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1.
Interdiscip Sci ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727340

RESUMO

BACKGROUND AND OBJECTIVE: Under the background of urgent need for computer-aided technology to provide physicians with objective decision support, aiming at reducing the false positive rate of nodule CT detection in pulmonary nodules detection and improving the accuracy of lung nodule recognition, this paper puts forward a method based on ensemble learning to distinguish between malignant and benign pulmonary nodules. METHODS: Firstly, trained on a public data set, a multi-layer feature fusion YOLOv3 network is used to detect lung nodules. Secondly, a CNN was trained to differentiate benign from malignant pulmonary nodules. Then, based on the idea of ensemble learning, the confidence probability of the above two models and the label of the training set are taken as data features to build a Logistic regression model. Finally, two test sets (public data set and private data set) were tested, and the confidence probability output by the two models was fused into the established logistic regression model to determine benign and malignant pulmonary nodules. RESULTS: The YOLOv3 network was trained to detect chest CT images of the test set. The number of pulmonary nodules detected in the public and private test sets was 356 and 314, respectively. The accuracy, sensitivity and specificity of the two test sets were 80.97%, 81.63%, 78.75% and 79.69%, 86.59%, 72.16%, respectively. With CNN training pulmonary nodules benign and malignant discriminant model analysis of two kinds of test set, the result of accuracy, sensitivity and specificity were 90.12%, 90.66%, 89.47% and 88.57%, 85.62%, 90.87%, respectively. Fused model based on YOLOv3 network and CNN is tested on two test sets, and the result of accuracy, sensitivity and specificity were 93.82%, 94.85%, 92.59% and 92.31%, 92.68%, 91.89%, respectively. CONCLUSION: The ensemble learning model is more effective than YOLOv3 network and CNN in removing false positives, and the accuracy of the ensemble. Learning model is higher than the other two networks in identifying pulmonary nodules.

2.
iScience ; 24(11): 103305, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34765923

RESUMO

HIV-1 infects blood CD4 T cells through the use of CD4 and CXCR4 or CCR5 receptors, which can be targeted through blocking viral binding to CD4/CXCR4/CCR5 or virus-cell fusion. Here we describe a novel mechanism by which HIV-1 nuclear entry can also be blocked through targeting a non-entry receptor, CD2. Cluster of differentiation 2 (CD2) is an adhesion molecule highly expressed on human blood CD4, particularly, memory CD4 T cells. We found that CD2 ligation with its cell-free ligand LFA-3 or anti-CD2 antibodies rendered blood resting CD4 T cells highly resistant to HIV-1 infection. We further demonstrate that mechanistically, CD2 binding initiates competitive signaling leading to cofilin activation and localized actin polymerization around CD2, which spatially inhibits HIV-1-initiated local actin polymerization needed for viral nuclear migration. Our study identifies CD2 as a novel target to block HIV-1 infection of blood resting T cells.

3.
Food Funct ; 12(19): 9211-9228, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606547

RESUMO

The present study aims to investigate the protective effects of N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone-induced neurotoxicity. A neurotoxic model was established by subcutaneous injection of corticosterone (40 mg per kg bw) for 21 days. Depressive behaviors (the percentage of sucrose consumption, the immobility time in the forced swimming test, and the total distance in the open field test) were observed. The levels of the brain-derived neurotrophic factor, the contents of tumor necrosis factor-α and interleukin-6, and the numbers of positive cells of doublecortin and bromodeoxyuridine in the hippocampus were measured. The density of hippocampal neurons was calculated. The morphological changes of hippocampal neurons (the density of dendritic spines, the dendritic length, and the area and volume of dendritic cell bodies) were observed. The expression levels of synaptophysin, synapsin I, and postsynaptic density protein 95 were measured. Behavioral experiments showed that M 18:3 (5 and 25 mg per kg bw) could remarkably improve the depressive behaviors. The enzyme-linked immunosorbent assay showed that M 18:3 could considerably reduce hippocampal neuroinflammation and increase hippocampal neurotrophy. Nissl staining showed that M 18:3 could remarkably improve the corticosterone-induced decrease in the hippocampal neuron density. Immunofluorescence analysis showed that M 18:3 could considerably promote hippocampal neurogenesis. Golgi staining showed that M 18:3 could remarkably improve the corticosterone-induced changes in the hippocampal dendritic structure. Western blotting showed that M 18:3 could considerably increase the expression levels of synaptic-structure-related proteins in the hippocampus. In conclusion, the protective effects of M 18:3 may be attributed to the anti-inflammatory, neurotrophic, and synaptic protection properties.

4.
Front Pharmacol ; 12: 728937, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630106

RESUMO

An optimized support vector machine model was used to construct a lung cancer diagnosis model based on serological indicators, and a molecular regulation model of Wogonin, a component of Scutellaria baicalensis, was established. Serological indexes of patients were collected, the grid search method was used to identify the optimal penalty coefficient C and parameter g of the support vector machine model, and the benign and malignant auxiliary diagnosis model of isolated pulmonary nodules based on serological indicators was established. The regulatory network and key targets of Wogonin in lung cancer were analyzed by network pharmacology, and key targets were detected by western blot. The relationship between serological susceptibility genes and key targets of Wogonin was established, and the signaling pathway of Wogonin regulating lung cancer was constructed. After support vector machine parameter optimization (C = 90.597, g = 32), the accuracy of the model was 90.8333%, with nine false positives and two false negative cases. Ontology functional analysis of 67 common genes between Wogonin targets and lung cancer-related genes showed that the targets were associated with biological processes involved in peptidye-serine modification and regulation of protein kinase B signaling; cell components in the membrane raft and chromosomal region; and molecular function in protein serine/threonine kinase activity and heme binding. Kyoto Encyclopedia of Genes and Genomes analysis showed that the regulation pathways involved the PI3K-Akt signaling pathway, ERBB signaling pathway, and EGFR tyrosine kinase inhibitor resistance. In vitro analyses using lung cancer cells showed that Wogonin led to significantly increased levels of cleaved caspase-3 and Bad and significantly decreased Bcl-2 expression in a concentration-dependent manner. ErbB4 expression also significantly decreased in lung cancer cells after treatment with Wogonin. A regulatory network of Wogonin regulating lung cancer cell apoptosis was constructed, including the participation of serological susceptibility genes. There is a certain regulatory effect between the serological indexes that can be used in the diagnosis of lung cancer and the key targets of Chinese herbal medicine treatment of lung cancer, which provides a new idea for the diagnosis, treatment and prognosis of clinical lung cancer.

5.
J Clin Transl Hepatol ; 9(4): 484-493, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34447677

RESUMO

Background and Aims: Previous studies reported that serum resistin levels were remarkably changed in patients with nonalcoholic fatty liver disease (NAFLD) but the conclusions were inconsistent. The aim of this study was to investigate accurate serum resistin levels in adult patients with NAFLD. Methods: A complete literature research was conducted in the PubMed, Embase, and Cochrane Library databases, and all the available studies up to 7 May 2020 were reviewed. The pooled standardized mean difference (SMD) values were calculated to investigate the serum resistin levels in patients with NAFLD and healthy controls. Results: A total of 28 studies were included to investigate the serum resistin levels in patients with NAFLD. Patients with NAFLD had higher serum resistin levels than controls (SMD=0.522, 95% confidence interval [CI]: 0.004-1.040, I 2=95.9%). Patients with nonalcoholic steatohepatitis (NASH) had lower serum resistin levels than the healthy controls (SMD=-0.44, 95% CI: -0.83-0.55, I 2=74.5%). In addition, no significant difference of serum resistin levels was observed between patients with NAFL and healthy controls (SMD=-0.34, 95% CI: -0.91-0.23, I 2=79.6%) and between patients with NAFL and NASH (SMD=0.15, 95% CI: -0.06-0.36, I 2=0.00%). Furthermore, subgroup and sensitivity analyses suggested that heterogeneity did not affect the results of meta-analysis. Conclusions: This meta-analysis investigated the serum resistin levels in adult patients with NAFLD comprehensively. Patients with NAFLD had higher serum resistin levels and patients with NASH had lower serum resistin levels than healthy controls. Serum resistin could serve as a potential biomarker to predict the development risk of NAFLD.

6.
Front Immunol ; 12: 687669, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248973

RESUMO

Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-ß), which promotes the generation of Foxp3+ Tregs from naïve CD4+ T cells in the local tumor microenvironment. TGF-ß activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at the Foxp3 locus and induces Foxp3 gene expression. TGF-ß also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-ß-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-ß. In vivo tumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3+ Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Curcumina/análogos & derivados , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Curcumina/farmacologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Carga Tumoral/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/metabolismo
7.
EBioMedicine ; 70: 103496, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34280776

RESUMO

BACKGROUND: Induction of autoantigen-specific Treg cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases. METHODS: In a model of experimental autoimmune uveitis (EAU) that mimics human uveitis, ocular inflammation was induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP). Mice were given intraperitoneal injection of αCD4 antibody (Ab) after the onset of disease, followed by administration of IRBP. EAU was evaluated clinically and functionally. Splenocytes, CD4+CD25- and CD4+CD25+ T cells were sorted and cultured with IRBP or αCD3 Ab. T cell proliferation and cytokine production were assessed. FINDINGS: The experimental approach resulted in remission of ocular inflammation and rescue of visual function in mice with established EAU. Mechanistically, the therapeutic effect was mediated by induction of antigen-specific Treg cells that inhibited IRBP-driven Th17 response in TGF-ß and IL-10 dependent fashion. Importantly, the Ab-mediated immune tolerance could be achieved in EAU mice by administration of retinal autoantigens, arrestin but not limited to IRBP only, in an antigen-nonspecific bystander manner. Further, these EAU-suppressed tolerized mice did not compromise their anti-tumor T immunity in melanoma model. INTERPRETATION: We successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis. FUNDING: This study was supported by the Natural Science Foundation of Guangdong Province and the Fundamental Research Fund of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center.

8.
Clin Transl Med ; 11(6): e448, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34185428

RESUMO

Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (TH 1) responses and regulatory T (Treg ) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of TH 1:Treg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of TH 1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by Treg cells. Importantly, interferon (IFN) -γ and tumor necrosis factor (TNF) -α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized Treg cell deficiency-mediated TH 1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.

9.
iScience ; 24(5): 102446, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33997712

RESUMO

Adipose-derived mesenchymal stromal cells (ADSCs) play important roles in the alleviation of inflammation and autoimmune diseases. Interleukin-33 (IL-33), a member of the IL-1 family, has been shown to regulate innate and adaptive immunity. However, it is still unknown whether ADSCs regulate immune responses via IL-33. We show here that ADSCs produced IL-33 in response to IL-1ß stimulation, which depended on TAK1, ERK, and p38 pathways. ADSCs-derived IL-33 drove the proliferation of CD4+Foxp3+ST2+ regulatory T cells (Tregs) and alleviated experimental autoimmune Sjögren syndrome in mice. Importantly, human ADSCs also produced IL-33 in response to IL-1ß. Thus, we have revealed a previously unrecognized immunoregulatory function of ADSCs by IL-33 production in experimental autoimmunity, which may have clinical applications for human immunopathology.

10.
Front Pharmacol ; 12: 650780, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981230

RESUMO

Ethnopharmacological relevance: Scutellaria baicalensis georgi is one of the most widely studied TCMs; its effects in ALI have been studied in a large number of experiments, and the efficacy of volatile oil from TCM remains to be studied. Aim: The volatile component of Scutellaria baicalensis georgi was selected to act on the key target of acute lung injury and was preliminarily studied for its specific molecular mechanism. Methods: The volatile active substances of Scutellaria baicalensis georgi were extracted by GC-MS, and the active ingredients related with the occurrence and development of acute lung injury were searched and matched by the TCMSP database. The pharmacologic data and analysis platform of TCM were used to retrieve and screen for the volatile active components and the possible therapeutic targets of Scutellaria baicalensis georgi. In addition, acute lung injury was searched in the disease target database to identify the corresponding disease target proteins, thereby establishing a protein-protein interaction network. Finally, the effects of wogonin on the apoptotic and inflammatory factors in the acute lung injury cell model were analyzed experimentally. Results: We identified 100 candidate targets and successfully constructed a complex target network. The targets identified by the above gene enrichment analysis played important roles in the autoimmune disease cell cycle apoptosis and related signaling pathways. The KEGG pathway analysis showed that most of the target genes were involved in the inflammatory response regulation of the TRP, PI3K-Akt, and IL-17 signaling pathways. The participation of wogonin in the specific regulatory pathways of PI3K-Akt signaling and IL-17 signaling was verified through experiments. In the lung-injured cell model, the results showed that wogonin inhibited the apoptosis of injured lung cells by inhibiting the expression of BAD gene and the activation of cleaved caspase-3 gene while increasing Bcl-2 expression. In addition, wogonin inhibited the expression of the abovementioned inflammatory factors and further inhibited the inflammatory response in the lung injury cells. Conclusion: The results of pharmacological network analysis can predict and explain the regulation mechanism of multi-target and multi-pathway of TCM components. This study identified the potential target and important pathway of wogonin in regulating acute lung injury. At the same time, the accuracy of network pharmacological prediction is also preliminarily verified by molecular biology experiment.

11.
Acta Biochim Biophys Sin (Shanghai) ; 53(6): 784-795, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33928341

RESUMO

Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces ß-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced ß-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.


Assuntos
Apoptose/efeitos dos fármacos , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Células Secretoras de Insulina/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Apoptose/imunologia , Autoanticorpos/isolamento & purificação , Autofagia/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Imunização/métodos , Imunoglobulina G/isolamento & purificação , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/imunologia , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Telmisartan/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
12.
Front Pharmacol ; 12: 646187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897434

RESUMO

Objective: To analyze the key targets and potential mechanisms underlying the volatile components of Scutellaria baicalensis Georgi acting on gliomas through network pharmacology combined with biological experiments. Methods: We have extracted the volatile components of Scutellaria baicalensis by gas chromatography-mass spectrometry (GC-MS) and determined the active components related to the onset and development of gliomas by combining the results with the data from the Traditional Chinese Medicine Systems Pharmacology database. We screened the same targets for the extracted active components and gliomas through network pharmacology and then constructed a protein-protein interaction network. Using a Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we analyzed the protein effects and regulatory pathways of the common targets. Lastly, we employed ELISA and Western blot in verifying the key targets in the regulatory pathway. Results: We ultimately determined that the active component in S. baicalensis Georgi related to the onset and development of gliomas was Wogonin. The results of the network pharmacology revealed 85 targets for glioma and Wogonin. We used gene ontology to analyze these target genes and found that they involved 30 functions, such as phosphatidylinositol phosphokinase activation, while the KEGG analysis showed that there were 10 regulatory pathways involved. Through the following analysis, we found that most of the key target genes are distributed in the PI3K-Akt and interleukin 17 signaling pathways. We then cultured U251 glioma cells for the experiments. Compared with the control group, no significant change was noted in the caspase-3 expression; however, cleaved caspase-3 expression increased significantly and was dose-dependent on Wogonin. The expression of Bad and Bcl-2 with 25 µM of Wogonin has remained unchanged, but when the Wogonin dose was increased to 100 µM, the expression of Bad and Bcl-2 was noted to change significantly (Bad was significantly upregulated, while Bcl-2 was significantly downregulated) and was dose-dependent on Wogonin. The ELISA results showed that, compared with the control group, the secretion of tumor necrosis factor alpha, IL-1ß, and IL-6 decreased as the Wogonin concentration increased. Tumor necrosis factor alpha downregulation had no significant dose-dependent effect on Wogonin, the inhibitory effect of 25 µM of Wogonin on IL-6 was not significant, and IL-1ß downregulation had a significant dose-dependent effect on Wogonin. Conclusion: Wogonin might promote the apoptosis of glioma cells by upregulating proapoptotic factors, downregulating antiapoptotic factors, and inhibiting the inflammatory response, thereby inhibiting glioma progression.

13.
Food Funct ; 11(9): 7762-7774, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32797129

RESUMO

This study investigated the protective effects of maca ethanol extract (EEM) and N-(3-methozybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone (CORT)-induced testicular toxicity. Male Wistar rats were divided into 5 groups. Except for the control group, CORT (40 mg per kg·bw) was injected subcutaneously for 21 consecutive days to induce testicular toxicity. 1 h before CORT injection, the rats were treated with EEM (400 mg per kg·bw) and M 18:3 (5 mg per kg·bw, 25 mg per kg·bw) by gavage, except for the control group and model group. Epididymal sperm and biochemical, and histological parameters were evaluated for the protective effects of the drugs. EEM (400 mg per kg·bw) and M 18:3 (5 mg per kg·bw, 25 mg per kg·bw) increased the sperm concentration and sperm motility, decreased the production of abnormal sperms, and increased the number of spermatogonia and primary spermatocytes in the seminiferous tubules of CORT-induced rats. Moreover, EEM and M 18:3 decreased the MDA levels and the positive expression rates of TUNEL, whereas they increased the activities of SOD, CAT, GSH-Px, and GST, and the contents of GSH in the testicles of CORT-induced rats. Furthermore, EEM and M 18:3 alleviated CORT-induced reduction in the positive expression rates of PCNA and Ki67 in the testicles of rats. Besides, EEM and M 18:3 reduced the expression levels of Keap-1 and increased the expression levels of Nrf2, HO-1, γ-GCS, and NQO1 in the testicles of CORT-induced rats. In summary, the protective effects of EEM and M 18:3 may be attributed to their anti-oxidative and anti-apoptotic properties.


Assuntos
Corticosterona/toxicidade , Lepidium/química , Extratos Vegetais/farmacologia , Testículo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/anormalidades , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Testículo/metabolismo
14.
Front Immunol ; 11: 1702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849598

RESUMO

TCRαß+CD8αα+ intraepithelial lymphocytes (IELs) are abundant in gastrointestinal (GI) tract and play an important role in regulation of mucosal immunity and tolerance in the gut. However, it is unknown whether TCRαß+CD8αα+ IELs exist in the oral mucosa and if yes, what controls their development. We here identified and characterized TCRαß+CD8αα+ IELs from the murine oral mucosa. We showed that the number and function of TCRαß+CD8αα+ IELs were regulated by TGF-ß. We further revealed that oral TCRαß+CD8αα+ IELs could be altered under systemic inflammatory conditions and by antibiotic treatment at the neonatal age of the mice. Our findings have revealed a previously unrecognized population of oral IELs that may regulate oral mucosal immune responses.


Assuntos
Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Linfócitos Intraepiteliais/imunologia , Mucosa Bucal/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Animais Recém-Nascidos , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Microbioma Gastrointestinal , Imunidade nas Mucosas/efeitos dos fármacos , Interferon gama/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Linfócitos Intraepiteliais/efeitos dos fármacos , Linfócitos Intraepiteliais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Fenótipo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
15.
Immunity ; 53(2): 371-383.e5, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32673566

RESUMO

Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31-/- mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-ß1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-ß-IL-31 axis with implications for treatment of wound itching.


Assuntos
Interleucinas/metabolismo , Células de Langerhans/fisiologia , Prurido/patologia , Células Receptoras Sensoriais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Feminino , Humanos , Interleucinas/genética , Células de Langerhans/transplante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Pele/citologia , Pele/crescimento & desenvolvimento , Pele/lesões , Canais de Cátion TRPV/metabolismo , Cicatrização/fisiologia
16.
DNA Cell Biol ; 39(4): 563-571, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32073892

RESUMO

Growth differentiation factor (GDF) 9 gene is involved in regulating reproductive traits in animals, but little is known about the promoter, single-nucleotide polymorphisms (SNPs), transcription factor binding sites, and regulating mechanism of GDF9 gene. In this study, the SNPs in the GDF9 promoter region were explored and their transcription mechanisms in regulating GDF9 expression were analyzed. Ear tissues of 267 Hu ewes were collected, and genomic DNA was extracted. GDF9 promoter region was amplified by PCRs, and identified SNPs genotyped by sequencing. SPSS16.0 software was used to analyze the association between genotypes and litter sizes. Flow cytometry assay was used to detect cell apoptosis, and dual-luciferase reporter assay was used to discover the promoter activity. A length of 1789 bp promoter region of GDF9 in Hu sheep was obtained by PCR amplification, and luciferase activity assay showed that there was a negative regulatory element in the region within -725 to -309 bp and a positive regulatory element in the region within -309 to +43 bp. Three complete linkage SNPs at -534A/G, -407T/G, and -332C/T were detected, resulting in three genotypes (namely, AA, AB, and BB). The association analysis indicated that the AA genotype ewes had larger litter size at average parity than those with the BB genotype. The -534A/G mutation created a novel binding site for the octamer transcription factor 1 (OCT1), and the Annexin V FITC/PI flow cytometry assay showed OCT1 promoted cell apoptosis in sheep ovarian granulosa cells. Overexpression of OCT1 considerably inhibited the luciferase activity of both genotypes and the inhibition effect of pGL3-BB was higher than that of pGL3-AA. Three complete linkage SNPs of the GDF9 gene regulate the litter size in Hu sheep probably via inhibition of the promoter activity by binding with OCT1 at -534 GG genotype and forming a complex between OCT1 and CCAAT/enhancer-binding protein (C/EBP).


Assuntos
Fator 9 de Diferenciação de Crescimento/genética , Tamanho da Ninhada de Vivíparos/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas/genética , Animais , Apoptose/fisiologia , Sítios de Ligação/genética , Células COS , Linhagem Celular , Chlorocebus aethiops , Feminino , Células da Granulosa/metabolismo , Fator 1 de Transcrição de Octâmero/genética , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Sequências Reguladoras de Ácido Nucleico/genética , Ovinos
17.
Nat Commun ; 11(1): 35, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911623

RESUMO

The molecular pathways underlying the development of innate lymphoid cells (ILCs) are mostly unknown. Here we show that TGF-ß signaling programs the development of ILC2s from their progenitors. Specifically, the deficiency of TGF-ß receptor II in bone marrow progenitors results in inefficient development of ILC2s, but not ILC1s or ILC3s. Mechanistically, TGF-ß signaling is required for the generation and maintenance of ILC2 progenitors (ILC2p). In addition, TGF-ß upregulates the expression of the IL-33 receptor gene Il1rl1 (encoding IL-1 receptor-like 1, also known as ST2) in ILC2p and common helper-like innate lymphoid progenitors (CHILP), at least partially through the MEK-dependent pathway. These findings identify a function of TGF-ß in the development of ILC2s from their progenitors.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular , Imunidade Inata , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Interleucina-33/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia
18.
Regul Toxicol Pharmacol ; 111: 104570, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31884156

RESUMO

Maca has been traditionally used to enhance sexual behavior and fertility. Recently, maca's neuroprotective effects have been reported. The purpose of this study was to investigate whether the ethanol extract of maca (EEM) (100 mg/kg/bw, 200 mg/kg/bw, 400 mg/kg/bw, p.o.) exerted neuroprotective effects in corticosterone (CORT)-induced (40 mg/kg/bw, s.c.) rats, to determine the neuroprotective effects of EEM (12.5, 25, 50 µg/ml) and macamides in H2O2-induced (50 µM) PC12 cells. The acute toxicity (2000 mg/kg/bw, p.o.) and subacute toxicity (200 mg/kg/bw, 500 mg/kg/bw, 1000 mg/kg/bw, p.o.) of EEM were evaluated by mouse models. EEM reversed CORT-induced abnormal behaviors, reduced the contents of TNF-α, IL-6 in hippocampi, and increased the positive cells of doublecortin (DCX), bromodeoxyuridine (BrdU) and DCX + BrdU in the hippocampus of rats. Moreover, EEM and 4 macamides remarkably increased the cell viability in H2O2-induced PC12 cells. EEM promoted the phosphorylation of IκBα and p65, suppressed the NF-κB activation, and inhibited the levels of pro-inflammatory cytokines such as TNF-α, IL-6 and their mRNA levels in H2O2-induced PC12 cells. In conclusion, EEM could exert neuroprotective effects in CORT-induced rats and in H2O2-induced PC12 cells. Moreover, EEM did not present relevant toxicity after exposure to single and repeated doses.


Assuntos
Corticosterona/antagonistas & inibidores , Corticosterona/toxicidade , Etanol/química , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/toxicidade , Lepidium/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Corticosterona/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peróxido de Hidrogênio/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Testes de Toxicidade Aguda
19.
J Clin Transl Hepatol ; 8(4): 371-376, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33447519

RESUMO

Background and Aims: Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that TCF7L2 rs7903146 was related to the risk of developing NAFLD but the conclusions are not consistent and no related study has been conducted in Chinese populations. The aim of this study was to investigate the association between TCF7L2 rs7903146 and the risk of developing NAFLD and CAD in a Chinese Han population. Methods: TCF7L2 rs7903146 genotypes were measured by the MALDI-TOF-MS from 143 NAFLD patients, 159 CAD patients, 131 NAFLD + CAD patients, and 212 healthy controls. The demographic data and serum lipid profiles of all subjects were collected. The distributions of genotype and allele frequency in each group were also tested. Logistic regression was used to investigate the risk of TCF7L2 rs7903146 with NAFLD and CAD. All statistical analyses were conducted using SPSS 23.0. Results: There were no significant differences in the distributions of TCF7L2 rs7903146 genotype and allele frequency in each of the two groups, and the TCF7L2 rs7903146 CT + TT genotype did not increase the risk of developing NAFLD, CAD, and NAFLD + CAD. Except for body mass index in the control group, the differences of clinical parameters between the TCF7L2 rs7903146 T allele carriers and non-carriers in each group were not significant. In the non-obese group, the TCF7L2 rs7903146 CT + TT genotype was a protective factor for the development of NAFLD in the non-obese subjects (odds ratio=0.359, 95% confidence interval: 0.134-0.961, p = 0.041). Conclusions: TCF7L2 rs7903146 was not associated with the risk of developing NAFLD, CAD, and NAFLD + CAD in the Chinese Han population. In the non-obese population, the TCF7L2 rs7903146 CT + TT genotype was a protective factor against the development of NAFLD.

20.
Lipids Health Dis ; 18(1): 165, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31470861

RESUMO

BACKGROUND: Present evidences suggested that TRIB1 rs17321515 polymorphism was tightly associated with the increased risk of NAFLD and CHD. CHD is one of the main complications of NAFLD, whether TRIB1 rs17321515 polymorphism could affect the risk of CHD in general population and NAFLD patients in Chinese Han population was remain unknown. The present study was designed to investigate the association between TRIB1 rs17321515 polymorphism and the risk of CHD in general population and NAFLD patients in Chinese Han population, and investigate the effect of TRIB1 rs17321515 polymorphism on serum lipid levels. PATIENTS AND METHODS: TRIB1 rs17321515 gene polymorphism was genotyped using the polymerase chain reaction (PCR) in healthy controls (n = 175), CHD patients (n = 155), NAFLD patients (n = 146), and NAFLD+CHD patients (n = 156). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 24.0 statistical software. RESULTS: The TRIB1 rs17321515 AA+GA genotypes were the significant risk factors for the CHD in general population (OR = 1.788; 95% CI: 1.104-2.897; P = 0.018) and in the NAFLD patients (OR = 1.760; 95% CI: 1.071-2.891; P = 0.026). After adjusted for age, gender, and body mass index, the risk for CHD in general population (OR = 1.857; 95% CI: 1.116-3.089; P = 0.017) and NAFLD patients was still significant (OR = 1.723; 95% CI: 1.033-2.873; P = 0.037). In addition, TRIB1 rs17321515 A carriers possess the higher lipid profiles in the included subjects. CONCLUSIONS: TRIB1 rs17321515 AA+GA genotypes were significant associated with the risk of CHD in general population and in NAFLD patients in Chinese Han population. The rs17321515 A allele increases the serum lipid profiles in included subjects.


Assuntos
Doença das Coronárias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Idoso , Grupo com Ancestrais do Continente Asiático , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Angiografia Coronária , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/etnologia , Feminino , Expressão Gênica , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/etnologia , Proteínas Serina-Treonina Quinases/sangue , Proteínas Serina-Treonina Quinases/genética , Risco , Triglicerídeos/sangue , Ultrassonografia
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