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3.
Int J Med Sci ; 17(16): 2511-2530, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33029094

RESUMEN

ShuFeng JieDu capsule (SFJDC), a traditional Chinese medicine, has been recommended for the treatment of COVID-19 infections. However, the pharmacological mechanism of SFJDC still remains vague to date. The active ingredients and their target genes of SFJDC were collected from TCMSP. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). NCP-related target genes were collected from GeneCards database. The ingredients-targets network of SFJDC and PPI networks were constructed. The candidate genes were screened by Venn diagram package for enrichment analysis. The gene-pathway network was structured to obtain key target genes. In total, 124 active ingredients, 120 target genes of SFJDC and 251 NCP-related target genes were collected. The functional annotations cluster 1 of 23 candidate genes (CGs) were related to lung and Virus infection. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the key target genes. The results suggested that SFJDC cloud be treated COVID-19 by multi-compounds and multi-pathways, and this study showed that the mechanism of traditional Chinese medicine (TCM) in the treatment of disease from the overall perspective.


Asunto(s)
Antivirales/farmacología , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Neumonía Viral/tratamiento farmacológico , Mapas de Interacción de Proteínas/efectos de los fármacos , Antivirales/química , Cápsulas/farmacología , Caspasa 3/genética , Caspasa 8/genética , Infecciones por Coronavirus/genética , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-6/genética , Proteína Quinasa 1 Activada por Mitógenos/genética , Pandemias , Neumonía Viral/genética , Mapas de Interacción de Proteínas/genética , Factor de Transcripción ReIA/genética
4.
Yakugaku Zasshi ; 140(10): 1199-1206, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999198

RESUMEN

Potential risks to the fetus or infant should be considered prior to medication during pregnancy and lactation. It is essential to evaluate the exposure levels of drugs and their related factors in addition to toxicological effects. Epilepsy is one of the most common neurological complications in pregnancy; some women continue to use antiepileptic drugs (AEDs) to control seizures. Benzodiazepines (BZDs) are widely prescribed for several women who experience symptoms such as anxiety and insomnia during the postpartum period. In this review, we describe the 1) transport mechanisms of AEDs across the placenta and the effects of these drugs on placental transporters, and 2) the transfer of BZDs into breast milk. Our findings indicated that carrier systems were involved in the uptake of gabapentin (GBP) and lamotrigine (LTG) in placental trophoblast cell lines. SLC7A5 was the main contributor to GBP transport in placental cells. LTG was transported by a carrier that was sensitive to chloroquine, imipramine, quinidine, and verapamil. Short-term exposure to 16 AEDs had no effect on folic acid uptake in placental cells. However, long-term exposure to valproic acid (VPA) affected the expression of folate carriers (FOLR1, SLC46A1). Furthermore, VPA administration changed the expression levels of various transporters in rat placenta, suggesting that sensitivity to VPA differed across gestational stages. Lastly, we developed a method for quantifying eight BZDs in human breast milk and plasma using LC/MS/MS, and successfully applied it to quantify alprazolam in breast milk and plasma donated by a lactating woman.


Asunto(s)
Anticonvulsivantes/metabolismo , Benzodiazepinas/metabolismo , Transporte Biológico/genética , Lactancia Materna , Gabapentina/metabolismo , Lactancia/metabolismo , Lamotrigina/metabolismo , Transportador de Aminoácidos Neutros Grandes 1/fisiología , Intercambio Materno-Fetal , Leche Humana/metabolismo , Placenta/metabolismo , Ácido Valproico/metabolismo , Anticonvulsivantes/efectos adversos , Benzodiazepinas/efectos adversos , Benzodiazepinas/uso terapéutico , Línea Celular , Epilepsia/tratamiento farmacológico , Femenino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Gabapentina/efectos adversos , Expresión Génica/efectos de los fármacos , Humanos , Lamotrigina/efectos adversos , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Transportador de Folato Acoplado a Protón/genética , Transportador de Folato Acoplado a Protón/metabolismo , Ácido Valproico/efectos adversos
5.
Yakugaku Zasshi ; 140(10): 1207-1212, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999199

RESUMEN

T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.


Asunto(s)
Canales de Calcio Tipo T/efectos de los fármacos , Canales de Calcio Tipo T/fisiología , Imidazoles/farmacología , Neuronas/fisiología , Compuestos de Espiro/farmacología , Acetilcolina/metabolismo , Animales , Encéfalo/fisiología , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Células Cultivadas , Sistema Nervioso Central/metabolismo , Fenómenos Electrofisiológicos , Epilepsia/etiología , Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Homeostasis , Ratones , Plasticidad Neuronal , Dolor/etiología , Ratas , Sueño/fisiología
6.
Signal Transduct Target Ther ; 5(1): 220, 2020 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-33024075
7.
Nat Commun ; 11(1): 4938, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009401

RESUMEN

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.


Asunto(s)
Antiinflamatorios/farmacología , Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Dimetilfumarato/agonistas , Factor 2 Relacionado con NF-E2/metabolismo , Neumonía Viral/tratamiento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacología , Betacoronavirus/metabolismo , Infecciones por Coronavirus/virología , Dimetilfumarato/farmacología , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Interferón Tipo I , Pulmón/patología , Masculino , Factor 2 Relacionado con NF-E2/genética , Pandemias , Neumonía Viral/virología , Transducción de Señal/efectos de los fármacos , Succinatos/farmacología , Replicación Viral/efectos de los fármacos
8.
Zhonghua Xin Xue Guan Bing Za Zhi ; 48(9): 777-781, 2020 Sep 24.
Artículo en Chino | MEDLINE | ID: mdl-32957762

RESUMEN

Objective: To investigate the expression pattern of tropomyosin 2(TPM2) in aorta of patients with aortic dissection and explore its clinical implication. Methods: Thirteen cases with acute type A aortic dissection(TAAD) diagnosed by transabdominal aortic angiography from 2015 in Tongji Hospital were included. During the operation, the aortic wall tissues of these patients were collected. Ten patients with heart transplantation were selected as control group, and normal aortic wall tissues were taken. The hematoxylin-eosin (HE) and Verhoeff's Van Gieson (EVG) staining were performed to observe the morphological changes of aorta. The mRNA expression level of TPM2 was measured by real-time fluorescent quantitative-PCR, and the protein levels of TPM2 were detected by Western blot and immunohistochemical staining. Image The J software was used to collect the optical density values of each point on the image, obtain the integrated optical density(IOD) value, and calculate the average density(%, IOD/area of the target distribution area). Results: HE and EVG staining revealed medial degeneration and broken elastic fiber in aorta of TAAD patients. The mRNA expression levels of TPM2 were significantly upregulated in aorta of TAAD patients as compared to the control group (P<0.05), so as the TPM2 protein expression levels ((9.73±1.20)% vs. (0.11±0.04)%, P<0.05). And TPM2 was mainly expressed in cytoplasm. Conclusion: The increased expression of TPM2 in TAAD patients hints that TPM2 might be involved in the pathogenesis of aortic dissection.


Asunto(s)
Aneurisma Disecante , Aneurisma de la Aorta Torácica , Aneurisma Disecante/genética , Aorta , Aneurisma de la Aorta Torácica/genética , Expresión Génica , Humanos , ARN Mensajero , Tropomiosina/metabolismo
9.
Yonsei Med J ; 61(9): 816-825, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32882766

RESUMEN

PURPOSE: To understand the pathophysiology of Best disease (BD) and autosomal recessive bestrophinopathy (ARB) by establishing an in vitro model using human induced pluripotent stem cell (iPSC). MATERIALS AND METHODS: Human iPSC lines were generated from mononuclear cells in peripheral blood of one ARB patient, one autosomal dominant BD patient, and two normal controls. Immunocytochemistry and reverse transcriptase polymerase chain reaction in iPSC lines were conducted to demonstrate the pluripotent markers. After the differentiation of iPSC into functional retinal pigment epithelium (RPE), morphological characteristics of the RPE were evaluated using confocal microscopy and immunocytochemistry. The rates of fluid flow across iPSC-RPE monolayer were measured to compare apical to basal fluid transports by RPE. RNA sequencing was performed on iPSC-RPE to identify the differences in gene expression profiles, and specific gene sets were tested using Gene Set Enrichment Analysis. RESULTS: Morphological characteristics, gene expression, and epithelial integrity of ARB iPSC were comparable to those of BD patient or normal control. Fluid transport from apical to basal was significantly decreased in ARB iPSC-RPE compared with BD iPSC-RPE or control iPSC-RPE. Gene Set Enrichment Analysis confirmed that ARB iPSC-RPE exhibited significant enrichments of epithelial-mesenchymal transition gene set and TNF-α signaling via NF-κB gene set compared to control iPSC-RPE or BD iPSC-RPE. CONCLUSION: A human iPSC model of ARB showed a functional deficiency rather than anatomical defects. ARB may be caused by RPE dysfunction following BEST1 mutation.


Asunto(s)
Bestrofinas/genética , Enfermedades Hereditarias del Ojo/genética , Células Madre Pluripotentes Inducidas , Enfermedades de la Retina/genética , Epitelio Pigmentado de la Retina , Distrofia Macular Viteliforme/genética , Distrofia Macular Viteliforme/fisiopatología , Diferenciación Celular , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/metabolismo , Enfermedades Hereditarias del Ojo/patología , Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Enfermedades de la Retina/diagnóstico , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/fisiopatología , Trastornos de la Visión , Agudeza Visual , Distrofia Macular Viteliforme/metabolismo
10.
Ecotoxicol Environ Saf ; 203: 110974, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32888622

RESUMEN

Ammonia (NH3), an environmental pollutant, poses a serious threat to human and avian health. Although previous studies have showed that NH3 caused kidney injury, the molecular mechanisms of nephrotoxicity induced by NH3 remain unclear. To explore the mechanisms of NH3 nephrotoxicity, a total of 36 broiler chicks at one day of age were exposed to NH3. After 42 days of exposure, blood samples were collected to determine creatinine and uric acid; and kidney samples were weighted and then collected to detect ultrastructural changes, oxidative stress parameters, ATPases, necroptosis- and mitochondrial dynamics-related genes. The results showed that chickens exposed to NH3 showed lower relative kidney weight and an increase concentration in serum creatinine and uric acid. NH3 exposure caused nephrocyte necrosis and increased the expression of necroptosis-related genes (TNF-α, RIPK1, RIPK3, MLKL, and JNK). Besides, the activities of antioxidant systems (SOD, CAT, GSH-Px, and T-AOC) were reduced, whereas the concentrations of H2O2 and MDA were elevated. Lower activities of ATPases were obtained in NH3 treatment groups. Furthermore, the mitochondrial fission-related genes drp1 and mff were activated, and mitochondrial fusion-related genes opa1, mfn1 and mfn2 were suppressed after NH3 exposure. Based on the above results, we conclude that NH3 caused-oxidative stress and mitochondrial dysfunction mediated nephrocyte necroptosis in chickens. This study may provide new insight into NH3 nephrotoxicity.


Asunto(s)
Amoníaco/toxicidad , Contaminantes Ambientales/toxicidad , Riñón/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Necroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Pollos , Expresión Génica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Riñón/ultraestructura , Pruebas de Función Renal , Dinámicas Mitocondriales/genética , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética
11.
Adv Exp Med Biol ; 1255: 73-81, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32949391

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a chronic complex lung disease with no specific treatment and poor prognosis, characterized by the pulmonary progressive fibrosis and dysfunctions that lead to respiratory failure. Several factors may impact the progress of IPF, including age, cigarette smoking, and dusts, of which genetic and epigenetic factors mainly contribute to lung tissue fibrosis. DNA methylation is one of epigenetic processes that occur in many diseases and regulate chromosomal and extrachromosomal DNA functions in response to environmental exposures. The methylation plays pivotal roles in regulation of gene expression to facilitate the formation of fibroblastic foci and lung fibrosis. This chapter will describe alterations and effects of the DNA methylation on gene expression, the potential application of DNA methylation as a biomarker, and significance as therapeutic targets. Those understanding will provide us new insight into the treatment and prognosis of IPF.


Asunto(s)
Metilación de ADN , Fibrosis Pulmonar Idiopática/genética , Epigénesis Genética , Epigenómica , Expresión Génica , Humanos
12.
Anim Sci J ; 91(1): e13456, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32926548

RESUMEN

In this study, we investigated whether bovine oviducts and endometria produce anti-Müllerian hormone (AMH) (for paracrine and autocrine signaling). Reverse transcription-polymerase chain reaction and western blotting detected AMH expression in oviductal and endometrial specimens. Immunohistochemistry revealed robust AMH expression in the ampulla and isthmus epithelia, and the glandular and luminal endometrial epithelia (caruncular endometria). AMH mRNA (measured by real-time PCR) and protein expression in these layers did not significantly differ among estrous phases in adult Japanese Black (JB) heifers (p > .1). Furthermore, the expression in these layers also did not differ among Holstein cows (93.8 ± 5.8 months old), JB heifers (25.5 ± 0.4 months old), and JB cows (97.9 ± 7.9 months old). We also compared AMH concentrations in the oviduct and uterine horn fluids among the three groups (measured by immunoassays). Interestingly, the AMH concentration in the oviduct fluid, but not in the uterine horn fluid, of Holstein cows was lower than those in JB heifers and cows (p < .05). Therefore, bovine oviducts and endometria express AMH and likely secrete it into the oviduct and uterine fluids.


Asunto(s)
Hormona Antimülleriana/genética , Hormona Antimülleriana/metabolismo , Endometrio/metabolismo , Células Epiteliales/metabolismo , Expresión Génica , Oviductos/metabolismo , Animales , Bovinos , Endometrio/citología , Ciclo Estral/metabolismo , Femenino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Útero/metabolismo
13.
Anim Sci J ; 91(1): e13451, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32926550

RESUMEN

This study assessed the effects of cryoprotectant concentration during equilibration on the efficiency of bovine blastocyst vitrification and the expression of selected developmentally important genes. In vitro produced bovine blastocysts were equilibrated in either 7.5% ethylene glycol (EG) + 7.5% DMSO (Va group) or in 2% EG + 2% DMSO (Vb group) then vitrified on Cryotop® sheets in 16.5% EG + 16.5% DMSO + 0.5M sucrose. After warming, embryos were cultured for 48 hr. Re-expansion, hatching, and the numbers of total and membrane damaged cells were compared among vitrified groups and a control. There was no significant difference between the vitrified groups in survival, cell numbers and the extent of membrane damage. Vitrification increased the number of membrane-damaged cells in both groups, however, in a greater extent in the Vb group. Vitrification increased (p < .05) the expression of the HSP70 gene in Va but not in Vb embryos. The expression of IGF2R, SNRPN, HDAC1, DNMT3B, BAX, OCT4, and IFN-t genes were the same in control and vitrified groups. In conclusion, the concentration of cryoprotectants during equilibration did not affect survival rates; however, normal cell numbers could be maintained only by equilibration in 15% cryoprotectants which was associated with increased HSP70 expression.


Asunto(s)
Blastocisto , Supervivencia Celular/efectos de los fármacos , Criopreservación/métodos , Criopreservación/veterinaria , Crioprotectores/farmacología , Fertilización In Vitro/métodos , Fertilización In Vitro/veterinaria , Vitrificación/efectos de los fármacos , Animales , Bovinos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo
15.
Molecules ; 25(18)2020 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-32927621

RESUMEN

Mass spectrometry and some other biophysical methods, have made substantial contributions to the studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human proteins interactions. The most interesting feature of SARS-CoV-2 seems to be the structure of its spike (S) protein and its interaction with the human cell receptor. Mass spectrometry of spike S protein revealed how the glycoforms are distributed across the S protein surface. X-ray crystallography and cryo-electron microscopy made huge impact on the studies on the S protein and ACE2 receptor protein interaction, by elucidating the three-dimensional structures of these proteins and their conformational changes. The findings of the most recent studies in the scope of SARS-CoV-2-Human protein-protein interactions are described here.


Asunto(s)
Betacoronavirus/química , Infecciones por Coronavirus/epidemiología , Pandemias , Peptidil-Dipeptidasa A/química , Neumonía Viral/epidemiología , Receptores Virales/química , Síndrome Respiratorio Agudo Grave/epidemiología , Glicoproteína de la Espiga del Coronavirus/química , Secuencia de Aminoácidos , Betacoronavirus/patogenicidad , Sitios de Unión , Infecciones por Coronavirus/virología , Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Modelos Moleculares , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Receptores Virales/genética , Receptores Virales/metabolismo , Virus del SRAS/química , Virus del SRAS/patogenicidad , Alineación de Secuencia , Síndrome Respiratorio Agudo Grave/virología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo
16.
Acta Odontol Latinoam ; 33(2): 125, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32920615

RESUMEN

Melatonin (MLT) is a potential signaling molecule in the homeostasis of bone metabolism and may be an important mediator of bone formation and stimulation. The aim of this in vitro study was to evaluate the effect of MLT on the viability, mRNA/protein expression and mineralization of pre-osteoblastic cells. The concentrations 5, 2.5, 1, 0.1 and 0.01 mM MLT were tested on pre-osteoblastic cells (MC3T3) compared to control (no MLT), evaluating proliferation and cell viability (C50), gene expression (RT-PCR) and secretion (ELISA) of COL-I and OPN at 24h, 48h and 72h, and the formation of mineral nodules (alizarin red and fast red) after 10 days of treatment. MLT at 5 and 2.5 mM proved to be cytotoxic (C50), so only 0.01, 0.1 and 1 mM were used for the subsequent analyses. OPN mRNA expression increased with MLT at 0.1 mM - 1 mM, which was followed by increased secretion of OPN both at 24h and 72h compared to the remaining groups (p <0.05). COL-I mRNA and COL-1 secretion followed the same pattern as OPN at 0.1 mM MLT at 72h of treatment (p <0.05). Regarding mineralization, all MLT doses (except 1mM) caused an increase (p <0.05) in the formation of mineral nodules compared to the control. Melatonin at 0.01mM - 1mM had a stimulatory effect on osteoblasts by upregulating COL-I and OPN expression/ secretion and mineralization, thereby fostering osteogenesis.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Melatonina/farmacología , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Osteopontina/metabolismo , Fragmentos de Péptidos/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/genética , Osteoblastos/metabolismo , Osteopontina/genética , Fragmentos de Péptidos/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
17.
Nat Commun ; 11(1): 4641, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32934213

RESUMEN

Despite recent advances in circuit engineering, the design of genetic networks in mammalian cells is still painstakingly slow and fraught with inexplicable failures. Here, we demonstrate that transiently expressed genes in mammalian cells compete for limited transcriptional and translational resources. This competition results in the coupling of otherwise independent exogenous and endogenous genes, creating a divergence between intended and actual function. Guided by a resource-aware mathematical model, we identify and engineer natural and synthetic miRNA-based incoherent feedforward loop (iFFL) circuits that mitigate gene expression burden. The implementation of these circuits features the use of endogenous miRNAs as elementary components of the engineered iFFL device, a versatile hybrid design that allows burden mitigation to be achieved across different cell-lines with minimal resource requirements. This study establishes the foundations for context-aware prediction and improvement of in vivo synthetic circuit performance, paving the way towards more rational synthetic construct design in mammalian cells.


Asunto(s)
Expresión Génica , Mamíferos/genética , MicroARNs/genética , Animales , Redes Reguladoras de Genes , Humanos , Mamíferos/metabolismo , Proteínas/genética , Proteínas/metabolismo
18.
Biomed Environ Sci ; 33(8): 583-592, 2020 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-32933610

RESUMEN

Objective: To screen the differentially expressed proteins (DEPs) in human bronchial epithelial cells (HBE) treated with atmospheric fine particulate matter (PM 2.5). Methods: HBE cells were treated with PM 2.5 samples from Shenzhen and Taiyuan for 24 h. To detect overall protein expression, the Q Exactive mass spectrometer was used. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Perseus software were used to screen DEPs. Results: Overall, 67 DEPs were screened in the Shenzhen sample-treated group, of which 46 were upregulated and 21 were downregulated. In total, 252 DEPs were screened in the Taiyuan sample-treated group, of which 134 were upregulated and 118 were downregulated. KEGG analysis demonstrated that DEPs were mainly enriched in ubiquitin-mediated proteolysis and HIF-1 signal pathways in Shenzhen PM 2.5 samples-treated group. The GO analysis demonstrated that Shenzhen sample-induced DEPs were mainly involved in the biological process for absorption of various metal ions and cell components. The Taiyuan PM 2.5-induced DEPs were mainly involved in biological processes of protein aggregation regulation and molecular function of oxidase activity. Additionally, three important DEPs, including ANXA2, DIABLO, and AIMP1, were screened. Conclusion: Our findings provide a valuable basis for further evaluation of PM 2.5-associated carcinogenesis.


Asunto(s)
Contaminantes Atmosféricos/análisis , Bronquios/metabolismo , Células Epiteliales/metabolismo , Expresión Génica/efectos de los fármacos , Material Particulado/análisis , Bronquios/efectos de los fármacos , Biología Computacional , Células Epiteliales/efectos de los fármacos , Humanos , Espectrometría de Masas , Tamaño de la Partícula , Proteómica
19.
Eur Cytokine Netw ; 31(2): 44-49, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32933891

RESUMEN

BACKGROUND: Evidence links COVID-19 severity to hyper-inflammation. Treatment with tocilizumab, a monoclonal antibody directed against the interleukin-6 (IL-6) receptor, was shown to lead to clinical improvement in patients with severe COVID-19. We, therefore, performed the present systematic review and meta-analysis to investigate whether the circulating levels of IL-6 is a reliable indicator of disease severity among patients affected with COVID-19. METHODS: A systematic search was conducted in PubMed, Scopus, Web of Science, and Google Scholar on April 19, 2020. RESULTS: Eleven studies provided data of IL-6 levels in patients with severe to critical COVID-19 (severe) and patients with mild to moderate COVID-19 (non-severe). The included studies were of moderate to high quality. The mean patients' age was 60.9 years, ranging from 45.2 to 76.7 years in the severe group and 46.8 years, ranging from 37.9 to 61 years, in the nonsevere group. Fifty-two percent were male in the severe group, as compared to 46% in the non-severe group. An overall random effects meta-analysis showed significantly higher serum levels of IL-6 in the severe group than in the non-severe group with a mean difference of +23.1 pg/mL (95% CI: 12.42-33.79) and the overall effect of 4.24 (P-value < 0.001). Meta-regressions showed that neither age nor sex significantly influenced the mean difference of IL-6 between the groups. CONCLUSIONS: Meta-analysis and meta-regression reveal a reliable relationship between IL-6 and COVID-19 severity, independent of age and sex. Future research is, however, required to assess the effect of BMI on the pattern of IL-6 production in patients with COVID-19. Also, there might be confounding factors that influence the relationship between IL-6 and COVID-19 severity and remain as yet unknown.


Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antivirales/uso terapéutico , Betacoronavirus/inmunología , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Neumonía Viral/tratamiento farmacológico , Anciano , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Síndrome de Liberación de Citoquinas/virología , Femenino , Expresión Génica , Humanos , Unidades de Cuidados Intensivos , Interleucina-6/genética , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Neumonía Viral/virología , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del Tratamiento
20.
Sci Adv ; 6(31)2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32937590

RESUMEN

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico , Síndrome de Liberación de Citoquinas/diagnóstico , Proteínas de la Matriz Extracelular/inmunología , Leucocitos Mononucleares/inmunología , Neumonía Viral/diagnóstico , Procesamiento Proteico-Postraduccional , Insuficiencia Respiratoria/diagnóstico , Factor de Crecimiento Transformador beta/inmunología , Acetilación , Anticuerpos Neutralizantes/farmacología , Betacoronavirus/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Proteínas de la Matriz Extracelular/antagonistas & inhibidores , Proteínas de la Matriz Extracelular/genética , Expresión Génica , Humanos , Unidades de Cuidados Intensivos , Recuento de Leucocitos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/virología , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Lisina/metabolismo , FN-kappa B/genética , FN-kappa B/inmunología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/inmunología , Neumonía Viral/patología , Cultivo Primario de Células , Pronóstico , Insuficiencia Respiratoria/sangre , Insuficiencia Respiratoria/inmunología , Insuficiencia Respiratoria/patología , Índice de Severidad de la Enfermedad , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/genética
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