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1.
Brief Bioinform ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33418563

RESUMO

Matched molecular pairs analysis (MMPA) has become a powerful tool for automatically and systematically identifying medicinal chemistry transformations from compound/property datasets. However, accurate determination of matched molecular pair (MMP) transformations largely depend on the size and quality of existing experimental data. Lack of high-quality experimental data heavily hampers the extraction of more effective medicinal chemistry knowledge. Here, we developed a new strategy called quantitative structure-activity relationship (QSAR)-assisted-MMPA to expand the number of chemical transformations and took the logD7.4 property endpoint as an example to demonstrate the reliability of the new method. A reliable logD7.4 consensus prediction model was firstly established, and its applicability domain was strictly assessed. By applying the reliable logD7.4 prediction model to screen two chemical databases, we obtained more high-quality logD7.4 data by defining a strict applicability domain threshold. Then, MMPA was performed on the predicted data and experimental data to derive more chemical rules. To validate the reliability of the chemical rules, we compared the magnitude and directionality of the property changes of the predicted rules with those of the measured rules. Then, we compared the novel chemical rules generated by our proposed approach with the published chemical rules, and found that the magnitude and directionality of the property changes were consistent, indicating that the proposed QSAR-assisted-MMPA approach has the potential to enrich the collection of rule types or even identify completely novel rules. Finally, we found that the number of the MMP rules derived from the experimental data could be amplified by the predicted data, which is helpful for us to analyze the medicinal chemical rules in local chemical environment. In summary, the proposed QSAR-assisted-MMPA approach could be regarded as a very promising strategy to expand the chemical transformation space for lead optimization, especially when no enough experimental data can support MMPA.

2.
Trials ; 21(1): 999, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33276811

RESUMO

OBJECTIVES: A severe epidemic of COVID-19 has broken out in China and has become a major global public health event. We focus on the Acute Respiratory Distress Syndrome (ARDS)-like changes and overactivation of Th17 cells (these produce cytokines) in patients with COVID-19. We aim to explore the safety and efficacy of ixekizumab (an injectable drug for the treatment of autoimmune diseases) to prevent organ injury caused by the immune response to COVID-19. Ixekizumab is a human monoclonal antibody that binds to interleukin-17A and inhibits the release of pro-inflammatory cytokines and chemokines. TRIAL DESIGN: The experiment is divided into two stages. In the first stage, the open trial, 3 patients with COVID-19 are treated with ixekizumab, and the safety and efficacy are observed for 7 days. In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. This is a two-center, open-label, randomized controlled pilot trial with 2-arm parallel group design (1:1 ratio). PARTICIPANTS: Patients with COVID-19 aged 18-75 with increased Interleukin (IL)-6 levels will be enrolled, but patients with severe infections requiring intensive care will be excluded. The trial will be undertaken in two centers. The first stage is carried out in Xiangya Hospital of Central South University, and the second stage is carried out simultaneously in the Third Xiangya Hospital of Central South University. INTERVENTION AND COMPARATOR: In the first stage, three subjects are given ixekizumab ("Taltz") (80 mg/ml, 160 mg as a single hypodermic injection) and antiviral therapy (α-interferon (administer 5 million U by aerosol inhalation twice daily), lopinavir/ritonavir (administer 100mg by mouth twice daily, for the course of therapy no more than 10 days), chloroquine (administer 500mg by mouth twice daily, for the course of therapy no more than 10 days), ribavirin (administer 500mg by intravenous injection two to three times a day, for the course of therapy no more than 10 days), or arbidol (administer 200mg by mouth three times a day, for the course of therapy no more than 10 days), but not more than 3 types). The treatment course of the first stage is 7 days. In the second stage, 40 randomized patients will receive the following treatments--Group 1: ixekizumab (80 mg/ml, 160 mg as a single hypodermic injection) with antiviral therapy (the same scheme as in the first stage); Group 2: antiviral therapy alone (the same scheme as in the first stage). The length of the second treatment course is 14 days. MAIN OUTCOMES: The primary outcome is a change in pulmonary CT severity score (an imaging tool for assessing COVID-19, which scores on the basis of all abnormal areas involved). Pulmonary CT severity score is assessed on the 7th day, 14th day, or at discharge. RANDOMISATION: In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. The eLite random system of Nanjing Medical University is used for randomization. BLINDING (MASKING): The main efficacy indicator, the CT results, will be evaluated by the third-party blinded and independent research team. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. TRIAL STATUS: Trial registration number is ChiCTR2000030703 (version 1.7 as of March 19, 2020). The recruitment is ongoing, and the date recruitment was initiated in June 2020. The anticipated date of the end of data collection is June 2021. TRIAL REGISTRATION: The name of the trial register is the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2000030703 ( http://www.chictr.org.cn/ ). The date of trial registration is 10 March 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

3.
Brief Bioinform ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33201188

RESUMO

BACKGROUND: Fluorescent detection methods are indispensable tools for chemical biology. However, the frequent appearance of potential fluorescent compound has greatly interfered with the recognition of compounds with genuine activity. Such fluorescence interference is especially difficult to identify as it is reproducible and possesses concentration-dependent characteristic. Therefore, the development of a credible screening tool to detect fluorescent compounds from chemical libraries is urgently needed in early stages of drug discovery. RESULTS: In this study, we developed a webserver ChemFLuo for fluorescent compound detection, based on two large and high-quality training datasets containing 4906 blue and 8632 green fluorescent compounds. These molecules were used to construct a group of prediction models based on the combination of three machine learning algorithms and seven types of molecular representations. The best blue fluorescence prediction model achieved with balanced accuracy (BA) = 0.858 and area under the receiver operating characteristic curve (AUC) = 0.931 for the validation set, and BA = 0.823 and AUC = 0.903 for the test set. The best green fluorescence prediction model achieved the prediction accuracy with BA = 0.810 and AUC = 0.887 for the validation set, and BA = 0.771 and AUC = 0.852 for the test set. Besides prediction model, 22 blue and 16 green representative fluorescent substructures were summarized for the screening of potential fluorescent compounds. The comparison with other fluorescence detection tools and theapplication to external validation sets and large molecule libraries have demonstrated the reliability of prediction model for fluorescent compound detection. CONCLUSION: ChemFLuo is a public webserver to filter out compounds with undesirable fluorescent properties, which will benefit the design of high-quality chemical libraries for drug discovery. It is freely available at http://admet.scbdd.com/chemfluo/index/.

4.
Cell Death Dis ; 11(11): 948, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144562

RESUMO

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.

5.
Cancer Lett ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246091

RESUMO

Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, is a critical regulator in tumor metabolism. PKM2 has been demonstrated to overexpressed in various cancers and promoted proliferation and metastasis of tumor cells. The errant expression of PKM2 has inspired people to investigate the function of PKM2 and the therapeutic potential in cancer. In addition, some studies have shown that the upregulation of PKM2 in tumor tissues is associated with the altered expression of lncRNAs and the poor survival. Therefore, researchers have begun to unravel the specific molecular mechanisms of lncRNA-mediated PKM2 expression in cancer metabolism. As the tumor microenvironment (TME) is essential in tumor development, it is necessary to identify the role of PKM2 in TME. In this review, we will introduce the role of PKM2 in different cancers as well as TME, and summarize the molecular mechanism of PKM2-related lncRNAs in cancer metabolism. We expect that this work will lead to a better understanding of the molecular mechanisms of PKM2 that may help in developing therapeutic strategies in clinic for researchers.

6.
Theranostics ; 10(25): 11428-11443, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052224

RESUMO

Background: Bromodomain and extra-terminal domain (BET) inhibitors have shown profound efficacy against hematologic malignancies and solid tumors in preclinical studies. However, the underlying molecular mechanism in melanoma is not well understood. Here we identified secreted phosphoprotein 1 (SPP1) as a melanoma driver and a crucial target of BET inhibitors in melanoma. Methods: Bioinformatics analysis and meta-analysis were used to evaluate the SPP1 expression in normal tissues, primary melanoma, and metastatic melanoma. Real-time PCR (RT-PCR) and Western blotting were employed to quantify SPP1 expression in melanoma cells and tissues. Cell proliferation, wound healing, and Transwell assays were carried out to evaluate the effects of SPP1 and BET inhibitors in melanoma cells in vitro. A xenograft mouse model was used to investigate the effect of SPP1 and BET inhibitors on melanoma in vivo. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the regulatory mechanism of BET inhibitors on SPP1. Results: SPP1 was identified as a melanoma driver by bioinformatics analysis, and meta-analysis determined it to be a diagnostic and prognostic biomarker for melanoma. SPP1 overexpression was associated with poor melanoma prognosis, and silencing SPP1 suppressed melanoma cell proliferation, migration, and invasion. Through a pilot drug screen, we identified BET inhibitors as ideal therapeutic agents that suppressed SPP1 expression. Also, SPP1 overexpression could partially reverse the suppressive effect of BET inhibitors on melanoma. We further demonstrated that bromodomain-containing 4 (BRD4) regulated SPP1 expression. Notably, BRD4 did not bind directly to the SPP1 promoter but regulated SPP1 expression through NFKB2. Silencing of NFKB2 resembled the phenotype of BET inhibitors treatment and SPP1 silencing in melanoma. Conclusion: Our findings highlight SPP1 as an essential target of BET inhibitors and provide a novel mechanism by which BET inhibitors suppress melanoma progression via the noncanonical NF-κB/SPP1 pathway.

7.
Oncogene ; 39(43): 6704-6718, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32958832

RESUMO

Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.

8.
J Med Internet Res ; 22(9): e22288, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32845850

RESUMO

BACKGROUND: The outbreak of COVID-19 has profoundly influenced people's lifestyles; these impacts have varied across subgroups of people. The pandemic-related impacts on the health outcomes of people with dermatological conditions are unknown. OBJECTIVE: The aim of this paper was to study the association of COVID-19 pandemic-related impacts with health-related quality of life in patients with skin diseases. METHODS: This was a cross-sectional study among Chinese patients with skin diseases. A self-administered web-based questionnaire was distributed through social media. Demographic and clinical data and pandemic-related impacts (isolation status, income changes, and employment status) were collected. The main outcomes included perceived stress (Visual Analog Scale), symptoms of anxiety (Generalized Anxiety Disorder-7) and depression (9-Item Patient Health Questionnaire), quality of life (Dermatology Life Quality Index), and health utility mapping based on the EQ-5D-3L descriptive system. Multivariable logistic regression was used to investigate the associations. RESULTS: A total of 506 patients with skin diseases completed the survey. The mean age of the patients was 33.5 years (SD 14.0), and 217/506 patients (42.9%) were male. Among the 506 respondents, 128 (25.3%) were quarantined, 102 (20.2%) reported unemployment, and 317 (62.6%) reported decrease or loss of income since the pandemic. The pandemic-related impacts were significantly associated with impaired mental well-being and quality of life with different effects. Unemployment and complete loss of income were associated with the highest risks of adverse outcomes, with increases of 110% to 162% in the prevalence of anxiety, depression, and impaired quality of life. CONCLUSIONS: Isolation, income loss, and unemployment are associated with impaired health-related quality of life in patients with skin diseases during the COVID-19 pandemic.


Assuntos
Ansiedade/epidemiologia , Betacoronavirus , Infecções por Coronavirus/psicologia , Depressão/epidemiologia , Pneumonia Viral/psicologia , Qualidade de Vida , Dermatopatias/complicações , Desemprego/psicologia , Adulto , China/epidemiologia , Infecções por Coronavirus/complicações , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Saúde Mental , Pandemias , Pneumonia Viral/complicações , Prevalência , Fatores Socioeconômicos
9.
Sci Rep ; 10(1): 12462, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719391

RESUMO

Melanoma is the most invasive type of skin cancer, in which the immune system plays a vital role. In this study, we aimed to establish a prognostic prediction nomogram for melanoma patients that incorporates immune-related genes (IRGs). Ninety-seven differentially expressed IRGs between melanoma and normal skin were screened using gene expression omnibus database (GEO). Among these IRGs, a two-gene signature consisting of CCL8 and DEFB1 was found to be closely associated with patient prognosis using the cancer genome atlas (TCGA) database. Survival analysis verified that the IRGs score based on the signature gene expressions efficiently distinguished between high- and low-risk patients, and was identified to be an independent prognostic factor. A nomogram integrating the IRGs score, age and TNM stage was established to predict individual prognosis for melanoma. The prognostic performance was validated by the TCGA/GEO-based concordance indices and calibration plots. The area under the curve demonstrated that the nomogram was superior than the conventional staging system, which was confirmed by the decision curve analysis. Overall, we developed and validated a nomogram for prognosis prediction in melanoma based on IRGs signatures and clinical parameters, which could be valuable for decision making in the clinic.

10.
J Dermatol Sci ; 99(3): 146-151, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32600738

RESUMO

Skin diseases bring great psychological and physical impacts on patients, however, a considerable number of skin diseases still lack effective treatments, such as psoriasis, systemic lupus erythematosus, melanoma and so on. Receptor-interacting serine threonine kinase 1 (RIPK1) plays an important role in cell death, especially necroptosis, associated with inflammation and tumor. As many molecules modulate the ubiquitination of RIPK1, disruption of this checkpoint can lead to skin diseases, which can be ameliorated by RIPK1 inhibitors. This review will focus on the molecular mechanism of RIPK1 activation in inflammation as well as the current knowledges on the contribution of RIPK1 in skin diseases.

11.
J Dermatol ; 47(8): 882-892, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32525225

RESUMO

Psoriasis is a chronic inflammatory skin disease, and the mechanism remains unknown. The present study found that the level of miR-205-5p was downregulated in psoriatic skin tissues. miR-205-5p inhibited proliferation in HaCaT cells. miR-205-5p impaired proliferation, migration and tube formation in human umbilical vein endothelial cells. Angiopoietin (Ang)-2, vascular endothelial growth factor (VEGFA) and bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) were confirmed as the targets of miR-205-5p. Moreover, miR-205-5p suppressed the phosphorylation of p38 and extracellular regulated protein kinase, and inhibited expression level of ß-catenin. In vivo, miR-205-5p significantly alleviated imiquimod (IMQ)-induced psoriasis in mice, and deactivated mitogen-activated protein kinase (MAPK) and Wnt/ß-catenin pathways. In summary, we demonstrated that miR-205-5p alleviated IMQ-induced psoriasis in mice by restraining epidermal hyperproliferation and excessive neovascularization. miR-205-5p may play its roles by targeting Ang-2, VEGFA and BAMBI, and deactivating the Wnt/ß-catenin and MAPK signaling pathways. These findings may provide a potential therapeutic target for clinical treatment of psoriasis.

12.
Int J Antimicrob Agents ; 56(2): 106051, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534186

RESUMO

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a pandemic. This study analysed 95 SARS-CoV-2-infected patients, including 62 moderate COVID-19 patients, 21 severe COVID-19 patients and 12 critical COVID-19 patients (6 patients died, all critical). The results showed that the mean serum procalcitonin (PCT) levels were over four times higher in severe patients than in moderate patients and were over eight times higher in critical patients than in moderate patients. For discharged patients, both high-normal PCT levels and abnormal PCT levels decreased during recovery. However, in death cases, serum levels of PCT increased as the disease worsened. We demonstrate that PCT may be an indicator of disease severity in COVID-19 and may contribute to determining the severity of patients infected with SARS-CoV-2. Moreover, serial PCT measurements may be useful in predicting the prognosis.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/metabolismo , Pneumonia Viral/metabolismo , Pró-Calcitonina/metabolismo , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença
14.
Int J Infect Dis ; 96: 467-474, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32425643

RESUMO

OBJECTIVES: Studies reported associations of inflammatory markers with the severity of COVID-19, but conclusions were inconsistent. We aimed to provide an overview of the association of inflammatory markers with the severity of COVID-19. METHODS: We searched PubMed, Embase, Cochrane Library, Wanfang and China National Knowledge Infrastructure (CNKI) database until March 20, 2020. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were pooled using random or fixed-effects models. RESULTS: A total of 16 studies comprising 3962 patients with COVID-19 were included in our analysis. Random-effect results demonstrated that patients with COVID-19 in the nonsevere group had lower levels for CRP (WMD = -41.78 mg/l, 95% CI = [-52.43, -31.13], P < 0.001), PCT (WMD = -0.13 ng/ml, 95% CI = [-0.20, -0.05], P < 0.001), IL-6 (WMD = -21.32 ng/l, 95% CI = [-28.34, -14.31], P < 0.001), ESR (WMD = -8 mm/h, 95% CI = [-14, -2], P = 0.005), SAA (WMD = -43.35 µg/ml, 95% CI = [-80.85, -5.85], P = 0.020) and serum ferritin (WMD = -398.80 mg/l, 95% CI = [-625.89, -171.71], P < 0.001), compared with those in the severe group. Moreover, survivors had a lower level of IL-6 than non-survivors (WMD = -4.80 ng/ml, 95% CI = [-5.87, -3.73], P < 0.001). These results were consistent through sensitivity analysis and publication bias assessment. CONCLUSIONS: The meta-analysis highlights the association of inflammatory markers with the severity of COVID-19. Measurement of inflammatory markers might assist clinicians to monitor and evaluate the severity and prognosis of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Inflamação/diagnóstico , Pandemias , Pneumonia Viral , Biomarcadores/análise , China , Humanos , Prognóstico
16.
Pigment Cell Melanoma Res ; 33(5): 731-743, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32339381

RESUMO

Although accumulating evidence had revealed that NFAT1 has oncogenic characteristics, the role of this molecule in melanoma cells remains unclear. Previous studies proved that CD147 plays a crucial function in melanoma cell metastasis and invasion through matrix metalloproteinase 9 (MMP-9) expression; however, the details of how CD147 regulates MMP-9 expression remain elusive. In this study, we demonstrated that CD147 and NFAT1 are overexpressed in the tissues of patients with primary and metastatic melanoma, which has shown a positive correlation. Further, we observed that CD147 regulates NFAT1 activation through the [Ca2+ ]i-calcineurin pathway. Knockdown of NFAT1 significantly suppresses melanoma metastasis, and we demonstrated that CD147 affects melanoma metastasis in an NFAT1-dependent manner. Moreover, we verified that NFAT1 directly binds to MMP-9 promoter. Inhibition of CD147 expression significantly abrogates MMP-9 promoter luciferase gene reporter activity as well as NFAT1 association with MMP-9 promoter. Taken together, this study demonstrated that CD147 affects MMP-9 expression through regulating NFAT1 activity and provided a novel mechanism by which NFAT1 contributes to melanoma metastasis through the regulation of MMP-9.

17.
Nat Commun ; 11(1): 1833, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286255

RESUMO

Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.


Assuntos
Comunicação Celular , Proteínas de Ciclo Celular/antagonistas & inibidores , Macrófagos/patologia , Neoplasias/patologia , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Desenho de Fármacos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Resultado do Tratamento
18.
J Ethnopharmacol ; 255: 112746, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32165173

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside Rb1 (GRb1), an active ingredient of traditional Chinese medicine Panax ginseng C. A. Meyer, has displayed various activities such as antioxidative stress, autophagic regulation and apoptotic inhibition. However, the role of GRb1 in natural aging process remains unclear. AIM OF THE STUDY: In this study, we investigated the anti-aging effect and underlying molecular mechanisms of ginsenoside Rb1 in natural aging process. MATERIALS AND METHODS: We treated the natural aging C57BL/6J mice by intragastrical administration of GRb1 (100 mg/kg·BW) every other day for 10 months and investigated the effect of GRb1 on aging symptoms. By RT-qPCR and WB analysis, we examined the expression levels of senescence-associated biomarkers and aging-related pathways, including cell cycle, apoptosis and inflammation in aging process. Further, metabolomics analysis was conducted to investigate the changes of aging-related metabolites after GRb1 treatment. RESULTS: Treatment with GRb1 significantly attenuated the aging-induced physiological changes, including slowed reduction of body weight, suppression of hair loss, decrease of arterial wall thickness and heart weight. We found that GRb1 treatment remarkably reversed the changed expression of p53-p21-Cdk2 axis in heart tissues of aging mice, which was responsible for the cell cycle repression. And the activations of apoptosis-associated factors (Bax and Caspase-3) were also inhibited by GRb1 treatment. Further, based on the serum metabolomics analysis using HPLC-MS/MS analysis, several metabolites were identified as potential biomarkers related to the anti-aging effect of GRb1, including glycerophospholipids, carboxylic acids and fatty acyls. Especially, the change of glycerophospholipid metabolism pathway was found to be the mostly changed. CONCLUSION: Our studies suggest that GRb1 retards the aging process in mice by regulating cell cycle and apoptotic pathway, which were associated with the alleviation of metabolic disorders.

19.
Theranostics ; 10(4): 1833-1848, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042339

RESUMO

Purpose: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. Methods: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both in vivo and in vitro. Results: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both in vivo and in vitro. Conclusions: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

20.
Circ Res ; 126(4): 471-485, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31910739

RESUMO

RATIONALE: BMX (bone marrow kinase on the X chromosome) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown. OBJECTIVE: We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture models. METHODS AND RESULTS: The cecal ligation and puncture model was applied to WT (wild type) and BMX-KO (BMX global knockout) mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect transendothelial electrical resistance in vitro and, the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early cecal ligation and puncture-induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells by 2- to 3-fold. The expression of BMX in macrophages, neutrophils, platelets, and lung epithelial cells was undetectable compared with that in endothelial cells, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-PAR1 (protease-activated receptor-1) signaling in endothelial cells by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pretreatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early cecal ligation and puncture-induced sepsis. CONCLUSIONS: Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.


Assuntos
Endotélio Vascular/fisiopatologia , Proteínas Tirosina Quinases/deficiência , Receptor PAR-1/metabolismo , Sepse/metabolismo , Trombina/metabolismo , Animais , Permeabilidade Capilar/genética , Células Cultivadas , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade/efeitos dos fármacos , Proteínas Tirosina Quinases/genética , Pirróis/farmacologia , Quinazolinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Receptor PAR-1/genética , Sepse/genética , Sepse/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
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