RESUMEN
Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease caused by the rodent-transmitted orthohantaviruses (HVs), with China possessing the most cases globally. The virus hosts in China are Apodemus agrarius and Rattus norvegicus, and the disease spread is strongly influenced by global climate dynamics. To assess and predict the spatiotemporal trends of HFRS from 2005 to 2098, we collected historical HFRS data in mainland China (2005-2020), historical and projected climate and population data (2005-2098), and spatial variables including biotic, environmental, topographical, and socioeconomic. Spatiotemporal predictions and mapping were conducted under 27 scenarios incorporating multiple integrated representative concentration pathway models and population scenarios. We identify the type of magistral HVs host species as the best spatial division, including four region categories. Seven extreme climate indices associated with temperature and precipitation have been pinpointed as key factors affecting the trends of HFRS. Our predictions indicate that annual HFRS cases will increase significantly in 62 of 356 cities in mainland China. Rattus regions are predicted to be the most active, surpassing Apodemus and Mixed regions. Eighty cities are identified as at severe risk level for HFRS, each with over 50 reported cases annually, including 22 new cities primarily located in East China and Rattus regions after 2020, while 6 others develop new risk. Our results suggest that the risk of HFRS will remain high through the end of this century, with Rattus norvegicus being the most active host, and that extreme climate indices are significant risk factors. Our findings can inform evidence-based policymaking regarding future risk of HFRS.
Asunto(s)
Fiebre Hemorrágica con Síndrome Renal , Ratas , Animales , Fiebre Hemorrágica con Síndrome Renal/epidemiología , Fiebre Hemorrágica con Síndrome Renal/etiología , Clima , Zoonosis , China/epidemiología , Murinae , IncidenciaRESUMEN
We reported that a 31-amino-acid Zfra protein (zinc finger-like protein that regulates apoptosis) blocks neurodegeneration and cancer growth. Zfra binds WW domain-containing oxidoreductase (WWOX) to both N- and C-termini, which leads to accelerated WWOX degradation. WWOX limits the progression of neurodegeneration such as Alzheimer's disease (AD) by binding tau and tau-hyperphosphorylating enzymes. Similarly, Zfra binds many protein targets and accelerates their degradation independently of ubiquitination. Furthermore, Zfra4-10 peptide strongly prevents the progression of AD-like symptoms in triple-transgenic (3xTg) mice during aging. Zfra4-10 peptide restores memory loss in 9-month-old 3xTg mice by blocking the aggregation of a protein cascade, including TPC6AΔ, TIAF1, and SH3GLB2, by causing aggregation of tau and amyloid ß. Zfra4-10 also suppresses inflammatory NF-κB activation. Zfra-activated Hyal-2+ CD3- CD19- Z cells in the spleen, via Hyal-2/WWOX/Smad4 signaling, are potent in cancer suppression. In this perspective review, we provide mechanistic insights regarding how Zfra overrides WWOX to induce cancer suppression and retard AD progression via Z cells.
Asunto(s)
Péptidos beta-Amiloides , Neoplasias , Ratones , Animales , Oxidorreductasa que Contiene Dominios WW/genética , Oxidorreductasa que Contiene Dominios WW/metabolismo , Apoptosis , Transducción de Señal/fisiología , Neoplasias/metabolismoRESUMEN
In this paper, Cu-BTC derived mesoporous CuS nanomaterial (m-CuS) was synthesized via a two-step process involving carbonization and sulfidation of Cu-BTC for colorimetric glutathione detection. The Cu-BTC was constructed by 1,3,5-benzenetri-carboxylic acid (H3BTC) and Cu2+ ions. The obtained m-CuS showed a large specific surface area (55.751 m2/g), pore volume (0.153 cm3/g), and pore diameter (15.380 nm). In addition, the synthesized m-CuS exhibited high peroxidase-like activity and could catalyze oxidation of the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue product. Peroxidase-like activity mechanism studies using terephthalic acid as a fluorescent probe proved that m-CuS assists H2O2 decomposition to reactive oxygen species, which are responsible for TMB oxidation. However, the catalytic activity of m-CuS for the oxidation of TMB by H2O2 could be potently inhibited in the presence of glutathione. Based on this phenomenon, the colorimetric detection of glutathione was demonstrated with good selectivity and high sensitivity. The linear range was 1-20 µM and 20-300 µM with a detection limit of 0.1 µM. The m-CuS showing good stability and robust peroxidase catalytic activity was applied for the detection of glutathione in human urine samples.
Asunto(s)
Colorimetría , Cobre , Glutatión , Peróxido de Hidrógeno , Nanoestructuras , Glutatión/análisis , Glutatión/química , Colorimetría/métodos , Cobre/química , Nanoestructuras/química , Catálisis , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/análisis , Porosidad , Oxidación-Reducción , Ácidos Ftálicos/química , Humanos , Bencidinas/química , Límite de DetecciónRESUMEN
When WWOX is downregulated in middle age, aggregation of a protein cascade, including TRAPPC6AΔ (TPC6AΔ), TIAF1, and SH3GLB2, may start to occur, and the event lasts more than 30 years, which results in amyloid precursor protein (APP) degradation, amyloid beta (Aß) generation, and neurodegeneration, as shown in Alzheimer's disease (AD). Here, by treating neuroblastoma SK-N-SH cells with neurotoxin MPP+, upregulation and aggregation of TPC6AΔ, along with aggregation of TIAF1, SH3GLB2, Aß, and tau, occurred. MPP+ is an inducer of Parkinson's disease (PD), suggesting that TPC6AΔ is a common initiator for AD and PD pathogenesis. Zfra, a 31-amino-acid zinc finger-like WWOX-binding protein, is known to restore memory deficits in 9-month-old triple-transgenic (3xTg) mice by blocking the aggregation of TPC6AΔ, SH3GLB2, tau, and amyloid ß, as well as inflammatory NF-κB activation. The Zfra4-10 peptide exerted a strong potency in preventing memory loss during the aging of 3-month-old 3xTg mice up to 9 months, as determined by a novel object recognition task (ORT) and Morris water maize analysis. Compared to age-matched wild type mice, 11-month-old Wwox heterozygous mice exhibited memory loss, and this correlates with pT12-WWOX aggregation in the cortex. Together, aggregation of pT12-WWOX may link to TPC6AΔ aggregation for AD progression, with TPC6AΔ aggregation being a common initiator for AD and PD progression.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Parkinson , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animales de Enfermedad , Trastornos de la Memoria , Ratones Transgénicos , Transducción de Señal , Proteínas tau/metabolismo , Enfermedad de Parkinson/metabolismoRESUMEN
The adrenal gland is an important endocrine organ of human body. CYP11B1 gene was specifically expressed in the zona fasciculata in adrenal cortex. In order to better study the function of genes specifically expressed in the zona fasciculata in adrenal cortex, the mice with Cre recombinase specifically expressed in the zona fasciculata in adrenal cortex were constructed. It was then confirmed that CYP11B1 was specifically expressed in adrenal glands. Then, using CRISPR/Cas9 technique, CYP11B1-2A-GfpCre recombinant vector was constructed and subsequently injected into the fertilized eggs of mice. It was confirmed that the Cre gene was mainly expressed in the zona fasciculata in adrenal cortex of CYP11B1Cre mice by using mTmG and LacZ staining. The CYP11B1Cre mice were then mated with cystathionine γ-lyase (CTH)f/f mice, thereby generating CTHf/f/CYP11B1Cre mice. It was also confirmed that CTH gene in the zona fasciculata in adrenal cortex was specifically knocked out in these mice. These results suggest that transgenic mice with specific Cre recombinase expression in the zona fasciculata in adrenal cortex were constructed successfully. This animal model can be a powerful tool for the study of the function of genes expressed in the zona fasciculata in adrenal cortex.
Asunto(s)
Corteza Suprarrenal/enzimología , Integrasas/metabolismo , Ratones Transgénicos , Zona Fascicular/enzimología , Animales , Sistemas CRISPR-Cas , Cistationina gamma-Liasa/genética , Integrasas/genética , RatonesRESUMEN
BACKGROUND: Tumor suppressor WWOX physically binds p53 and TIAF1 and together induces apoptosis and tumor suppression. To understand the molecular action, here we investigated the formation of WWOX/TIAF1/p53 triad and its regulation of cancer cell migration, anchorage-independent growth, SMAD promoter activation, apoptosis, and potential role in neurodegeneration. METHODS: Time-lapse microscopy was used to measure the extent of cell migration. Protein/protein interactions were determined by co-immunoprecipitation, FRET microscopy, and yeast two-hybrid analysis. The WWOX/TIAF1/p53 triad-mediated cancer suppression was determined by measuring the extent of cell migration, anchorage-independent growth, SMAD promoter activation, and apoptosis. p53-deficient lung cancer cell growth in nude mice was carried out to assess the tumor suppressor function of ectopic p53 and/or WWOX. RESULTS: Wwox-deficient MEF cells exhibited constitutive Smad3 and p38 activation and migrated individually and much faster than wild type cells. TGF-ß increased the migration of wild type MEF cells, but significantly suppressed Wwox knockout cell migration. While each of the triad proteins is responsive to TGF-ß stimulation, ectopically expressed triad proteins suppressed cancer cell migration, anchorage-independent growth, and SMAD promoter activation, as well as caused apoptosis. The effects are due in part to TIAF1 polymerization and its retention of p53 and WWOX in the cytoplasm. p53 and TIAF1 were effective in suppressing anchorage-independent growth, and WWOX ineffective. p53 and TIAF1 blocked WWOX or Smad4-regulated SMAD promoter activation. WWOX suppressed lung cancer NCI-H1299 growth and inhibited splenomegaly by inflammatory immune response, and p53 blocked the event in nude mice. The p53/WWOX-cancer mice exhibited BACE upregulation, APP degradation, tau tangle formation, and amyloid ß generation in the brain and lung. CONCLUSION: The WWOX/TIAF1/p53 triad is potent in cancer suppression by blocking cancer cell migration, anchorage-independent growth and SMAD promoter activation, and causing apoptosis. Yet, p53 may functionally antagonize with WWOX. p53 blocks WWOX inhibition of inflammatory immune response induced by cancer, and this leads to protein aggregation in the brain as seen in the Alzheimer's disease and other neurodegeneration.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias de la Mama/terapia , Neoplasias Pulmonares/terapia , Proteínas Nucleares/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Oxidorreductasa que Contiene Dominios WW/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Noqueados , Ratones Desnudos , Proteínas Nucleares/antagonistas & inhibidores , Agregado de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/deficiencia , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/deficiencia , Oxidorreductasa que Contiene Dominios WW/antagonistas & inhibidores , Oxidorreductasa que Contiene Dominios WW/deficienciaRESUMEN
Invariant NKT (iNKT) cells are innate lymphocytes that respond to glycolipids presented by the MHC class Ib molecule CD1d and are rapidly activated to produce large quantities of cytokines and chemokines. iNKT cell development uniquely depends on interactions between double-positive thymocytes that provide key homotypic interactions between signaling lymphocyte activation molecule (SLAM) family members. However, the role of SLAM receptors in the differentiation of iNKT cell effector subsets and activation has not been explored. In this article, we show that C57BL/6 mice containing the New Zealand Black Slam locus have profound alterations in Ly108, CD150, and Ly9 expression that is associated with iNKT cell hyporesponsiveness. This loss of function was only apparent when dendritic cells and iNKT cells had a loss of SLAM receptor expression. Using small interfering RNA knockdowns and peptide-blocking strategies, we demonstrated that trans-Ly108 interactions between dendritic cells and iNKT cells are critical for robust activation. LY108 costimulation similarly increased human iNKT cell activation. Thus, in addition to its established role in iNKT cell ontogeny, Ly108 regulates iNKT cell function in mice and humans.
Asunto(s)
Antígenos Ly/metabolismo , Células Dendríticas/metabolismo , Activación de Linfocitos , Células T Asesinas Naturales/inmunología , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Animales , Antígenos CD1d/inmunología , Antígenos Ly/genética , Antígenos Ly/inmunología , Diferenciación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Células T Asesinas Naturales/metabolismo , ARN Interferente Pequeño , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/deficiencia , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunologíaRESUMEN
Whether tumor suppressor WWOX (WW domain-containing oxidoreductase) stimulates immune cell maturation is largely unknown. Here, we determined that Tyr-33-phosphorylated WWOX physically binds non-phosphorylated ERK and IκBα in immature acute lymphoblastic leukemia MOLT-4 T cells and in the naïve mouse spleen. The IκBα·ERK·WWOX complex was shown to localize, in part, in the mitochondria. WWOX prevents IκBα from proteasomal degradation. Upon stimulating MOLT-4 with ionophore A23187/phorbol myristate acetate, endogenous IκBα and ERK undergo rapid phosphorylation in <5 min, and subsequently WWOX is Tyr-33 and Tyr-287 de-phosphorylated and Ser-14 phosphorylated. Three hours later, IκBα starts to degrade, and ERK returns to basal or non-phosphorylation, and this lasts for the next 12 h. Finally, expression of CD3 and CD8 occurs in MOLT-4 along with reappearance of the IκBα·ERK·WWOX complex near 24 h. Inhibition of ERK phosphorylation by U0126 or IκBα degradation by MG132 prevents MOLT-4 maturation. By time-lapse FRET microscopy, IκBα·ERK·WWOX complex exhibits an increased binding strength by 1-2-fold after exposure to ionophore A23187/phorbol myristate acetate for 15-24 h. Meanwhile, a portion of ERK and WWOX relocates to the nucleus, suggesting their role in the induction of CD3 and CD8 expression in MOLT-4.
Asunto(s)
Núcleo Celular/metabolismo , Oxidorreductasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/genética , Animales , Calcimicina/farmacología , Núcleo Celular/genética , Núcleo Celular/patología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HEK293 , Humanos , Células Jurkat , Ratones , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Inhibidor NF-kappaB alfa/genética , Inhibidor NF-kappaB alfa/metabolismo , Oxidorreductasas/genética , Fosforilación/efectos de los fármacos , Fosforilación/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Dominios Proteicos , Proteolisis/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Proteínas Supresoras de Tumor/genética , Células U937 , Oxidorreductasa que Contiene Dominios WWRESUMEN
BACKGROUND: Hydrogen sulfide (H2S), known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI) induced by endotoxemia. METHODS: Male ICR mice were divided in six groups: (1) Control group; (2) GYY4137treatment group; (3) L-NAME treatment group; (4) lipopolysaccharide (LPS) treatment group; (5) LPS with GYY4137 treatment group; and (6) LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich) reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting. RESULTS: GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC) and theactivities of catalase (CAT) and superoxide dismutase (SOD) but decreased a marker of peroxynitrite (ONOO-) action and 3-nitrotyrosine (3-NT) in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL)-6, IL-8, and myeloperoxidase (MPO) and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA), hydrogenperoxide (H2O2) and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio) and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS) expression and nitric oxide (NO) production in the endotoxemia lung. CONCLUSIONS: GYY4137 conferred protection against acute endotoxemia-associated lung injury, which may have beendue to the anti-oxidant, anti-nitrative and anti-inflammatory properties of GYY4137. The present findings warrant further exploration of the clinical applicability of H2S in the prevention and treatment of ALI.
Asunto(s)
Lesión Pulmonar Aguda/patología , Sulfuro de Hidrógeno/farmacología , Inflamación/patología , Estrés Oxidativo/efectos de los fármacos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/complicaciones , Animales , Antioxidantes/metabolismo , Endotoxemia/complicaciones , Endotoxemia/metabolismo , Endotoxemia/patología , Peróxido de Hidrógeno , Inflamación/complicaciones , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Malondialdehído/metabolismo , Ratones Endogámicos ICR , Morfolinas/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitrosación/efectos de los fármacos , Compuestos Organotiofosforados/farmacología , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
We have recently demonstrated that endotoxin causes oxidative stress and overproduction of nitric oxide in adrenal glands, thereby leading to adrenocortical insufficiency. The aim of this study is to investigate the effects of resveratrol, a natural plant polyphenol with anti-oxidant and anti-nitrative properties, on endotoxemia-associated adrenocortical insufficiency. Resveratrol was administered immediately before injection of lipopolysaccharide (LPS). Twenty four hours later, the adrenocorticotropic hormone (ACTH) stimulation tests was been performed to measure the plasma corticosterone level and the adrenal gland tissues were collected for histopathologic examination, and determination of malondialdehyde (MDA), total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) and peroxynitrite production. Treatment with resveratrol significantly inhibited endotoxemia-induced iNOS expression, NO production, and peroxynitrite formation and also attenuated LPS-induced oxidative stress in the adrenal gland, as evidenced by the decrease of pro-oxidant biomarker (MDA), and the increases of anti-oxidant biomarkers (T-AOC, CAT and SOD activity). H&E staining demonstrated that administration of LPS resulted in increased into the adrenal gland. H&E-stained sections of adrenal glands demonstrated signs of leukocyte infiltration and hemorrhage during endotoxemia, which were significantly improved by resveratrol treatment. In addition, resveratrol reversed the LPS-induced downregulation of ACTH receptor and silent information regulator 1 (SIRT1) in adrenal gland, as well as adrenocortical hyporesponsiveness to ACTH. Resveratrol exerts protective effects against endotoxemia-associated adrenocortical insufficiency by suppressing oxidative/nitrative stress. These findings support the potential for resveratrol as a possible pharmacological agent to improve adrenocortical insufficiency resulting from oxidative/nitrative damage.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Insuficiencia Suprarrenal/prevención & control , Citoprotección/efectos de los fármacos , Endotoxemia/complicaciones , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Glándulas Suprarrenales/metabolismo , Insuficiencia Suprarrenal/etiología , Animales , Antioxidantes/farmacología , Endotoxemia/inducido químicamente , Endotoxemia/prevención & control , Peroxidación de Lípido/efectos de los fármacos , Lipopolisacáridos , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos ICR , Óxido Nítrico/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ResveratrolRESUMEN
Abnormal cardiac valve morphogenesis is a common cause of human congenital heart disease. The molecular mechanisms regulating endocardial cell proliferation and differentiation into cardiac valves remain largely unknown, although great progress has been made on the endocardial contribution to the atrioventricular cushion and valve formation. We found that scotch tape(te382) (sco(te382)) encodes a novel transmembrane protein that is crucial for endocardial cell proliferation and heart valve development. The zebrafish sco(te382) mutant showed diminished endocardial cell proliferation, lack of heart valve leaflets and abnormal common cardinal and caudal veins. Positional cloning revealed a C946T nonsense mutation of a novel gene pku300 in the sco(te382) locus, which encoded a 540-amino-acid protein on cell membranes with one putative transmembrane domain and three IgG domains. A known G3935T missense mutation of fbn2b was also found â¼570 kb away from pku300 in sco(te382) mutants. The genetic mutant sco(pku300), derived from sco(te382), only had the C946T mutation of pku300 and showed reduced numbers of atrial endocardial cells and an abnormal common cardinal vein. Morpholino knockdown of fbn2b led to fewer atrial endocardial cells and an abnormal caudal vein. Knockdown of both pku300 and fbn2b phenocopied these phenotypes in sco(te382) genetic mutants. pku300 transgenic expression in endocardial and endothelial cells, but not myocardial cells, partially rescued the atrial endocardial defects in sco(te382) mutants. Mechanistically, pku300 and fbn2b were required for endocardial cell proliferation, endocardial Notch signaling and the proper formation of endocardial cell adhesion and tight junctions, all of which are crucial for cardiac valve development. We conclude that pku300 and fbn2b represent the few genes capable of regulating endocardial cell proliferation and signaling in zebrafish cardiac valve development.
Asunto(s)
Endocardio/embriología , Válvulas Cardíacas/embriología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Pez Cebra/genética , Pez Cebra/embriología , Anomalías Múltiples/genética , Animales , Diferenciación Celular/genética , Proliferación Celular , Células Cultivadas , Endocardio/citología , Endocardio/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica/genética , Cardiopatías Congénitas/genética , Válvulas Cardíacas/anomalías , Válvulas Cardíacas/citología , Humanos , Deformidades Congénitas de las Extremidades/genética , Morfogénesis/genética , Morfolinos/genética , Mutación/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Pez Cebra/genéticaRESUMEN
Previous studies suggest that the B cells of patients with Systemic Lupus Erythematosus (SLE) are hyper-responsive to BCR crosslinking; however, it has been unclear whether this is the result of altered B cell signaling or differences in various B cell subpopulations in SLE patients as compared to healthy controls. Here we have developed a novel Phosflow technique that permits examination of cell signaling in distinct B cell subpopulations stratified based upon developmental stage and cell surface IgM levels, which we use to show that the naïve B cells of SLE patients are hyper-responsive to IgM receptor crosslinking, resulting in increased SYK phosphorylation. We further demonstrate that this hyper-responsiveness is most marked in the transitional B cell subset and that it is associated with altered function, resulting in decreased apoptosis and increased proliferation of these cells. Examination of repeated samples from the same patients revealed that the hyper-responsiveness fluctuated over time, suggesting that it may be mediated by pro-inflammatory factors rather than genetic variations between patients. In support of this concept, incubation of healthy control B cells with IFN-α or SLE plasma induced the hyper-responsive phenotype, which was blocked by anti-IFN-α antibody. Furthermore, no obvious correlation was seen between genetic variants that are proposed to alter BCR signaling and the increased SYK phosphorylation. The findings suggest that pro-inflammatory factors, in particular Type I IFNs, modulate B cell function in SLE in a way that could contribute to the breach of tolerance in this condition.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Inmunoglobulina M/metabolismo , Interferón-alfa/inmunología , Lupus Eritematoso Sistémico/inmunología , Adolescente , Adulto , Apoptosis/efectos de los fármacos , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Interferón-alfa/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Quinasa Syk , Adulto JovenRESUMEN
PURPOSE: Pterygium was traditionally regarded as a degenerative disease, but certain characteristics suggest that pterygium is probably premalignant tissue. The human WWOX gene, encoding the WW domain containing oxidoreductase (WWOX, FOR, or WOX1), is a candidate tumor suppressor gene. In this study, we investigated the WWOX gene and protein expression in pterygium. METHODS: Pterygium tissues were obtained from patients (n=16, primary=8, recurrent=8) who received surgical excisions. Each tissue sample was further divided into head and body regions. The WWOX gene and protein expression were examined with immunohistochemistry, western blot, and quantitative PCR. For comparison, normal superior temporal bulbar conjunctivas were used as controls. RESULTS: Compared to the controls, upregulation of WWOX and its Tyr33 phosphorylation was observed in the head region of all pterygium specimens. In the head and body of the pterygium specimens, WWOX expression was significantly higher than in the controls. In addition, WWOX expression was stronger in recurrent pterygia than in primary pterygia. CONCLUSIONS: Increased WWOX expression, especially in the head region, is probably due to the invasiveness of the pterygium. Our results indicate that WWOX may play a role in pterygium progression and recurrence.
Asunto(s)
Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Pterigion/enzimología , Pterigion/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Anciano , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Oxidorreductasas/química , Fosforilación , Pterigion/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Recurrencia , Proteínas Supresoras de Tumor/química , Regulación hacia Arriba , Oxidorreductasa que Contiene Dominios WWRESUMEN
Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly. However, the etiology underlying these folate deficiency-associated diseases is not completely understood. In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH). Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis. Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. When folate deficiency was induced in aged fish accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections. Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation. Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.
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Envejecimiento/genética , Enfermedad de Alzheimer/etiología , Deficiencia de Ácido Fólico , Defectos del Tubo Neural/etiología , Estrés Oxidativo/genética , Acetilcisteína/metabolismo , Acetilcisteína/farmacología , Enfermedad de Alzheimer/genética , Animales , Animales Modificados Genéticamente , Catepsina B/genética , Catepsina B/metabolismo , Movimiento Celular/genética , Embrión no Mamífero , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/complicaciones , Deficiencia de Ácido Fólico/genética , Deficiencia de Ácido Fólico/patología , Proteínas Fluorescentes Verdes/genética , Calor/efectos adversos , Proteínas Asociadas a Microtúbulos/metabolismo , Cresta Neural/fisiología , Defectos del Tubo Neural/genética , Estrés Oxidativo/efectos de los fármacos , Factores de Tiempo , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , gamma-Glutamil Hidrolasa/metabolismoRESUMEN
BACKGROUND: Resveratrol, a natural plant polyphenol, has received increasing attention because its varied bioactivities, including the inhibition of tumorigenesis, lipid modification and calorie-restriction. We aimed to investigate the effect of resveratrol on oxidative/nitrative stress in endotoxemia-associated acute lung injury. METHODS: Mice were injected with lipopolysaccharide (LPS, 5 mg/kg, ip). Resveratrol at a dose of 0.3 mg/kg was administered alone or immediately before injection of LPS. Twenty four hours later, lung tissues were collected for histopathologic examination, and determination of malondialdehyde (MDA), H2O2, reduced/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) and peroxynitrite production. RESULTS: Resveratrol treatment improves histopathological changes in the lung during endotoxemia. Increased oxidative stress in endotoxemic lung was reversed by resveratrol treatment, as evidenced by the decreases of pro-oxidant biomarker (MDA and H2O2), and the increases of anti-oxidant biomarkers (GSH/GSSG ratio, T-AOC, CAT and SOD activity). Treatment with resveratrol inhibited endotoxemia-induced iNOS expression and NO production. Moreover, peroxynitrite formation in endotoxemic lung was significantly attenuated after resveratrol treatment. CONCLUSIONS: Resveratrol exerts protective effects against acute endotoxemia-associated lung injury. These beneficial effects may be due to both the anti-oxidant and anti-nitrative properties of resveratrol. These findings support the potential for resveratrol as a possible pharmacological agent to reduce acute lung injury resulting from oxidative/nitrative damage.
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Lesión Pulmonar Aguda/prevención & control , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Animales , Modelos Animales de Enfermedad , Endotoxemia/complicaciones , Endotoxemia/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Ácido Peroxinitroso/metabolismo , Resveratrol , Superóxido Dismutasa/metabolismoRESUMEN
A pH-mediated stacking method in capillary electrophoresis as an assay for low concentrations of melamine in milk products was established. Real samples were treated with acetone and sodium acetate and injected directly after centrifugation and filtration. Several experimental factors, such as buffer pH, buffer concentration, sample matrix, injection/sweeping ratio, sweeping time/voltages, separation voltages, as well as sample pretreatment, which affected stacking and separation, were investigated and optimized. Under the selected condition, a low LOD of 0.01 µmol/L (S/N = 5) and a wide range of linearity of 0.01â¼1.0 µmol/L could be easily achieved with a good reproducibility (RSDs < 5.8% for both migration time and peak area) and an acceptable recovery of 94.0â¼103.2% (for milk, infant formula, yogurt, and milk products). The proposed method was suitable for routine assay of melamine in real milk samples.
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Leche/química , Triazinas/análisis , Animales , Electroforesis Capilar , Concentración de Iones de HidrógenoRESUMEN
The co-occurrence of microplastics (MPs) and heavy metal(loid)s (HMs) has attracted growing scientific interest because of their wide distribution and environmental toxicity. Nevertheless, the interactions between MPs and HMs in soil-plant systems remain unclear. We conducted a meta-analysis with 3226 observations from 87 independent studies to quantify the impact of MPs addition on the plant biomass and HMS accumulation. Co-occurrence of MPs and HMs (except for As) induced synergistic toxicity to plant growth. MPs promoted their uptake in the shoot by 11.0% for Cd, 30.0% for Pb, and 47.1% for Cu, respectively. In contrast, MPs caused a significant decrease (22.6%, 17.9-26.9%) in the shoot As accumulation. The type and dose of MPs were correlated with the accumulation of HMs. MPs increased available concentrations of Cd, Pb, and Cu, but decreased available As concentration in soils. Meanwhile, MPs addition significantly lowered soil pH. These findings may provide explanations for MPs-mediated effects on influencing the accumulation of HMs in plants. Using a machine learning approach, we revealed that soil pH and total HMs concentration are the major contributors affecting their accumulation in shoot. Overall, our study indicated that MPs may increase the environmental risks of HMs in agroecosystems, especially metal cations.
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Metales Pesados , Contaminantes del Suelo , Cadmio/análisis , Microplásticos , Plásticos , Plomo/análisis , Metales Pesados/análisis , Plantas , Suelo , Contaminantes del Suelo/toxicidad , Contaminantes del Suelo/análisisRESUMEN
Introduction: Plague is a significant global infectious disease, its spread is linked to host and flea populations. Meteorological conditions can impact flea populations and host densities, hence influencing plague outbreaks. Investigating the connection between meteorological factors, flea populations, and rodent densities in Inner Mongolia's natural plague foci can aid in predicting and managing plague outbreaks. Methods: Monthly data on flea index, rodent density, meteorological factors, and normalized difference vegetation index (NDVI) were collected for the study area. Generalized additive modeling (GAM) was used to analyze the non-linear and lag effects of meteorological factors on flea index and rodent density. Structural equation modeling (SEM) was employed to investigate the relationships among meteorological factors, NDVI, flea index, and rodent density. Results: GAM analysis revealed that temperature, precipitation, relative humidity, and NDVI had significant linear, non-linear, and time-lagged impacts on the density of Mongolian gerbils and the flea index. SEM analysis indicated that meteorological factors could directly influence the density and flea index of Mongolian gerbils, or indirectly impact NDVI, subsequently influencing gerbil density and the flea index. Conclusions: Meteorological factors primarily influence gerbil density and flea index indirectly by affecting NDVI and the relationship between flea index and gerbil density. This study offers additional support for the significance of meteorological factors and NDVI in influencing the vector-rodent system, offering valuable insights for predicting and managing plague outbreaks.
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Pulex simulans and Polygenis gwyni are vectors of many flea-borne diseases. They were widely recorded in the United States and Mexico between 1970 and 2000. Maximum entropy models were used to explore the habitats of both fleas under different climate scenarios to provide the scientific basis for the surveillance and control of flea-borne diseases. We screened climate variables by principal component analysis and Pearson's correlation test and evaluated model performance by ROC curve. ArcMap was used to visualize expressions. Under current climatic conditions, the medium and highly suitable areas for P. simulans are estimated to be 9.16 × 106 km2 and 4.97 × 106 km2, respectively. These regions are predominantly located in South America, along the Mediterranean coast of Europe, the southern part of the African continent, the Middle East, North China, and Australia. For P. gwyni, the medium and highly suitable areas under current climatic conditions are approximately 4.01 × 106 and 2.04 × 106 km2, respectively, with the primary distribution in North China extending to the Himalayas, near the Equator in Africa, and in a few areas of Europe. Under future climate scenarios, in the SSP3-7.0 scenario for the years 2081-2100, the area of high suitability for P. simulans is projected to reach its maximum. Similarly, in the SSP2-4.5 scenario for 2061-2080, the area of high suitability for P. gwyni is expected to reach its maximum. Under global climate change, there is a large range in the potential distribution for both fleas, with an overall upward trend in the area of habitat under future climate scenarios. Governments should develop scientific prevention and control measures to prevent the invasive alien species flea.
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Arsenic (As) and cadmium (Cd) are two toxic metal(loid)s that pose significant risks to food security and human health. Silicon (Si) has attracted substantial attention because of its positive effects on alleviating the toxicity and accumulation of As and Cd in crops. However, our current knowledge of the comprehensive effects and detailed mechanisms of Si amendment is limited. In this study, a global meta-analysis of 248 original articles with over 7000 paired observations was conducted to evaluate Si-mediated effects on growth and As and Cd accumulation in rice (Oryza sativa L.), wheat (Triticum aestivum L.), and maize (Zea mays L.). Si application increases the biomass of these crops under As and/or Cd contamination. Si amendment also decreased shoot As and Cd accumulation by 24.1 % (20.6 to 27.5 %) and 31.9 % (29.0 to 31.9 %), respectively. Furthermore, the Si amendment reduced the human health risks posed by As (2.6 %) and Cd (12.9 %) in crop grains. Si-induced inhibition of Cd accumulation is associated with decreased Cd bioavailability and the downregulation of gene expression. The regulation of gene expression by Si addition was the driving factor limiting shoot As accumulation. Overall, our analysis demonstrated that Si amendment has great potential to reduce the toxicity and accumulation of As and/or Cd in crops, providing a scientific basis for promoting food safety globally.