontal cortex, and orbitofrontal cortex (OFC), in response to optogenetic activation (40 Hz and 0.5 s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillation (50-80 Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in norepinephrine levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a go/no-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing.


Assuntos
Percepção Auditiva , Discriminação Psicológica , Locus Cerúleo , Optogenética , Animais , Locus Cerúleo/fisiologia , Camundongos , Masculino , Percepção Auditiva/fisiologia , Discriminação Psicológica/fisiologia , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Estimulação Acústica/métodos , Ritmo Gama/fisiologia , Neurônios/fisiologia , Córtex Cerebral/fisiologia
4.
Circulation ; 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38214194

RESUMO

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

5.
PLoS Genet ; 18(12): e1010515, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36459518

RESUMO

Millions of patients suffer from silicosis, but it remains an uncurable disease due to its unclear pathogenic mechanisms. Though the Nlrp3 inflammasome is involved in silicosis pathogenesis, inhibition of its classic downstream factors, Caspase-1 and Gsdmd, fails to block pyroptosis and cytokine release. To clarify the molecular mechanism of silicosis pathogenesis for new therapy, we examined samples from silicosis patients and genetic mouse models. We discovered an alternative pyroptotic pathway which requires cleavage of Gsdme by Caspases-3/8 in addition to Caspase-1/Gsdmd. Consistently, Gsdmd-/-Gsdme-/- mice showed markedly attenuated silicosis pathology, and Gsdmd-/-Gsdme-/- macrophages were resistant to silica-induced pyroptosis. Furthermore, we found that in addition to Caspase 1, Caspase-8 cleaved IL-1ß in silicosis, explaining why Caspase-1-/- mice also suffered from silicosis. Finally, we found that inhibitors of Caspase-1, -3, -8 or an FDA approved drug, dimethyl fumarate, could dramatically alleviate silicosis pathology through blocking cleavage of Gsdmd and Gsdme. This study highlights that Caspase-1/Gsdmd and Caspase-3/8/Gsdme-dependent pyroptosis is essential for the development of silicosis, implicating new potential targets and drug for silicosis treatment.


Assuntos
Silicose , Camundongos , Animais , Caspase 8 , Caspase 1/genética , Caspase 3/genética , Silicose/tratamento farmacológico , Silicose/genética , Piroptose/genética
6.
Am J Respir Cell Mol Biol ; 70(3): 178-192, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38029327

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática , Animais , Humanos , Camundongos , Bleomicina , Matriz Extracelular , Fibroblastos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Proteínas de Membrana/genética , Camundongos Knockout , Regulação para Cima
7.
J Cell Mol Med ; 28(14): e18532, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39039705

RESUMO

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA-seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post-UL. Through trans-target prediction analysis integrating differentially co-expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA-mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT-qPCR. Our RNA-seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co-expression network analysis (WGCNA), we identified 11 co-expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4- and 14-days post-UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT-qPCR results corroborated the RNA-seq data, validating our findings. This study offers novel insights into the lncRNA-mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context.


Assuntos
Perfilação da Expressão Gênica , Redes Reguladoras de Genes , RNA Longo não Codificante , RNA Mensageiro , Núcleos Vestibulares , Vestíbulo do Labirinto , Animais , Núcleos Vestibulares/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Masculino , Vestíbulo do Labirinto/cirurgia , Vestíbulo do Labirinto/metabolismo , Regulação da Expressão Gênica , Ratos Sprague-Dawley , Transcriptoma/genética
8.
Mol Cancer ; 23(1): 148, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39048965

RESUMO

Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.


Assuntos
Enzimas Desubiquitinantes , Neoplasias , Complexo de Endopeptidases do Proteassoma , Ubiquitinação , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Enzimas Desubiquitinantes/metabolismo , Proteólise , Ubiquitina/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Processamento de Proteína Pós-Traducional , Terapia de Alvo Molecular , Ubiquitina-Proteína Ligases/metabolismo
9.
Plant Cell Physiol ; 65(2): 199-215, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-37951591

RESUMO

Previous studies on the intricate interactions between plants and microorganisms have revealed that fungal volatile compounds (VCs) can affect plant growth and development. However, the precise mechanisms underlying these actions remain to be delineated. In this study, we discovered that VCs from the soilborne fungus Tolypocladium inflatum GT22 enhance the growth of Arabidopsis. Remarkably, priming Arabidopsis with GT22 VCs caused the plant to display an enhanced immune response and mitigated the detrimental effects of both pathogenic infections and copper stress. Transcriptomic analyses of Arabidopsis seedlings treated with GT22 VCs for 3, 24 and 48 h revealed that 90, 83 and 137 genes were differentially expressed, respectively. The responsive genes are known to be involved in growth, hormone regulation, defense mechanisms and signaling pathways. Furthermore, we observed the induction of genes related to innate immunity, hypoxia, salicylic acid biosynthesis and camalexin biosynthesis by GT22 VCs. Among the VCs emitted by GT22, exposure of Arabidopsis seedlings to limonene promoted plant growth and attenuated copper stress. Thus, limonene appears to be a key mediator of the interaction between GT22 and plants. Overall, our findings provide evidence that fungal VCs can promote plant growth and enhance both biotic and abiotic tolerance. As such, our study suggests that exposure of seedlings to T. inflatum GT22 VCs may be a means of improving crop productivity. This study describes a beneficial interaction between T. inflatun GT22 and Arabidopsis. Our investigation of microorganism function in terms of VC activities allowed us to overcome the limitations of traditional microbial application methods. The importance of this study lies in the discovery of T. inflatun GT22 as a beneficial microorganism. This soilborne fungus emits VCs with plant growth-promoting effects and the ability to alleviate both copper and pathogenic stress. Furthermore, our study offers a valuable approach to tracking the activities of fungal VC components via transcriptomic analysis and sheds light on the mechanisms through which VCs promote plant growth and induce resistance. This research significantly advances our knowledge of VC applications and provides an example for further investigations within this field.


Assuntos
Arabidopsis , Hypocreales , Arabidopsis/genética , Cobre/farmacologia , Cobre/metabolismo , Limoneno/metabolismo , Limoneno/farmacologia , Hypocreales/metabolismo , Plantas/metabolismo , Plântula/metabolismo , Regulação da Expressão Gênica de Plantas
10.
BMC Med ; 22(1): 226, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840198

RESUMO

BACKGROUND: Previous studies have linked adolescent motherhood to adverse neurodevelopmental outcomes in offspring, yet the sex-specific effect and underlying mechanisms remain unclear. METHODS: This study included 6952 children aged 9-11 from the Adolescent Brain Cognitive Development study. The exposed group consisted of children of mothers < 20 years at the time of birth, while the unexposed group was composed of children of mothers aged 20-35 at birth. We employed a generalized linear mixed model to investigate the associations of adolescent motherhood with cognitive, behavioral, and autistic-like traits in offspring. We applied an inverse-probability-weighted marginal structural model to examine the potential mediating factors including adverse perinatal outcomes, family conflict, and brain structure alterations. RESULTS: Our results revealed that children of adolescent mothers had significantly lower cognitive scores (ß, - 2.11, 95% CI, - 2.90 to - 1.31), increased externalizing problems in male offspring (mean ratio, 1.28, 95% CI, 1.08 to 1.52), and elevated internalizing problems (mean ratio, 1.14, 95% CI, 0.99 to 1.33) and autistic-like traits (mean ratio, 1.22, 95% CI, 1.01 to 1.47) in female. A stressful family environment mediated ~ 70% of the association with internalizing problems in females, ~ 30% with autistic-like traits in females, and ~ 20% with externalizing problems in males. Despite observable brain morphometric changes related to adolescent motherhood, these did not act as mediating factors in our analysis, after adjusting for family environment. No elevated rate of adverse perinatal outcomes was observed in the offspring of adolescent mothers in this study. CONCLUSIONS: Our results reveal distinct sex-specific neurodevelopmental outcomes impacts of being born to adolescent mothers, with a substantial mediating effect of family environment on behavioral outcomes. These findings highlight the importance of developing sex-tailored interventions and support the hypothesis that family environment significantly impacts the neurodevelopmental consequences of adolescent motherhood.


Assuntos
Transtorno Autístico , Encéfalo , Cognição , Comportamento Problema , Humanos , Feminino , Masculino , Criança , Encéfalo/crescimento & desenvolvimento , Adolescente , Cognição/fisiologia , Conflito Familiar , Mães , Adulto , Gravidez , Adulto Jovem , Gravidez na Adolescência , Fatores Sexuais
11.
Small ; 20(30): e2312168, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38377284

RESUMO

Hydroxides are the archetype of layered crystals with metal-oxygen (M-O) octahedron units, which have been widely investigated as oxygen evolution reaction (OER) catalysts. However, the better crystallinity of hydroxide materials, the more perfect octahedral symmetry and atomic ordering, resulting in the less exposed metal sites and limited electrocatalytic activity. Herein, a glassy state hydroxide material featuring with short-range order and long-range disorder structure is developed to achieve high intrinsic activity for OER. Specifically, a rapid freezing point precipitation method is utilized to fabricate amorphous multi-component hydroxide. Owing to the freezing-point crystallization environment and chaotic M-O (M = Ni/Fe/Co/Mn/Cr etc.) structures, the as-fabricated NiFeCoMnCr hydroxide exhibit a highly-disordered glassy structure, as-confirmed by X-ray/electron diffraction, enthalpic response, and pair distribution function analysis. The as-achieved glassy-state hydroxide materials display a low OER overpotential of 269 mV at 20 mA cm-2 with a small Tafel slope of 33.3 mV dec-1, outperform the benchmark noble-metal RuO2 catalyst (341 mV, 84.9 mV dec-1) . Operando Raman and density functional theory studies reveal that the glassy state hydroxide converted into disordered active oxyhydroxide phase with optimized oxygen intermediates adsorption under low OER overpotentials, thus boosting the intrinsic electrocatalytic activity.

12.
Small ; : e2407178, 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39434470

RESUMO

With the rapid advancements in wireless communication and radar detection technologies, there has been a significant uptick in the utilization frequency of electromagnetic waves across both civilian and military sectors, consequently generating substantial electromagnetic radiation and interference. These electromagnetic pollutants present a considerable threat to public health and information security. Consequently, materials capable of absorbing and mitigating electromagnetic pollution have garnered significant attention. The nanomaterials with multiple components and various heterogeneous interfaces have been considered as preferred efficient electromagnetic wave (EMW) absorbers. In this work, carbon nanofibers doped with magnetic metal oxide particles (Co/Ni-CNFs) are prepared by electrospinning and heat treatment. In these samples, the minimum reflection loss can reach -40.13 dB at 4.6 mm, and the widest effective absorption bandwidth is 4.4 GHz. The excellent microwave absorption is attributed to the appropriate impedance matching. The electromagnetic parameters of Co/Ni-CNFs are balanced by adjusting the concentration of magnetic metal-organic framework material (MOFs) in the precursor solution. It is believed that this work can provide a reference for developing lightweight, flexible, and robust electromagnetic wave-absorbing materials.

13.
Respir Res ; 25(1): 326, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39210401

RESUMO

OBJECTIVES: In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH). METHODS: Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH. RESULTS: The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression. CONCLUSIONS: NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.


Assuntos
Enzima de Conversão de Angiotensina 2 , Ubiquitina-Proteína Ligases Nedd4 , Hipertensão Arterial Pulmonar , Ubiquitinação , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/biossíntese , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ubiquitina-Proteína Ligases Nedd4/genética , Humanos , Células Cultivadas , Masculino , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/enzimologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Animais , Proliferação de Células/fisiologia , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/biossíntese , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/enzimologia , Feminino , Ratos , Ratos Sprague-Dawley
14.
Respir Res ; 25(1): 362, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39369217

RESUMO

BACKGROUND: The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression. METHODS: Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells. RESULTS: Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-ß1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts. CONCLUSIONS: Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Progressão da Doença , Fibrose Pulmonar Idiopática , Neoplasias Pulmonares , Osteopontina , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Camundongos , Osteopontina/metabolismo , Osteopontina/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia , Camundongos Endogâmicos C57BL , Masculino
15.
Psychol Med ; 54(6): 1102-1112, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37997447

RESUMO

BACKGROUND: COVID-19 lockdowns increased the risk of mental health problems, especially for children with autism spectrum disorder (ASD). However, despite its importance, little is known about the protective factors for ASD children during the lockdowns. METHODS: Based on the Shanghai Autism Early Developmental Cohort, 188 ASD children with two visits before and after the strict Omicron lockdown were included; 85 children were lockdown-free, while 52 and 51 children were under the longer and the shorter durations of strict lockdown, respectively. We tested the association of the lockdown group with the clinical improvement and also the modulation effects of parent/family-related factors on this association by linear regression/mixed-effect models. Within the social brain structures, we examined the voxel-wise interaction between the grey matter volume and the identified modulation effects. RESULTS: Compared with the lockdown-free group, the ASD children experienced the longer duration of strict lockdown had less clinical improvement (ß = 0.49, 95% confidence interval (CI) [0.19-0.79], p = 0.001) and this difference was greatest for social cognition (2.62 [0.94-4.30], p = 0.002). We found that this association was modulated by parental agreeableness in a protective way (-0.11 [-0.17 to -0.05], p = 0.002). This protective effect was enhanced in the ASD children with larger grey matter volumes in the brain's mentalizing network, including the temporal pole, the medial superior frontal gyrus, and the superior temporal gyrus. CONCLUSIONS: This longitudinal neuroimaging cohort study identified that the parental agreeableness interacting with the ASD children's social brain development reduced the negative impact on clinical symptoms during the strict lockdown.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , COVID-19 , Criança , Humanos , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Estudos de Coortes , Fatores de Proteção , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis , China/epidemiologia
16.
Cereb Cortex ; 33(11): 6742-6760, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-36757182

RESUMO

Auditory gating (AG) is an adaptive mechanism for filtering out redundant acoustic stimuli to protect the brain against information overload. AG deficits have been found in many mental illnesses, including schizophrenia (SZ). However, the neural correlates of AG remain poorly understood. Here, we found that the posterior parietal cortex (PPC) shows an intermediate level of AG in auditory thalamocortical circuits, with a laminar profile in which the strongest AG is in the granular layer. Furthermore, AG of the PPC was decreased and increased by optogenetic inactivation of the medial dorsal thalamic nucleus (MD) and auditory cortex (AC), respectively. Optogenetically activating the axons from the MD and AC drove neural activities in the PPC without an obvious AG. These results indicated that AG in the PPC is determined by the integrated signal streams from the MD and AC in a bottom-up manner. We also found that a mouse model of SZ (postnatal administration of noncompetitive N-methyl-d-aspartate receptor antagonist) presented an AG deficit in the PPC, which may be inherited from the dysfunction of MD. Together, our findings reveal a neural circuit underlying the generation of AG in the PPC and its involvement in the AG deficit of SZ.


Assuntos
Córtex Auditivo , Vigília , Camundongos , Animais , Lobo Parietal/fisiologia , Tálamo , Núcleo Mediodorsal do Tálamo , Encéfalo , Córtex Auditivo/fisiologia
17.
Environ Res ; 261: 119692, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39068968

RESUMO

BACKGROUND: Dyslipidemia is increasingly recognized as an essential risk factor for cardiovascular diseases. However, few studies illustrated the effects of ambient temperature exposure (TE) on lipid levels in children. The study aimed to examine the association between ambient TE and lipid levels in children. METHODS: Based on a prospective cohort, a total of 2423 children (with 4466 lipids measure person-time) were collected from 2014 to 2019. The meteorological observation data and adjusted variables were collected. Mixed-effect models and generalized additive mixed model (GAMM) were applied to investigate the association between ambient TE and lipid levels. RESULTS: A significant negative association was observed between TE and low-density lipoprotein cholesterol (LDL-C) or total cholesterol (TC) levels both in all children [LDL-C, ß(95%CI) = -0.350(-0.434,-0.265), P < 0.001; TC, ß(95%CI) = -0.274(-0.389,-0.160), P < 0.001] and by different sex group. However, no significant association was found in low-density lipoprotein cholesterol (HDL-C) or triglycerides (TG) levels. The estimated optimal ambient TEs for LDL-C were 18.273 °C and 18.024 °C for girls and boys, respectively. For TC, the optimal ambient TEs were 17.949 °C and 18.024 °C, respectively. With ambient TE decreased, the risk of dyslipidemia increased for both boys [OR = 0.032(0.006,0.179), P < 0.001] and girls [OR = 0.582(0.576,0.587), P < 0.001]. CONCLUSION: This study provided a comprehensive illustration about the associations between ambient TE and lipid levels in different sex and ages from a prospective cohort study. The findings will provide evidence for the government to prevent dyslipidemia in vulnerable children through regulating TE.


Assuntos
Metabolismo dos Lipídeos , Temperatura , Humanos , Criança , Feminino , Masculino , Estudos Prospectivos , Pré-Escolar , Dislipidemias/epidemiologia , Adolescente , Triglicerídeos/sangue , Colesterol/sangue , LDL-Colesterol/sangue , Lipídeos/sangue , China
18.
Lipids Health Dis ; 23(1): 98, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570797

RESUMO

Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.


Assuntos
Fibrose Pulmonar , Humanos , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Análise da Expressão Gênica de Célula Única , Metabolismo dos Lipídeos/genética , Células Endoteliais/metabolismo , Fosfolipídeos/metabolismo , Colesterol/metabolismo , Fosfatidilcolinas
19.
Am J Respir Crit Care Med ; 207(2): 160-172, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35984444

RESUMO

Rationale: Sustained activation of lung fibroblasts and the resulting oversynthesis of the extracellular matrix are detrimental events for patients with interstitial lung diseases (ILDs). Lung biopsy is a primary evaluation technique for the fibrotic status of ILDs, and is also a major risk factor for triggering acute deterioration. Fibroblast activation protein (FAP) is a long-known surface biomarker of activated fibroblasts, but its expression pattern and diagnostic implications in ILDs are poorly defined. Objectives: The present study aims to comprehensively investigate whether the expression intensity of FAP could be used as a potential readout to estimate or measure the amounts of activated fibroblasts in ILD lungs quantitatively. Methods: FAP expression in human primary lung fibroblasts as well as in clinical lung specimens was first tested using multiple experimental methods, including real-time quantitative PCR (qPCR), Western blot, immunofluorescence staining, deep learning measurement of whole slide immunohistochemistry, as well as single-cell sequencing. In addition, FAP-targeted positron emission tomography/computed tomography imaging PET/CT was applied to various types of patients with ILD, and the correlation between the uptake of FAP tracer and pulmonary function parameters was analyzed. Measurements and Main Results: Here, it was revealed, for the first time, FAP expression was upregulated significantly in the early phase of lung fibroblast activation event in response to a low dose of profibrotic cytokine. Single-cell sequencing data further indicate that nearly all FAP-positive cells in ILD lungs were collagen-producing fibroblasts. Immunohistochemical analysis validated that FAP expression level was closely correlated with the abundance of fibroblastic foci on human lung biopsy sections from patients with ILDs. We found that the total standard uptake value (SUV) of FAP inhibitor (FAPI) PET (SUVtotal) was significantly related to lung function decline in patients with ILD. Conclusions: Our results strongly support that in vitro and in vivo detection of FAP can assess the profibrotic activity of ILDs, which may aid in early diagnosis and the selection of an appropriate therapeutic window.


Assuntos
Doenças Pulmonares Intersticiais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Fibrose , Fibroblastos/metabolismo
20.
BMC Pulm Med ; 24(1): 410, 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39187801

RESUMO

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension with a low incidence. Despite pulmonary endarterectomy(PEA) being the preferred treatment for CTEPH, for patients who failed medical therapy and who are not suitable candidates for PEA, lung transplantation (LT) is still the only effective treatment for end-stage CTEPH; however, there are currently very few reports on the efficacy of LT for CTEPH. METHODS: We retrospectively analyzed the clinical data of seven patients diagnosed with CTEPH between July 2019 and July 2021. The follow-up deadline was March, 2022. RESULTS: The mean age at admission was 54 ± 12 years. The average value of mean pulmonary artery pressure (mPAP) was 40 ± 5 mmHg. The mean preoperative oxygenation index(PaO2/FiO2) was 203 ± 56 mm Hg. After evaluation, one patient underwent left LT and the rest underwent bilateral LT. Three patients received intraoperative veno-venous extracorporeal membrane oxygenation (ECMO) support, and four patients received intraoperative veno-arterial ECMO support. The average postoperative mPAP was 19 ± 4 mmHg. The mean postoperative oxygenation index(PaO2/FiO2) was 388 ± 83 mmHg. There was a significant difference between the preoperative and postoperative mPAP and oxygenation index(PaO2/FiO2). All patients recovered well and were discharged 37 ± 19 days postoperatively. The mean follow-up duration was 19 ± 8 months. There was no recurrence of CTEPH. CONCLUSIONS: LT is an effective treatment for end-stage CTEPH, which can improve cardiopulmonary function and quality of life and prolong survival. Patients who are unable to tolerate PEA should be considered for LT as early as possible when internal medicine failed.


Assuntos
Hipertensão Pulmonar , Transplante de Pulmão , Embolia Pulmonar , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Estudos Retrospectivos , Hipertensão Pulmonar/cirurgia , Embolia Pulmonar/cirurgia , Embolia Pulmonar/complicações , Adulto , Doença Crônica , Resultado do Tratamento , Oxigenação por Membrana Extracorpórea/métodos , Idoso , Endarterectomia/métodos
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