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1.
Ann Hepatol ; 27(4): 100705, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35398571

RESUMO

It is well known that the quality of life (QoL) of patients with chronic hepatitis C (HCV) is lower than that of the general population and that therapy with direct-acting antivirals (DAA) for HCV is safe and effective. However, data on the QoL of patients are scanty. The purpose of this study was to assess the effect of DAA drugs on patients' QoL. The literature included in this meta-analysis was due in March 2021. The random effect model of heterogeneous data and the fixed effect model of homogeneous data were used to analyze the data. QoL had to be evaluated using the Short Form Health Survey (SF-36) questionnaire with at least one measure at baseline (T0) and one measure at 12 weeks (T12) or 24 weeks (T24) after the end of therapy. The meta-analysis included eight studies, which involved 1,619 patients. At T12, the meta-analysis showed all items of the SF-36 questionnaire improved from the pretreatment to post-treatment period and reached statistical significance (p < 0.05) except for the bodily pain (mean difference: 1.16, 95%CI -0.43-2.74) and role limitations-emotional (mean difference: 4.10, 95%CI -1.32-9.52). However, after subgroup analysis (whether ribavirin was being used or not), the bodily pain domain (mean difference: 3.34, 95%CI 1.03-5.65) became statistically significant again. At T24, the results indicated that all items of the SF-36 questionnaire improved from the pretreatment to the post-treatment period and reached statistical significance (p < 0.05) except for the role limitations-emotional domain (mean difference: 4.50, 95%CI -2.66-11.66). There is evidence indicating that DAA therapy is accompanied by an improvement in QoL. Patients receiving DAA medication have a clinically relevant improvement in most domains of the SF-36 questionnaire at T12 or T24, except for a few aspects including role limitations-emotional.

2.
Nat Cell Biol ; 24(1): 88-98, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35027735

RESUMO

The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCßII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCßII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCßII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCßII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCßII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.


Assuntos
Coenzima A Ligases/metabolismo , Ferroptose/fisiologia , Peroxidação de Lipídeos/fisiologia , Proteína Quinase C beta/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Fosforilação , Proteína Quinase C beta/genética
3.
Liver Int ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35007392

RESUMO

Non-alcoholic fatty liver disease (NAFLD), recently re-defined and re-classified as metabolic dysfunction-associated fatty liver disease (MAFLD), has become increasingly prevalent and emerged as a public health problem worldwide. To date, the precise pathogenic mechanisms underpinning MAFLD are not entirely understood, and there is no effective pharmacological therapy for NAFLD/MAFLD. As a newly discovered form of iron-dependent programmed cell death, ferroptosis can be involved in the development and progression of various chronic diseases, but the pathogenic connections and mechanisms that link MAFLD and ferroptosis have not been fully elucidated. The main characteristics of ferroptosis are the accumulation of lipid peroxides and reactive oxygen species. In this brief narrative review, the mechanisms of ferroptosis and its putative pathogenic role in MAFLD are discussed to highlight potential new research directions and ideas for the prevention and treatment of MAFLD.

4.
Signal Transduct Target Ther ; 6(1): 401, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34848680

RESUMO

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias Hepáticas/metabolismo , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Carcinoma Hepatocelular/genética , Células HeLa , Humanos , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Mitocôndrias Hepáticas/genética , Proteínas Mitocondriais/genética , Fosforilação , Proteínas Proto-Oncogênicas c-met/genética
5.
Int J Gen Med ; 14: 8621-8630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34849007

RESUMO

BACKGROUND: The aim of the study was to develop a nomogram to predict the overall survival (OS) of patients with solitary plasmacytoma of bone (SBP). MATERIALS AND METHODS: Patients diagnosed with SBP between 1993 and 2012 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. All eligible patients were randomly allocated to the training sets and the validation sets. The nomogram was developed with the training set and validated with the validation set using the concordance index (C-index), calibration plots, and decision curve analyses (DCA). RESULTS: Age, marital status, tumor grade, treatment were independent prognostic indicators for OS (P<0.05) and were integrated to construct the nomogram. C-indexes for OS prediction in the training and validation sets were 0.78 and 0.73, respectively. The calibration plots demonstrated good consistency between the predicted and actual survival. DCA demonstrated that the new model has great benefits. In the total cohort, the median OS of patients in the low- and high-risk groups were 12.17 (95% CI 11.92-12.42) and 3.92 (95% CI 2.83-5.01) years, respectively. CONCLUSION: The nomogram showed excellent applicability and accuracy, which could be a reliable tool for predicting OS in SBP patients.

6.
Mol Med ; 27(1): 141, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732133

RESUMO

BACKGROUND: We aimed to investigate the functions and underlying mechanism of lncRNA SNHG1 in bone differentiation and angiogenesis in the development of osteoporosis. METHODS: The differential gene or proteins expressions were measured by qPCR or western blot assays, respectively. The targeted relationships among molecular were confirmed through luciferase reporter, RIP and ChIP assays, respectively. Alkaline phosphatase (ALP), alizarin red S (ARS) and TRAP staining were performed to measure the osteoblast/osteoclast differentiation of BMSCs. The viability, migration and angiogenesis in BM-EPCs were validated by CCK-8, clone formation, transwell and tube formation assays, respectively. Western blot and immunofluorescence detected the cytosolic/nuclear localization of ß-catenin. Ovariectomized (OVX) mice were established to confirm the findings in vitro. RESULTS: SNHG1 was enhanced and miR-181c-5p was decreased in serum and femoral tissue from OVX mice. SNHG1 directly inhibited miR-181c-5p to activate Wnt3a/ß-catenin signaling by upregulating SFRP1. In addition, knockdown of SNHG1 promoted the osteogenic differentiation of BMSCs by increasing miR-181c-5p. In contrast, SNHG1 overexpression advanced the osteoclast differentiation of BMSCs and inhibited the angiogenesis of BM-EPCs, whereas these effects were all reversed by miR-181c-5p overexpression. In vivo experiments indicated that SNHG1 silencing alleviated osteoporosis through stimulating osteoblastogenesis and inhibiting osteoclastogenesis by modulating miR-181c-5p. Importantly, SNHG1 could be induced by SP1 in BMSCs. CONCLUSIONS: Collectively, SP1-induced SNHG1 modulated SFRP1/Wnt/ß-catenin signaling pathway via sponging miR-181c-5p, thereby inhibiting osteoblast differentiation and angiogenesis while promoting osteoclast formation. Further, SNHG1 silence might provide a potential treatment for osteoporosis.


Assuntos
Remodelação Óssea/genética , MicroRNAs , Osteoporose/genética , RNA Longo não Codificante , Fator de Transcrição Sp1/genética , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Transdução de Sinais , Células-Tronco/citologia , Proteína Wnt3A/metabolismo
7.
Nat Prod Res ; : 1-8, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33951987

RESUMO

Amino acid-directed strategy becomes an efficient way to explore the alkaloids' biosynthetic potential of marine fungi. The metabolites of marine fungus Monascus albidus BB3 were regulated obviously when cultured in GPY medium supplemented with L-tryptophan, L-phenylalanine, D,L-methionine, L-threonine, L-lysine, L-serine and L-valine. Four new γ-lactams, monascuslactams A-D (1-4), together with two known compounds pulchellalactam (5) and O-acetylperlolyrine (6) were obtained. Their structures were determined by comprehensive analysis on the 1 D and 2 D NMR, HRESIMS, UV and IR data, and their absolute configurations were assigned by the experimental and calculated ECD data analysis. Compounds 3, 4 and 6 showed moderate cytotoxicity against human cancer cell lines SUNE1, HepG2, QGY7701, GLC82, HCT116 and MDA-MB-231.

8.
Autophagy ; 17(12): 4323-4340, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33977871

RESUMO

Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer.Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol 3-kinase UPS: ubiquitin-proteasome system.


Assuntos
Autofagia , Proteínas Culina , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Proteínas Culina/metabolismo , Humanos , Ubiquitina/metabolismo , Ubiquitinação
9.
Nat Commun ; 12(1): 2672, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976130

RESUMO

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.


Assuntos
Antígenos B7/metabolismo , Fucosiltransferases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antígenos B7/genética , Linhagem Celular Tumoral , Feminino , Fucose/metabolismo , Fucosiltransferases/genética , Técnicas de Inativação de Genes , Glicosilação , Células HEK293 , Humanos , Imunidade , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos SCID , Polissacarídeos/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
J Hepatobiliary Pancreat Sci ; 28(7): 593-603, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33908180

RESUMO

BACKGROUND: The presence of significant liver fibrosis is a key determinant of long-term prognosis in non-alcoholic fatty liver disease (NAFLD). We aimed to develop a novel machine learning algorithm (MLA) to predict fibrosis severity in NAFLD and compared it with the most widely used non-invasive fibrosis biomarkers. METHODS: We used a cohort of 553 adults with biopsy-proven NAFLD, who were randomly divided into a training cohort (n = 278) for the development of both logistic regression model (LRM) and MLA, and a validation cohort (n = 275). Significant fibrosis was defined as fibrosis stage F ≥ 2. MLA and LRM were derived from variables that were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm. RESULTS: In the training cohort, the variables selected by LASSO algorithm were body mass index, pro-collagen type III, collagen type IV, aspartate aminotransferase and albumin-to-globulin ratio. The diagnostic accuracy of MLA showed the highest values of area under the receiver operator characteristic curve (AUROC: 0.902, 95% CI 0.869-0.904) for identifying fibrosis F ≥ 2. The LRM AUROC was 0.764, 95% CI 0.710-0.816 and significantly better than the AST-to-Platelet ratio (AUROC 0.684, 95% CI 0.605-0.762), FIB-4 score (AUROC 0.594, 95% CI 0.503-0.685) and NAFLD Fibrosis Score (AUROC 0.557, 95% CI 0.470-0.644). In the validation cohort, MLA also showed the highest AUROC (0.893, 95% CI 0.864-0.901). The diagnostic accuracy of MLA outperformed that of LRM in all subgroups considered. CONCLUSIONS: Our newly developed MLA algorithm has excellent diagnostic performance for predicting fibrosis F ≥ 2 in patients with biopsy-confirmed NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Algoritmos , Biomarcadores , Biópsia , Fibrose , Humanos , Cirrose Hepática/diagnóstico , Aprendizado de Máquina , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Valor Preditivo dos Testes , Curva ROC , Índice de Gravidade de Doença
11.
Chem Biodivers ; 18(5): e2100068, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33811740

RESUMO

Five new decalins, monalbidins A-E (1, 2 and 7-9), together with 16 known compounds (3-6 and 10-21), were isolated from the AcOEt extract of marine derived fungus Monascus albidus BB3 cultured in GPY medium. Among the known compounds, 1-hydroxymonacolin L (11), dehydromonacolin J (15), 8-O-acetylmonacolin J (19) and O-acetylmonacolin K (21) were separated from natural sources for the first time. Their structures were determined by comprehensive analysis on the 1D and 2D NMR, HR-ESI-MS, UV and IR data, and their absolute configurations were assigned by experimental and calculated ECD data, and X-ray single-crystal diffraction analysis. Monalbidins C and D (7 and 8), monacolin K methyl ester (13), dehydromonacolin L (14), dehydromonacolin K (16), monacolin K (20) and O-acetylmonacolin K (21) showed moderate cytotoxicity against human cancer cell lines SUNE1, HepG2, QGY7701, HCT116 and MDA-MB-231.


Assuntos
Antineoplásicos/farmacologia , Monascus/química , Naftalenos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Naftalenos/química , Naftalenos/isolamento & purificação , Estereoisomerismo
12.
Oncogene ; 40(13): 2422-2436, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664452

RESUMO

Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Proliferação de Células , Cromatina , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Histonas/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Ubiquitinação/genética
13.
J Med Virol ; 93(1): 323-335, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32648973

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recently declared a pandemic by the World Health Organization. In addition to its acute respiratory manifestations, SARS-CoV-2 may also adversely affect other organ systems. To date, however, there is a very limited understanding of the extent and management of COVID-19-related conditions outside of the pulmonary system. This narrative review provides an overview of the current literature about the extrapulmonary manifestations of COVID-19 that may affect the urinary, cardiovascular, gastrointestinal, hematological, hematopoietic, neurological, or reproductive systems. This review also describes the current understanding of the extrapulmonary complications caused by COVID-19 to improve the management and prognosis of patients with COVID-19.


Assuntos
COVID-19/complicações , COVID-19/fisiopatologia , Infecções Cardiovasculares/virologia , Gastroenteropatias/virologia , Doenças Hematológicas/virologia , Humanos , Doenças do Sistema Nervoso/virologia , Infecções do Sistema Genital/virologia , Doenças Urológicas/virologia
14.
Autophagy ; 17(10): 3011-3029, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33213267

RESUMO

The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy ability during hypoxia. As a result, the accumulation of damaged, ROS-generating mitochondria leads to activation of the NLRP3 inflammasome, which induces abnormal soluble cytokines secretion, then promotes the differentiation and maturation of osteoclasts, and ultimately results in bone metastasis. Notably, phosphorylation of ULK1 by MAPK1/ERK2-MAPK3/ERK1 kinase triggers its interaction with BTRC and subsequent K48-linked ubiquitination and proteasome degradation. Also, a clearly negative correlation between the expression levels of ULK1 and p-MAPK1/3 was observed in human breast cancer tissues. The MAP2K/MEK inhibitor trametinib is sufficient to restore mitophagy function via upregulation of ULK1, leading to inhibition of NLRP3 inflammasome activation, thereby reduces bone metastasis. These results indicate that ULK1 knockout-mediated mitophagy defect promotes breast cancer bone metastasis and provide evidence to explore MAP2K/MEK- MAPK1/3 pathway inhibitors for therapy, especially in cancers displaying low levels of ULK1.Abbreviations: ATG: autophagy-related; Baf A1: bafilomycin A1; BTRC/ß-TrCP: beta-transducin repeat containing E3 ubiquitin protein ligase; CHX: cycloheximide; CM: conditioned media; FBXW7/FBW7: F-box and WD repeat domain containing 7; MAPK1: mitogen-activated protein kinase 1; MTDR: MitoTracker Deep Red; mtROS: mitochondrial reactive oxygen species; microCT: micro-computed tomography; mtROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; SQSTM1: sequestosome 1; ACP5/TRAP: acid phosphatase, tartrate resistant; ULK1: unc-51 like autophagy activating kinase 1.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Neoplasias Ósseas , Neoplasias da Mama , Peptídeos e Proteínas de Sinalização Intracelular , Proteína Quinase 1 Ativada por Mitógeno , Proteína Quinase 3 Ativada por Mitógeno , Mitofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Microtomografia por Raio-X
15.
Drug Deliv ; 27(1): 1729-1740, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33307843

RESUMO

Chemoembolization for hepatocellular carcinoma (HCC) is often suboptimal due to multiple involved signaling and lack of effective drugs. Arsenic trioxide (ATO) is a potent chemotherapeutic agent, which can target multiple signaling and have substantial efficacy on HCC. However, its usage is limited due to systemic toxicity. Using ATO-eluting beads/microspheres for chemoembolization can have locoregional drug delivery and avoid systemic exposure but will require high drug load, which has not been achieved due to low solubility of ATO. Through an innovative approach, we generated the transiently formed ATO microcrystals via micronization and stabilized these microcrystals by solvent exchange. By encapsulating ATO microcrystals, but not individual molecules, with poly(lactide-co-glycolic acid) (PLGA), we developed microspheres cored with extremely high dense ATO. The molar ratio between ATO and PLGA was 157.4:1 and drug load was 40.1%, which is 4-20 fold higher than that of reported ATO nano/microparticles. These microspheres sustainably induced reactive oxygen species, apoptosis, and cytotoxicity on HCC cells and reduced tumor growth by 80% via locoregional delivery. Chemoembolization on mice model showed that ATO-microcrystal loaded microspheres, but not ATO, inhibited HCC growth by 60-75%, which indicates ATO within these microspheres gains the chemoembolizing function via our innovative approach.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/uso terapêutico , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos Nus , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espécies Reativas de Oxigênio , Solventes , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mol Med Rep ; 22(4): 2705-2714, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32945374

RESUMO

Hepatocellular carcinoma (HCC) was the third most common cause of cancer­associated mortality in China in 2015. Early detection of HCC and hepatic cirrhosis (HC) can serve a crucial role in the prevention and therapeutic intervention of these diseases. Current early detection methods rely on less sensitive imaging modalities compared with the pathological examination. In the present study, a total of 64 patients with HCC, 44 patients with HC and 298 individuals with no evidence of disease (NED) were recruited, and the ability of methylated septin 9 (mSEPT9) in diagnosing HCC and HC was investigated. The overall detection sensitivity of mSEPT9 for HCC and HC was 76.7 and 34.1%, respectively, with a 95.9% specificity (HCC vs. NED). The sensitivity of mSEPT9 for HCC was significantly higher than that of α­fetoprotein (AFP; χ2 test; 56.7%; P<0.05). The areas under the curve from the receiver operating characteristic curves of mSEPT9 for detection of HCC vs. NED, HC vs. NED and HCC vs. HC were 0.85, 0.77 and 0.66, respectively, while those of AFP for the same groups were 0.80, 0.55 and 0.77, respectively. Although both markers exhibited stage­dependent sensitivity in HCC, mSEPT9 was demonstrated to be more sensitive than AFP. The net reclassification index of mSPET9 for HCC detection was 0.212 compared with AFP, suggesting an improved diagnostic performance of mSEPT9 compared with AFP. In addition, Kaplan­Meier survival analysis revealed that mSEPT9 is able to predict the long­term survival of patients with HCC. Further analysis suggested that patients >50 years of age exhibited higher sensitivity compared with those <50 years old in mSEPT9, but not in AFP. No significant difference in sensitivity was observed between compensated and decompensated patients with HC, and in patients with HC with a history of hepatitis B or C virus infection. No difference was observed between male and female subjects in the HC and HCC groups for mSEPT9 and AFP. In conclusion, mSEPT9 may detect HCC with an overall improved sensitivity compared with AFP and may help in predicting the long­term survival of patients with HCC. The present clinical study was retrospectively registered to the Chinese Clinical Trial Registry on April 4, 2020 (http://www.chictr.org.cn/enIndex.aspx; registration no. ChiCTR2000031547).


Assuntos
Carcinoma Hepatocelular/diagnóstico , Metilação de DNA , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Septinas/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/etiologia , Estudos de Casos e Controles , Diagnóstico Precoce , Epigênese Genética , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sensibilidade e Especificidade , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
17.
SN Compr Clin Med ; 2(10): 1717-1723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864573

RESUMO

On February 6, 2020, Xiaogan City became the second most seriously affected city with coronavirus disease 2019 (COVID-19), outside Wuhan district, Hubei Province, China. The objectives are to study the clinical features of COVID-19 patients and assess the relationship between the severity of COVID-19, age, and C-reactive protein (CRP) levels. The retrospective data of 134 COVID-19 patients hospitalized in 3 hospitals of Xiaogan City, between February 1 and March 1, 2020, was collected. This study documented COVID-19 patients. Clinical data in terms of body temperature, history of travel, and direct contact with COVID-19 patients, and incubation period was collected. Out of the 134 patients, only 5 required intensive care. Moreover, 2 patients succumbed during this period. The median age of patients was 45 (33-56) years. The most common symptoms at the onset of disease were fever (66.4%), cough (33, 6%), and sore throat (14.7%). Amongst the medicines used, antiviral agents (92.3%) followed by the traditional Chinese medicine (89.5%) were most commonly used. In both the crude and adjusted (I to III) models, odds ratio and its 95% confidence interval for both age and CRP levels were > 1. Moreover, the smooth curve fitting graph reflected that the severity of COVID-19 was positively correlated with both age and CRP levels (all P value < 0.05). The signs and symptoms of COVID-19 patients were fairly moderate. The health care professionals treating the COVID-19 patients should be aware of the increased likelihood of progression to severe COVID-19 in elderly patients and those with high CRP levels.

18.
Nat Commun ; 11(1): 3806, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732922

RESUMO

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+ T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.


Assuntos
Autofagia/imunologia , Linfócitos T CD8-Positivos/imunologia , Tenascina/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Autofagia/genética , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia Adotiva , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Evasão Tumoral/genética
19.
Mol Cancer ; 19(1): 122, 2020 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771023

RESUMO

BACKGROUND: Super-enhancers (SEs) play a crucial role in cancer, which is often associate with activated oncogenes. However, little is known about how SEs facilitate tumour suppression. Individuals with Down syndrome exhibit a remarkably reduced incidence of breast cancer (BC), moving the search for tumor suppressor genes on human chromosome 21 (HSA21). In this study, we aim to identify and explore potential mechanisms by which SEs are established for tumor suppressor RCAN1.4 on HSA21 in BC. METHODS: In silico analysis and immunohistochemical staining were used to assess the expression and clinical relevance of RCAN1.4 and RUNX3 in BC. Function experiments were performed to evaluate the effects of RCAN1.4 on the malignancy of breast carcinoma in vitro and in vivo. ChIP-seq data analysis, ChIP-qPCR, double-CRISPR genome editing, and luciferase reporter assay were utilized to confirm RUNX3 was involved in regulating RCAN1.4-associated SE in BC. The clinical value of co-expression of RCAN1.4 and RUNX3 was evaluated in BC patients. RESULTS: Here, we characterized RCAN1.4 as a potential tumour suppressor in BC. RCAN1.4 loss promoted tumour metastasis to bone and brain, and its overexpression inhibited tumour growth by blocking the calcineurin-NFATc1 pathway. Unexpectedly, we found RCAN1.4 expression was driven by a ~ 23 kb-long SE. RCAN1.4-SEdistal was sensitive to BRD4 inhibition, and its deletion decreased RCAN1.4 expression by over 90% and induced the malignant phenotype of BC cells. We also discovered that the binding sites in the SE region of RCAN1.4 were enriched for consensus sequences of transcription factor RUNX3. Knockdown of RUNX3 repressed the luciferase activity and also decreased H3K27ac enrichment binding at the SE region of RCAN1.4. Furthermore, abnormal SE-driven RCAN1.4 expression mediated by RUNX3 loss could be physiologically significant and clinically relevant in BC patients. Notably, we established a prognostic model based on RCAN1.4 and RUNX3 co-expression that effectively predicted the overall survival in BC patients. CONCLUSIONS: These findings reveal an important role of SEs in facilitating tumour suppression in BC. Considering that the combination of low RCAN1.4 and low RUNX3 expression has worse prognosis, RUNX3-RCAN1.4 axis maybe a novel prognostic biomarker and therapeutic target for BC patients.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Proteínas Musculares/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Calcineurina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Biologia Computacional/métodos , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Biológicos , Proteínas Musculares/metabolismo , Fatores de Transcrição NFATC/metabolismo , Prognóstico , Ligação Proteica , Transdução de Sinais , Fatores de Transcrição/metabolismo
20.
Ying Yong Sheng Tai Xue Bao ; 31(4): 1341-1348, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32530210

RESUMO

To investigate the characteristics of heavy metal pollution caused by traffic and its potential ecological risks, we measured the amount of metal elements in samples collected from a traffic trunk road in Lanzhou City with atomic absorption spectrophotometer. The single factor index method and potential ecological risk index method were used to evaluate the degree of pollution and potential ecological risks, and then the effects of heavy metal pollution on chlorophyll and calcium (Ca) contents in greening plants were analyzed. The results showed that the amount of heavy metals including chromium (Cr), manganese (Mn), zinc (Zn), copper (Cu) and nickel (Ni) in the soils increased significantly, with Cr, Cu and Pb reaching moderate pollution level. The degree of potential ecological risk was Cu>Pb>Cr>Ni>Zn>Mn. Sophora japonica, Rosa chinesis, Prunus ceraifera, and Euonymus japonicas showed different accumulation effects on Pb, Mn, Zn, and Ni. The content of chlorophyll in the leaves of deciduous species S. japonica, R. chinesis and P. ceraifera was higher in the roadside sampling point than that in the control point, while the pattern was just the opposite in evergreen species E. japonicas and P. orientalis. Foliar Ca content of greening plants in the roadside sampling point was higher than that in the control point, suggesting that high chlorophyll and Ca contents might be beneficial to plant survival in the heavy metal contaminated area. Taken together, traffic operation led to the accumulation of heavy metals (Cr, Mn, Zn, Cu, and Ni) in the soil of the study area. S. japonica, R. chinesis, P. ceraifera and E. japonicas could accumulate Pb, Mn, Zn and Ni, which could be used as greening plants in soils polluted by those heavy metals.


Assuntos
Metais Pesados , Poluentes do Solo , China , Cidades , Monitoramento Ambiental , Medição de Risco , Solo
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