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BACKGROUND: Both genetic factors and environmental air pollution contribute to the risk of stroke. However, it is unknown whether the association between air pollution and stroke risk is influenced by the genetic susceptibilities of stroke and its risk factors. METHODS: This prospective cohort study included 40â 827 Chinese adults without stroke history. Satellite-based monthly fine particulate matter (PM2.5) estimation at 1-km resolution was used for exposure assessment. Based on 534 identified genetic variants from genome-wide association studies in East Asians, we constructed 6 polygenic risk scores for stroke and its risk factors, including atrial fibrillation, blood pressure, type 2 diabetes, body mass index, and triglyceride. The Cox proportional hazards model was applied to evaluate the hazard ratios and 95% CIs for the associations of PM2.5 and polygenic risk score with incident stroke and the potential effect modifications. RESULTS: Over a median follow-up of 12.06 years, 3147 incident stroke cases were documented. Compared with the lowest quartile of PM2.5 exposure, the hazard ratio (95% CI) for stroke in the highest quartile group was 2.72 (2.42-3.06). Among individuals at high genetic risk, the relative risk of stroke was 57% (1.57; 1.40-1.76) higher than those at low genetic risk. Although no statistically significant interaction was found, participants with both the highest PM2.5 and high genetic risk showed the highest risk of stroke, with ≈4× that of the lowest PM2.5 and low genetic risk group (hazard ratio, 3.55 [95% CI, 2.84-4.44]). Similar upward gradients were observed in the risk of stroke when assessing the joint effects of PM2.5 and genetic risks of blood pressure, type 2 diabetes, body mass index, atrial fibrillation, and triglyceride. CONCLUSIONS: Long-term exposure to PM2.5 was associated with a higher risk of incident stroke across different genetic susceptibilities. Our findings highlighted the great importance of comprehensive assessment of air pollution and genetic risk in the prevention of stroke.
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Contaminantes Atmosféricos , Contaminación del Aire , Fibrilación Atrial , Diabetes Mellitus Tipo 2 , Accidente Cerebrovascular , Adulto , Humanos , Material Particulado/efectos adversos , Material Particulado/análisis , Estudios Prospectivos , Fibrilación Atrial/complicaciones , Estudio de Asociación del Genoma Completo , Exposición a Riesgos Ambientales/efectos adversos , Incidencia , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/inducido químicamente , Contaminación del Aire/efectos adversos , Factores de Riesgo , Predisposición Genética a la Enfermedad , Triglicéridos , Contaminantes Atmosféricos/efectos adversosRESUMEN
BACKGROUND: Transplant renal artery stenosis (TRAS) is a vascular complication after kidney transplantation associated with poor outcomes. This study aimed to analyze the efficacy and safety of low-dose aspirin for preventing TRAS. METHODS: After kidney transplantation, patients were enrolled from January 2018 to December 2020 in Henan Provincial People's Hospital. A total of 351 enrolled recipients were randomized to an aspirin group with low-dose intake of aspirin in addition to standard treatment ( n = 178), or a control group with only standard treatment ( n = 173). The patients was initially diagnosed as TRAS (id-TRAS) by Doppler ultrasound, and confirmed cases were diagnosed by DSA (c-TRAS). RESULTS: In the aspirin and control groups, 15.7% (28/178) and 22.0% (38/173) of the recipients developed id-TRAS, respectively, with no statistical difference. However, for c-TRAS, the difference of incidence and cumulative incidence was statistically significant. The incidence of c-TRAS was lower in the aspirin group compared with the control group (2.8% [5/178] vs. 11.6% [20/173], P = 0.001). Kaplan-Meier estimates and Cox regression model identified the cumulative incidence and hazard ratio (HR) of TRAS over time in two groups, showing that recipients treated with aspirin had a significantly lower risk of c-TRAS than those who were not treated (log-rank P â=â0.001, HRâ=â0.23, 95% confidence interval [CI]: 0.09-0.62). The levels of platelet aggregation rate ( P â<â0.001), cholesterol ( P â=â0.028), and low-density lipoprotein cholesterol ( P â=â0.003) in the aspirin group were decreased compared with the control group in the third-month post-transplantation. For the incidence of adverse events, there was no statistical difference. CONCLUSION: Clinical application of low-dose aspirin after renal transplant could prevent the development of TRAS with no significant increase in adverse effects. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04260828.
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Obstrucción de la Arteria Renal , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Angiografía , AspirinaRESUMEN
The utility of the polygenic risk score (PRS) to identify individuals at higher risk of stroke beyond clinical risk remains unclear, and we clarified this using Chinese population-based prospective cohorts. Cox proportional hazards models were used to estimate the 10-year risk, and Fine and Gray's models were used for hazard ratios (HRs), their 95% confidence intervals (CIs), and the lifetime risk according to PRS and clinical risk categories. A total of 41,006 individuals aged 30-75 years with a mean follow-up of 9.0 years were included. Comparing the top versus bottom 5% of the PRS, the HR was 3.01 (95%CI 2.03-4.45) in the total population, and similar findings were observed within clinical risk strata. Marked gradients in the 10-year and lifetime risk across PRS categories were also found within clinical risk categories. Notably, among individuals with intermediate clinical risk, the 10-year risk for those in the top 5% of the PRS (7.3%, 95%CI 7.1%-7.5%) reached the threshold of high clinical risk (⩾7.0%) for initiating preventive treatment, and this effect of the PRS on refining risk stratification was evident for ischemic stroke. Even among those in the top 10% and 20% of the PRS, the 10-year risk would also exceed this level when aged ⩾50 and ⩾60 years, respectively. Overall, the combination of the PRS with the clinical risk score improved the risk stratification within clinical risk strata and distinguished actual high-risk individuals with intermediate clinical risk.
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Pueblos del Este de Asia , Medición de Riesgo , Accidente Cerebrovascular , Humanos , Pueblo Asiatico/genética , Estudios Prospectivos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/genética , Adulto , Persona de Mediana Edad , AncianoRESUMEN
OBJECTIVE: To examine whether adherence to ideal cardiovascular health (CVH) can mitigate the genetic risk of coronary artery disease (CAD) in non-European populations. METHODS: Fine and Grey's models were used to calculate HRs and their corresponding 95% CIs, as well as the lifetime risk of CVH metrics across Polygenic Risk Score (PRS) categories. RESULTS: We included 39 755 individuals aged 30-75 years in Chinese prospective cohorts. 1275 CAD cases were recorded over a mean follow-up of 12.9 years. Compared with unfavourable CVH profile (zero to three ideal CVH metrics), favourable CVH profile (six to seven ideal CVH metrics) demonstrated similar relative effects across PRS categories, with the HRs of 0.40 (95% CI 0.24 to 0.67), 0.41 (95% CI 0.32 to 0.52) and 0.36 (95% CI 0.26 to 0.52) in low (bottom quintile of PRS), intermediate (two to four quintiles of PRS) and high (top quintile of PRS) PRS categories, respectively. For the absolute risk reduction (ARR), individuals with high PRS achieved the greatest benefit from favourable CVH, mitigating the risk to the average level of population (from 21.1% to 8.7%), and the gradient was strengthened in individuals at the top 5% of PRS. Moreover, compared with individuals at low PRS, those at high PRS obtained longer CAD-free years (2.6 vs 1.1) from favourable CVH at the index age of 35 years. CONCLUSION: Favourable CVH profile reduced the CAD relative risk by similar magnitude across PRS categories, while the ARR from favourable CVH was most pronounced in high PRS category. Attaining favourable CVH should be encouraged for all individuals, especially in individuals with high genetic susceptibility.
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Adulto , Humanos , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Pueblos del Este de Asia , Factores de Riesgo , Estado de SaludRESUMEN
Mesenchymal stem cells (MSCs) have potential role in organ regeneration therapy. Previous work indicating that MSCs confer protection against liver disease. Here, we aimed to determine the potential application in liver regeneration of human placenta-derived MSCs extracellular vesicles (hPMSCs-EVs) via experimental hepatectomy. hPMSCs-EVs were administered intravenously 24 h before 70% partial hepatectomy, the specific composition of hPMSCs-EVs was identified by sequencing and validated by the quantitative polymerase chain reaction, including circ-RBM23. The role of circ-RBM23 in L02 cell was evaluated and it was found that circ-RBM23 knockdown inhibited L02 cell proliferation both in vitro and in vivo. The competing endogenous RNA function of circ-RBM23 was evaluated by the RNA immunoprecipitation assay and found that circ-RBM23 shares miRNA response elements with RRM2. Overexpressed circ-RBM23 bound competitively to miR-139-5p, preventing the miRNA-mediated degradation of RRM2, activating the expression of eIF4G and AKT/mTOR, and facilitating liver regeneration. These results indicate that hPMSCs-EVs prevent hepatic dysfunction and improve liver regeneration in vivo and hepatocytes proliferation in vitro, potentially via circ-RBM23 delivery.
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AIMS: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. METHODS AND RESULTS: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS. CONCLUSION: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.
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Enfermedad de la Arteria Coronaria , Pueblo Asiatico , China/epidemiología , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial/genética , Estudios Prospectivos , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce acute inflammatory response like acute lung inflammation (ALI) or acute respiratory distress syndrome, leading to severe progression and mortality. Therapeutics for treatment of SARS-CoV-2-triggered respiratory inflammation are urgent to be discovered. Our previous study shows that Salvianolic acid C potently inhibits SARS-CoV-2 infection. In this study, we investigated the antiviral effects of a Salvia miltiorrhiza compound, Danshensu, in vitro and in vivo, including the mechanism of S protein-mediated virus attachment and entry into target cells. In authentic and pseudo-typed virus assays in vitro, Danshensu displayed a potent antiviral activity against SARS-CoV-2 with EC50 of 0.97 µM, and potently inhibited the entry of SARS-CoV-2 S protein-pseudo-typed virus (SARS-CoV-2 S) into ACE2-overexpressed HEK-293T cells (IC50 = 0.31 µM) and Vero-E6 cell (IC50 = 4.97 µM). Mice received SARS-CoV-2 S via trachea to induce ALI, while the VSV-G treated mice served as controls. The mice were administered Danshensu (25, 50, 100 mg/kg, i.v., once) or Danshensu (25, 50, 100 mg·kg-1·d-1, oral administration, for 7 days) before SARS-CoV-2 S infection. We showed that SARS-CoV-2 S infection induced severe inflammatory cell infiltration, severely damaged lung tissue structure, highly expressed levels of inflammatory cytokines, and activated TLR4 and hyperphosphorylation of the NF-κB p65; the high expression of angiotensinogen (AGT) and low expression of ACE2 at the mRNA level in the lung tissue were also observed. Both oral and intravenous pretreatment with Danshensu dose-dependently alleviated the pathological alterations in mice infected with SARS-CoV-2 S. This study not only establishes a mouse model of pseudo-typed SARS-CoV-2 (SARS-CoV-2 S) induced ALI, but also demonstrates that Danshensu is a potential treatment for COVID-19 patients to inhibit the lung inflammatory response.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Animales , Humanos , Lactatos , Ratones , Glicoproteína de la Espiga del CoronavirusRESUMEN
Hepatocellular carcinoma (HCC) is one of the commonest lethal malignancies worldwide, and often diagnosed at an advanced stage, without any curative therapy. Immune checkpoint blockers targeting the programmed death receptor 1 (PD-1) have shown impressive antitumor activity in patients with advanced-stage HCC, while the response rate is only 30%. Inducible PD-L1 overexpression may result in a lack of response to cancer immunotherapy, which is attributed to a mechanism of adaptive immune resistance. Our study investigated that the overexpression of PD-L1 promoted the invasion and migration of liver cancer cells in vitro, and the induced overexpression of PD-L1 in the tumor microenvironment could weaken the effects of anti-PD-1 immunotherapy in a BALB/c mouse model of liver cancer. CPI-203, a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor, which can potently inhibit PD-L1 expression in vitro and in vivo, combined with PD-1 antibody improved the response to immunotherapy in a liver cancer model. Cell transfection and chromatin immunoprecipitation assay manifested that BRD4 plays a key role in PD-L1 expression; CPI-203 can inhibit PD-L1 expression by inhibiting the BRD4 occupation of the PD-L1 promoter region. This study indicates a potential clinical immunotherapy method to reduce the incidence of clinical resistance to immunotherapy in patients with HCC.
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Acetamidas/administración & dosificación , Azepinas/administración & dosificación , Antígeno B7-H1/genética , Proteínas de Ciclo Celular/metabolismo , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Factores de Transcripción/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Acetamidas/farmacología , Animales , Azepinas/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Regiones Promotoras Genéticas/efectos de los fármacos , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Association between tea consumption and incident hypertension remains uncertain. This study conducted to examine the health effects of tea consumption on blood pressure progression and hypertension incidence. METHODS: A population-based cohort of 38,913 Chinese participants without hypertension at baseline were included in the current study. Information on tea consumption was collected through standardized questionnaires. Associations of tea consumption with blood pressure progression and incident hypertension were analyzed using logistic regression models and Cox proportional hazards regression models, respectively. RESULTS: During a median follow-up of 5.9 years, 17,657 individuals had experienced progression to a higher blood pressure stage and 5,935 individuals had developed hypertension. In multivariate analyses, habitual tea drinkers (≥ 3 times/week for at least six months) had a 17% lower risk for blood pressure progression [odds ratio (OR) = 0.83, 95% CI: 0.79-0.88] and a 14% decreased risk for incident hypertension [hazard ratio (HR) = 0.86, 95% CI: 0.80-0.91] compared with non-habitual tea drinkers. Individuals in different baseline blood pressure groups could obtain similar benefit from habitual tea drinking. In terms of tea consumption amount, an inverse, linear dose-response relation between monthly consumption of tea leaves and risk of blood pressure progression was observed, while the risk of incident hypertension did not reduce further after consuming around 100 g of tea leaves per month. CONCLUSIONS: Our study demonstrated that habitual tea consumption could provide preventive effect against blood pressure progression and hypertension incidence.
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Two lanthanide coordination polymers (CPs) {[Er(Hmtbd)(H2mtbd)(H2O)3]·2H2O}n (1) and [Yb(Hmtbd)(H2mtbd)(H2O)3]n (2) carrying an N-heterocyclic carboxylate ligand 5-(3-methylformate-1H-1,2,4-triazole-1-methyl)benzen-1,3-dicarboxylate (H3mtbd) were prepared under solvothermal conditions. The single-crystal X-ray diffraction data demonstrate that 1 and 2 are isostructural and display 1D chain structure. Alternating current (AC) impedance measurements illustrate that the highest proton conductivities of 1 and 2 can attain 5.09 × 10-3 and 3.09 × 10-3 S·cm-1 at 100 °C and 98% relative humidity (RH), respectively. The value of 1 exceeds those of most reported lanthanide-based crystalline materials and ranks second among the described Er-CPs under similar conditions, whereas the value for 2 is the highest proton conductivity among the previous Yb-CPs. Coupled with the structural analyses of the two CPs and H2O vapor adsorption, the calculated Ea values help to deduce their proton conductive mechanisms. Notably, the N-heterocyclic units (triazole), carboxyl, and hydrogen-bonding network all play key roles in the proton-transfer process. The prominent proton conductive abilities of both CPs show great promise as efficient proton conductors.
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OBJECTIVE: To construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke. METHODS: Using a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals. RESULTS: During a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66-2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%-27.7%) and 13.6% (95% CI 11.6%-15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%-49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%). CONCLUSIONS: Our metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that metaPRS is predictive of stroke risk.
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Predisposición Genética a la Enfermedad , Factores de Riesgo de Enfermedad Cardiaca , Medición de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Adulto , Anciano , Pueblo Asiatico , Estudios de Casos y Controles , China/epidemiología , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Modelos Estadísticos , Herencia Multifactorial , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Medición de Riesgo/normas , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/prevención & controlRESUMEN
SARS-CoV-2 caused the emerging epidemic of coronavirus disease in 2019 (COVID-19). To date, there are more than 82.9 million confirmed cases worldwide, there is no clinically effective drug against SARS-CoV-2 infection. The conserved properties of the membrane fusion domain of the spike (S) protein across SARS-CoV-2 make it a promising target to develop pan-CoV therapeutics. Herein, two clinically approved drugs, Itraconazole (ITZ) and Estradiol benzoate (EB), are found to inhibit viral entry by targeting the six-helix (6-HB) fusion core of SARS-CoV-2 S protein. Further studies shed light on the mechanism that ITZ and EB can interact with the heptad repeat 1 (HR1) region of the spike protein, to present anti-SARS-CoV-2 infections in vitro, indicating they are novel potential therapeutic remedies for COVID-19 treatment. Furthermore, ITZ shows broad-spectrum activity targeting 6-HB in the S2 subunit of SARS-CoV and MERS-CoV S protein, inspiring that ITZ have the potential for development as a pan-coronavirus fusion inhibitor.
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A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC50 value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (e.g., t1/2 of â¼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.
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Antígeno B7-H1/antagonistas & inhibidores , Carcinoma Hepatocelular/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Neoplasias Hepáticas , Éteres Fenílicos/química , Piperidinas/farmacología , Piperidinas/farmacocinética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Resorcinoles/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular , Humanos , Inhibidores de Puntos de Control Inmunológico/química , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Piperidinas/química , Ratas Sprague-Dawley , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound NP19 inhibited the human PD-1/PD-L1 interaction with IC50 values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, NP19 dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, NP19 displayed significant in vivo antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that NP19 activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows NP19 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.
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Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Éteres Fenílicos/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Resorcinoles/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Éteres Fenílicos/química , Éteres Fenílicos/uso terapéutico , Receptor de Muerte Celular Programada 1/metabolismo , Mapas de Interacción de Proteínas/efectos de los fármacos , Ratas Sprague-Dawley , Resorcinoles/química , Resorcinoles/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
The global spread of the novel coronavirus SARS-CoV-2 urgently requires discovery of effective therapeutics for the treatment of COVID-19. The spike (S) protein of SARS-CoV-2 plays a key role in receptor recognition, virus-cell membrane fusion and virus entry. Our previous studies have reported that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) serves as a viral entry inhibitor to prevent several kinds of virus infection. Here, our results reveal that HP-OVA can effectively inhibit SARS-CoV-2 replication and S protein-mediated cell-cell fusion in a dose-dependent manner without obvious cytopathic effects. Further analysis suggests that HP-OVA can bind to both the S protein of SARS-CoV-2 and host angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and disrupt the S protein-ACE2 interaction, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that HP-OVA can serve as a potential therapeutic agent for the treatment of deadly COVID-19.
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Background: Circular RNAs (circRNAs) play a pivotal regulatory role in a variety of tumors.Nevertheless, the detailed function of circ_0000003 in non-small cell lung cancer (NSCLC) and its regulatory mechanism remain elusive.Methods: RT-PCR was carried out to detect the expressions of circ_0000003, miR-338-3p and insulin receptor substrate 2 (IRS2)in NSCLC tissues. Besides, western blot was done to monitor IRS2 expression in NSCLC cells. The correlation between circ_0000003 and clinicopathologic characteristics of NSCLC patients was analyzed as well.CCK8 and BrdUassays were used to monitor cell proliferation; flow cytometry was used to detect apoptosis; and transwell assay was conducted to detect its migration and invasion.Moreover, dual luciferase reporter gene assay was done to verify the targeting relationship between circ_0000003 and miR-338-3p.Additionally, the effect of circ_0000003 on the growth of NSCLC cells in vivo was evaluated by tumorigenesis assay in nude mice.Results: The expression of circ_0000003 was significantly high in NSCLC tissues and cell lines, and its high expression level was notably correlated with lymph node metastasis andTNM staging.In vitro experiments showed that overexpression of circ_0000003 facilitated the proliferation, migration, invasion and inhibited the apoptosis of NSCLC cells, while the knockdown of circ_0000003 had the opposite effect.In vivo experiments revealed that knockdown of circ_0000003 impeded tumor growth and metastasis. Further, the underlying mechanism showed that circ_0000003 functioned as endogenous competitive RNA and directly targeted miR-338-3p to positively regulated IRS2 expression.Conclusion: Circ_0000003 promotes the proliferation and metastasis of NSCLC cells via modulating miR-338-3p/IRS2 axis.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Sustrato del Receptor de Insulina/genética , MicroARNs/genética , ARN Circular/genética , Animales , Apoptosis/genética , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Metástasis de la Neoplasia , Estadificación de NeoplasiasRESUMEN
OBJECTIVE: Apogossypolone (ApoG2), a new derivative of gossypol, is a potent cell-growth inhibitor. ApoG2 has been demonstrated to have superior anti-tumor activity than gossypol in Bcl-2 transgenic mice. The purpose of this study was to investigate the inhibitory effect of ApoG2 on breast cancer cell line MCF-7 in vitro and in vivo, and to investigate its anti-tumor mechanism. METHODS: MCF-7 cell line in culture was treated with ApoG2. The inhibitory effects of ApoG2 on cell growth were measured by MTT and colony-formation assay. The cell apoptotic rate and cell cycle were analyzed by use of flow cytometry (FCM). The ultrastructural changes were observed by transmission electron microscopy. Autophagy was detected by acridine orange staining. Expression of Bcl-2, Bax, and Beclin 1 proteins was measured by western blot analysis. RESULTS: The inhibitory effect of ApoG2 on MCF-7 cell proliferation was dose and time-dependent. The maximum effect was observed when cells were incubated for 72 h with 40 µM ApoG2. ApoG2 at 5 µM also inhibited colony formation. FCM assay indicated that ApoG2 induced cell apoptosis and caused cell arrest in the S phase and G2/M phase. Transmission electron microscopic examination and acridine orange staining showed that ApoG2 induced intracellular autolysosome formation. Furthermore, ApoG2 reduced Bcl-2 expression, and enhanced expression of Bax and Beclin 1. Xenografting of MCF-7 cells in mice can also be inhibited by ApoG2. CONCLUSION: ApoG2, a novel anti-apoptotic Bcl-2 agent, inhibits proliferation of breast cancer cell line MCF-7 by inducing cell apoptosis and autophagy.