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1.
Gene ; 766: 145022, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32758579

RESUMEN

BACKGROUND: A better understanding of the mechanism(s) underlying cardioembolic stroke can promote recovery and reduce the risk of recurrent embolisms. METHODS: Peripheral blood mononuclear cell (PBMC) gene expression datasets from cardioembolic patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database (GSE58294). The Limma software package was utilized to identify differentially-expressed genes (DEGs). Protein-protein interaction (PPI) analysis of the DEGs was performed using STRING. A weighted gene co-expression network analysis (WGCNA) was used to build a gene co-expression network. In vitro experiments assessed the effects on neutrophils exposed to oxygen and glucose-deprived (OGD) cortical neurons. An in vivo murine model of thromboembolic stroke was constructed through thrombin injection to examine effects on circulating neutrophils. Mechanistic in vitro studies were conducted using the proteasome inhibitor MG132, the p53-Mdm2 binding inhibitor Nutlin-3a, Mdm2 small-interfering RNA (siRNA), and Ctnnb1 siRNA. RESULTS: DEG analysis identified 44 upregulated and 66 downregulated genes in cardioembolic stroke PBMCs. PPI analysis of these DEGs yielded one eight-node protein module with ß-catenin (CTNNB1) as the central hub protein. Integration of the DEGs with WGCNA-derived hub genes revealed the key hub DEGs CTNNB1 and mouse double minute 2 (MDM2). Follow-up experiments revealed Mdm2, p53, and phospho-ß-catenin upregulation in neutrophils exposed to OGD neurons in vitro and following thromboembolic stroke in vivo. Mechanistic studies revealed that neutrophils transcriptionally upregulate Ctnnb1 expression to compensate for Mdm2/p53-mediated ß-catenin degradation induced by exposure to OGD neurons, thereby promoting neutrophil survival. CONCLUSION: Compensatory Ctnnb1 transcriptional upregulation in neutrophils induced by ischemic neuron exposure may be involved in promoting neutrophil survival following cardioembolic stroke.


Asunto(s)
Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba/genética , beta Catenina/genética , Animales , Células Cultivadas , Regulación hacia Abajo/genética , Expresión Génica/genética , Redes Reguladoras de Genes/genética , Corazón/fisiopatología , Humanos , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Transcripción Genética/genética , Activación Transcripcional/genética
2.
Chemosphere ; 262: 127841, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32784060

RESUMEN

Environmental pollutants suspected of disrupting the endocrine system are considered etiologic factors in the epidemic of metabolic disorders. As regulation of energy metabolism relies on the integrated action of a large number of hormones, we hypothesized that certain chemicals could trigger changes in glucocorticoid signaling. To this end, we exposed C57Bl6/J female and male mice between 5 and 20 weeks of age to a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (20 pg/kg body weight/day [bw/d]), polychlorobiphenyl 153 (200 ng/kg bw/d), di-[2-ethylhexyl]-phthalate (500 µg/kg bw/d) and bisphenol A (40 µg/kg bw/d). In female mice fed a standard diet (ST), we observed a decrease in plasma levels of leptin as well as a reduced expression of corticoid receptors Nr3c1 and Nr3c2, of leptin and of various canonical genes related to the circadian clock machinery in visceral (VAT) but not subcutaneous (SAT) adipose tissue. However, Nr3c1 and Nr3c2 mRNA levels did not change in high-fat-fed females exposed to pollutants. In ST-fed males, pollutants caused the same decrease of Nr3c1 mRNA levels in VAT observed in ST-fed females but levels of Nr3c2 and other clock-related genes found to be down-regulated in female VAT were enhanced in male SAT and not affected in male VAT. The expression of corticoid receptors was not affected in the livers of both sexes in response to pollutants. In summary, exposure to a mixture of pollutants at doses lower than the no-observed adverse effect levels (NoAELs) resulted in sex-dependent glucocorticoid signaling disturbances and clock-related gene expression modifications in the adipose tissue of ST-fed mice.


Asunto(s)
Contaminantes Ambientales/toxicidad , Glucocorticoides/metabolismo , Tejido Adiposo/metabolismo , Animales , Compuestos de Bencidrilo , Peso Corporal , Contaminantes Ambientales/metabolismo , Femenino , Expresión Génica , Leptina/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenoles , Dibenzodioxinas Policloradas/metabolismo , ARN Mensajero/metabolismo , Sensibilidad y Especificidad
3.
Gene ; 766: 145150, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32949695

RESUMEN

There are a few studies indicating that small molecular compounds affect the proliferation, differentiation, apoptosis, and autophagy of female germline stem cells (FGSCs). However, whether small molecular compound 28 (C28) affect development of FGSCs remains unknown. In this study, we found that C28 reduced the viability and proliferation of FGSCs, respectively. Additionally, western blotting showed that the expression of autophagy marker light chain 3 beta II (LC3B-II) was significantly increased and expression of sequestosome-1 (SQSTM1) was significantly reduced in C28-treated groups. Immunofluorescence showed that, in C28-treated groups, the number of LC3B-II-positive puncta was increased significantly. These results indicated that C28 induced autophagy of FGSCs in vitro. Furthermore, data from Chromatin Immunoprecipitation Sequencing for H3K27ac showed that autophagy-related biological processes such as regulation of mitochondrial membrane potential, Golgi vesicle transport, and cellular response to reactive oxygen species were different after C28-treated. In addition, RNA-Seq showed that the expression of genes (Trib3, DDIT3, and ATF4) related to endoplasmic reticulum (ER) stress was enhanced by C28. These results suggest that the changes of H3K27ac and ER stress might be associated with C28-induced FGSC autophagy.


Asunto(s)
Acetilación/efectos de los fármacos , Autofagia/efectos de los fármacos , Histonas/genética , Células Madre Oogoniales/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Transcriptoma/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Células Madre Oogoniales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
4.
Sci Total Environ ; 752: 141784, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32889265

RESUMEN

Emerging evidence suggests that perinatal dioxin exposure affects neurodevelopment and impairs multiple brain functions, including cognitive, language, learning and emotion, in the offspring. However, the impacts of gestational and lactational exposure to dioxin on behavior and related molecular events are still not fully understood. In this study, female C57BL/6J mice were orally administered three doses of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (0.1 or 10 µg/kg body weight (bw)) during the pregnancy and lactation periods. The locomotion, exploration and anxiety-related behaviors were examined by an open field test of the young adult female offspring at postnatal day 68. We found that the maternal TCDD exposure, particularly at a low dose, increased movement ability, novelty-exploration and certain anxiety-related behaviors in the offspring. Such hyperactivity-like behaviors were accompanied by the upregulation of certain genes associated with cholinergic neurotransmission or synaptogenesis in the offspring brain. In accordance with the potential enhancement of cholinergic neurotransmission due to the gene upregulations, the enzymatic activity of acetylcholinesterase was decreased, which might lead to excess acetylcholine and consequent hyper-excitation at the synapses. Thus, we found that gestational and lactational TCDD exposure at low dose caused hyperactivity-like behaviors in young adult female offspring and speculated the enhancement of cholinergic neurotransmission and synaptogenesis as potential molecular events underlying the neurobehavioral effects.


Asunto(s)
Dibenzodioxinas Policloradas , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Humanos , Lactancia , Exposición Materna/efectos adversos , Ratones , Ratones Endogámicos C57BL , Dibenzodioxinas Policloradas/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente
5.
Nihon Yakurigaku Zasshi ; 155(6): 390-394, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-33132256

RESUMEN

The current therapeutic drugs for major depression mainly modulate monoaminergic signaling. Since they are not effective for all patients, the development of novel therapeutic target is required. Recently, it has been reported that inflammation-related molecules are increased in the blood from patients with major depression. Therefore, neuroinflammation is a possible cause of these disorders. However, we still do not know whether neuroinflammation induces depression. Since social and environmental stress is a risk factor for mental illnesses, repeated social defeat stress is employed as an animal model of depression. We found that prostaglandin E2 (PGE2) suppresses mesocortical dopaminergic pathway to induce behavioral changes and cyclooxygenase-1 (COX-1), a key enzyme for PGE2 production, is essential for repeated stress-induced PGE2 production and behavioral changes. Based on the finding that COX-1 is expressed in microglia in the brain, we are wondering if microglia plays an important role in stress-induced behavioral changes. We revealed that Toll-like receptor (TLR) 2 and 4 in prefrontal microglia are crucial for repeated stress-induced behavioral changes. Our results indicate that repeated social defeat stress induces microglial activation through TLR2 and 4, thereby leading to neuronal and behavioral changes through proinflammatory cytokines such as TNFα and IL-1α. These findings revealed the essential role and molecular basis of neuroinflammation. In addition, we developed the drug screening platform which targets neuroinflammation for neurodegenerative disease such as amyotrophic lateral sclerosis. Our findings pave the way for the development of therapeutic drugs for major depression targeting neuroinflammation which causes neurological disorders.


Asunto(s)
Depresión , Evaluación Preclínica de Medicamentos , Inflamación , Enfermedades Neurodegenerativas , Animales , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Microglía , Estrés Psicológico
6.
Nat Commun ; 11(1): 5671, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168804

RESUMEN

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions. The mutational signatures of human and mouse OSCC overlap extensively. Mutational burden is higher in moderate dysplasias and invasive SCCs than in hyperplasias and mild dysplasias, although mutations in p53, Notch1 and Fat1 occur in early lesions. Laminin-α3 mutations are associated with tumour invasiveness and Notch1 mutant tumours have an increased immune infiltrate. Computational modelling of clonal dynamics indicates that high genetic heterogeneity may be a feature of those mild dysplasias that are likely to progress to more aggressive tumours. These studies provide a foundation for exploring OSCC evolution, heterogeneity and progression.


Asunto(s)
Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Genómica , Neoplasias de la Boca/genética , 4-Nitroquinolina-1-Óxido/efectos adversos , Animales , Cadherinas/genética , Carcinogénesis/inducido químicamente , Carcinoma de Células Escamosas/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Exoma/genética , Genes Relacionados con las Neoplasias , Genes p53/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias de la Boca/patología , Mutación , Invasividad Neoplásica , Receptor Notch1/genética
7.
Nat Commun ; 11(1): 5666, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168815

RESUMEN

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl4, we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Acuaporina 3/antagonistas & inhibidores , Acuaporina 3/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Animales , Acuaporina 3/genética , Células CHO , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Quimiocina CCL4/efectos adversos , Cricetulus , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Glicerol/metabolismo , Peróxido de Hidrógeno/metabolismo , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Medicina Molecular , FN-kappa B/metabolismo , Estrés Oxidativo , Transducción de Señal , Transcriptoma
8.
Nat Commun ; 11(1): 5661, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168829

RESUMEN

Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.


Asunto(s)
Envejecimiento/fisiología , Estrés del Retículo Endoplásmico/fisiología , Proteína 3 de Unión a Ácidos Grasos/metabolismo , Lípidos de la Membrana/metabolismo , Músculo Esquelético/metabolismo , Animales , Línea Celular , Factor 2 Eucariótico de Iniciación/metabolismo , Proteína 3 de Unión a Ácidos Grasos/genética , Femenino , Técnicas de Silenciamiento del Gen , Lipidómica , Fluidez de la Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/patología , Mioblastos/patología , Mioblastos/fisiología , Fosfolípidos/metabolismo , Proteínas Serina-Treonina Quinasas , Sarcopenia , Regulación hacia Arriba
9.
Zhonghua Yi Xue Za Zhi ; 100(42): 3332-3337, 2020 Nov 17.
Artículo en Chino | MEDLINE | ID: mdl-33202497

RESUMEN

Objective: Modeling the immune-related adverse events (irAE) colitis in mice, and explore the protective effect and related mechanism of Lactobacillus rhamnosus GG (LGG) on irAE colitis. Methods: C57BL/6 mice were divided into dextran sodium sulfate (DSS) group (n=3), DSS+anti-programmed death receptor 1 (PD-1) group (n=4), DSS+anti-PD-1+anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) Group (n=4), DSS+anti-PD-1+anti-CTLA-4+LGG group (n=4), all were given corresponding drugs and probiotics intervention. The severity of colitis were assessed by weight loss, disease activity index (DAI), colon length, colon histopathological score. The inflammatory cytokines and T cell immunity of CD4+, CD8+, FoxP3+regulatory T cells (Treg), were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining respectively. Results: Compared to DSS group, the Day 9 weight [(87.40±1.79)% vs (94.57±0.53)%, P<0.05], colon length [(5.33±0.27)cm vs (6.63±0.12)cm, P<0.05] were lower, and DAI score(2.66±0.24 vs 0.89±0.48), colon histopathological score (12.50±1.04 vs 5.67±0.33), tumor necrosis factor-α (TNF-α) (6.73±1.68 vs 0.91±0.40) (P<0.05), as well CD8+T cells (156.80±8.84 vs 89.00±6.66) and FoxP3+Treg cells (103.80±2.66 vs 48.33±3.18) (P<0.05) were higher in DSS+anti-PD-1+anti-CTLA-4 group. Compared to DSS+anti-PD-1+anti-CTLA-4 group, the DAI score(1.83±0.17 vs 2.66±0.24), colonic histopathology score (8.75±0.63 vs 12.50±1.04), TNF-α level (1.32±0.18 vs 6.73±1.68) (P<0.05) were lower; and CD8+T cells(97.75±3.75 vs 156.80±8.84, P<0.01) level was lower with higher FoxP3+Treg cells (126.00±8.33 vs 103.80±2.66, P=0.046) in DSS+anti-PD-1+anti-CTLA-4+LGG group. Conclusion: DSS combined with anti-PD-1 and anti-CTLA-4 can successfully modeling the irAE colitis in mice, LGG can reduce irAE colitis severity by regulating Treg cells.


Asunto(s)
Colitis , Lactobacillus rhamnosus , Animales , Colitis/inducido químicamente , Colon , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL
10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 865-870, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33148379

RESUMEN

Objective To investigate dynamic changes of type 3 innate lymphoid cells (ILC3) in lungs of mice with bronchopulmonary dysplasia (BPD). Methods Forty newborn C57BL/6 mice were randomized into air group and the hyperoxia group, 20 mice in each group. C57BL/6 newborn mice were delivered by caesarean section on the 19th day of pregnancy and exposed to 850 mL/L O2 for replication of the BPD model. Five mice in each group were sacrificed 1 day, 3, 7, 14 days after they were born for procurement of fresh lung tissues. HE staining was used to observe the pathological changes of lung tissues. ELISA was used to detect the protein content of downstream cytokines interleukin-17 (IL-17), IL-22 and granulocyte-macrophage colony stimulating factor (GM-CSF) in lung homogenate. Flow cytometry was used for measuring the proportion of ILC3 in lymphocytes as well as the proportions of IL-17+ ILC3 and IL-22+ ILC3 in the lung. Results The proportion of ILC3 in lung tissues reached the peak on the 7th day after birth. In contrast with the air group, the proportion of ILC3 in the hyperoxia group was significantly elevated at the same time points. The protein content of IL-17 and IL-22 in the hyperoxia group went up significantly in comparison with those in the air group at the same time points, while the GM-CSF content in the hyperoxia group showed no significant changes. The proportions of IL-17+ILC3 and IL-22+ILC3 in the hyperoxia group significantly increased as compared with those in the air group at the same time points. Conclusion The secretion of IL-17 and IL-22 derived from ILC3 is associated with BPD.


Asunto(s)
Displasia Broncopulmonar/inmunología , Interleucina-17/inmunología , Interleucinas/inmunología , Linfocitos/citología , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Hiperoxia , Inmunidad Innata , Pulmón/citología , Pulmón/inmunología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Embarazo , Distribución Aleatoria
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 871-876, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33148380

RESUMEN

Objective To investigate the effects of inorganic arsenic exposure on the differentiation of renal CD4+T lymphocytes and the possible mechanism. Methods Female C57BL/6 mice were randomly divided into control group, (2.5, 5, 10) mg/kg NaAsO2 exposure groups, 10 mice in each group. As was administered once intragastrically for 24 hours, and control mice were treated with normal saline. Real-time fluorescence quantitative PCR was used to detect T helper type 1 (Th1) cell-specific transcription factor T-box expressed in T cells (T-bet) and IFN-γ, Th2 cell-specific transcription factor GATA-binding protein 3 (GATA3) and interleukin 4 (IL-4), Th17 cell-specific transcription factor retinoic acid related orphan nuclear receptor γt (ROR-γt) and cytokine IL-22, regulatory T cells (Tregs)-specific transcription factor forkhead box P3 (FOXP3) and cytokine transforming growth factor-ß (TGF-ß) mRNA levels. We used commercial kits to detect catalase (CAT) activity and total antioxidant capacity (T-AOC) in serum as well as renal malondialdehyde (MDA) and superoxide dismutase (SOD). Results Compared with the control group, the body mass, renal mass and kidney index of the mice in all arsenic-treated groups have no significant changes. The levels of the master transcription factors T-bet, GATA3, ROR-γt and FOXP3 as well as related cytokines IFN-γ, IL-4, IL-22 and TGF-ß of Th1, Th2, Th17 cells and Tregs decreased in the arsenic-treated groups. Serum CAT activity and T-AOC level in the arsenic-treated mice dropped greatly. In addition, arsenic markedly increased renal MDA level while decreased SOD activity. Conclusion Inorganic arsenic exposure can suppress renal T cell subpopulation function and induce renal oxidative injure.


Asunto(s)
Arsénico/toxicidad , Riñón/efectos de los fármacos , Estrés Oxidativo , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Animales , Citocinas/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción GATA3/metabolismo , Riñón/inmunología , Ratones , Ratones Endogámicos C57BL
12.
Zhongguo Zhong Yao Za Zhi ; 45(19): 4692-4698, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33164434

RESUMEN

The aim of this paper was to investigate the effect of total polysaccharide from Balanophora henryi(TBP) on alcoholic liver disease(ALD) and explore the possible mechanism. C57 BL/6 N mice were randomly divided into 4 groups: pair-feeding group, alcohol-feeding model group, model+TBP group and TBP drug control group. The Gao-binge method was used to prepare the chronic ALD model, and at the same time, 400 mg·kg~(-1) TBP was given for interventional therapy. After feeding for 6 weeks, the serum, liver and colon tissues were collected for detection. As compared with the pair-feeding group, the model group mice showed obvious fatty degeneration and a large number of infiltration of inflammatory cells in the liver, with increased serum ALT and AST levels. After TBP intervention, histopathological changes in liver tissues were significantly improved, with decreased lipid deposition, closer arrangement of hepatocytes, lower expression level of inflammatory factors, and reduced activity of serum ALT and AST, indicating that TBP had a significant improvement effect on ALD. The observation of colonic tissues in mice showed that TBP effectively maintained the integrity of intestinal tissue structure of mice with ALD, enhanced the expression of tight junction protein occludin and reduced miR-122 a expression level. More importantly, TBP significantly reduced serum lipopolysaccharide(LPS) level in model mice. These results indicated that TBP may improve ALD by maintaining and enhancing intestinal barrier function. In vitro experiments showed that TBP significantly inhibited the expression level of miR-122 a in Caco-2 cells exposed to ethanol. Overexpression of miR-122 a in Caco-2 cells induced the inhibition of occludin protein production, and the addition of TBP significantly interfered with the effect. These results suggested that TBP could improve ALD by maintaining the stability of intestinal barrier function and reducing LPS content into the liver, and the mechanism may be partially related to inhibiting miR-122 a expression.


Asunto(s)
Hepatopatías Alcohólicas , MicroARNs , Animales , Células CACO-2 , Humanos , Hígado , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/genética , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Ocludina/genética
13.
Zhongguo Zhong Yao Za Zhi ; 45(19): 4732-4739, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33164440

RESUMEN

This study aims to observe the improvement of non-alcoholic steatohepatitis(NASH) after using water extracts of Polygoni Multiflori Radix and Polygoni Multiflori Radix Praeparata and explore their preliminary mechanism. Mice were fed with methionine-choline-deficent diet(MCD) for 6 weeks for modeling, and mice were orally given with 50, 100, 200 mg·kg~(-1) of Polygoni Multiflori Radix water extract(PMRWE) or Polygoni Multiflori Radix Praeparata water extract(PMRPWE) at the last 4 weeks. During the whole experimental procedure, the body weight changes of the mice were monitored and recorded. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) activities were detected; liver histopathological evaluation and NAFLD activity score(NAS) calculation were conducted, and the levels of reactive oxygen species(ROS) in liver tissues were analyzed. The contents of triglyceride(TG) and non-esterified fatty acids(NEFA) in liver tissues were detected, and oil red O staining of the liver tissues was conducted and observed. Quantitative polymerase chain reaction(qPCR) was used to detect hepatic mRNA expression of ß-oxidation-related genes in mice. The results showed that PMRWE(100, 200 mg·kg~(-1)) and PMRPWE(50, 100, 200 mg·kg~(-1)) alleviated liver damage in MCD-induced NASH in mice. PMRWE(100, 200 mg·kg~(-1)) and PMRPWE(50, 100, 200 mg·kg~(-1)) reduced hepatic li-pid accumulation in mice with NASH. Different doses of PMRPWE inversed the decreased hepatic mRNA expression of ß-oxidation-related genes in mice with NASH. This study indicated that PMRPWE and PMRWE could ameliorate MCD-induced NASH in mice by promoting fatty acid ß oxidation, reducing liver lipid accumulation, and alleviating liver damage. Moreover, the protective effect of PMRPWE against MCD-induced NASH was better than PMRWE.


Asunto(s)
Medicamentos Herbarios Chinos , Enfermedad del Hígado Graso no Alcohólico , Polygonum , Animales , Hígado , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Raíces de Plantas , Agua
14.
Nat Commun ; 11(1): 5196, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33060592

RESUMEN

Pericytes play essential roles in blood-brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders although the underlying mechanism remains largely unknown. However, the scarcity of material sources hinders the application of BBB models in vitro for pathophysiological studies. Additionally, whether pericytes can be used to treat neurological disorders remains to be elucidated. Here, we generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) through the intermediate stage of the cranial neural crest (CNC) and reveal that the cranial neural crest-derived pericyte-like cells (hPSC-CNC PCs) express typical pericyte markers including PDGFRß, CD146, NG2, CD13, Caldesmon, and Vimentin, and display distinct contractile properties, vasculogenic potential and endothelial barrier function. More importantly, when transplanted into a murine model of transient middle cerebral artery occlusion (tMCAO) with BBB disruption, hPSC-CNC PCs efficiently promote neurological functional recovery in tMCAO mice by reconstructing the BBB integrity and preventing of neuronal apoptosis. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases.


Asunto(s)
Isquemia Encefálica/metabolismo , Pericitos/metabolismo , Recuperación de la Función/fisiología , Accidente Cerebrovascular/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Isquemia Encefálica/patología , Diferenciación Celular/genética , Infarto de la Arteria Cerebral Media , Masculino , Ratones , Ratones Endogámicos C57BL , Cresta Neural/metabolismo , Células Madre Pluripotentes/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Recuperación de la Función/genética , Accidente Cerebrovascular/patología , Transcriptoma
15.
Nat Commun ; 11(1): 5207, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33060630

RESUMEN

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.


Asunto(s)
Sistema Nervioso Central/fisiología , Miedo/fisiología , Memoria/fisiología , Vías Nerviosas/fisiología , Sustancia Gris Periacueductal/fisiología , Amígdala del Cerebelo/fisiología , Animales , Sistema Nervioso Central/patología , Cerebelo/diagnóstico por imagen , Cerebelo/fisiología , Condicionamiento Clásico/fisiología , Condicionamiento Operante/fisiología , Aprendizaje , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Optogenética
16.
J Pharmacol Sci ; 144(4): 189-196, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33070837

RESUMEN

Pneumonia is a common illness that continues to be the major killer of remaining to be a significant source of morbidity and mortality in the patient population. Many microorganisms cause pneumonia, and now concern is turning to the importance of the cause the new therapies for viral pneumonia. In the current study, we report the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on poly I: C-induced pneumonia. Andrographolide sulfonate was administrated through intraperitoneal injection to mice with poly I: C-induced pneumonia. Recruitment of airway inflammatory cells, alteration of lung histological induced by Poly I: C were significantly ameliorated by andrographolide sulfonate. The protein levels of pro-inflammatory cytokines in bronchoalveolar fluid (BALF) and serum were reduced by andrographolide sulfonate treatment. The levels of MUC5AC and MUC5B in lung tissue were also suppressed. These results reveal that andrographolide sulfate remarkably alleviated pneumonia induced by poly I:C in mice. Moreover, andrographolide sulfonate markedly inhibited the activation of nuclear factor-κB (NF-κB). Taken together, we demonstrated that andrographolide sulfonate ameliorated poly I: C-induced pneumonia in mice, suggesting the possible use of andrographolide sulfonate for virus-induced pneumonia in clinical.


Asunto(s)
Diterpenos/administración & dosificación , Diterpenos/farmacología , FN-kappa B/metabolismo , Fitoterapia , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Poli I-C/efectos adversos , Animales , Citocinas/sangre , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratones Endogámicos C57BL , Mucina 5AC/metabolismo , Mucina 5B/metabolismo , Neumonía/inducido químicamente , Neumonía/patología , Neumonía Viral/tratamiento farmacológico
17.
J Pharmacol Sci ; 144(4): 229-236, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33070842

RESUMEN

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/complicaciones , Adenina/efectos adversos , Anemia/tratamiento farmacológico , Anemia/etiología , Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Inhibidores de Prolil-Hidroxilasa , Pirazoles/uso terapéutico , Triazoles/uso terapéutico , Lesión Renal Aguda/metabolismo , Animales , Modelos Animales de Enfermedad , Eritropoyetina/metabolismo , Masculino , Ratones Endogámicos C57BL , Pirazoles/administración & dosificación , Pirazoles/farmacología , Triazoles/administración & dosificación , Triazoles/farmacología
18.
Nat Commun ; 11(1): 5292, 2020 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-33087715

RESUMEN

Recent advances have enabled the direct induction of human tissue-specific stem and progenitor cells from differentiated somatic cells. However, it is not known whether human hepatic progenitor cells (hHepPCs) can be generated from other cell types by direct lineage reprogramming with defined transcription factors. Here, we show that a set of three transcription factors, FOXA3, HNF1A, and HNF6, can induce human umbilical vein endothelial cells to directly acquire the properties of hHepPCs. These induced hHepPCs (hiHepPCs) propagate in long-term monolayer culture and differentiate into functional hepatocytes and cholangiocytes by forming cell aggregates and cystic epithelial spheroids, respectively, under three-dimensional culture conditions. After transplantation, hiHepPC-derived hepatocytes and cholangiocytes reconstitute damaged liver tissues and support hepatic function. The defined transcription factors also induce hiHepPCs from endothelial cells circulating in adult human peripheral blood. These expandable and bipotential hiHepPCs may be useful in the study and treatment of human liver diseases.


Asunto(s)
Técnicas de Reprogramación Celular/métodos , Células Endoteliales/citología , Hepatocitos/citología , Células Madre/citología , Animales , Conductos Biliares/citología , Conductos Biliares/fisiología , Agregación Celular , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Reprogramación Celular/genética , Reprogramación Celular/fisiología , Células Endoteliales/fisiología , Femenino , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/fisiología , Factor Nuclear 3-gamma del Hepatocito/genética , Factor Nuclear 3-gamma del Hepatocito/fisiología , Factor Nuclear 6 del Hepatocito/genética , Factor Nuclear 6 del Hepatocito/fisiología , Hepatocitos/fisiología , Hepatocitos/trasplante , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Esferoides Celulares/citología , Esferoides Celulares/fisiología , Células Madre/fisiología
19.
Nat Commun ; 11(1): 5355, 2020 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-33097705

RESUMEN

Water and lipids are key participants in many biological processes, but there are few non-invasive methods that provide quantification of these components in vivo, and none that can isolate and quantify lipids in the blood. Here we develop a new imaging modality termed shortwave infrared meso-patterned imaging (SWIR-MPI) to provide label-free, non-contact, spatial mapping of water and lipid concentrations in tissue. The method utilizes patterned hyperspectral illumination to target chromophore absorption bands in the 900-1,300 nm wavelength range. We use SWIR-MPI to monitor clinically important physiological processes including edema, inflammation, and tumor lipid heterogeneity in preclinical models. We also show that SWIR-MPI can spatially map blood-lipids in humans, representing an example of non-invasive and contact-free measurements of in vivo blood lipids. Together, these results highlight the potential of SWIR-MPI to enable new capabilities in fundamental studies and clinical monitoring of major conditions including obesity, cancer, and cardiovascular disease.


Asunto(s)
Rayos Infrarrojos , Lípidos/sangre , Imagen Óptica/métodos , Ondas de Radio , Espectroscopía Infrarroja Corta/métodos , Agua/análisis , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Pardo/patología , Adulto , Animales , Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico por imagen , Edema/diagnóstico por imagen , Edema/patología , Femenino , Xenoinjertos , Humanos , Inflamación/diagnóstico por imagen , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Obesidad/diagnóstico por imagen , Imagen Óptica/instrumentación , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Espectroscopía Infrarroja Corta/instrumentación
20.
Nat Commun ; 11(1): 5356, 2020 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-33097716

RESUMEN

Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.


Asunto(s)
Tronco Encefálico/enzimología , Tronco Encefálico/crecimiento & desarrollo , Tronco Encefálico/metabolismo , Galactosilceramidasa/genética , Galactosilceramidasa/metabolismo , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/metabolismo , Animales , Tronco Encefálico/embriología , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Fenotipo , Psicosina/metabolismo , Tamoxifeno , Transcriptoma
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