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1.
Nat Commun ; 12(1): 1547, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33707436

RESUMEN

Hypertension, exercise, and pregnancy are common triggers of cardiac remodeling, which occurs primarily through the hypertrophy of individual cardiomyocytes. During hypertrophy, stress-induced signal transduction increases cardiomyocyte transcription and translation, which promotes the addition of new contractile units through poorly understood mechanisms. The cardiomyocyte microtubule network is also implicated in hypertrophy, but via an unknown role. Here, we show that microtubules are indispensable for cardiac growth via spatiotemporal control of the translational machinery. We find that the microtubule motor Kinesin-1 distributes mRNAs and ribosomes along microtubule tracks to discrete domains within the cardiomyocyte. Upon hypertrophic stimulation, microtubules redistribute mRNAs and new protein synthesis to sites of growth at the cell periphery. If the microtubule network is disrupted, mRNAs and ribosomes collapse around the nucleus, which results in mislocalized protein synthesis, the rapid degradation of new proteins, and a failure of growth, despite normally increased translation rates. Together, these data indicate that mRNAs and ribosomes are actively transported to specific sites to facilitate local translation and assembly of contractile units, and suggest that properly localized translation - and not simply translation rate - is a critical determinant of cardiac hypertrophy. In this work, we find that microtubule based-transport is essential to couple augmented transcription and translation to productive cardiomyocyte growth during cardiac stress.


Asunto(s)
Cardiomegalia/patología , Microtúbulos/metabolismo , Miocitos Cardíacos/patología , Biosíntesis de Proteínas/fisiología , ARN Mensajero/metabolismo , Ribosomas/metabolismo , Animales , Remodelación Atrial/fisiología , Transporte Biológico/fisiología , Células Cultivadas , Humanos , Cinesina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Transducción de Señal/fisiología , Remodelación Ventricular/fisiología
2.
Commun Biol ; 4(1): 290, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674719

RESUMEN

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.


Asunto(s)
/inmunología , Degranulación de la Célula , Interferones/fisiología , Neutrófilos/fisiología , Anciano , Animales , Antígenos CD36/fisiología , Colágeno/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Pulmón/metabolismo , Macaca mulatta , Masculino , Persona de Mediana Edad , Receptores Notch/fisiología , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/fisiología , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/fisiología
3.
Nat Commun ; 12(1): 1438, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664246

RESUMEN

Germ cells are physically coupled to somatic support cells of the gonad during differentiation, but this coupling must be disrupted when they are mature, freeing them to participate in fertilization. In mammalian females, coupling occurs via specialized filopodia that project from the ovarian follicular granulosa cells to the oocyte. Here, we show that signaling through the epidermal growth factor receptor (EGFR) in the granulosa, which becomes activated at ovulation, uncouples the germ and somatic cells by triggering a massive and temporally synchronized retraction of the filopodia. Although EGFR signaling triggers meiotic maturation of the oocyte, filopodial retraction is independent of the germ cell state, being regulated solely within the somatic compartment, where it requires ERK-dependent calpain-mediated loss of filopodia-oocyte adhesion followed by Arp2/3-mediated filopodial shortening. By uncovering the mechanism regulating germ-soma uncoupling at ovulation, our results open a path to improving oocyte quality in human and animal reproduction.


Asunto(s)
Adhesión Celular/fisiología , Receptores ErbB/metabolismo , Células de la Granulosa/metabolismo , Oocitos/metabolismo , Ovulación/fisiología , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Animales , Calpaína/metabolismo , Comunicación Celular/fisiología , Células Cultivadas , Femenino , Meiosis/fisiología , Ratones , Seudópodos/fisiología , Transducción de Señal/fisiología , Porcinos
4.
Nat Commun ; 12(1): 1789, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741976

RESUMEN

Sensory perception and metabolic homeostasis are known to deteriorate with ageing, impairing the health of aged animals, while mechanisms underlying their deterioration remain poorly understood. The potential interplay between the declining sensory perception and the impaired metabolism during ageing is also barely explored. Here, we report that the intraflagellar transport (IFT) in the cilia of sensory neurons is impaired in the aged nematode Caenorhabditis elegans due to a daf-19/RFX-modulated decrease of IFT components. We find that the reduced IFT in sensory cilia thus impairs sensory perception with ageing. Moreover, we demonstrate that whereas the IFT-dependent decrease of sensory perception in aged worms has a mild impact on the insulin/IGF-1 signalling, it remarkably suppresses AMP-activated protein kinase (AMPK) signalling across tissues. We show that upregulating daf-19/RFX effectively enhances IFT, sensory perception, AMPK activity and autophagy, promoting metabolic homeostasis and longevity. Our study determines an ageing pathway causing IFT decay and sensory perception deterioration, which in turn disrupts metabolism and healthy ageing.


Asunto(s)
Envejecimiento , Caenorhabditis elegans/metabolismo , Cilios/metabolismo , Flagelos/metabolismo , Células Receptoras Sensoriales/fisiología , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Animales Modificados Genéticamente , Transporte Biológico , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Longevidad/genética , Percepción/fisiología , Interferencia de ARN , Factor Regulador X1/genética , Factor Regulador X1/metabolismo , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
5.
Arch Immunol Ther Exp (Warsz) ; 69(1): 6, 2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33683459

RESUMEN

The pathophysiology of rotator cuff tendinopathy is not fully understood, particularly in terms of the local inflammatory process. This study aimed to investigate the expression of selected molecules in the tumour necrosis factor (TNF)-α transduction pathway, including TNF-α, TNF receptor 1 (TNFR1), neutral sphingomyelinase activation associated factor (NSMAF), caspase 3 (Casp3), and interleukin (IL)-8, in patients with rotator cuff tendinopathy that had undergone surgical treatment. We included 44 participants that underwent arthroscopy, due to rotator cuff tendinopathy. Samples from the injured tendon were collected during arthroscopy, and RT-PCR was performed to determine gene expression. Pearson correlation analyses or U-Mann-Whitney test were performed to identify associations with the following parameters: sex, age at admission, body mass index, the presence of night pain, previous treatment (nonsteroidal anti-inflammatory drugs and/or steroids), medical history of the shoulder injury, upper subluxation of the humeral head, and the number of tendons injured. RT-PCR showed that the selected pro-inflammatory factors involved in the TNF-α signalling pathway expression levels were expressed in the tendon tissues. However, the levels of expression varied from patient to patient. Variations were over 250-fold for TNF-α, about 130-fold for TNFR1, NSMAF, and Casp3, and 1000-fold for IL-8. We could not confirm that any of the clinical parameters investigated were associated with the level of gene expression in the TNF-α pathway and IL-8.


Asunto(s)
Lesiones del Manguito de los Rotadores/inmunología , Tendones/inmunología , Factor de Necrosis Tumoral alfa/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Caspasa 3/genética , Femenino , Humanos , Interleucina-8/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Lesiones del Manguito de los Rotadores/cirugía , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/genética
6.
Methods Mol Biol ; 2218: 85-97, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33606225

RESUMEN

The correct assembly, migration, and segregation of the mRNAs of the germ plasm during the first cell divisions are intimately connected to the cytoskeleton and cytokinesis.RhoA is a key regulator of germ plasm localization during the first two cell division cycles in zebrafish embryos. Pharmacological inhibition of RhoA and his effector ROCK affected the correct assembly of microtubules in the cleavage furrow with the concomitant abnormal localization of germ plasm mRNAs. The inhibition of RhoA/ROCK pathway caused a significant decrease in the germ cell population later in development.


Asunto(s)
Células Germinativas/metabolismo , Células Germinativas/fisiología , Transducción de Señal/fisiología , Proteína de Unión al GTP rhoA/metabolismo , Animales , Citoplasma/metabolismo , Citoesqueleto/metabolismo , Embrión no Mamífero/metabolismo , Femenino , Masculino , Microtúbulos/metabolismo , ARN Mensajero/metabolismo , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo
7.
Methods Mol Biol ; 2218: 169-183, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33606231

RESUMEN

In some animal species, fertilization occurs through a funnel-like canal called the "micropyle." In teleost fishes, the micropyle is formed by a very specialized follicle cell, called the micropylar cell (MC). Very little is known about the mechanisms underlying the specification and differentiation of the MC, a unique cell among hundreds that compose the follicle cell layer. The Hippo pathway effector Taz is essential for this process and is the first reported MC marker. Here, we describe a method to identify and mark the micropylar cell following the immunostaining procedure on cryosections or combining it with the RNA in situ hybridization on whole-mount follicles.


Asunto(s)
Folículo Ovárico/fisiología , Pez Cebra/fisiología , Animales , Diferenciación Celular/fisiología , Femenino , Fertilización/fisiología , Masculino , Oocitos/metabolismo , Oocitos/fisiología , Folículo Ovárico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo
8.
Virus Res ; 296: 198350, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33626380

RESUMEN

The open reading frame 8 (orf8) is an accessory protein of SARS-CoV-2. It has 121 amino acids with two genotypes, orf8L and orf8S. In this study, we overexpressed the orf8L and orf8S of SARS-CoV-2 as well as the orf8b of SARS-CoV to investigate their roles in the regulation of endoplasmic reticulum (ER) stress and the inhibition of interferon beta (IFNß) production. We found that the two genotypes of SARS-CoV-2 orf8 are capable of inducing ER stress without significant difference by triggering the activating transcription factor 6 (ATF6) and inositol-requiring enzymes 1 (IRE1) branches of the ER stress pathway. However, the third branch of ER stress pathway, i.e. the protein kinase-like ER kinase (PERK), was unaffected by the overexpression of SARS-CoV-2 orf8L or orf8S. Moreover, both orf8L and orf8S of SARS-CoV-2 are capable of down regulating the production of IFNß and interferon-stimulated genes (ISG), ISG15 and ISG56 induced by polyinosinic-polycytidylic acid (poly (I:C)). Moreover, we also found decreased nuclear translocation of Interferon regulatory factor 3 (IRF3), after overexpressing orf8L and orf8S induced by poly (I:C). Our data demonstrated that SARS-CoV-2 orf8 protein could induce ER stress by activating the ATF6 and IRE1 pathways, but not the PERK pathway, and functions as an interferon antagonist to inhibit the production of IFNß. However, these functions appeared not to be affected by the genotypes of SARS-CoV-2 orf8L and orf8S.


Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Evasión Inmune , Interferón beta/antagonistas & inhibidores , Proteínas Virales/fisiología , Factor de Transcripción Activador 6/fisiología , Endorribonucleasas/fisiología , Células HEK293 , Humanos , Interferón beta/biosíntesis , Proteínas Serina-Treonina Quinasas/fisiología , Alineación de Secuencia , Transducción de Señal/fisiología , Respuesta de Proteína Desplegada , Proteínas Virales/química , Proteína 1 de Unión a la X-Box/fisiología , eIF-2 Quinasa/fisiología
9.
Stem Cell Reports ; 16(3): 437-445, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33631122

RESUMEN

COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.


Asunto(s)
Encéfalo/virología , Células Madre Pluripotentes Inducidas/virología , Pulmón/virología , Células-Madre Neurales/virología , Organoides/virología , /patogenicidad , Apoptosis/fisiología , Encéfalo/metabolismo , Células Cultivadas , Proteínas del Sistema Complemento/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/virología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Inflamación/metabolismo , Inflamación/virología , Pulmón/metabolismo , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Neuronas/virología , Organoides/metabolismo , Serina Endopeptidasas/metabolismo , Transducción de Señal/fisiología , Células Madre/metabolismo , Células Madre/virología
10.
Nat Commun ; 12(1): 1318, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637744

RESUMEN

Cell-cell interactions mediated by Notch are critical for the maintenance of skeletal muscle stem cells. However, dynamics, cellular source and identity of functional Notch ligands during expansion of the stem cell pool in muscle growth and regeneration remain poorly characterized. Here we demonstrate that oscillating Delta-like 1 (Dll1) produced by myogenic cells is an indispensable Notch ligand for self-renewal of muscle stem cells in mice. Dll1 expression is controlled by the Notch target Hes1 and the muscle regulatory factor MyoD. Consistent with our mathematical model, our experimental analyses show that Hes1 acts as the oscillatory pacemaker, whereas MyoD regulates robust Dll1 expression. Interfering with Dll1 oscillations without changing its overall expression level impairs self-renewal, resulting in premature differentiation of muscle stem cells during muscle growth and regeneration. We conclude that the oscillatory Dll1 input into Notch signaling ensures the equilibrium between self-renewal and differentiation in myogenic cell communities.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Diferenciación Celular/fisiología , Desarrollo de Músculos/fisiología , Músculos/metabolismo , Células Madre/fisiología , Animales , Proteínas de Unión al Calcio/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Desarrollo de Músculos/genética , Mutación , Proteína MioD/genética , Proteína MioD/metabolismo , Transducción de Señal/fisiología , Factor de Transcripción HES-1/metabolismo , Transcriptoma
11.
Metabolism ; 117: 154725, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33571540

RESUMEN

RATIONALE: Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, has become an increasingly severe public health problem. However, the underlying mechanism for the occurrence and development of NAFLD remains largely unknown. S100 calcium-binding protein A11 (S100A11) is a multifunctional protein previously reported to be a poor prognostic indicator of hepatocellular carcinoma, while the role of S100A11 affects NAFLD is still not clear. METHODS: Immunohistochemical staining was performed using human NAFLD and control biopsy specimens. Serum level of S100A11 were analyzed by Elisa assays. The S100A11 over-expressed/ knocked-down model was established in vitro or in vivo. The expression levels of genes related to lipid metabolism in liver tissue were performed by quantitative PCR and western blotting. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. RESULTS: We showed that the concentration of serum S100A11 was significantly elevated in NAFLD patients, and expression of S100A11 was remarkedly increased in the livers of NAFLD patients and mouse models. Overexpression of S100A11 in vivo markedly increased liver steatosis, body weight, and serum aspartate aminotransaminase (AST) levels. Mechanistically, our results demonstrated that S100A11 acted as a positive regulator of AKT/mTOR signaling to induce lipid synthesis and aggravate lipid deposition. CONCLUSIONS: These results provide evidence for a novel role of S100A11 that contributes to hepatic steatosis, suggesting that targeting S100A11 may be an alternative approach for the treatment of NAFLD.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Hígado Graso/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Proteínas S100/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Adulto , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Metabolismo de los Lípidos/fisiología , Lipogénesis/fisiología , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo
12.
Life Sci ; 271: 119185, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577846

RESUMEN

AIMS: Melanoma is a malignant tumor of the skin with a high metastasis rate and poor prognosis. Glaucocalyxin A (GLA), isolated from Rabdosia japonica, is a diterpenoid compound with anticancer properties. Here, we investigated the anticancer properties and explored the mechanisms underlying GLA activity in melanoma cells in vitro and in vivo. MAIN METHODS: Cell Counting Kit-8 and colony formation assays were used to assess the effects of GLA on cell proliferation. Flow cytometry was used to evaluate the cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS), and western blot analysis and immunofluorescence staining were used to examine protein expression. Immunohistochemical analysis was performed to examine animal tissues and tumors in mice. KEY FINDINGS: GLA could effectively inhibit cell proliferation and induce cell apoptosis. GLA induced an overproduction of cellular ROS, decreased MMP, and upregulated the Bax/Bcl-2 ratio, which is an indicator of apoptosis. Phosphorylation of nuclear factor κB (NF-κB)/p65 and NF-κB/p65 nuclear expression decreased after GLA treatment in vitro and in vivo, suggesting that the anticancer effects of GLA are mediated through the NF-κB/p65 pathway. Moreover, we observed that GLA was effective in inhibiting tumor growth without obvious toxicity to major organs in mice. SIGNIFICANCE: This is the first study to show that GLA inhibits cell proliferation, arrests the cell cycle in the G2/M phase, and induces mitochondrial apoptosis via the NF-κB/p65 pathway in melanoma cells. Overall, our results demonstrate that GLA may be a potential anticancer agent for the treatment of melanoma.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/farmacología , Melanoma/metabolismo , Factor de Transcripción ReIA/metabolismo , Animales , Antineoplásicos/uso terapéutico , Apoptosis/fisiología , Puntos de Control del Ciclo Celular/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Diterpenos de Tipo Kaurano/uso terapéutico , Relación Dosis-Respuesta a Droga , Humanos , Melanoma/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor de Transcripción ReIA/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
13.
Life Sci ; 271: 119197, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577847

RESUMEN

AIMS: To investigate the improvement and mechanisms of silymarin on renal injury in mouse podocytes and streptozotocin (STZ)-induced diabetic nephropathy model (DN) rats. MAIN METHODS: Firstly, the effects of silymarin on the cell viability and cellular injury-related indicators of high-glucose incubated mouse podocytes MPC-5 were assessed by CCK-8 and western blotting (WB) methods, respectively. The STZ-induced diabetic rats with DN were treated with silymarin nanoliposomes at three doses for consecutive 8-week. General metabolic indicators, renal functions and lipid accumulation-related factors were all measured. The renal tissue sections were stained and observed via hematoxylin-eosin (H&E) staining method. Real-time RT-PCR and WB methods were utilized to measure the expression of JAK2/STAT3/SOCS1 and TGF-ß/Smad signaling pathway related factors. KEY FINDINGS: Silymarin significantly improve the high-glucose induced up-regulation of podoxin and nephrin, as well as the expression of inflammatory cytokines IL-6, ICAM-1 and TNF-α, and the cell survival rates were also significantly increased in a dose-dependent manner. Significant improvement on body weight/kidney ratio, renal functions and lipid profiles in renal tissues were observed in STZ-induced diabetic rats after chronic silymarin treatment. The H&E staining exhibited that the pathological damages in renal tissues were obviously improved. Moreover, silymarin nanoliposomes treatment notably suppressed expression levels of inflammation-related proteins as well as IL-6 and ICAM-1, and regulated JAK2/STAT3/SOCS1 and TGF-ß/Smad signaling pathway, thereby exhibited protective effects on kidney of DN model rats. SIGNIFICANCE: Silymarin nanoliposomes ameliorate STZ-induced kidney injury by improving oxidative stress, renal fibrosis, and co-inhibiting JAK2/STAT3/SOCS1 and TGF-ß/Smad signaling pathways in diabetic rats.


Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Janus Quinasa 2/antagonistas & inhibidores , Nanopartículas/administración & dosificación , Factor de Transcripción STAT3/antagonistas & inhibidores , Silimarina/administración & dosificación , Proteína 1 Supresora de la Señalización de Citocinas/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Antioxidantes/administración & dosificación , Línea Celular , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Janus Quinasa 2/metabolismo , Liposomas , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas Smad/antagonistas & inhibidores , Proteínas Smad/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
14.
Life Sci ; 271: 119192, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577850

RESUMEN

AIMS: GYY4137 [GYY, morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate] is a novel and perfect hydrogen sulfide (H2S) donor that is stable in vivo and in vitro. H2S, along with CO and NO, has been recognized as the third physiological gas signaling molecule that plays an active role in fighting various lung infections. However, the mechanism by which GYY4137 affects cecal ligation and puncture (CLP)-induced acute lung injury (ALI) is not understood. This study aimed to investigate whether GYY4137 inhibits the activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome by inhibiting the PDGFRß/Akt/NF-κB pathway. MAIN METHODS: The model of CLP-induced ALI was established in vivo. The mice were subsequently treated with GYY4137 (25 µg/g and 50 µg/g) to simulate the realistic conditions of pathogenesis. Western blotting and immunohistochemical staining were used to examine protein expression, hematoxylin and eosin staining was used for the histopathological analysis, and the levels of inflammatory factors were determined using enzyme-linked immunosorbent assays (ELISAs). KEY FINDINGS: GYY4137 significantly increased the 7-day survival of mice with septic peritonitis and protected against CLP-induced ALI, including decreasing neutrophil infiltration, improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, and attenuating the severity of lung injury in mice. The protective effect of GYY4137 was undoubtedly dose-dependent. We discovered that GYY4137 reduced the levels of the p-PDGFRß, p-NF-κB, ASC, NLRP3, caspase-1, and p-Akt proteins in septic mouse lung tissue. Akt regulates the generation of proinflammatory cytokines in endotoxemia-associated ALI by enhancing the nuclear translocation of NF-κB. SIGNIFICANCE: These results indicate a new molecular mechanism explaining the effect of GYY4137 on the treatment of CLP-induced ALI in mice.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Morfolinas/uso terapéutico , FN-kappa B/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Compuestos Organotiofosforados/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Morfolinas/farmacología , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Compuestos Organotiofosforados/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células RAW 264.7 , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Sepsis/complicaciones , Sepsis/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
15.
Life Sci ; 271: 119237, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33600859

RESUMEN

AIMS: Echinacoside (ECH) is a natural compound extracted from the stem of the Cistanche deserticola plant, has significant biological properties, including antioxidant, anti-inflammatory, neuroprotective, anti-tumor, hepatoprotective, and immunomodulatory properties. In this study, we aimed to explore the protection effects and mechanisms of ECH on diabetic liver injury in db/db mice. MAIN METHODS: Overall, 6-week-old db/db mice (n = 20) were randomly allocated to 2 groups: diabetic model group (db/db group, intragastric administration of normal saline, n = 10) and ECH-treated group (db/db + ECH group, n = 10). Additionally, the normal control group comprised 6-week-old db/m mice (db/m group, normal saline intragastric administration, n = 10). ECH was administered once a day for 10 weeks. Weight and fasting blood glucose (FBG) were measured biweekly. HE staining and Oil O staining were used to evaluate liver tissue pathological changes and lipid accumulation respectively. Immunofluorescence staining, Western blot and RT-PCR analysis were used to detect the expression of components of the AMPK/SIRT1 signaling axis. KEY FINDINGS: The results showed that the administration of echinacoside for 10 weeks could significantly improve liver injury and insulin resistance in db/db mice (p < 0.01). Also, echinacoside treatment helped to reduce blood lipids and blood glucose (p < 0.01). Moreover, ECH actived AMPK/SIRT1 signaling, upregulated peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), proliferator-activated receptor-α (PPARα), carnitine palmitoyl transferase-1A (CPT1A) in db/db mice (p < 0.01). SIGNIFICANCE: The effect of ECH may be elicited by the activation of the liver AMPK/SIRT1 pathway and its downstream factors to improve adiposity, insulin resistance, and dyslipidemia.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glicósidos/uso terapéutico , Hígado/metabolismo , Proteínas Quinasas/metabolismo , Sirtuina 1/metabolismo , Animales , Glicósidos/farmacología , Hígado/efectos de los fármacos , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
16.
Nat Metab ; 3(2): 228-243, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33619380

RESUMEN

Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.


Asunto(s)
Adiposidad/genética , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo , Obesidad/genética , Adipocitos/metabolismo , Adipocitos Marrones/fisiología , Adipocitos Blancos/fisiología , Tejido Adiposo/metabolismo , Alelos , Metabolismo Energético/fisiología , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Familia de Multigenes/genética , Obesidad/complicaciones , Medición de Riesgo , Transducción de Señal/fisiología
17.
Cell Prolif ; 54(3): e12999, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33522060

RESUMEN

OBJECTIVE: As an inhibitor of the AhR signalling pathway, StemRegenin 1 (SR1) not only promotes the expansion of CD34+ cells but also increases CD34- cell numbers. These CD34- cells influenced the ex vivo expansion of CD34+ cells. In this work, the effects of periodically removing CD34- cells combined with SR1 addition on the ex vivo expansion and biological functions of HSCs were investigated. MATERIALS AND METHODS: CD34- cells were removed periodically with SR1 addition to investigate cell subpopulations, cell expansion, biological functions, expanded cell division mode and supernatant TGF-ß1 contents. RESULTS: After 10-day culture, the expansion of CD34+ cells in the CD34- cell removal plus SR1 group was significantly higher than that in the control group and the SR1 group. Moreover, periodically removing CD34- cells with SR1 addition improved the biological function of expanded CD34+ cells and significantly increased the percentage of self-renewal symmetric division of CD34+ cells. In addition, the concentration of total TGF-ß1 and activated TGF-ß1 in the supernatant was significantly lower than those in the control group and the SR1 group. RT-qPCR results showed that the periodic removal of CD34- cells with cooperation from SR1 further reduced the expression of AhR-related genes. CONCLUSIONS: Periodic removal of CD34- cells plus cooperation with SR1 improved the expansion of CD34+ cells, maintained better biological function of expanded CD34+ cells and reduced the TGF-ß1 contents by downregulating AhR signalling.


Asunto(s)
Antígenos CD34/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Purinas/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Antígenos CD34/análisis , Antígenos CD34/metabolismo , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/genética , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Humanos , Purinas/metabolismo , Transducción de Señal/fisiología
18.
Med Sci Monit ; 27: e926492, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33563887

RESUMEN

BACKGROUND The aim of this study was to evaluate the potential role of dual oxidase 1 (DUOX1) in wound healing. MATERIAL AND METHODS Primary fibroblasts were isolated from wound granulation tissue. Fibroblasts cell lines were established using DUOX1 overexpression and interference. Cell proliferation and reactive oxygen species (ROS) production were measured and compared among the groups. RESULTS DUOX1 expression was highest in the slow-healing tissues (P<0.05). Knockdown of DUOX1 significantly increased cell proliferation and inhibited ROS production and cell apoptosis (P<0.01). Moreover, expression of malondialdehyde (MDA) was significantly reduced, while expression of superoxide dismutase (SOD) expression was significantly increased (P<0.01). In addition, DUOX1 silencing significantly upregulated collagen I, collagen III, and NF-kappaB protein levels in the cytoplasm, and inhibited the protein levels of P21, P16, and NF-kappaB in the nucleus (P<0.01). Overexpression of DUOX1 caused a reverse reaction mediated by knockdown of DUOX1. When DUOX1-overexpressing cells were treated with the ROS inhibitor N-acetyl-L-cysteine (NAC), the protein levels that were increased by DUOX1 overexpression were reversed. CONCLUSIONS These results suggest that knockdown of DUOX1 significantly benefits wound healing, likely by the regulation of oxidative stress via NF-kappaB pathway activation.


Asunto(s)
Oxidasas Duales/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cicatrización de Heridas/fisiología , Acetilcisteína/farmacología , Adulto , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Oxidasas Duales/genética , Femenino , Fibroblastos , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Superóxido Dismutasa/metabolismo , Cicatrización de Heridas/efectos de los fármacos
19.
Nat Commun ; 12(1): 1272, 2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627672

RESUMEN

Cellular responses to environmental changes are encoded in the complex temporal patterns of signaling proteins. However, quantifying the accumulation of information over time to direct cellular decision-making remains an unsolved challenge. This is, in part, due to the combinatorial explosion of possible configurations that need to be evaluated for information in time-course measurements. Here, we develop a quantitative framework, based on inferred trajectory probabilities, to calculate the mutual information encoded in signaling dynamics while accounting for cell-cell variability. We use it to understand NFκB transcriptional dynamics in response to different immune threats, and reveal that some threats are distinguished faster than others. Our analyses also suggest specific temporal phases during which information distinguishing threats becomes available to immune response genes; one specific phase could be mapped to the functionality of the IκBα negative feedback circuit. The framework is generally applicable to single-cell time series measurements, and enables understanding how temporal regulatory codes transmit information over time.


Asunto(s)
Simulación de Dinámica Molecular , Humanos , FN-kappa B/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología
20.
Hum Cell ; 34(2): 698-699, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33527306

RESUMEN

The current COVID-19 is one of the deadliest pandemics in recent decades. In the lack of a specific treatment for this novel infection, knowing the role of cell signaling pathways in the pathogenesis of this infection could be useful in finding effective drugs against this disease. The mammalian or mechanistic target of rapamycin (mTOR) is an important cell signaling pathway that has important role in the regulation of cell growth, protein synthesis, and metabolism in reactance to upstream signals in both pathological and normal physiological conditions. Recently, some researchers have suggested the therapeutic potential of mTOR inhibitors such as rapamycin against COVID-19. However, it is important to consider the role of activation of this pathway in controlling immune system response against viral activity in drug repositioning of rapamycin and other mTOR inhibitors in SARS-CoV-2 infection.


Asunto(s)
/tratamiento farmacológico , Reposicionamiento de Medicamentos , Sistema Inmunológico/inmunología , Transducción de Señal/genética , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/fisiología , /inmunología , Humanos , Transducción de Señal/fisiología
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