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1.
J Med Internet Res ; 25: e45187, 2023 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-37310779

RESUMO

BACKGROUND: Gun violence research is characterized by a dearth of data available for measuring key constructs. Social media data may offer a potential opportunity to significantly reduce that gap, but developing methods for deriving firearms-related constructs from social media data and understanding the measurement properties of such constructs are critical precursors to their broader use. OBJECTIVE: This study aimed to develop a machine learning model of individual-level firearm ownership from social media data and assess the criterion validity of a state-level construct of ownership. METHODS: We used survey responses to questions on firearm ownership linked with Twitter data to construct different machine learning models of firearm ownership. We externally validated these models using a set of firearm-related tweets hand-curated from the Twitter Streaming application programming interface and created state-level ownership estimates using a sample of users collected from the Twitter Decahose application programming interface. We assessed the criterion validity of state-level estimates by comparing their geographic variance to benchmark measures from the RAND State-Level Firearm Ownership Database. RESULTS: We found that the logistic regression classifier for gun ownership performs the best with an accuracy of 0.7 and an F1-score of 0.69. We also found a strong positive correlation between Twitter-based estimates of gun ownership and benchmark ownership estimates. For states meeting a threshold requirement of a minimum of 100 labeled Twitter users, the Pearson and Spearman correlation coefficients are 0.63 (P<.001) and 0.64 (P<.001), respectively. CONCLUSIONS: Our success in developing a machine learning model of firearm ownership at the individual level with limited training data as well as a state-level construct that achieves a high level of criterion validity underscores the potential of social media data for advancing gun violence research. The ownership construct is an important precursor for understanding the representativeness of and variability in outcomes that have been the focus of social media analyses in gun violence research to date, such as attitudes, opinions, policy stances, sentiments, and perspectives on gun violence and gun policy. The high criterion validity we achieved for state-level gun ownership suggests that social media data may be a useful complement to traditional sources of information on gun ownership such as survey and administrative data, especially for identifying early signals of changes in geographic patterns of gun ownership, given the immediacy of the availability of social media data, their continuous generation, and their responsiveness. These results also lend support to the possibility that other computationally derived, social media-based constructs may be derivable, which could lend additional insight into firearm behaviors that are currently not well understood. More work is needed to develop other firearms-related constructs and to assess their measurement properties.


Assuntos
Armas de Fogo , Mídias Sociais , Humanos , Benchmarking , Propriedade , Bases de Dados Factuais
2.
Int J Mol Sci ; 24(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36614246

RESUMO

Phytophthora root rot is a destructive soybean disease worldwide, which is caused by the oomycete pathogen Phytophthora sojae (P. sojae). Wall-associated protein kinase (WAK) genes, a family of the receptor-like protein kinase (RLK) genes, play important roles in the plant signaling pathways that regulate stress responses and pathogen resistance. In our study, we found a putative Glycine max wall-associated protein kinase, GmWAK1, which we identified by soybean GmLHP1 RNA-sequencing. The expression of GmWAK1 was significantly increased by P. sojae and salicylic acid (SA). Overexpression of GmWAK1 in soybean significantly improved resistance to P. sojae, and the levels of phenylalanine ammonia-lyase (PAL), SA, and SA-biosynthesis-related genes were markedly higher than in the wild-type (WT) soybean. The activities of enzymatic superoxide dismutase (SOD) and peroxidase (POD) antioxidants in GmWAK1-overexpressing (OE) plants were significantly higher than those in in WT plants treated with P. sojae; reactive oxygen species (ROS) and hydrogen peroxide (H2O2) accumulation was considerably lower in GmWAK1-OE after P. sojae infection. GmWAK1 interacted with annexin-like protein RJ, GmANNRJ4, which improved resistance to P. sojae and increased intracellular free-calcium accumulation. In GmANNRJ4-OE transgenic soybean, the calmodulin-dependent kinase gene GmMPK6 and several pathogenesis-related (PR) genes were constitutively activated. Collectively, these results indicated that GmWAK1 interacts with GmANNRJ4, and GmWAK1 plays a positive role in soybean resistance to P. sojae via a process that might be dependent on SA and involved in alleviating damage caused by oxidative stress.


Assuntos
Glycine max , Phytophthora , Glycine max/genética , Glycine max/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Phytophthora/fisiologia , Proteínas Quinases/metabolismo , Peróxido de Hidrogênio/metabolismo , Plantas Geneticamente Modificadas/genética , Proteínas de Soja/genética , Doenças das Plantas/genética , Resistência à Doença/genética
3.
Int J Mol Sci ; 24(7)2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-37046998

RESUMO

Phytophthora root and stem rot caused by Phytophthora sojae Kaufmann and Gerdemann is a soil-borne disease severely affecting soybean production worldwide. Losses caused by P. sojae can be controlled by both major genes and quantitative trait locus. Here, we tested 112 short-season soybean cultivars from Northeast China for resistance to P. sojae. A total of 58 germplasms were resistant to 7-11 P. sojae strains. Among these, Mengdou 28 and Kejiao 10-262 may harbor either Rps3a or multiple Rps genes conferring resistance to P. sojae. The remaining 110 germplasms produced 91 reaction types and may contain new resistance genes or gene combinations. Partial resistance evaluation using the inoculum layer method revealed that 34 soybean germplasms had high partial resistance, with a mean disease index lower than 30. Combining the results of resistance and partial resistance analyses, we identified 35 excellent germplasm resources as potential elite materials for resistance and tolerance in future breeding programs. In addition, we compared the radicle inoculation method with the inoculum layer method to screen for partial resistance to P. sojae. Our results demonstrate that the radicle inoculation method could potentially replace the inoculum layer method to identify partial resistance against P. sojae, and further verification with larger samples is required in the future.


Assuntos
Resistência à Doença , Phytophthora , Resistência à Doença/genética , Glycine max/genética , Estações do Ano , Doenças das Plantas/genética , Melhoramento Vegetal , Genótipo
4.
Int J Mol Sci ; 23(15)2022 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-35897735

RESUMO

Ethylene response factors (ERFs) are involved in biotic and abiotic stress; however, the drought resistance mechanisms of many ERFs in soybeans have not been resolved. Previously, we proved that GmERF113 enhances resistance to the pathogen Phytophthora sojae in soybean. Here, we determined that GmERF113 is induced by 20% PEG-6000. Compared to the wild-type plants, soybean plants overexpressing GmERF113 (GmERF113-OE) displayed increased drought tolerance which was characterized by milder leaf wilting, less water loss from detached leaves, smaller stomatal aperture, lower Malondialdehyde (MDA) content, increased proline accumulation, and higher Superoxide dismutase (SOD) and Peroxidase (POD) activities under drought stress, whereas plants with GmERF113 silenced through RNA interference were the opposite. Chromatin immunoprecipitation and dual effector-reporter assays showed that GmERF113 binds to the GCC-box in the GmPR10-1 promoter, activating GmPR10-1 expression directly. Overexpressing GmPR10-1 improved drought resistance in the composite soybean plants with transgenic hairy roots. RNA-seq analysis revealed that GmERF113 downregulates abscisic acid 8'-hydroxylase 3 (GmABA8'-OH 3) and upregulates various drought-related genes. Overexpressing GmERF113 and GmPR10-1 increased the abscisic acid (ABA) content and reduced the expression of GmABA8'-OH3 in transgenic soybean plants and hairy roots, respectively. These results reveal that the GmERF113-GmPR10-1 pathway improves drought resistance and affects the ABA content in soybean, providing a theoretical basis for the molecular breeding of drought-tolerant soybean.


Assuntos
Secas , Glycine max , Ácido Abscísico/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Glycine max/metabolismo , Estresse Fisiológico/genética
5.
Am J Physiol Renal Physiol ; 320(3): F359-F374, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427061

RESUMO

Lysophosphatidic acid (LPA) increases platelet-derived growth factor-B (PDGFB) and connective tissue growth factor (CTGF) production and secretion by proximal tubule (PT) cells through LPA2 receptor-Gqα-αvß6-integrin-mediated activation of transforming growth factor-ß1 (TGFB1). LPA2, ß6-integrin, PDGFB, and CTGF increase in kidneys after ischemia-reperfusion injury (IRI), coinciding with fibrosis. The TGFB1 receptor antagonist SD-208 prevents increases of ß6-integrin, TGFB1-SMAD signaling, and PDGFB/CTGF expression after IRI and ameliorates fibrosis (Geng H, Lan R, Singha PK, Gilchrist A, Weinreb PH, Violette SM, Weinberg JM, Saikumar P, Venkatachalam MA. Am J Pathol 181: 1236-1249, 2012; Geng H, Lan R, Wang G, Siddiqi AR, Naski MC, Brooks AI, Barnes JL, Saikumar P, Weinberg JM, Venkatachalam MA. Am J Pathol 174: 1291-1308, 2009). We report now that LPA1 receptor signaling through epidermal growth factor receptor (EGFR)-ERK1/2-activator protein-1 cooperates with LPA2-dependent TGFB1 signaling to additively increase PDGFB/CTGF production and secretion by PT cells. Conversely, inhibition of both pathways results in greater suppression of PDGFB/CTGF production and secretion and promotes greater PT cellular differentiation than inhibiting one pathway alone. Antagonism of the LPA-generating enzyme autotaxin suppressed signaling through both pathways. After IRI, kidneys showed not only more LPA2, nuclear SMAD2/3, and PDGFB/CTGF but also increased LPA1 and autotaxin proteins, together with enhanced EGFR/ERK1/2 activation. Remarkably, the TGFB1 receptor antagonist SD-208 prevented all of these abnormalities excepting increased LPA2. SD-208 inhibits only one arm of LPA signaling: LPA2-Gqα-αvß6-integrin-dependent production of active TGFB1 and its receptor-bound downstream effects. Consequently, far-reaching protection by SD-208 against IRI-induced signaling alterations and tubule-interstitial pathology is not fully explained by our data. TGFB1-dependent feedforward modulation of LPA1 signaling is one possibility. SD-208 effects may also involve mitigation of injury caused by IRI-induced TGFB1 signaling in endothelial cells and monocytes. Our results have translational implications for using TGFB1 receptor antagonists, LPA1 and LPA2 inhibitors concurrently, and autotaxin inhibitors in acute kidney injury to prevent the development of chronic kidney disease.


Assuntos
Injúria Renal Aguda/metabolismo , Citocinas/metabolismo , Túbulos Renais Proximais/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Animais , Linhagem Celular , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Túbulos Renais Proximais/patologia , Linfocinas/metabolismo , Masculino , Camundongos , Fosforilação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
J Exp Bot ; 72(22): 7891-7908, 2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34338731

RESUMO

Phytophthora root and stem rot in soybean (Glycine max) is a destructive disease worldwide, and hence improving crop resistance to the causal pathogen, P. sojae, is a major target for breeders. However, it remains largely unclear how the pathogen regulates the various affected signaling pathways in the host, which consist of complex networks including key transcription factors and their targets. We have previously demonstrated that GmBTB/POZ enhances soybean resistance to P. sojae and the associated defense response. Here, we demonstrate that GmBTB/POZ interacts with the transcription factor GmAP2 and promotes its ubiquitination. GmAP2-RNAi transgenic soybean hairy roots exhibited enhanced resistance to P. sojae, whereas roots overexpressing GmAP2 showed hypersensitivity. GmWRKY33 was identified as a target of GmAP2, which represses its expression by directly binding to the promoter. GmWRKY33 acts as a positive regulator in the response of soybean to P. sojae. Overexpression of GmBTB/POZ released the GmAP2-regulated suppression of GmWRKY33 in hairy roots overexpressing GmAP2 and increased their resistance to P. sojae. Taken together, our results indicate that GmBTB/POZ-GmAP2 modulation of the P. sojae resistance response forms a novel regulatory mechanism, which putatively regulates the downstream target gene GmWRKY33 in soybean.


Assuntos
Domínio BTB-POZ , Phytophthora , Resistência à Doença/genética , Humanos , Doenças das Plantas/genética , Proteínas Repressoras , Glycine max/genética , Fatores de Transcrição/genética , Ubiquitinação
7.
Heart Surg Forum ; 22(1): E038-E044, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30802196

RESUMO

Background Intravenous sufentanil-midazolam and inhalational sevoflurane are widely used for anesthetic induction in children undergoing cardiac surgery. However, knowledge about their effects on hemodynamics and cardiac efficiency remains limited due largely to the lack of direct monitoring method. We used minimally invasive technique pressure recording analytical method (PRAM) to directly monitor hemodynamics and cardiac efficiency and compared the effects of the two anesthetic regimens in children undergoing ventricular septal defect repair. Methods Forty-Four children (2.3±0.9 years) were randomly divided into two groups to receive either intravenous sufentanil (1 µg/kg) and midazolam (0.2 mg/kg) (Group SM) or 2.0 minimal alveolar concentration (MAC) sevoflurane (Group S) to complete induction after sedation was obtained with 2.0 MAC sevoflurane. Systemic hemodynamic data recorded by PRAM included heart rate (HR), systolic (SBP) and mean (MBP) blood pressure, stroke volume index (SVI), cardiac index (CI), systemic vascular resistance index (SVRI), the maximal slope of systolic upstroke (dp/dtmax) and cardiac cycle efficiency (CCE) after sedation obtained, 1, 2, 5 min after induction achieved, 1, 2, 5 and 10 min after intubation. Results HR, SVRI showed a decrease in Group SM but an increase in Group S (Ptime*group<0.0001) in the study period. SVI and CCE showed an increase in Group SM but a decrease in Group S (Ptime*group<0.0001). SBP, MBP and CI were related to time after polynomial transformation, and showed an increase after intubation in Group SM but a decrease in Group S (Ptime2*group<0.0001). Conclusion PRAM provides meaningful and direct monitoring of hemodynamics and cardiac efficiency during the dynamic period of anesthetic induction in children undergoing cardiac surgery. As compared to inhalational sevoflurane, intravenous sufentanil-midazolam exerts more favorable effects on systemic hemodynamics and cardiac efficiency during anesthetic induction in this group of patients.


Assuntos
Anestesia Geral/métodos , Comunicação Interventricular/cirurgia , Hemodinâmica/fisiologia , Monitorização Intraoperatória/métodos , Sevoflurano/administração & dosagem , Sufentanil/administração & dosagem , Analgésicos Opioides , Anestésicos Inalatórios/administração & dosagem , Pré-Escolar , Feminino , Seguimentos , Comunicação Interventricular/fisiopatologia , Humanos , Injeções Intramusculares , Masculino , Estudos Prospectivos , Fatores de Tempo
8.
BMC Anesthesiol ; 18(1): 197, 2018 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-30579328

RESUMO

BACKGROUND: Although the neuroprotective role of propofol has been identified recently, the regulatory mechanism associated with microRNAs (miRNAs/miRs) in neuronal cells remains to be poorly understood. We aimed to explore the regulatory mechanism of propofol in hypoxia-injured rat pheochromocytoma (PC-12) cells. METHODS: PC-12 cells were exposed to hypoxia, and cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry assay/Western blot analysis, respectively. Effects of propofol on hypoxia-injured cells were measured, and the expression of miR-153 was determined by stem-loop RT-PCR. After that, whether propofol affected PC-12 cells under hypoxia via miR-153 was verified, and the downstream protein of miR-153 as well as the involved signaling cascade was finally explored. RESULTS: Hypoxia-induced decrease of cell viability and increase of apoptosis were attenuated by propofol. Then, we found hypoxia exposure up-regulated miR-153 expression, and the level of miR-153 was further elevated by propofol in hypoxia-injured PC-12 cells. Following experiments showed miR-153 inhibition reversed the effects of propofol on hypoxia-treated PC-12 cells. Afterwards, we found BTG3 expression was negatively regulated by miR-153 expression, and BTG3 overexpression inhibited the mTOR pathway and AMPK activation. Besides, hypoxia inhibited the mTOR pathway and AMPK, and these inhibitory effects could be attenuated by propofol. CONCLUSION: Propofol protected hypoxia-injured PC-12 cells through miR-153-mediataed down-regulation of BTG3. BTG3 could inhibit the mTOR pathway and AMPK activation.


Assuntos
Hipóxia Celular/efeitos dos fármacos , MicroRNAs/genética , Fármacos Neuroprotetores/farmacologia , Propofol/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Citometria de Fluxo , Células PC12 , Proteínas/genética , Ratos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
J Allergy Clin Immunol ; 139(3): 844-854, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27658763

RESUMO

BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS: Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.


Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Conjuntivite Alérgica/imunologia , Pyroglyphidae/imunologia , Rinite Alérgica/imunologia , Administração por Inalação , Adulto , Animais , Conjuntivite Alérgica/genética , Resistência à Doença , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Proteínas Filagrinas , Humanos , Contagem de Leucócitos , Masculino , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Rinite Alérgica/genética , Transcriptoma
10.
Pediatr Cardiol ; 38(1): 184-190, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27837303

RESUMO

Fluid management is challenging in infants after cardiopulmonary bypass. Pulse pressure variation (PPV) derived from pressure recording analytical method (PRAM) is based on lung-heart interaction during mechanical ventilation. A prospective observational study conducted in operating room tested PPV to predict fluid responsiveness in ventricular septal defect infants. Infants in open chest conditions with median sternotomy (n = 26) or minimally invasive right thoracotomy (n = 29) undergoing ventricular septal defect repair were enrolled. After cardiopulmonary bypass and modified ultrafiltration, all patients received fluid challenge. PPV was recorded using PRAM along with heart rate, diastolic blood pressure, stroke volume index (SVI), and cardiac index (CI) before and after volume replacement. Patients were considered as responders to fluid loading when CI increased ≥15%. In infants with median sternotomy, 12 were responders and 14 non-responders. PPV in responders was higher than that in non-responders (24.7 ± 6.4 vs. 16.6 ± 5.0%, P < 0.01). Area under the curve was 0.85 (95% confidence interval, 0.69-1, P = 0.001) and cutoff value 19% with a sensitivity of 92% and a specificity of 71%. In infants with minimally invasive right thoracotomy, 16 were responders and 13 non-responders. PPV in responders was higher than that in non-responders (25.0 ± 6.8 vs. 18.2 ± 5.3, P < 0.01). Area under the curve was 0.83 (95 confidence interval, 0.66-0.98, P = 0.001) and cutoff value 18% with a sensitivity of 94% and a specificity of 69%. PPV sensitively predicts fluid responsiveness in ventricular septal defect infants after surgical repair in open chest conditions both with median sternotomy and minimally invasive right thoracotomy.


Assuntos
Determinação da Pressão Arterial/métodos , Pressão Sanguínea/fisiologia , Ponte Cardiopulmonar/métodos , Hidratação/métodos , Comunicação Interventricular/cirurgia , Área Sob a Curva , Feminino , Comunicação Interventricular/fisiopatologia , Hemodinâmica/fisiologia , Humanos , Lactente , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Esternotomia/métodos , Toracotomia/métodos
11.
J Allergy Clin Immunol ; 136(3): 658-66, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26026342

RESUMO

BACKGROUND: Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. OBJECTIVE: We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. METHODS: Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. RESULTS: The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C- > M+P+C+ > M+P-C- > M+P-C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C- participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C- status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). CONCLUSIONS: C+ status is associated with mitigation of AR symptom severity in adults with AR.


Assuntos
Alérgenos/administração & dosagem , Baratas/imunologia , Conjuntivite Alérgica/terapia , Dessensibilização Imunológica/métodos , Pólen/imunologia , Rinite Alérgica Sazonal/terapia , Adulto , Alérgenos/química , Alérgenos/imunologia , Ambrosia/química , Ambrosia/imunologia , Animais , Baratas/química , Conjuntivite Alérgica/diagnóstico , Conjuntivite Alérgica/imunologia , Conjuntivite Alérgica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pólen/química , Pyroglyphidae/química , Pyroglyphidae/imunologia , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/fisiopatologia , Estações do Ano , Índice de Gravidade de Doença , Testes Cutâneos
12.
bioRxiv ; 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37961304

RESUMO

CC-chemokine ligand 2 (CCL2) is involved in the pathogenesis of several diseases associated with monocyte/macrophage recruitment, such as HIV-associated neurocognitive disorder (HAND), tuberculosis, and atherosclerosis. The rs1024611 (alleles:A>G; G is the risk allele) polymorphism in the CCL2 cis-regulatory region is associated with increased CCL2 expression in vitro and ex vivo, leukocyte mobilization in vivo, and deleterious disease outcomes. However, the molecular basis for the rs1024611-associated differential CCL2 expression remains poorly characterized. It is conceivable that genetic variant(s) in linkage disequilibrium (LD) with rs1024611 could mediate such effects. Previously, we used rs13900 (alleles:_C>T) in the CCL2 3' untranslated region (3' UTR) that is in perfect LD with rs1024611 to demonstrate allelic expression imbalance (AEI) of CCL2 in heterozygous individuals. Here we tested the hypothesis that the rs13900 could modulate CCL2 expression by altering mRNA turnover and/or translatability. The rs13900 T allele conferred greater stability to the CCL2 transcript when compared to the rs13900 C allele. The rs13900 T allele also had increased binding to Human Antigen R (HuR), an RNA-binding protein, in vitro and ex vivo. The rs13900 alleles imparted differential activity to reporter vectors and influenced the translatability of the reporter transcript. We further demonstrated a role for HuR in mediating allele-specific effects on CCL2 expression in overexpression and silencing studies. The presence of the rs1024611G-rs13900T conferred a distinct transcriptomic signature related to inflammation and immunity. Our studies suggest that the differential interactions of HuR with rs13900 could modulate CCL2 expression and explain the interindividual differences in CCL2-mediated disease susceptibility.

13.
Rheumatol Int ; 32(8): 2479-85, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21773883

RESUMO

A common single nucleotide polymorphism (SNP) in the gene of brain-derived neurotrophic factor (BDNF) results from a substitution at position 66 from valine (Val) to methionine (Met) and may predispose to human neuropsychiatric disorders. We proposed to determine whether these BDNF gene SNPs were associated with fibromyalgia syndrome (FMS) and/or any of its typical phenotypes. Patients with FMS (N = 95) and healthy normal controls (HNC, N = 58) were studied. Serum high-sensitivity C-reactive protein (hsCRP) levels were measured using an enzyme-linked immunosorbent assay (ELISA). The BDNF SNPs were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The BDNF SNP distribution was 65 (68%) Val/Val, 28 (30%) Val/Met, and 2 (2%) Met/Met for FMS and 40 (69%), 17(29%), and 1 (2%) for HNC, respectively. The serum high-sensitivity C-reactive protein (hsCRP)and body mass index (BMI) in FMS were higher than in HNC. The FMS with BDNF Val66Val had significantly higher mean BMI (P = 0.0001) and hsCRP (P = 0.02) than did FMS carrying the Val66Met genotype. This pattern was not found in HNC. Phenotypic measures of subjective pain, pain threshold, depression, or insomnia did not relate to either of the BDNF SNPs in FMS. The relative distribution BDNF SNPs did not differ between FMS and HNC. The BDNF Val66Met polymorphism is not selective for FMS. The BDNF Val66Val SNP identifies a subgroup of FMS with elevated hsCRP and higher BMI. This is the first study to associate a BDNF polymorphism with a FMS subgroup phenotype.


Assuntos
Índice de Massa Corporal , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína C-Reativa/análise , Fibromialgia/genética , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Ensaio de Imunoadsorção Enzimática , Feminino , Fibromialgia/sangue , Fibromialgia/diagnóstico , Fibromialgia/imunologia , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Medição de Risco , Fatores de Risco , Texas , Regulação para Cima
14.
Cancers (Basel) ; 14(4)2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35205640

RESUMO

Organ-confined prostate cancer of low-grade histopathology is managed with radiation, surgery, active surveillance, or watchful waiting and exhibits a 5-year overall survival (OS) of 95%, while metastatic prostate cancer (PCa) is incurable, holding a 5-year OS of 30%. Treatment options for advanced PCa-metastatic and non-metastatic-include hormone therapy that inactivates androgen receptor (AR) signaling, chemotherapy and genome-targeted therapy entailing synthetic lethality of tumor cells exhibiting aberrant DNA damage response, and immune checkpoint inhibition (ICI), which suppresses tumors with genomic microsatellite instability and/or deficient mismatch repair. Cancer genome sequencing uncovered novel somatic and germline mutations, while mechanistic studies are revealing their pathological consequences. A microRNA has shown biomarker potential for stratifying patients who may benefit from angiogenesis inhibition prior to ICI. A 22-gene expression signature may select high-risk localized PCa, which would not additionally benefit from post-radiation hormone therapy. We present an up-to-date review of the molecular and therapeutic aspects of PCa, highlight genomic alterations leading to AR upregulation and discuss AR-degrading molecules as promising anti-AR therapeutics. New biomarkers and druggable targets are shaping innovative intervention strategies against high-risk localized and metastatic PCa, including AR-independent small cell-neuroendocrine carcinoma, while presenting individualized treatment opportunities through improved design and precision targeting.

15.
Neurotox Res ; 40(6): 1895-1901, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36223054

RESUMO

This study attempted to explore whether miR-363-3p play a role in the isoflurane (ISO)-mediated protective effect of cardiomyocyte injury induced by hypoxia/reoxygenation (H/R). A myocardial cell injury model was established, and the different preconditioning ISO concentrations were screened and determined. The miR-363-3p level was detected by RT-qPCR. The effects of miR-363-3p on proliferation and apoptosis of H9c2 cells were detected by CCK-8 assay and flow cytometry. Myocardial injury indexes were determined by enzyme-linked immunosorbent assay (ELISA). The interaction of miR-363-3p with the 3'-UTR of the KLF2 gene was confirmed by luciferase reporter gene assay. ISO pretreatment can reduce the up-regulation of miR-363-3p after H/R injury. ISO pretreatment reduces the inhibition of cell viability and the promotion of cell apoptosis induced by H/R stimuli, while the overexpression of miR-363-3p counteracts the protective effect of ISO pretreatment. Meanwhile, ISO pretreatment also reduced the level of markers of H/R-induced myocardial injury. Moreover, luciferase reporter analysis showed that KLF2 was the downstream target gene of miR-363-3p. ISO pretreatment may alleviate H/R-induced cardiomyocyte injury by regulating miR-363-3p.


Assuntos
Isoflurano , MicroRNAs , Humanos , Miócitos Cardíacos , Isoflurano/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Hipóxia Celular , Hipóxia/metabolismo , Apoptose
16.
Front Plant Sci ; 12: 513388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33584766

RESUMO

Phytophthora root rot, caused by Phytophthora sojae is a destructive disease of soybean (Glycine max) worldwide. We previously confirmed that the bHLH transcription factor GmPIB1 (P. sojae-inducible bHLH transcription factor) reduces accumulation of reactive oxygen species (ROS) in cells by inhibiting expression of the peroxidase-related gene GmSPOD thus improving the resistance of hairy roots to P. sojae. To identify proteins interacting with GmPIB1 and assess their participation in the defense response to P. sojae, we obtained transgenic soybean hairy roots overexpressing GmPIB1 by Agrobacterium rhizogenes mediated transformation and examined GmPIB1 protein-protein interactions using immunoprecipitation combined with mass spectrometry. We identified 392 proteins likely interacting with GmPIB1 and selected 20 candidate genes, and only 26S proteasome regulatory subunit GmPSMD (Genbank accession no. XP_014631720) interacted with GmPIB1 in luciferase complementation and pull-down experiments and yeast two-hybrid assays. Overexpression of GmPSMD (GmPSMD-OE) in soybean hairy roots remarkably improved resistance to P. sojae and RNA interference of GmPSMD (GmPSMD -RNAi) increased susceptibility. In addition, accumulation of total ROS and hydrogen peroxide (H2O2) in GmPSMD-OE transgenic soybean hairy roots were remarkably lower than those of the control after P. sojae infection. Moreover, in GmPSMD-RNAi transgenic soybean hairy roots, H2O2 and the accumulation of total ROS exceeded those of the control. There was no obvious difference in superoxide anion (O2 -) content between control and transgenic hairy roots. Antioxidant enzymes include peroxidase (POD), glutathione peroxidase (GPX), superoxide dismutase (SOD), catalase (CAT) are responsible for ROS scavenging in soybean. The activities of these antioxidant enzymes were remarkably higher in GmPSMD-OE transgenic soybean hairy roots than those in control, but were reduced in GmPSMD-RNAi transgenic soybean hairy roots. Moreover, the activity of 26S proteasome in GmPSMD-OE and GmPIB1-OE transgenic soybean hairy roots was significantly higher than that in control and was significantly lower in PSMD-RNAi soybean hairy roots after P. sojae infection. These data suggest that GmPSMD might reduce the production of ROS by improving the activity of antioxidant enzymes such as POD, SOD, GPX, CAT, and GmPSMD plays a significant role in the response of soybean to P. sojae. Our study reveals a valuable mechanism for regulation of the pathogen response by the 26S proteasome in soybean.

17.
Mol Hum Reprod ; 15(10): 665-73, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19505996

RESUMO

Transforming growth factor beta 1 (TGF-beta1) levels are increased in the peritoneal fluid of endometriosis patients, and endometrial cells express TGF-beta signaling components; however, little is known regarding the role of TGF-beta in endometriosis. Our objective was to examine the effects of TGF-beta1 on (i) the expression of macrophage colony-stimulating factor receptor encoded by the c-fms gene, (ii) transmesothelial invasiveness of endometrial cells, (iii) cellular proliferation and (iv) attachment to peritoneal mesothelial cells (PMCs). Effects of TGF-beta1 on c-fms mRNA expression were determined by real-time RT-PCR and c-fms cell-surface expression by flow cytometry. Effects of TGF-beta1 on the invasiveness of the immortalized endometrial epithelial cell (EEC) line EM42 and primary EECs were examined using a three-dimensional in vitro system modeling the peritoneum. Cellular proliferation and attachment to PMCs were also examined using established techniques. TGF-beta1 had little or no effect on cellular proliferation and endometrial cell attachment to PMCs. TGF-beta1 significantly induced the expression of c-fms mRNA and c-fms cell-surface expression. TGF-beta1 enhanced transmesothelial invasion by EM42 cells and EECs. Antagonists of TGF-beta1 signaling significantly inhibited both the induction of c-fms expression and cellular invasiveness, suggesting that additional studies are warranted to assess the therapeutic potential of TGF-beta antagonists in endometriosis.


Assuntos
Endométrio/citologia , Células Epiteliais/citologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Imunoprecipitação da Cromatina , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Feminino , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Regiões Promotoras Genéticas/genética , Piridinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/fisiologia
18.
Chem Res Toxicol ; 22(10): 1705-12, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19694485

RESUMO

A new class of platinum(II) coordination complexes and their dye tagged conjugates has been synthesized from N-substituted diaminocyclohexane ligands. The in vitro anticancer activities of the platinum compounds have been validated against the breast cancer cell-line MCF-7 and the normal cell-line MCF-10A via sulforhodamine B and colony formation assay. The platinum compounds and the corresponding metal-free ligands exhibited higher drug efficiencies than cisplatin and oxaliplatin against MCF-7 cells. Cellular uptake and DNA-bound Pt were demonstrated by atomic absorption spectroscopy. The platinum complexes displayed increased cellular accumulation and DNA binding as compared with cisplatin. Real-time reverse transcription polymerase chain reaction assay was employed to investigate drug effects on mRNA expression in MCF-7 cells. The results indicated that the study compounds are effective in regulating cyclin D1, Bcl-2, and p53 genes; yet, oxaliplatin is less effective in manipulating those genes. The luminescent probe that was integrated into the platinum complexes made it possible to monitor cellular drug distribution using optical imaging. Targeting of tumor cell nuclei by the study compounds was confirmed by confocal microscopy. Taken together, these new platinum(II)-based antitumor agents are different from marketed platinum drugs in several critical aspects and could have potential in cancer therapy.


Assuntos
Antineoplásicos/toxicidade , Corantes Fluorescentes/química , Compostos Organoplatínicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Cisplatino/toxicidade , Ciclina D1/genética , Ciclina D1/metabolismo , DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Microscopia Confocal , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
19.
Cancer Res ; 67(5): 1918-26, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17332318

RESUMO

Cervical cancer is the third most common gynecologic cancer in the United States. The presence and possible involvement of several cytokines have been studied in cervical cancer; however, very little data, if any, are available on whether cervical tumors are responsive to stimulation by the macrophage colony-stimulating factor-1 (CSF-1). Given the involvement of c-fms and its ligand CSF-1 in gynecologic cancers, such as that of the uterus and the ovaries, we have examined the expression of c-fms and CSF-1 in cervical tumor (n = 17) and normal cervix (n = 8) samples. The data show that c-fms and its ligand are significantly higher in cervical carcinomas compared with normal samples. Immunohistochemistry not only showed that tumor cells expressed significantly higher levels of c-fms but also c-fms levels were markedly higher in tumor cells than tumor-associated stromal cells. Blocking c-fms activity in cervical cancer cells, which express CSF-1 and c-fms, resulted in increased apoptosis and decreased motility compared with control, suggesting that CSF-1/c-fms signaling may be involved in enhanced survival and possibly invasion by cervical cancer cells via an autocrine mechanism. Combined, the data show for the first time the induction of CSF-1 and c-fms in cervical carcinomas and suggest that c-fms activation may play a role in cervical carcinogenesis. Additionally, our data suggest that transforming growth factor-beta1 may be a factor in inducing the expression of c-fms in cervical cancer cells. The data suggest that c-fms may be a valuable therapeutic target in cervical cancer.


Assuntos
Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator de Crescimento Transformador beta1/fisiologia , Neoplasias do Colo do Útero/genética , Apoptose/efeitos dos fármacos , Carcinoma/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo
20.
Cancer Genomics Proteomics ; 4(6): 377-85, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18204200

RESUMO

UNLABELLED: A growing body of evidence suggests that early growth response-1 (Egr-1), a transcription factor, may function as a tumor suppressor. The aim of this study was to gain more evidence to support the role of Egr-1 in the suppression of cancer cell growth and to examine the potential correlation between Egr-1 and gelsolin. MATERIALS AND METHODS: Histochemical staining coupled with breast cancer tissue arrays were used to examine the expression levels of Egr-1 and gelsolin. Reporter assays and gel shift were used to study the transcriptional activity of Egr-1 on the regulation of gelsolin. RESULTS: Our data showed that most normal mammary tissues expressed high levels of Egr-1, while the majority of breast cancer tissues expressed very small amounts of Egr-1. The expression pattern of Egr-1 in human breast cancer tissues was highly correlated with gelsolin expression. Induction of Egr-1 by serum stimulation accompanied the increase of gelsolin expression. In cells lacking the induction of Egr-1 in response to serum stimulation, gelsolin expression remained unchanged. Furthermore, gelsolin promoter activity was profoundly reduced in Egr-1 null mouse embryonic fibroblasts compared to Egr-1 wild-type mouse embryonic fibroblasts. Gel shift experiments indicated that Egr-1 can directly bind to the gelsolin promoter. CONCLUSION: Our results suggest that Egr-1 may be an important breast cancer marker and that an as yet uncharacterized pathway involved in Egr-1 and gelsolin expression exists which leads to breast cancer cell development.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Gelsolina/genética , Gelsolina/metabolismo , Regulação Neoplásica da Expressão Gênica , Animais , Sítios de Ligação , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Imuno-Histoquímica , Camundongos , Regiões Promotoras Genéticas/genética , Fatores de Tempo
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