RESUMEN

The cell-intrinsic mechanisms underlying the decision of a stem/progenitor cell to either proliferate or differentiate remain incompletely understood. Here, we identify the transmembrane protein Lrig1 as a physiological homeostatic regulator of FGF2-driven proliferation and self-renewal of neural progenitors at early-to-mid embryonic stages of cortical development. We show that Lrig1 is expressed in cortical progenitors (CPs), and its ablation caused expansion and increased proliferation of radial/apical progenitors and of neurogenic transit-amplifying Tbr2+ intermediate progenitors. Notably, our findings identify a previously unreported EGF-independent mechanism through which Lrig1 negatively regulates neural progenitor proliferation by modulating the FGF2-induced IL6/Jak2/Stat3 pathway, a molecular cascade that plays a pivotal role in the generation and maintenance of CPs. Consistently, Lrig1 knockout mice showed a significant increase in the density of pyramidal glutamatergic neurons placed in superficial layers 2 and 3 of the postnatal neocortex. Together, these results support a model in which Lrig1 regulates cortical neurogenesis by influencing the cycling activity of a set of progenitors that are temporally specified to produce upper layer glutamatergic neurons.

Asunto(s)

Janus Quinasa 2 , Glicoproteínas de Membrana , Ratones Noqueados , Células-Madre Neurales , Neurogénesis , Neuronas , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Janus Quinasa 2/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Ratones , Neurogénesis/genética , Neuronas/metabolismo , Neuronas/citología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Proliferación Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/embriología , Diferenciación Celular , Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas del Tejido Nervioso

RESUMEN

Alzheimer's disease is the most common form of dementia, characterized by the pathological accumulation of amyloid-beta (Aß) plaques and tau neurofibrillary tangles. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized as playing a central role in Aß clearance and microglia activation in AD. The TREM2 gene transcriptional product is alternatively spliced to produce three different protein isoforms. The canonical TREM2 isoform binds to DAP12 to activate downstream pathways. However, little is known about the function or interaction partners of the alternative TREM2 isoforms. The present study utilized a computational approach in a systematic search for new interaction partners of the TREM2 isoforms by integrating several state-of-the-art structural bioinformatics tools from initial large-scale screening to one-on-one corroborative modeling and eventual all-atom visualization. CD9, a cell surface glycoprotein involved in cell-cell adhesion and migration, was identified as a new interaction partner for two TREM2 isoforms, and CALM, a calcium-binding protein involved in calcium signaling, was identified as an interaction partner for a third TREM2 isoform, highlighting the potential role of cell adhesion and calcium regulation in AD.

Asunto(s)

Empalme Alternativo , Enfermedad de Alzheimer , Glicoproteínas de Membrana , Unión Proteica , Isoformas de Proteínas , Receptores Inmunológicos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Humanos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Biología Computacional/métodos

RESUMEN

Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.

Asunto(s)

Glioma , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Receptor trkB , Humanos , Femenino , Lactante , Pirazoles/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Receptor trkB/genética , Receptor trkB/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Fusión Oncogénica/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Clasificación del Tumor , Resultado del Tratamiento , Glicoproteínas de Membrana/genética

RESUMEN

The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been studied to advance the treatment of neurodegenerative disorders. Here, we explored the transplantation efficacy of different cell subsets and delivery routes with the goal of favoring the establishment of a stable and exclusive engraftment of HSPCs and their progeny in the CNS of female mice. In this setting, we show that the CNS environment drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype. Intra-CNS transplantation of HSPCs engineered to overexpress TREM2 decreased neuroinflammation, Aß aggregation and improved memory in 5xFAD female mice. Our proof of concept study demonstrates the therapeutic potential of HSPC gene therapy for Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Terapia Genética , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Ratones Transgénicos , Microglía , Animales , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Terapia Genética/métodos , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Ratones , Microglía/metabolismo , Células Madre Hematopoyéticas/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Péptidos beta-Amiloides/metabolismo , Diferenciación Celular , Humanos , Ratones Endogámicos C57BL

RESUMEN

Alzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Hipocampo , MicroARNs , Neuroglía , Neuronas , Animales , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Neuronas/metabolismo , Neuroglía/metabolismo , Hipocampo/metabolismo , Ratones Transgénicos , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Regulación de la Expresión Génica , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Corteza Prefrontal/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Masculino

RESUMEN

Background: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc = 0.017; 0.010, respectively) and total-tau (T-tau) (pc = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer , Biomarcadores , Glicoproteínas de Membrana , Receptores Inmunológicos , Proteínas Supresoras de Tumor , Proteínas tau , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Femenino , Proteínas Supresoras de Tumor/genética , Masculino , Anciano , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Anciano de 80 o más Años , Proteínas Nucleares

RESUMEN

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients' fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1, Nos1ap, and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism.

Asunto(s)

Diferenciación Celular , Glicoproteínas de Membrana , Proteínas de Microfilamentos , Osteogénesis , Pez Cebra , Pez Cebra/metabolismo , Pez Cebra/genética , Animales , Osteogénesis/genética , Humanos , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Fibroblastos/metabolismo , Osteoblastos/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Técnicas de Silenciamiento del Gen

RESUMEN

Rabies is a fatal neurological infectious disease caused by rabies virus (RABV), which invades the central nervous system (CNS). RABV with varying virulence regulates chemokine expression, and the mechanisms of signaling pathway activation remains to be elucidated. The relationship between Toll-like receptors (TLRs) and immune response induced by RABV has not been fully clarified. Here, we investigated the role of TLR7 in the immune response induced by RABV, and one-way analysis of variance (ANOVA) was employed to evaluate the data. We found that different RABV strains (SC16, HN10, CVS-11) significantly increased CCL2, CXCL10 and IL-6 production. Blocking assays indicated that the TLR7 inhibitor reduced the expression of CCL2, CXCL10 and IL-6 (p < 0.01). The activation of the Myd88 pathway in BV-2 cells stimulated by RABV was TLR7-dependent, whereas the inhibition of Myd88 activity reduced the expression of CCL2, CXCL10 and IL-6 (p < 0.01). Meanwhile, the RABV stimulation of BV-2 cells resulted in TRL7-mediated activation of NF-κB and induced the nuclear translocation of NF-κB p65. CCL2, CXCL10 and IL-6 release was attenuated by the specific NF-κB inhibitor used (p < 0.01). The findings above demonstrate that RABV-induced expression of CCL2, CXCL10 and IL-6 involves Myd88 and NF-κB pathways via the TLR7 signal.

Asunto(s)

Factor 88 de Diferenciación Mieloide , FN-kappa B , Virus de la Rabia , Transducción de Señal , Receptor Toll-Like 7 , Receptor Toll-Like 7/metabolismo , Animales , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Virus de la Rabia/patogenicidad , Virus de la Rabia/inmunología , Ratones , FN-kappa B/metabolismo , Línea Celular , Interleucina-6/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Rabia/virología , Rabia/metabolismo , Rabia/inmunología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Inflamación/metabolismo

RESUMEN

Epithelial membrane protein 3 (EMP3) belongs to the peripheral myelin protein 22 kDa (PMP22) gene family, characterized by four transmembrane domains and widespread expression across various human tissues and organs. Other members of the PMP22 family, including EMP1, EMP2, and PMP22, have been linked to various cancers, such as glioblastoma, laryngeal cancer, nasopharyngeal cancer, gastric cancer, breast cancer, and endometrial cancer. However, few studies report on the function and relevance of EMP3 in tumorigenicity. Given the significant structural similarities among members of the PMP22 family, there are likely potential functional similarities as well. Previous studies have established the regulatory role of EMP3 in immune cells like T cells and macrophages. Additionally, EMP3 is found to be involved in critical signaling pathways, including HER-2/PI3K/Akt, MAPK/ERK, and TGF-beta/Smad. Furthermore, EMP3 is associated with cell cycle regulation, cellular proliferation, and apoptosis. Hence, it is likely that EMP3 participates in cancer development through these aforementioned pathways and mechanisms. This review aims to systematically examine and summarize the structure and function of EMP3 and its association to various cancers. EMP3 is expected to emerge as a significant biological marker for tumor prognosis and a potential target in cancer therapeutics.

Asunto(s)

Biomarcadores de Tumor , Glicoproteínas de Membrana , Terapia Molecular Dirigida , Neoplasias , Humanos , Biomarcadores de Tumor/metabolismo , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/genética , Pronóstico , Terapia Molecular Dirigida/métodos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Transducción de Señal

RESUMEN

Dopamine (DA) D2 receptors (D2Rs) have 2 isoforms, a long form (D2L) and a short form (D2S). D2L is predominantly postsynaptic in the striatal medium spiny neurons and cholinergic interneurons. D2S is principally presynaptic autoreceptors in the nigrostriatal DA neurons. Recently, we demonstrated that L-3,4-dihydroxyphenylalanine (L-DOPA) augments D2L function through the coupling between D2L and GPR143, a receptor of L-DOPA that was originally identified as the gene product of ocular albinism 1. Here we show that GPR143 modifies the functions of D2L and D2S in an opposite manner. Haloperidol-induced catalepsy was attenuated in DA neuron-specific Gpr143 gene-deficient (Dat-cre;Gpr143flox/y) mice, compared with wild-type (Wt) mice. Haloperidol increased in vivo DA release from the dorsolateral striatum, and this increase was augmented in Gpr143-/y mice compared with Wt mice. A D2R agonist quinpirole-induced increase in the phosphorylation of GSK3ß(pGSK3ß(S9)) was enhanced in Chinese hamster ovary (CHO) cells coexpressing D2L and GPR143 compared with cells expressing D2L alone, while it was suppressed in cells coexpressing D2S and GPR143 compared with D2S alone, suggesting that GPR143 differentially modifies D2R functions depending on its isoforms of D2L and D2S.

Asunto(s)

Cricetulus , Dopamina , Haloperidol , Receptores de Dopamina D2 , Animales , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Haloperidol/farmacología , Células CHO , Dopamina/metabolismo , Cuerpo Estriado/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Ratones , Levodopa/farmacología , Catalepsia/inducido químicamente , Catalepsia/genética , Catalepsia/metabolismo , Ratones Endogámicos C57BL , Fosforilación , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Quinpirol/farmacología , Neuronas Dopaminérgicas/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo

RESUMEN

Retinal degeneration is a collection of devastating conditions with progressive loss of vision which often lead to blindness. Research on retinal microglial cells offers great therapeutic potential in deterring the progression of degeneration. This study explored the mechanisms underlying the TREM2-mediated protective function of activated microglial cells during retinal degeneration. N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was established in C57BL/6 J (WT) and Trem2 knockout (Trem2-/-) mice. We discovered that MNU treatment led to the concurrent processes of photoreceptor apoptosis and microglia infiltration. A significant upregulation of disease-associated microglia signature genes was observed during photoreceptor degeneration. Following MNU treatment, Trem2-/- mice showed exacerbated photoreceptor cell death, decreased microglia migration and phagocytosis, reduced microglial PPARγ activation and CD36 expression. Pharmaceutical activation of PPARγ promoted microglial migration, ameliorated photoreceptor degeneration and restored CD36 expression in MNU-treated Trem2-/- mice. Inhibition of CD36 activity worsened photoreceptor degeneration in MNU-treated WT mice. Our findings suggested that the protective effect of microglia during retinal degeneration was dependent on Trem2 expression and carried out via the activation of PPARγ and the consequent upregulation of CD36 expression. Our study linked TREM2 signaling with PPARγ activation, and provided a potential therapeutic target for the management of retinal degeneration.

Asunto(s)

Antígenos CD36 , Glicoproteínas de Membrana , Microglía , PPAR gamma , Receptores Inmunológicos , Degeneración Retiniana , Animales , Ratones , Apoptosis/efectos de los fármacos , Antígenos CD36/metabolismo , Antígenos CD36/genética , Movimiento Celular , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Metilnitrosourea/toxicidad , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , Fagocitosis , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/patología , PPAR gamma/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Degeneración Retiniana/patología , Degeneración Retiniana/metabolismo

RESUMEN

BACKGROUND: This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR). METHODS: Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal-Wallis and Dunn. RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p < 0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50 ± 0.12; T 1.52 ± 0.10; SNAC 1.56 ± 0.12; TNAC 1.62 ± 0.14 * mm; * p < 0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4 ± 5.01; T 36.4 ± 2.96; SNAC 39.7 ± 3.44; TNAC 41.6 ± 3.57 * mm/s; * p < 0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210 ± 48; T 182 ± 43; SNAC 159 ± 33 *; TNAC 110 ± 23 *# nmol/g tissue; * p < 0.05 vs S, # p < 0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66-1.66); T 0.78 (0.61-1.04) *; SNAC 1.07 (1.01-1.38); TNAC 1.06 (1.01-1.15) arbitrary units; * p < 0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups. CONCLUSION: N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.

Asunto(s)

Acetilcisteína , Hipertensión , NADPH Oxidasas , Estrés Oxidativo , Ratas Endogámicas SHR , Remodelación Ventricular , Animales , Masculino , Estrés Oxidativo/efectos de los fármacos , Acetilcisteína/farmacología , Remodelación Ventricular/efectos de los fármacos , Hipertensión/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , NADPH Oxidasas/metabolismo , NADPH Oxidasas/genética , Ratas , Antioxidantes/farmacología , Condicionamiento Físico Animal , Modelos Animales de Enfermedad , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , NADPH Oxidasa 4/metabolismo , NADPH Oxidasa 4/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Miocardio/metabolismo , Miocardio/patología , Peróxidos Lipídicos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Suplementos Dietéticos , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Hipertrofia Ventricular Izquierda/metabolismo

RESUMEN

The inflammatory response is a significant factor in acetaminophen (APAP)-induced acute liver injury. And it can be mediated by macrophages of different origins. However, whether Kupffer cells and mononuclear-derived macrophages play an injury or protective role in APAP hepatotoxicity is still unclear. In this study, C57/BL6N mice were performed to establish the APAP acute liver injury model. Intervention experiments were also carried out using clodronate liposomes or TREM2 knockout. We found that APAP overdose triggered the activation of inflammatory factors and enhanced the expression of the RIPK1-MLKL pathway in mice's livers. Moreover, our study showed that inflammation-related protein expression was increased after clodronate liposome administration or TREM2 knockout. The RIPK1-MLKL-mediated necroptosis was also significantly activated after the elimination of Kupffer cells or the inhibition of mononuclear-derived macrophages. More importantly, clodronate liposomes treatment and TREM2 deficiency all worsen APAP-induced liver damage in mice. In conclusion, the results indicate that Kupffer cells and mononuclear macrophages play a protective role in APAP-induced liver injury by regulating necroptosis. Therefore, macrophages hold as a potential therapeutic target for APAP-induced liver damage.

Asunto(s)

Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Macrófagos del Hígado , Macrófagos , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Inmunológicos , Animales , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ácido Clodrónico/farmacología , Hígado/patología , Hígado/metabolismo , Hígado/inmunología , Hígado/efectos de los fármacos , Necroptosis , Liposomas , Modelos Animales de Enfermedad , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de Señal

RESUMEN

Systemic viral infection of insects typically begins with the primary infection of midgut epithelial cells (enterocytes) and subsequent transit of the progeny virus in an apical-to-basal orientation into the hemocoel. For insect-vectored viruses, an oppositely oriented process (basal-to-apical transit) occurs upon secondary infection of salivary glands and is necessary for virus transmission to non-insect hosts. To examine this inversely oriented virus transit in these polarized tissues, we assessed the intracellular trafficking of two model viral envelope proteins (baculovirus GP64 and vesicular stomatitis virus G) in the midgut and salivary gland cells of the model insect, Drosophila melanogaster. Using fly lines that inducibly express either GP64 or VSV G, we found that each protein, expressed alone, was trafficked basally in midgut enterocytes. In salivary gland cells, VSV G was trafficked apically in most but not all cells, whereas GP64 was consistently trafficked basally. We demonstrated that a YxxØ motif present in both proteins was critical for basal trafficking in midgut enterocytes but dispensable for trafficking in salivary gland cells. Using RNAi, we found that clathrin adaptor protein complexes AP-1 and AP-3, as well as seven Rab GTPases, were involved in polarized VSV G trafficking in midgut enterocytes. Our results indicate that these viral envelope proteins encode the requisite information and require no other viral factors for appropriately polarized trafficking. In addition, they exploit tissue-specific differences in protein trafficking pathways to facilitate virus egress in the appropriate orientation for establishing systemic infections and vectoring infection to other hosts. IMPORTANCE: Viruses that use insects as hosts must navigate specific routes through different insect tissues to complete their life cycles. The routes may differ substantially depending on the life cycle of the virus. Both insect pathogenic viruses and insect-vectored viruses must navigate through the polarized cells of the midgut epithelium to establish a systemic infection. In addition, insect-vectored viruses must also navigate through the polarized salivary gland epithelium for transmission. Thus, insect-vectored viruses appear to traffic in opposite directions in these two tissues. In this study, we asked whether two viral envelope proteins (VSV G and baculovirus GP64) alone encode the signals necessary for the polarized trafficking associated with their respective life cycles. Using Drosophila as a model to examine tissue-specific polarized trafficking of these viral envelope proteins, we identified one of the virus-encoded signals and several host proteins associated with regulating the polarized trafficking in the midgut epithelium.

Asunto(s)

Drosophila melanogaster , Transporte de Proteínas , Glándulas Salivales , Proteínas del Envoltorio Viral , Animales , Glándulas Salivales/virología , Glándulas Salivales/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Proteínas del Envoltorio Viral/genética , Drosophila melanogaster/virología , Drosophila melanogaster/metabolismo , Insectos Vectores/virología , Insectos Vectores/metabolismo , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Enterocitos/virología , Enterocitos/metabolismo , Tracto Gastrointestinal/virología , Tracto Gastrointestinal/metabolismo

RESUMEN

Alveolar type 2 epithelial (AT2) cells synthesize surfactant protein C (SPC) and repair an injured alveolar epithelium. A mutated surfactant protein C gene (SftpcL184Q, Gene ID: 6440) in newborns has been associated with respiratory distress syndrome and pulmonary fibrosis. However, the underlying mechanisms causing Sftpc gene mutations to regulate AT2 lineage remain unclear. We utilized three-dimensional (3D) feeder-free AT2 organoids in vitro to simulate the alveolar epithelium and compared AT2 lineage characteristics between WT (C57BL/6) and SftpcL184Q mutant mice using colony formation assays, immunofluorescence, flow cytometry, qRT-PCR, and Western blot assays. The AT2 numbers were reduced significantly in SftpcL184Q mice. Organoid numbers and colony-forming efficiency were significantly attenuated in the 3D cultures of primary SftpcL184Q AT2 cells compared to those of WT mice. Podoplanin (PDPN, Alveolar type 1 cell (AT1) marker) expression and transient cell count was significantly increased in SftpcL184Q organoids compared to in the WT mice. The expression levels of CD74, heat shock protein 90 (HSP90), and ribosomal protein S3A1 (RPS3A1) were not significantly different between WT and SftpcL184Q AT2 cells. This study demonstrated that humanized SftpcL184Q mutation regulates AT2 lineage intrinsically. This regulation is independent of CD74, HSP90, and RPS3A1 pathways.

Asunto(s)

Células Epiteliales Alveolares , Proteína C Asociada a Surfactante Pulmonar , Animales , Humanos , Ratones , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/citología , Diferenciación Celular/genética , Linaje de la Célula/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos C57BL , Mutación , Organoides/metabolismo , Organoides/citología , Proteína C Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Masculino , Femenino

RESUMEN

Postmenopausal osteoporosis (PMO) is characterized by bone loss and microstructural damage, and it is most common in older adult women. Currently, there is no cure for PMO. The flavonoid chemical 7,8-dihydroxyflavone (7,8-DHF) specifically activates tropomyosin receptor kinase B (TRKB). Furthermore, 7,8-DHF has various biological characteristics, including anti-inflammatory and antioxidant effects. However, the specific implications and fundamental mechanisms of 7,8-DHF in PMO remain unclear. We used protein imprinting, flow cytometry, tissue staining, and other methods to estimate the preventive mechanisms of 7,8-DHF against hydrogen peroxide (H2O2)-induced apoptosis in primary mouse bone marrow mesenchymal stem cells (BMSCs), osteogenic differentiation ability, and bone mass in ovariectomized (OVX) mice. We found that 7,8-DHF effectively prevented H2O2-induced reductions in the viability and osteogenic differentiation capacity of primary BMSCs. Mechanistically, 7,8-DHF induced the TRKB to activate the PI3K/AKT/NRF2 pathway. In vivo experiments with the OVX mouse model confirmed that 7,8-DHF can inhibit oxidative stress and promote bone formation, indicating that 7,8-DHF improves the viability and osteogenic differentiation ability of BMSCs stimulated via H2O2 by activating the TRKB/PI3K/AKT and NRF2 pathways, thereby improving PMO.

Asunto(s)

Flavonas , Peróxido de Hidrógeno , Células Madre Mesenquimatosas , Factor 2 Relacionado con NF-E2 , Osteogénesis , Osteoporosis Posmenopáusica , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Receptor trkB , Transducción de Señal , Animales , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Ratones , Femenino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Flavonas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Osteoporosis Posmenopáusica/metabolismo , Osteoporosis Posmenopáusica/patología , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Humanos , Receptor trkB/metabolismo , Receptor trkB/genética , Diferenciación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ovariectomía , Ratones Endogámicos C57BL

RESUMEN

While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.

Asunto(s)

Macrófagos del Hígado , Cirrosis Hepática , Macrófagos , Glicoproteínas de Membrana , Receptores Inmunológicos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Animales , Ratones , Macrófagos/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Masculino , Lípidos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , Ratones Noqueados

RESUMEN

INTRODUCTION: First reports associated mutations in triggering receptors expressed on myeloid cells 2 (TREM2) with autosomal recessive Nasu-Hakola disease characterized by painful bone cysts and progressive presenile dementia with psychotic symptoms; however, recent TREM2 biallelic rare variants are suggested to be causative also for the behavioral variant of frontotemporal dementia (bvFTD) without bone involvement. MATERIAL AND METHODS: Clinical data of three unrelated bvFTD patients carrying TREM2 biallelic variants were evaluated. All patients underwent neurological, psychiatric, and cognitive evaluation and neuroimaging. A full neuropsychological assessment was performed in two cases. RESULTS: Two patients carried compound heterozygous TREM2 variants, p.R62C and p.T66M, and one carried the homozygous p.D87N variant. Based on all obtained clinical and neuroimaging data, a behavioral variant of frontotemporal dementia was diagnosed in all cases. Their clinical manifestation was typical with neuropsychiatric and cognitive features, without bone abnormalities. CONCLUSIONS: Despite all three subjects partially resembling clinical manifestations of Nasu-Hakola disease with TREM2 mutations, we reveal some distinct features, including age of onset, neuroimaging findings, or disease course.

Asunto(s)

Demencia Frontotemporal , Glicoproteínas de Membrana , Receptores Inmunológicos , Humanos , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/genética , Masculino , Femenino , Persona de Mediana Edad , Mutación/genética , Panencefalitis Esclerosante Subaguda/genética , Adulto , Osteocondrodisplasias/genética , Lipodistrofia/genética

RESUMEN

Enterovirus 71 (EV-71) has strong neurotropism, and it is the main pathogen causing severe hand, foot, and mouth disease (HFMD). In clinical observations, significant differences were observed in the severity and prognosis of HFMD among children who were also infected with EV-71. Genetic differences among individuals could be one of the important causes of differences in susceptibility to EV-71-induced HFMD. As P-selectin glycoprotein ligand-1 (PSGL-1) is an important receptor of EV-71, the correlation between single-nucleotide polymorphisms (SNPs) in PSGL-1 and the susceptibility to severe HFMD following EV-71 infection is worth studying. Given the role of PSGL-1 in immunity, the correlations between PSGL-1 SNPs and the immune status after EV-71 infection are also worth studying. Meanwhile, PSGL-1 variable number of tandem repeats (VNTR) represents a research hotspot in cardiovascular and cerebrovascular diseases, but PSGL-1 VNTR polymorphism has not been investigated in HFMD caused by EV-71 infection. In this study, specific gene fragments were amplified by polymerase chain reaction, and PSGL-1 VNTR sequences were genotyped using an automatic nucleic acid analyzer. The correlations of PSGL-1 VNTR polymorphism with the susceptibility to EV-71-associated severe HFMD and the post-infection immune status were analyzed. The PSGL-1 VNTR A allele was identified as a susceptible SNP for severe HFMD. The risk of severe HFMD was higher for AA + AB genotype carriers than for BB genotype carriers. The counts of peripheral blood lymphocyte subsets were lower in AA + AB genotype carries than in BB genotype carries. In conclusion, PSGL-1 VNTR polymorphism is associated with the susceptibility to EV-71-induced severe HFMD and the immune status after infection. PSGL-1 VNTR might play a certain role in the pathogenesis of severe cases.

Asunto(s)

Enterovirus Humano A , Predisposición Genética a la Enfermedad , Enfermedad de Boca, Mano y Pie , Glicoproteínas de Membrana , Repeticiones de Minisatélite , Humanos , Enfermedad de Boca, Mano y Pie/genética , Enfermedad de Boca, Mano y Pie/inmunología , Enfermedad de Boca, Mano y Pie/virología , Glicoproteínas de Membrana/genética , Enterovirus Humano A/inmunología , Enterovirus Humano A/genética , Masculino , Femenino , Lactante , Repeticiones de Minisatélite/genética , Preescolar , Polimorfismo de Nucleótido Simple , Genotipo , Niño

RESUMEN

The single nucleotide polymorphism (SNP)-rs6922617 in the triggering receptor expressed on myeloid cells (TREM) gene cluster is a potential risk factor for Alzheimer's disease (AD). Here, we examined whether rs6922617 is associated with AD-defining neuropathological hallmarks and memory performance. We assessed the interaction between the variant rs6922617 and levels of beta-amyloid (Aß), tau pathology, neurodegeneration, namely amyloid-tau-neurodegeneration framework, and cognition functions in 660 healthy controls, 794 mild cognitively impaired, and 272 subjects with AD. We employed linear regression and linear mixed models to examine the association. Here we find that the SNP-rs6922617 in the TREM gene cluster is associated with a higher global amyloid-ligands positron emission tomography (Aß-PET) burden and lower fluorodeoxyglucose positron emission tomography (FDG-PET) load. Interestingly, rs6922617 risk allele carriers exhibit a significantly reduced tau accumulation compared to the non-carriers, indicating a discrepant association with Aß and tau pathologies. Though the participants carrying the rs6922617 risk allele do not show a correlation with poorer cognitive performance, stronger neuropathological phenotypes, and memory impairments are evident in ApoE ε4 carriers with the rs6922617 risk allele. These results support the notion that the SNP-rs6922617 in the TREM gene cluster is associated with AD-related neuropathological hallmarks, such as Aß and FDG-mediated neurodegeneration, rather than tau accumulation. Although the direct association with memory impairment in the Alzheimer's continuum remains inconclusive, our findings suggest a potential role of rs6922617 in facilitating neuropathology hallmarks.

Asunto(s)

Enfermedad de Alzheimer , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Masculino , Femenino , Anciano , Péptidos beta-Amiloides/metabolismo , Proteínas tau/genética , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Tomografía de Emisión de Positrones , Receptores Inmunológicos/genética , Factores de Riesgo , Glicoproteínas de Membrana/genética , Predisposición Genética a la Enfermedad , Anciano de 80 o más Años