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1.
JAMA Intern Med ; 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35759254

RESUMO

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. Exposures: The hemoglobin beta S (HbS) allele (rs334-T). Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

2.
Front Immunol ; 13: 836820, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603160

RESUMO

Studies implicate that gut dysbiosis is related with many neurological diseases. However, the potential role of gut dysbiosis in cryptogenic stroke (CS) has not been elucidated yet. In this study, a high prevalence of gastrointestinal (GI) dysfunction and gut inflammation with increased intestinal permeability have been found in CS patients compared with normal controls (NCs). The systemic inflammation in CS patients was also identified by measuring the levels of plasma C-reactive protein (CRP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and white blood cells (WBC) count. Using 16S rRNA sequencing, we found increased alpha diversity, accompanied by a higher abundance of Enterobacteriaceae, Streptococcaceae, and Lactobacillaceae at the family level and Escherichia-Shigella, Streptococcus, Lactobacillus, and Klebsilla at the genus level in the intestinal microbiota of CS patients compared to NCs. Our results showed that the abundance of Klebsilla was positively correlated with the systemic inflammation, the National Institutes of Health Stroke Scale (NIHSS) scores, and the infarct volumes. In conclusion, gut dysbiosis in CS patients was associated with the severity of CS and the systemic inflammation. Maintaining the intestinal homeostasis may be a potential strategy for the treatment of CS.


Assuntos
Gastroenteropatias , AVC Isquêmico , Disbiose/metabolismo , Humanos , Inflamação , RNA Ribossômico 16S/genética , Síndrome de Resposta Inflamatória Sistêmica , Estados Unidos
3.
Nat Commun ; 13(1): 2835, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595767

RESUMO

Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors against CDK2 are ATP competitors that are either nonspecific or highly toxic, and typically fail clinical trials. One alternative approach is to develop non-ATP competitive inhibitors; they disrupt interactions between CDK2 and either its partners or substrates, resulting in specific inhibition of CDK2 activities. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. Further, we demonstrate that HHT induces autophagic degradation of the CDK2 protein via tripartite motif 21 (Trim21) in cancer cells, which is confirmed in a leukemia mouse model and in human primary leukemia cells. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers.


Assuntos
Autofagia , Quinases relacionadas a CDC2 e CDC28 , Ciclina A , Quinase 2 Dependente de Ciclina , Leucemia , Animais , Linhagem Celular Tumoral/metabolismo , Ciclina A/antagonistas & inibidores , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Mepesuccinato de Omacetaxina/metabolismo , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Camundongos , Ribonucleoproteínas
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(2): 146-152, 2022 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-35356883

RESUMO

Objective To investigate the role of circular RNA cleavage and polyadenylation specificity factor 6 (circRNA CPSF6) in the apoptosis of trophoblast cells induced by homocysteine (Hcy) and its mechanism. Methods HTR-8/SVneo human chorionic trophoblast cells were cultured in vitro and divided into control group (0 mmol/L Hcy treatment) and 1 mmol/L Hcy treatment group. Immunofluorescence cytochemical staining was used to detect the expression of caspase-3 in trophoblasts, and Western blot analysis was used to detect the caspase-3 protein level. The mRNA expression level of circRNA CPSF6 was detected by real-time quantitative PCR. Small interfering RNA (siRNA) was used to knock down the expression of circRNA CPSF6 in trophoblast cells. The expressions of caspase-3, caspase-9, Bcl2, and BAX were detected by Western blot analysis. Real-time quantitative PCR was used to detect the expression level of circRNA CPSF6 in the cytoplasm/nucleus of trophoblast cells before and after Hcy treatment. Results Compared with those in the control group, the expressions of caspase-3 and circRNA CPSF6 mRNA in the Hcy treatment group significantly increased. After knocking down circRNA CPSF6, the expression of caspase-3 decreased, and the mitochondrial apoptosis pathway was inhibited. In normal cultured trophoblast cells, circRNA CPSF6 was expressed in large amounts in the cytoplasm, and after Hcy treatment, circRNA CPSF6 was mainly expressed in the nucleus. Conclusion The mitochondrial apoptotic pathway is activated by circRNA CPSF6 nuclear translocation to promote trophoblast apoptosis induced by Hcy.


Assuntos
RNA Circular , Trofoblastos , Apoptose/genética , Homocisteína/metabolismo , Homocisteína/farmacologia , Humanos , Mitocôndrias/metabolismo , Trofoblastos/metabolismo
5.
PLoS Pathog ; 18(3): e1010396, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35358290

RESUMO

The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184.


Assuntos
Vírus da Imunodeficiência Símia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Anti-HIV , Humanos , Macaca mulatta , Receptores CCR5
6.
Sci Adv ; 8(6): eabm4606, 2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35148184

RESUMO

The solid electrolyte interface (SEI) formed on the anode is one of the key factors that determine the life span of sodium metal batteries (SMBs). However, the continuous evolution of SEI during charging/discharging processes complicates the fundamental understanding of its chemistry and structure. In this work, we studied the underlying mechanisms of the protection effect offered by the SEI derived from sodium difluoro(oxalato)borate (NaDFOB). In situ nuclear magnetic resonance (NMR) shows that the prior reduction of DFOB anion contributes to the SEI formation, and it suppresses the decomposition of carbonate solvents. Depth-profiling x-ray photoelectron spectroscopy and high-resolution solid-state NMR reveal that the DFOB anion is gradually turned into borate and fluoride-rich SEI with cycling. The protection effect of SEI reaches the optimum at 50 cycles, which triples the life span of SMB. The detailed investigations provide valuable guidelines for the SEI engineering.

7.
Nat Commun ; 13(1): 662, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115533

RESUMO

Increasingly, antibodies are being used to treat and prevent viral infections. In the context of HIV, efficacy is primarily attributed to dose-dependent neutralization potency and to a lesser extent Fc-mediated effector functions. It remains unclear whether augmenting effector functions of broadly neutralizing antibodies (bNAbs) may improve their clinical potential. Here, we use bNAb 10E8v4 targeting the membrane external proximal region (MPER) to examine the role of antibody-mediated effector and complement (C') activity when administered prophylactically against SHIV challenge in rhesus macaques. With sub-protective dosing, we find a 78-88% reduction in post-acute viremia that is associated with 10E8v4-mediated phagocytosis acting at the time of challenge. Neither plasma nor tissue viremic outcomes in vivo is improved with an Fc-modified variant of 10E8v4 enhanced for C' functions as determined in vitro. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to efficacy against SHIVSF162P3 in the absence of plasma neutralizing titers, while C' functions are dispensable in this setting, informing design of bNAb modifications for improving protective efficacy.


Assuntos
Anticorpos Amplamente Neutralizantes/imunologia , Proteínas do Sistema Complemento/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Fagocitose/imunologia , Viremia/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Anticorpos Amplamente Neutralizantes/metabolismo , Anticorpos Amplamente Neutralizantes/farmacologia , Linhagem Celular Tumoral , Proteínas do Sistema Complemento/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Anticorpos Anti-HIV/metabolismo , Anticorpos Anti-HIV/farmacologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macaca mulatta , Masculino , Fagocitose/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Viremia/sangue , Viremia/prevenção & controle
8.
Nat Commun ; 13(1): 234, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017515

RESUMO

Environmental enteric dysfunction is associated with malnutrition as well as infant growth stunting and has been classically defined by villous blunting, decreased crypt-to-villus ratio, and inflammation in the small intestine. Here, we characterized environmental enteric dysfunction among infant rhesus macaques that are naturally exposed to enteric pathogens commonly linked to human growth stunting. Remarkably, despite villous atrophy and histological abnormalities observed in the small intestine, poor growth trajectories and low serum tryptophan levels were correlated with increased histopathology in the large intestine. This work provides insight into the mechanisms underlying this disease and indicates that the large intestine may be an important target for therapeutic intervention.


Assuntos
Intestino Grosso/patologia , Intestino Delgado/patologia , Macaca mulatta/crescimento & desenvolvimento , Animais , Duodeno/patologia , Feminino , Trato Gastrointestinal , Expressão Gênica , Transtornos do Crescimento/patologia , Humanos , Íleo/patologia , Inflamação , Enteropatias , Mucosa Intestinal , Jejuno/patologia , Masculino , Desnutrição
9.
Adv Drug Deliv Rev ; 182: 114108, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34990792

RESUMO

Within the past decades, extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in both prokaryotes and higher eukaryotes to regulate a diverse range of biological processes. Besides EVs, exosome-like nanoparticles (ELNs) derived from plants were also emerging. Comparing to EVs, ELNs are source-widespread, cost-effective and easy to obtain. Their definite activities can be utilized for potential prevention/treatment of an abundance of diseases, including metabolic syndrome, cancer, colitis, alcoholic hepatitis and infectious diseases, which highlights ELNs as promising biotherapeutics. In addition, the potential of ELNs as natural or engineered drug carriers is also attractive. In this review, we tease out the timeline of plant EVs and ELNs, introduce the arising separation, purification and characterization techniques, state the stability and transport manner, discuss the therapeutic opportunities as well as the potential as novel drug carriers. Finally, the challenges and the direction of efforts to realize the clinical transformation of ELNs are also discussed.


Assuntos
Química Farmacêutica/métodos , Portadores de Fármacos/farmacologia , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Plantas/metabolismo , Animais , Biomarcadores , Comunicação Celular/fisiologia , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Estabilidade de Medicamentos , Humanos , /farmacologia , /toxicidade
10.
Neuropsychopharmacology ; 47(4): 847-856, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34837077

RESUMO

A major barrier to remission from an alcohol use disorder (AUD) is the continued risk of relapse during abstinence. Assessing the neuroadaptations after chronic alcohol and repeated abstinence is important to identify mechanisms that may contribute to relapse. In this study, we used a rhesus macaque model of long-term alcohol use and repeated abstinence, providing a platform to extend mechanistic findings from rodents to primates. The central amygdala (CeA) displays elevated GABA release following chronic alcohol in rodents and in abstinent male macaques, highlighting this neuroadaptation as a conserved mechanism that may underlie excessive alcohol consumption. Here, we determined circulating interleukin-1ß (IL-1ß) levels, CeA transcriptomic changes, and the effects of IL-1ß and corticotropin releasing factor (CRF) signaling on CeA GABA transmission in male controls and abstinent drinkers. While no significant differences in peripheral IL-1ß or the CeA transcriptome were observed, pathway analysis identified several canonical immune-related pathways. We addressed this potential dysregulation of CeA immune signaling in abstient drinkers with an electrophysiological approach. We found that IL-1ß decreased CeA GABA release in controls while abstinent drinkers were less sensitive to IL-1ß's effects, suggesting adaptations in the neuromodulatory role of IL-1ß. In contrast, CRF enhanced CeA GABA release similarly in controls and abstinent drinkers, consistent with rodent studies. Notably, CeA CRF expression was inversely correlated with intoxication, suggesting that CRF levels during abstinence may predict future intoxication. Together, our findings highlight conserved and divergent actions of chronic alcohol on neuroimmune and stress signaling on CeA GABA transmission across rodents and macaques.


Assuntos
Abstinência de Álcool , Núcleo Central da Amígdala , Hormônio Liberador da Corticotropina , Interleucina-1beta , Transmissão Sináptica , Animais , Núcleo Central da Amígdala/fisiopatologia , Hormônio Liberador da Corticotropina/metabolismo , Potenciais Pós-Sinápticos Inibidores , Interleucina-1beta/metabolismo , Macaca mulatta , Masculino , Ácido gama-Aminobutírico/metabolismo
12.
Am J Obstet Gynecol ; 226(1): 130.e1-130.e11, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364844

RESUMO

BACKGROUND: Prenatal alcohol exposure is the most common cause of birth defects and intellectual disabilities and can increase the risk of stillbirth and negatively impact fetal growth. OBJECTIVE: To determine the effect of early prenatal alcohol exposure on nonhuman primate placental function and fetal growth. We hypothesized that early chronic prenatal alcohol would alter placental perfusion and oxygen availability that adversely affects fetal growth. STUDY DESIGN: Rhesus macaques self-administered 1.5 g/kg/d of ethanol (n=12) or isocaloric maltose-dextrin (n=12) daily before conception through the first 60 days of gestation (term is approximately 168 days). All animals were serially imaged with Doppler ultrasound to measure fetal biometry, uterine artery volume blood flow, and placental volume blood flow. Following Doppler ultrasound, all animals underwent both blood oxygenation level-dependent magnetic resonance imaging to characterize placental blood oxygenation and dynamic contrast-enhanced magnetic resonance imaging to quantify maternal placental perfusion. Animals were delivered by cesarean delivery for placental collection and fetal necropsy at gestational days 85 (n=8), 110 (n=8), or 135 (n=8). Histologic and RNA-sequencing analyses were performed on collected placental tissue. RESULTS: Placental volume blood flow was decreased at all gestational time points in ethanol-exposed vs control animals, but most significantly at gestational day 110 by Doppler ultrasound (P<.05). A significant decrease in total volumetric blood flow occurred in ethanol-exposed vs control animals on dynamic contrast-enhanced magnetic resonance imaging at both gestation days 110 and 135 (P<.05); moreover, a global reduction in T2∗, high blood deoxyhemoglobin concentration, occurred throughout gestation (P<.05). Similarly, evidence of placental ischemic injury was notable by histologic analysis, which revealed a significant increase in microscopic infarctions in ethanol-exposed, not control, animals, largely present at middle to late gestation. Fetal biometry and weight were decreased in ethanol-exposed vs control animals, but the decrease was not significant. Analysis with RNA sequencing suggested the involvement of the inflammatory and extracellular matrix response pathways. CONCLUSION: Early chronic prenatal alcohol exposure significantly diminished placental perfusion at mid to late gestation and also significantly decreased the oxygen supply to the fetal vasculature throughout pregnancy, these findings were associated with the presence of microscopic placental infarctions in the nonhuman primate. Although placental adaptations may compensate for early environmental perturbations to fetal growth, placental blood flow and oxygenation were reduced, consistent with the evidence of placental ischemic injury.


Assuntos
Etanol/efeitos adversos , Macaca mulatta , Efeitos Tardios da Exposição Pré-Natal/etiologia , Animais , Modelos Animais de Doenças , Etanol/farmacologia , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Placenta/efeitos dos fármacos , Gravidez
13.
Transl Neurodegener ; 11(1): 4, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35090576

RESUMO

Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid ß (Aß) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aß accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Humanos , Neurônios/patologia , Preparações Farmacêuticas
14.
J Ovarian Res ; 14(1): 159, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789307

RESUMO

BACKGROUND: There is an urgent need to identify potential targets in anticancer therapy to improve the survival and prognosis of patients with ovarian cancer (OC). Herein, we investigated the functional significance of chemokine (C-X-C motif) ligand 14 (CXCL14) in OC cell growth and epithelial-mesenchymal transition (EMT). METHODS: qRT PCR and western blotting was used to detect CXCL14 mRNA level and protein expression, respectively. The functional mechanism of CXCL14 in OC was investigated by CCK-8, colony formation and transwell assays. The migration ability of OC cell was determined using wound healing. The protein expressions of CXCL14 and ß-catenin in OC tissues were determined by immumohistochemical staining. RESULTS: We demonstrated that high levels of CXCL14 were associated with a worse prognosis in patients with OC. CXCL14 knockdown considerably restrained the growth, migration and invasion of OC cell in vitro. In contrast, ectopic CXCL14 overexpression yielded the opposite results. Investigations to determine the underlying molecular mechanisms revealed that the Wnt/ß-catenin signaling pathway is involved in CXCL14-facilitated OC cell invasiveness. CONCLUSION: These data collectively demonstrate that CXCL14 contributes to OC cell growth and metastatic potential by regulating the Wnt/ß-catenin signaling pathway.


Assuntos
Quimiocinas CXC/metabolismo , Neoplasias Ovarianas/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocinas CXC/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico , Regulação para Cima
15.
Phytomedicine ; 92: 153735, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601221

RESUMO

BACKGROUND: Current antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown. PURPOSE: The objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach. RESULTS: We found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis. CONCLUSION: Our study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.


Assuntos
Depressão , Triptofano , Animais , Antidepressivos/farmacologia , Hidrocarbonetos Aromáticos com Pontes , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo , Camundongos , Fosfolipídeos , Estresse Psicológico
16.
J Oncol ; 2021: 3603030, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603446

RESUMO

Previous studies have indicated the important role of block of proliferation 1 (BOP1) in the progression of several malignant tumors; no comprehensive pan-cancer analysis of BOP1 has been performed. Here, we aim to systematically identify the expression, prognostic value, and potential immunological functions of BOP1 in 33 malignancies. We obtained the gene expression data and clinical information from multiple public databases to assess the expression level and prognostic value of BOP1 in 33 cancers. We also analyzed the relationship between BOP1 expression and DNA methylation, tumor microenvironment (TME), microsatellite instability (MSI), tumor mutational burden (TMB), and immune checkpoints. Moreover, we conducted gene set enrichment analysis (GSEA) to investigate the biological function and signal transduction pathways of BOP1 in different types of tumors. Finally, we validated the expression of BOP1 in lung cancer cell line and detected the influence of BOP1 on lung cancer cell migration and the expression of epithelial-mesenchymal transition- (EMT-) related genes. Collectively, our findings elucidated that BOP1 has the potential to be a promising molecular prognostic biomarker for predicting poor survival in various malignant tumors, as well as a cancer-promoting gene involved in tumorigenesis and tumor immunity.

17.
NPJ Precis Oncol ; 5(1): 92, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34667258

RESUMO

In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

18.
Clin Epigenetics ; 13(1): 177, 2021 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-34538263

RESUMO

BACKGROUND: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes. RESULTS: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers. CONCLUSIONS: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 .


Assuntos
Ácido Ascórbico/farmacologia , Metilação de DNA/efeitos dos fármacos , Placenta/fisiopatologia , Fumar/efeitos adversos , Adulto , Ácido Ascórbico/administração & dosagem , Suplementos Nutricionais/normas , Suplementos Nutricionais/estatística & dados numéricos , Feminino , Humanos , Placenta/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar/fisiopatologia
19.
Mamm Genome ; 32(6): 508-516, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34586488

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Tyrosine kinase inhibitors (TKIs) are currently the most effective chemotherapy for NSCLC. However, most cancer patients develop TKI resistance at tumor relapse stage. We firstly measured the expression change of miR-519d-3p in TKI resistance NSCLC cells. We then ectopically expressed miR-519-3p in TKI resistant cells to study its functional impact on cell proliferation, migration, invasion and cell sensitivity to gefitinib. The downstream target of miR-519-3p was identified by bioinformatics and validated in luciferase reporter assay and western blotting analysis. We also studied the reversing effect of the candidate target in NSCLC cells expressing miR-519d-3p. Lastly, we compared the miR-519d-3p level in NSCLC patients with good or poor response to gefitinib. miR-519d-3p level was downregulated in TKI resistant NSCLC cells. The restoration of miR-519d-3p in these NSCLC cells inhibited cell proliferation, invasion and migration; enhanced cell sensitivity to gefitinib. EPAS1 was identified and validated as downstream target of miR-519d-3p. Co-expressing EPAS1 antagonized the inhibitory effect of miR-519d-3p on NSCLC cells. MiR-519d-3p was downregulated in NSCLC patients with poor response to gefitinib. Targeting miR-519d-3p/EPAS1 axis may provide alternative treatment for TKI-resistant NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
20.
Blood Adv ; 5(21): 4515-4520, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34587228

RESUMO

Recurrent disease remains the principal cause for treatment failure in acute myeloid leukemia (AML) across age groups. Reliable biomarkers of AML relapse risk and disease burden have been problematic, as symptoms appear late and current monitoring relies on invasive and cost-ineffective serial bone marrow (BM) surveillance. In this report, we discover a set of unique microRNA (miRNA) that circulates in AML-derived vesicles in the peripheral blood ahead of the general dissemination of leukemic blasts and symptomatic BM failure. Next-generation sequencing of extracellular vesicle-contained small RNA in 12 AML patients and 12 controls allowed us to identify a panel of differentially incorporated miRNA. Proof-of-concept studies using a murine model and patient-derived xenografts demonstrate the feasibility of developing miR-1246, as a potential minimally invasive AML biomarker.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Animais , Biomarcadores , Medula Óssea , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Camundongos , MicroRNAs/genética
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