RESUMO
Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT, which is critical to innate immunity.
Assuntos
Carcinogênese/genética , Linfoma/genética , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/metabolismo , Ubiquitinação , Linhagem Celular Tumoral , Células HEK293 , Humanos , Mutação , Fator 88 de Diferenciação Mieloide/metabolismoRESUMO
INTRODUCTION: The synergy of health care and elderly social care organizations has become the focus of the research on integrated health care and social care. This study aims to propose a collaborative strategy among health care and elderly social care service providers. METHODS: An evolutionary game model is applied for performance analysis and optimization of the cooperation between health care and elderly social care organizations. The behavioural strategies and the impact of key parameters on promoting the cooperation of the players are presented in detail. RESULTS: Simulation experiments and sensitivity analysis results indicate that (1) the behavioural evolution of health care organizations and elderly social care organizations forms three types of integrated health care and social care services, namely, the bilateral cooperation type, health care organization-led type and elderly social care organization-led type. (2) Increasing the additional benefits for cooperation and reducing the additional costs for cooperation can promote the willingness to synergize to provide integrated health care and elderly social care services. At the early stage of evolution, increasing the costs that elderly social care organizations pay to purchase health care services or pay for negotiation in the bilateral cooperation type can provide incentives for health care organizations to cooperate while reducing the cooperation preferences of elderly social care organizations. However, the long-term impact of the costs on the behavioural strategies for cooperation of the two players cannot be determined. CONCLUSION: The behavioural decisions on cooperation between health care and elderly social care organizations influence each other; commitment to integration and effective collaboration can be achieved by increasing the additional benefits and reducing the marginal costs. The findings suggest that the political-economic context and government policies have a greater influence on promoting cooperation, thus yielding positive or negative results for integrated care practice.
Assuntos
Atenção à Saúde , Serviço Social , Idoso , China/epidemiologia , Humanos , Apoio SocialRESUMO
Vinblastine (VBL) has been considered as a first-line anti-tumor drug for many years. However, vinblastine-caused myocardial damage has been continually reported. The underlying molecular mechanism of the myocardial damage remains unknown. Here, we show that vinblastine induces myocardial damage and necroptosis is involved in the vinblastine-induced myocardial damage both in vitro and in vivo. The results of WST-8 and flow cytometry analysis show that vinblastine causes damage to H9c2 cells, and the results of animal experiments show that vinblastine causes myocardial cell damage. The necrosome components, receptor-interacting protein 1 (RIP1) receptor-interacting protein 3 (RIP3), are significantly increased in vinblastine-treated H9c2 cells, primary neonatal rat ventricular myocytes and rat heart tissues. And the downstream substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was also increased. Pre-treatment with necroptosis inhibitors partially inhibits the necrosome components and MLKL levels and alleviates vinblastine-induced myocardial injury both in vitro and in vivo. This study indicates that necroptosis participated in vinblastine-evoked myocardial cell death partially, which would be a potential target for relieving the chemotherapy-related myocardial damage.
Assuntos
Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Necroptose , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Vimblastina/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Masculino , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fosforilação , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
On-road driving emissions of six liquefied natural gas (LNG) and diesel semi-trailer towing vehicles (STTVs) which met China Emission Standard IV and V were tested using Portable Emission Measurement System (PEMS) in northern China. Emission characteristics of these vehicles under real driving conditions were analyzed and proved that on-road emissions of heavy-duty vehicles (HDVs) were underestimated in the past. There were large differences among LNG and diesel vehicles, which also existed between China V vehicles and China IV vehicles. Emission factors showed the highest level under real driving conditions, which probably be caused by frequent acceleration, deceleration, and start-stop. NOx emission factors ranged from 2.855 to 20.939â¯g/km based on distance-traveled and 6.719-90.557â¯g/kg based on fuel consumption during whole tests, which were much higher than previous researches on chassis dynamometer. It was inferred from tests that the fuel consumption rate of the test vehicles had a strong correlation with NOx emission, and the exhaust temperature also affected the efficiency of Selected Catalytic Reduction (SCR) after-treatment system, thus changing the NOx emission greatly. THC emission factors of LNG vehicles were 2.012-10.636â¯g/km, which were much higher than that of diesel vehicles (0.029-0.185â¯g/km). Unburned CH4 may be an important reason for this phenomenon. Further on-road emission tests, especially CH4 emission test should be carried out in subsequent research. In addition, the Particulate Number (PN) emission factors of diesel vehicles were at a very high level during whole tests, and Diesel Particulate Filter (DPF) should be installed to reduce PN emission.
Assuntos
Poluentes Atmosféricos , Gás Natural , Emissões de Veículos/análise , China , Gasolina , Veículos AutomotoresRESUMO
Deguelin, a natural rotenoid isolated from several plants, has been reported to exert anti-tumour effects in various cancers. However, the molecular mechanism of this regulation remains to be fully elucidated. Here, we found that deguelin inhibited the growth of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo by downregulation of Bmi1 expression. Our data showed that Bmi1 is highly expressed in human NSCLC tissues and cell lines. Knockdown of Bmi1 significantly suppressed NSCLC cell proliferation and colony formation. Deguelin treatment attenuated the binding activity of Bmi1 to the Noxa promoter, thus resulting in Noxa transcription and apoptosis activation. Knockdown of Bmi1 promoted Noxa expression and enhanced deguelin-induced apoptosis, whereas overexpression of Bmi1 down-regulated Noxa protein level and deguelin-induced apoptosis. Overall, our study demonstrated a novel apoptotic mechanism for deguelin to exert its anti-tumour activity in NSCLC cells.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteína Quinase 7 Ativada por Mitógeno/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Rotenona/análogos & derivados , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Neoalbaconol, derived from Albatrellus confluens, shows anti-cancer activities in the previously study, but its role in angiogenesis is unknown. Here, we determined whether neoalbaconol could attenuate angiogenesis and how does it occur. Data demonstrated that neoalbaconol could inhibit the proliferation of breast cancer cells and induce apoptosis. Also, neoalbaconol suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. VEGF receptor activation and the downstream signal transduction cascades activation were inhibited by neoalbaconol. Additionally, neoalbaconol blocked EGFR-mediated VEGF production. EGFR overexpression reversed the neoalbaconol-induced VEGF reduction, confirming the importance of the EGFR inhibition in anti-angiogenesis of neoalbaconol. Furthermore, neoalbaconol inhibited tumor growth and tumor angiogenesis in a breast cancer xenograft model in vivo. Taken together, these results indicate that neoalbaconol could inhibit tumor angiogenesis and growth through direct suppression effects on vascular endothelial cells and reduction of proangiogenic factors in cancer cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/metabolismo , Neovascularização Patológica/tratamento farmacológico , Sesquiterpenos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos Nus , Neovascularização Patológica/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed. METHODS: We used reverse transcription-RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin. RESULTS: The present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage. CONCLUSIONS: The current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/secundário , Cisplatino/farmacologia , Neoplasias Esofágicas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Imunoprecipitação , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Phosphatase and tensin homolog (PTEN) loss or mutation consistently activates the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which contributes to the progression and invasiveness of prostate cancer. Furthermore, the PTEN/PI3-K/Akt and Ras/MAPK pathways cooperate to promote the epithelial-mesenchymal transition (EMT) and metastasis initiated from prostate stem/progenitor cells. For these reasons, the PTEN/PI3-K/Akt pathway is considered as an attractive target for both chemoprevention and chemotherapy. Herein we report that eupafolin, a natural compound found in common sage, inhibited proliferation of prostate cancer cells. Protein content analysis indicated that phosphorylation of Akt and its downstream kinases was inhibited by eupafolin treatment. Pull-down assay and in vitro kinase assay results indicated that eupafolin could bind with PI3-K and attenuate its kinase activity. Eupafolin also exhibited tumor suppressive effects in vivo in an athymic nude mouse model. Overall, these results suggested that eupafolin exerts antitumor effects by targeting PI3-K.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Flavonas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologiaRESUMO
Chrysin (5,7-dihydroxyflavone), a natural flavonoid widely distributed in plants, reportedly has chemopreventive properties against various cancers. However, the anticancer activity of chrysin observed in in vivo studies has been disappointing. Here, we report that a chrysin derivative, referred to as compound 69407, more strongly inhibited EGF-induced neoplastic transformation of JB6 P(+) cells compared with chrysin. It attenuated cell cycle progression of EGF-stimulated cells at the G1 phase and inhibited the G1/S transition. It caused loss of retinoblastoma phosphorylation at both Ser-795 and Ser-807/811, the preferred sites phosphorylated by Cdk4/6 and Cdk2, respectively. It also suppressed anchorage-dependent and -independent growth of A431 human epidermoid carcinoma cells. Compound 69407 reduced tumor growth in the A431 mouse xenograft model and retinoblastoma phosphorylation at Ser-795 and Ser-807/811. Immunoprecipitation kinase assay results showed that compound 69407 attenuated endogenous Cdk4 and Cdk2 kinase activities in EGF-stimulated JB6 P(+) cells. Pulldown and in vitro kinase assay results indicated that compound 69407 directly binds with Cdk2 and Cdk4 in an ATP-independent manner and inhibited their kinase activities. A binding model between compound 69407 and a crystal structure of Cdk2 predicted that compound 69407 was located inside the Cdk2 allosteric binding site. The binding was further verified by a point mutation binding assay. Overall results indicated that compound 69407 is an ATP-noncompetitive cyclin-dependent kinase inhibitor with anti-tumor effects, which acts by binding inside the Cdk2 allosteric pocket. This study provides new insights for creating a general pharmacophore model to design and develop novel ATP-noncompetitive agents with chemopreventive or chemotherapeutic potency.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Flavonoides/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Regulação Alostérica/efeitos dos fármacos , Animais , Sítios de Ligação , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Flavonoides/química , Fase G1/efeitos dos fármacos , Fase G1/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Inibidores de Proteínas Quinases/química , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Fase S/efeitos dos fármacos , Fase S/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies with a 5-year survival rate less than 15%. Understanding of the molecular mechanisms involved in the pathogenesis of ESCC becomes critical to develop more effective treatments. METHODS: Mcl-1 expression was measured by reverse transcription (RT)-PCR and Western blotting. Human Mcl-1 promoter activity was evaluated by reporter gene assay. The interactions between DNA and transcription factors were confirmed by electrophoretic mobility shift assay (EMSA) in vitro and by chromatin immunoprecipitation (ChIP) assay in cells. RESULTS: Four human ESCC cell lines, TE-1, Eca109, KYSE150 and KYSE510, are revealed increased levels of Mcl-1 mRNA and protein compare with HaCaT, an immortal non-tumorigenic cell line. Results of reporter gene assays demonstrate that human Mcl-1 promoter activity is decreased by mutation of kappaB binding site, specific NF-kappaB inhibitor Bay11-7082 or dominant inhibitory molecule DNMIkappaBalpha in TE-1 and KYSE150 cell lines. Mcl-1 protein level is also attenuated by Bay11-7082 treatment or co-transfection of DNMIkappaBalpha in TE-1 and KYSE150 cells. EMSA results indicate that NF-kappaB subunits p50 and p65 bind to human Mcl-1-kappaB probe in vitro. ChIP assay further confirm p50 and p65 directly bind to human Mcl-1 promoter in intact cells, by which regulates Mcl-1 expression and contributes to the viability of TE-1 cells. CONCLUSIONS: Our data provided evidence that one of the mechanisms of Mcl-1 expression in human ESCC is regulated by the activation of NF-kappaB signaling. The newly identified mechanism might provide a scientific basis for developing effective approaches to treatment human ESCC.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , NF-kappa B/biossíntese , NF-kappa B/genética , NF-kappa B/metabolismo , Linhagem Celular Transformada , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Carcinoma de Células Escamosas do Esôfago , Humanos , Transdução de Sinais/genéticaRESUMO
Epstein-Barr virus (EBV) reactivation into the lytic cycle plays certain roles in the development of EBV-associated diseases, including nasopharyngeal carcinoma and lymphoma. In this study, we investigated the effects of the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) on EBV spontaneous lytic infection and the mechanism(s) involved in EBV-positive cells. We found that EGCG could effectively inhibit the constitutive lytic infection of EBV at the DNA, gene transcription and protein levels by decreasing the phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. By using cellular signaling pathway-specific inhibitors, we also explored the signaling mechanisms underlying the inhibitory effects of EGCG on EBV spontaneous lytic infection in cell models. Results show that specific inhibitors of Mitogen-Activated Protein Kinase Kinase (MEK) (PD98059) and phosphatidylinositol 3-kinase [PI3-K (LY294002)] markedly downregulated gene transcription and expression of BZLF1 and BMRF1 indicating that the MEK/ERK1/2 and PI3-K/Akt pathways are involved in the EBV spontaneous lytic cycle cascade. Therefore, one of the mechanisms by which EGCG inhibits EBV spontaneous lytic infection appears to involve the suppression of the activation of MEK/ERK1/2 and PI3-K/Akt signaling.
Assuntos
Antivirais/farmacologia , Catequina/análogos & derivados , Herpesvirus Humano 4/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Ativação Viral/efeitos dos fármacos , Catequina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , DNA Viral/metabolismo , Ativação Enzimática , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Flavonoides/farmacologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , Humanos , Linfoma/metabolismo , Linfoma/virologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Morfolinas/farmacologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virologia , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Virais/metabolismoRESUMO
Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers coinhibitory signals to T cells, thereby suppressing their function and allowing evasion of antitumor immunity. Most companion or complementary diagnostic devices for assessing PD-L1 expression levels in tumor cells used in the clinic or in clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency led to fewer PD-L1 proteins on the tumor cell surface and promoted antitumor immunity in mice. Mechanistically, MIB2 catalyzed nonproteolytic K63-linked ubiquitination of PD-L1, facilitating PD-L1 trafficking through Ras-associated binding 8-mediated (RAB8-mediated) exocytosis from the TGN to the plasma membrane, where it bound PD-1 extrinsically to prevent tumor cell killing by T cells. Our findings demonstrate that nonproteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cell immune evasion.
Assuntos
Antígeno B7-H1 , Evasão Tumoral , Animais , Camundongos , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Evasão da Resposta Imune , Receptor de Morte Celular Programada 1/metabolismo , UbiquitinaçãoRESUMO
Cardiovascular disease (CVD) is the leading cause of death in the world, with a high incidence and a youth-oriented tendency. RNA modification is ubiquitous and indispensable in cell, maintaining cell homeostasis and function by dynamically regulating gene expression. Accumulating evidence has revealed the role of aberrant gene expression in CVD caused by dysregulated RNA modification. In this review, we focus on nine common RNA modifications: N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) RNA editing, and modifications of U34 on tRNA wobble. We summarize the key regulators of RNA modification and their effects on gene expression, such as RNA splicing, maturation, transport, stability, and translation. Then, based on the classification of CVD, the mechanisms by which the disease occurs and progresses through RNA modifications are discussed. Potential therapeutic strategies, such as gene therapy, are reviewed based on these mechanisms. Herein, some of the CVD (such as stroke and peripheral vascular disease) are not included due to the limited availability of literature. Finally, the prospective applications and challenges of RNA modification in CVD are discussed for the purpose of facilitating clinical translation. Moreover, we look forward to more studies exploring the mechanisms and roles of RNA modification in CVD in the future, as there are substantial uncultivated areas to be explored.
Assuntos
Doenças Cardiovasculares , Humanos , Adolescente , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/terapia , Adenosina/genética , RNA/metabolismo , Processamento Pós-Transcricional do RNA/genética , RNA de Transferência/metabolismoRESUMO
BACKGROUND: Tongue diagnosis is a crucial traditional Chinese medicine (TCM) inspection method for TCM syndrome differentiation and treatment. OBJECTIVE: The primary research focus was on tongue image characteristic parameters of patients with non-small cell lung cancer (NSCLC). Analysis of the tongue image parameters of various pathological stages of NSCLC provides technical support for establishing an integrated Chinese and Western auxiliary diagnosis and efficacy evaluation medicine system for lung cancer that integrates tongue image features. METHODS: Tongue image characteristics of 309 patients with NSCLC and 206 controls were collected and analyzed clinically. The T-test or rank sum test and logistic regression analysis were applied to analyze the characteristics of tongue image indicators of different pathological stages of NSCLC. RESULTS: There were differences in tongue image characteristics in the NSCLC group compared to the control group. The tongue quality and brightness of the tongue coating in the NSCLC group increased, the red component was reduced, the tongue coating thickened, and the yellow component increased compared to the healthy control group. A comparison of tongue image indexes of NSCLC in different pathological stages showed that stage IV had lower TB-b and higher TB-a than stage I. In addition, stage IV had lower TB-b than stage II + III, showing an increase in the blue and red components of the tongue in stage IV and the appearance of cyanotic tongue features. CONCLUSION: The tongue image characteristics of NSCLC patients differed from those of the control group. Tongue imaging indicators can reflect the characteristics of tongue images of patients with NSCLC. The tongue image characteristics of patients with stage IV lung cancer are bluish and purple compared with those with stage I, II, and III. It is suggested that the tongue's image characteristics can be used as a reference for the pathological classification of NSCLC and judgment of the disease process.
RESUMO
Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant NSCLC cells. Accordingly, inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin in vitro and in vivo. Mechanistically, Skp2 interacts and promotes ubiquitination-mediated degradation of MLKL in cisplatin-resistant NSCLC cells. Our results provide evidence of an Skp2-dependent mechanism regulating MLKL degradation and cisplatin resistance, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Quinases , Proteínas Quinases Associadas a Fase S , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismoRESUMO
Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies, including oral squamous cell carcinoma (OSCC). Thus, survivin has been proposed as an attractive target for new antitumor interventions. In the present study, we found that a natural compound, Dioscin, inhibited OSCC cells by reducing the survivin protein level and activating apoptotic signaling. Dioscin inhibits survivin expression by interrupting EGFR binding to the AT-rich sequences (ATRSs) at the survivin promoter, eventually promoting survivin-mediated cell apoptosis. The in vivo study showed that Dioscin suppressed the tumor development of SCC25 cells. Furthermore, the immunohistochemistry (IHC) results revealed that treated with Dioscin reduced the protein levels of EGFR and survivin in SCC25 xenograft tumors. Overall, our findings indicate that targeting the EGFR-survivin axis might be a promising OSCC treatment strategy.
RESUMO
A 71-year-old woman with recurrent papillary thyroid carcinoma (PTC) was referred to our hospital. A computed tomography scan revealed extensive recurrence in the neck, invading sternocleidomastoid muscle, internal jugular vein, sternal end of the clavicle, strap muscle and skin; and lateral compartment and subclavian lymph nodes were also involved. Multiple pulmonary micrometastases also noticed. The tumor was considered unresectable; however, the patient was unwilling to accept highly invasive surgery. Therefore, we initiated neoadjuvant therapy with anlotinib, 12mg p.o. daily with a 2-week on/1-week off regimen. The tumor shrunk to resectable state after 4 cycles of treatment, and after 3 weeks of withdrawal, successful surgical resection without gross tumor residual was performed. Pathology confirmed as classic PTC harboring coexistent TERT promoter and BRAFV600E mutations by NGS. After anlotinib therapy, apoptosis induction was observed, and proliferation increased, which was due to three weeks of anlotinib withdraw. Structual recurrence was recorded at 6 months after operation due to no further treatment was taken. Our finding suggests that anlotinib could represent as a good treatment option for patients with locally advanced (with or without distant metastasis) PTC; Anlotinib treatment resulted in sufficient reduction of the tumor mass to enable total thyroidectomy and radioactive iodine treatment, providing long-term control of the disease.
Assuntos
Carcinoma Papilar , Telomerase , Neoplasias da Glândula Tireoide , Feminino , Humanos , Idoso , Câncer Papilífero da Tireoide/tratamento farmacológico , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Proteínas Proto-Oncogênicas B-raf/genética , Terapia Neoadjuvante , Radioisótopos do Iodo , Carcinoma Papilar/cirurgia , Recidiva Local de Neoplasia/genética , Mutação , Telomerase/genéticaRESUMO
Phosphatidylinositol 3-kinase (PI3-K) amplification and phosphatase and tensin homolog (PTEN) deletion-caused Akt activation contribute to the development of prostate cancer. Mammalian target of rapamycin complex 2 (mTORC2) is a kinase complex comprised of mTOR, Rictor, mSin1, mLST8/GßL and PRR5 and functions in the phosphorylation of Akt at Ser473. Herein, we report that mTORC2 plays an important role in PC3 androgen refractory prostate cell proliferation and anchorage-independent growth. Aloe-emodin, a natural compound found in aloe, inhibited both proliferation and anchorage-independent growth of PC3 cells. Protein content analysis suggested that activation of the downstream substrates of mTORC2, Akt and PKCα, was inhibited by aloe-emodin treatment. Pull-down assay and in vitro kinase assay results indicated that aloe-emodin could bind with mTORC2 in cells and inhibit its kinase activity. Aloe-emodin also exhibited tumor suppression effects in vivo in an athymic nude mouse model. Collectively, our data suggest that mTORC2 plays an important role in prostate cancer development and aloe-emodin suppresses prostate cancer progression by targeting mTORC2.
Assuntos
Antraquinonas/farmacologia , Neoplasias da Próstata/prevenção & controle , Serina-Treonina Quinases TOR/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
Primary cardiac tumors are extremely uncommon in young children and infants. Cardiac myxoma are typically found in the atria, predominately in the left atrium, with relatively few found on the right side, such as in the right ventricle or pulmonary artery. Numerous significant complications, including sudden death, can result from obstruction of the main pulmonary artery trunk and right ventricular outflow tract. Here, we describe the case of a 14-year-old Chinese girl diagnosed with a right ventricular myxoma located in the right ventricle and extended into the main pulmonary trunk. Complete resection of the myxoma and histological confirmation were performed.
RESUMO
The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of Akt and upregulated GSK3ß activity, resulting in increased myeloid cell leukemia-1 (MCL-1) S159 phosphorylation, which disrupted the interaction of MCL-1 with Josephin domain containing 1 (JOSD1), and ultimately induced MCL-1 ubiquitination and degradation. Moreover, TRAF4 was positively correlated with MCL-1 in primary and in radiotherapy-treated, relapsed tumor tissues. An MCL-1 inhibitor overcame radioresistance in vitro and in vivo. Altogether, the present findings suggest that TRAF4 confers radioresistance in OSCC by stabilizing MCL-1 through Akt signaling, and that targeting TRAF4 may be a promising therapeutic strategy to overcome radioresistance in OSCC.