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Background: Nirmatrelvir/Ritonavir is an orally administered anti-SARS-Cov-2 drug used in mild-to-moderate COVID-19 patients. Our retrospective cohort study aims to evaluate the efficacy and safety of Nirmatrelvir/Ritonavir in severe hospitalized patients with Omicron infection, as well as in patients at high risk for progression to critical illness in real-world settings. Methods: A total of 350 patients received Nirmatrelvir/Ritonavir while 350 matched controls did not. Patients with confirmed COVID-19 were administered Nirmatrelvir 300â mg and Ritonavir 100â mg orally twice a day for 5 days, with the medication initiated on the first day after admission. The primary endpoint of the study was a composite outcome of hospitalization or death from any cause within 28 days. Secondary endpoints included the occurrence of adverse events and the evaluation of serum levels of IL-6 and viral load. Results: We documented the mortality risk from any cause within 28 days, viral load, serum IL-6 levels, and adverse events. Nirmatrelvir/Ritonavir reduced the 28-day risk of all-cause mortality by 86% (P = .011, hazard ratio (HR) = 0.14, 95% confidence interval (CI) = 0.03, 0.64). At baseline, the serum level of IL-6 was significantly higher in the antiviral treatment group compared to the control group (P < .001), but no significant difference (P = .990) was found between the two groups at discharge. In CKD patients undergoing hemodialysis, no significant worsening of renal function was observed in the Nirmatrelvir/Ritonavir treatment group compared to the control group. Conclusion: Nirmatrelvir/Ritonavir may reduce the 28-day risk of all-cause mortality in critically ill patients with COVID-19 and in patients at high risk for critical disease progression.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Enfermedad Crítica , Progresión de la Enfermedad , Ritonavir , SARS-CoV-2 , Humanos , Ritonavir/uso terapéutico , Ritonavir/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Antivirales/uso terapéutico , Antivirales/efectos adversos , COVID-19/mortalidad , COVID-19/complicaciones , Hospitalización/estadística & datos numéricos , Resultado del Tratamiento , Carga Viral , Combinación de MedicamentosRESUMEN
Zearalenone (ZEA), a common mycotoxin in animal feed, is harmful to public health and causes huge economic losses. The potential target proteins of ZEA and its derivatives were screened using the PharmMapper database and the related genes (proteins) of the testis were obtained from Genecards. We obtained 144 potential targets of ZEA and its derivatives related to the testis using Venn diagrams. The PPI analysis showed that ZEA had the most targets in testis, followed by ZAN, α-ZAL, ß-ZEL, α-ZEL, and ß-ZAL. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses evaluated the metabolic and cancer pathways. We further screened four hub genes: RAC3, CCND1, EP300, and CTNNB1. Eight key biological processes were obtained by GO analysis, and four important pathways were identified by KEGG analysis. Animal and cell experimental results confirmed that ZEA could inhibit the expression of four key KEGG pathway protein components and four hub proteins that interfere with cell adhesion by inhibiting the focal adhesion structure of the testis, Leydig cells, and Sertoli cells. Collectively, our findings reveal that the destruction of the focal adhesion structure in the testis is the mechanism through which ZEA damages the male reproductive system.
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Adhesiones Focales , Testículo , Zearalenona , Animales , Masculino , Ratas , Adhesiones Focales/efectos de los fármacos , Adhesiones Focales/patología , Células Intersticiales del Testículo/metabolismo , Micotoxinas/efectos adversos , Micotoxinas/toxicidad , Testículo/efectos de los fármacos , Testículo/patología , Zearalenona/efectos adversos , Zearalenona/toxicidadRESUMEN
The potential impact of the combination of a high-fat diet (HFD) and polystyrene nanoplastics (PS-NPs) on fertility cannot be ignored, especially when the fertility rate is declining. However, it has not attracted considerable attention. In this study, an obese mouse model was established using an HFD, and the reproductive function of male mice was evaluated after intragastric administration of 100 µL of a 10 mg/mL PS-NP suspension for 4 weeks. By determining the morphology and vitality of sperm and related indicators of testosterone production, it was found that PS-NPs aggravated the destruction of sperm mitochondrial structure, decrease sperm activity, and testosterone production in HFD-fed mice. To comprehensively analyze the injury mechanism, the integrity of the blood testicular barrier (BTB) and the function of Leydig and Sertoli cells were further analyzed. It was found that PS-NPs could destroy BTB, promote the degeneration of Leydig cells, reduce the number of Sertoli cells, and decrease lactate secretion in HFD-fed mice. PS-NPs further interfered with redox homeostasis in the testicular tissues of HFD-fed mice. This study found that PS-NPs could aggravate the damage to the reproductive system of obese male mice by further perturbing its redox homeostasis and revealed the potential health risk of PS-NPs exposure under an HFD.
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Poliestirenos , Testículo , Masculino , Ratones , Animales , Testículo/metabolismo , Poliestirenos/toxicidad , Ratones Obesos , Microplásticos , Semen , Obesidad/metabolismo , Testosterona/metabolismo , Oxidación-ReducciónRESUMEN
Zearalenone (ZEA) and deoxynivalenol (DON) are two common mycotoxins produced by the genus Fusarium and have potential immunotoxic effects that may lead to a weak immune response against bacterial infections. Listeria monocytogenes (L. monocytogenes), a food-borne pathogenic microorganism ubiquitous in the environment, actively multiplies in the liver, where hepatocytes are capable of resistance through mediated innate immune responses. At present, it is not clear if ZEA and DON affect hepatocyte immune responses to L. monocytogenes infection or the mechanisms involved. Therefore, in this study, in vivo and in vitro models were used to investigate the effects of ZEA and DON on the innate immune responses of hepatocytes and related molecules after L. monocytogenes infection. In vivo studies revealed that ZEA and DON inhibited the toll-like receptors 2 (TLR2)/nuclear factor kappa-B (NFκB) pathway in the liver tissue of L. monocytogenes-infected mice, downregulating the expression levels of Nitric oxide (NO), in the liver and repressing the immune response. In addition, ZEA and DON inhibited Lipoteichoic acid (LTA)-induced expression of TLR2 and myeloid differentiation factor 88 (MyD88) in Buffalo Rat Liver (BRL 3A) cells in vitro, downregulating the TLR2/NFκB signaling pathway and resulting in the decreased expression levels of NO, causing immunosuppressive effects. In summary, ZEA and DON can negatively regulate NO levels through TLR2/NFκB, inhibiting the innate immune responses of the liver, and aggravate L. monocytogenes infections in mouse livers.
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Fusarium , Listeria monocytogenes , Listeriosis , Micotoxinas , Zearalenona , Ratas , Ratones , Animales , Zearalenona/metabolismo , Micotoxinas/metabolismo , Fusarium/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , FN-kappa B/metabolismo , Hepatocitos/metabolismo , Inmunidad Innata , Transducción de SeñalRESUMEN
The low delivery efficiency of nano-drugs and limited tumour penetration are still huge challenges in treating solid tumours. Herein, we developed a pH-responsive nano-drug delivery system, CALS/PDMA@DOX, with a size conversion-layered delivery function. The system is composed of a pH-responsive cationic liposome loaded with DOX (CALS) and a polyamidoamine dendrimer loaded with DOX (PAMAM@DOX) modified with 2,3-dimethylmaleic anhydride (PDMA@DOX) using electrostatic adsorption. In the tumour microenvironment, the positively-charged large-size CALS and the positively-charged small-size PAMAM@DOX were dissociated to exert anti-tumour effects. CALS preferentially targeted tumour angiogenesis endothelial cells. Because of its small size and positive charge, PAMAM@DOX showed excellent tumour penetration. Significant tumour suppression by the system in vivo was confirmed in a 4T1 tumour xenograft mouse model. This pH-triggered size-switching layered delivery nanosystem is a safe and effective cancer treatment delivery platform that improves drug permeability and therapeutic efficacy.
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Dendrímeros , Nanopartículas , Neoplasias , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Células Endoteliales/patología , Humanos , Concentración de Iones de Hidrógeno , Liposomas , Ratones , Sistema de Administración de Fármacos con Nanopartículas , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Microambiente TumoralRESUMEN
The unbalanced charge transport is always a key influencing factor on the device performance of quantum dot light-emitting diodes (QLEDs), particularly for the blue QLEDs due to their large optical band gap. Here, a method of electron transport layer (ETL) doping was developed to regulate the energy levels and the carrier mobility of the ETL, which resulted in more balanced charge injection, transport and recombination in the blue emitting CdZnS/ZnS core/shell QLEDs. Consequently, an enhanced performance of blue QLEDs was achieved by modulating the charge balance through ETL doping. The maximum external quantum efficiency and luminance was dramatically increased from 2.2% to 7.3% and from 3786 cd m-2to 9108 cd m-2, respectively. The results illustrate that charge transport layer doping is a simple and effective strategy to regulate the charge injection barrier and carrier mobility of QLEDs.
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Zearalenone, which is ubiquitous in grains and animal feed, is a mycotoxin that can cause serious damage to animals and humans. Sertoli cells (SCs) can be used to study ZEA male reproductive toxicity in vitro. SCs provide energy for germ cells, where AMPK regulates intracellular energy. In order to explore the regulatory effect of AMPK on ZEA-induced lactate decline, we activated AMPK by AICAR and then inhibited AMPK by Compound C with ZEA-treated SCs for 24 h to detect intracellular lactate production-related indicators. Cell viability in the presence of 20 µmol/L ZEA and either 50 µmol/L AICAR or 5 µmol/L Compound C, respectively, did not damage SCs, and could effectively either activate or inhibit AMPK. Inhibition of AMPK promoted the production of pyruvate and lactate via increased expression of the glycolysis-related genes Pgam1 and the lactate production-related proteins GLUT1, LDHA, and MCT4. Activating AMPK inhibited the production of lactate and pyruvate by suppressing the expression of glycolysis-related genes HK1, Pgam1, and Gpi1 and that of lactate production-related proteins LDHA and MCT4. Zearalenone destroys the energy balance in SCs, activates P-AMPK, which inhibit the production of lactate and pyruvate in SCs. This also leads to the decrease of energy supply of SCs to spermatogenic cells, damages to reproductive system.
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Proteínas Quinasas Activadas por AMP/metabolismo , Estrógenos no Esteroides/toxicidad , Ácido Láctico/metabolismo , Células de Sertoli/efectos de los fármacos , Zearalenona/toxicidad , Animales , Metabolismo Energético/efectos de los fármacos , Glucólisis/efectos de los fármacos , Glucólisis/genética , Masculino , Ácido Pirúvico/metabolismo , Ratas , Células de Sertoli/metabolismoRESUMEN
Three series of sulfonate derivatives of paeonol were synthesized and screened in vitro for their anti-oomycete activity against P. capsici, respectively. Among all the compounds, 4m displayed the best promising and pronounced anti-oomycete activity against P. capsici than zoxamide, with the EC50 values of 24.51 and 26.87 mg/L, respectively. The results show that acetyl and 4-OCH3 are two necessary groups. The existence of these two sites is closely related to the anti-oomycete activity. Relatively speaking, hydroxyl group is well tolerated, and the results showed that after modification of hydroxyl group with sulfonyl, the anti-oomycete activity was significantly increased. [Formula: see text].
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Acetofenonas , Acetofenonas/farmacología , Estructura MolecularRESUMEN
Anlotinib is a new type of small-molecule multi-target tyrosine kinase inhibitor with inhibitory effects against angiogenesis and tumor growth. An effective targeted nano-delivery system is urgently needed to effectively utilize anlotinib for the treatment of melanoma and lung metastases. In this study, an anlotinib-loaded reduction-sensitive nanomicelle, cyclic RGD peptide (cRGDyk)-anlotinib-reduction sensitive micelles (cARM), was developed as a tumor microenvironment-responsive delivery platform. The micelle carrier was formed by the self-assembly of reduction-sensitive amphiphilic copolymers DSPE-SS-PEG2k and DSPE-PEG2k-cRGDyk. The disulfide bonds in the amphiphilic block of micelles are responsive to elevated GSH in tumor cells for controlled drug release. In a B16F10 tumor-bearing mouse model, cRGDyk-anlotinib-RM (cARM) showed better tumor tissue accumulation and internalization than those for non-reduction-sensitive micelles. Therefore, this reduction-sensitive drug delivery system benefits from its specificity, prolonged blood circulation time, effective absorption by tumor cells, and rapid release of intracellular drugs and is therefore a promising strategy.
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Indoles/química , Péptidos Cíclicos/química , Quinolinas/química , Animales , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Melanoma/metabolismo , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Micelas , Cicatrización de Heridas/efectos de los fármacosRESUMEN
BACKGROUND: It has indicated that single nuclear polymorphisms (SNPs) in the regions encoding non-coding transcripts are associated with lung cancer susceptibility. In a previous microarray study, we identified 13 differentially expressed long non-coding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) and associations of SNPs in these lncRNA genes with lung cancer were unknown. We conducted a case-control study to address this issue. METHODS: Using the TaqMan method, we genotyped 17 SNPs located in the 13 lncRNA genes in 1294 cases with NSCLC and 1729 healthy controls. Unconditional logistic regression and Cox proportional hazards regression were used to analyze the associations of these SNPs with NSCLC risk and patient survival, respectively. These analyses were also repeated in subgroups of cases and controls stratified by gender, age group, smoking status, disease stage, and histological type. RESULTS: We identified three SNPs associated with NSCLC risk. For SNP rs498238, CC genotype was associated with lower risk compared to TT genotype (adjusted OR = 0.33, 95%CI: 0.11-0.97, P = 0.043). For rs16901995, CT/TT genotypes were associated with lower risk compared to CC genotype in non-smokers (adjusted OR = 0.78, 95%CI: 0.62-0.98, P = 0.035). Variant genotypes in rs219741 were associated with NSCLC risk in young patients, and the adjusted OR was 1.47 (95%CI: 1.03-2.10, P = 0.033) when compared to the wild genotype. No SNPs were found to be associated with patient overall survival in the study. CONCLUSION: The study suggests that some genetic polymorphisms in the lncRNA genes may influence the risk of NSCLC among Chinese.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , Anciano , Pueblo Asiatico/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
Zearalenone (ZEA) is a phenolic resorcylic acid lactone mycotoxin produced by several Fusarium species that grow on temperate and tropical crops. The number of reports documenting the immunotoxic effects of ZEA is increasing, but the underlying mechanism is not clear. The purpose of this study was to investigate the effects of ZEA on T cell chemotaxis and evaluate changes in adhesion and migration proteins associated with this process. Specifically, T cells were isolated from BALB/C mouse splenic lymphocytes, activated by concanavalin A (Con A), and then exposed to different concentrations of ZEA. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used observe the ultrastructural changes inside the cell and on the cell surface, respectively. The transwell migration assay was used to evaluate the effect of ZEA on T cell chemotaxis in the presence of CCL19 or CCL21. A confocal 3D laser was used to capture the morphology of perforated cells and western blot was used to detect the expression of proteins associated with cell migration and adhesion. Additionally, we used flow cytometry to examine the expression of chemokine receptors on T cells. Finally, the chemokine (RANTES and MIP-1α) levels secreted by T cells were assessed using cytometric bead array. Overall, our data showed that treatment with ZEA caused ultrastructural damage on the surface as well as inside of T cells. Moreover, ZEA inhibited T cell chemotaxis which was mediated by CCL19 or CCL21 and disrupted the balance of T cell subtypes. The expression of T cell adhesion and migration proteins was also inhibited by ZEA. The expression of T cell chemokine receptor as well as secretion of RANTES and MIP-1α by T cells was suppressed after ZEA treatment. In summary, our results indicate that ZEA reduced the chemotactic effect of T cells mediated by chemokines, which was likely linked to the inhibition of T cell motility and accompanied by decreased expression of adhesion and migration proteins.
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Adhesión Celular/efectos de los fármacos , Quimiocinas/biosíntesis , Quimiotaxis/efectos de los fármacos , Receptores de Quimiocina/biosíntesis , Linfocitos T/efectos de los fármacos , Zearalenona/toxicidad , Animales , Movimiento Celular/efectos de los fármacos , Quimiocina CCL19/biosíntesis , Quimiocina CCL21/biosíntesis , Quimiocina CCL5/biosíntesis , Citometría de Flujo , Humanos , Ratones Endogámicos BALB C , Linfocitos T/inmunologíaRESUMEN
Zearalenone (ZEA) interferes with the function of the male reproductive system, but its molecular mechanism has yet to be completely elucidated. Sertoli cells (SCs) are important in the male reproductive system. Silencing information regulator 1 (SIRT1) is a cell metabolism sensor and resveratrol (RSV) is an activator of SIRT1. In this study we investigated whether SIRT1 is involved in the regulation of ZEA-induced lactate metabolism disorder in SCs. The results showed that the cytotoxicity of ZEA toward SCs increased with increasing ZEA concentration. Moreover, ZEA induced a decrease in the production of lactic acid and pyruvate of SCs and inhibited the expression of glycolytic genes and lactic acid production-related proteins. ZEA also led to a decreased expression of SIRT1 in energy receptors and decreased ATP levels in SCs. However, the ZEA-induced cytotoxicity and decline in lactic acid production in SCs were alleviated by the use of RSV, which is an activator of SIRT1. In summary, ZEA decreased lactic acid production in SCs, while the treatment with an SIRT1 activator, RSV, restored the inhibition of lactic acid production in SCs and reduced cytotoxicity of ZEA toward SCs.
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Ácido Láctico/metabolismo , Resveratrol/farmacología , Células de Sertoli/metabolismo , Sirtuina 1/metabolismo , Zearalenona/farmacología , Adenosina Trifosfato/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Masculino , Ratas Wistar , Células de Sertoli/citología , Células de Sertoli/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Ecological studies have shown that air pollution and prevalence of cigarette smoking are positively correlated. Evidence also suggests a synergistic effect of cigarette smoking and PM2.5 exposure (Environmental Particulate Matter ≤ 2.5 µm in diameter) on lung cancer risk. We aimed to evaluate the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality and determine its underlying mechanisms in vitro. METHODS: "MOVER" method was used to analyze the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality. Cell autophagy and malignant behaviors induced by cigarette smoke extract (CSE) and PM2.5 exposure were examined in vitro. Gene expression was examined by qRT-PCR and western blot. RNA and protein interaction was determined using a RNA binding protein immunoprecipitation assay. RESULTS: An increased risk for lung cancer death (RERI (the relative excess risk) =0.28) was observed with a synergistic interaction between cigarette smoking and PM2.5 pollution. Cell migration, invasion, EMT (epithelial-mesenchymal transition) and autophagy were elevated when lung cancer cells were treated with CSE and PM2.5 in combination. A lncRNA, named lung cancer progression-association transcript 1 (LCPAT1), was up-regulated after the treatment of CSE and PM2.5, and knocking down the lncRNA impaired the effect of CSE and PM2.5 on lung cancer cells. In addition, LCPAT1 was shown to bind to RCC2, and RCC2 mediated the effect of LCPAT1 on cell autophagy, migration, invasion and EMT in lung cancer. CONCLUSIONS: Our results suggest that combined exposure to CSE and PM2.5 induces LCPAT1 expression, which up-regulates autophagy, and promotes lung cancer progression via RCC2.
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Autofagia , Proteínas Cromosómicas no Histona/metabolismo , Transición Epitelial-Mesenquimal , Factores de Intercambio de Guanina Nucleótido/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Material Particulado/toxicidad , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Fumar/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/patología , MasculinoRESUMEN
BACKGROUND: Chlamydia is a group of bacterial pathogens distributed worldwide that can lead to serious reproductive and other health problems. The rise of antibiotic-resistant pathogens promotes the development of novel antichlamydial agents. The aim of this study is to assess in vitro antichlamydial activity of our previously synthesized 1,2,3,5- tetrasubstituted pyrroles. METHODS: The derivatives were screened for their antichlamydial activity against three Chlamydia strains by calculating IC50 values using concentration-response inhibition data between 1 and 32 µM. The action of the compounds on Chlamydia elementary body (EB) infectivity and the impact of the chemicals' administration time on their antichlamydial effect were evaluated to reveal the inhibitory mechanism. RESULTS: Some of the compounds moderately inhibited the Chlamydia strains. Compound 10 exhibited the strongest inhibitory activity, with IC50 values from 4.34 to 5.83 µM. These pyrrole derivatives inhibited Chlamydia infection by reducing EB infectivity during the early stage and disturbing Chlamydia growth by targeting the early-to-middle stage prior to 12 h of the chlamydial life cycle. CONCLUSION: Our findings highlight the potential of 1,2,3,5-tetrasubstituted pyrrole derivatives as promising lead molecules for the development of antichlamydial agents.
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BACKGROUND: Evidence shows that individuals who are under long-term exposure to environmental PM2.5 are at increased risk of lung cancer. Various laboratory experiments also suggest several mechanistic links between PM2.5 exposure and lung carcinogenesis. However, a long non-coding RNA (lncRNA) mediated pathogenic change after PM2.5 exposure and its potential roles in tumorigenesis and disease progression have not been reported. METHODS: Cytotoxicity induced by PM2.5 was assessed by using scanning electron microscopy and transmission electron microscopy. ROS generation, autophagy, and metastasis induced by PM2.5 were detected by using comprehensive approaches. Expression of lncRNA-loc146880 and lc3b (autophagy marker) in A549 cells, lung tissue and serum were determined by RT-PCR and Western blotting. RESULTS: PM2.5 could be internalized into lung cancer cells, resulting in marked increases in ROS levels and autophagy. ROS may be responsible for increased expression of loc146880 which further up-regulates autophagy. Both loc146880 and autophagy could promote lung tumor cell migration, invasion and EMT. In addition, a positive correlation was observed between loc146880 expression and lc3b levels in tumor tissues and serum of lung cancer patients. CONCLUSION: Taken together, our data suggest that PM2.5 exposure induces ROS, which activates loc146880 expression. The lncRNA, in turn, up-regulates autophagy and promotes the malignant behaviors of lung cancer cells. GENERAL SIGNIFICANCE: The results show the toxicological effects of PM2.5 in lung tumor progression and metastasis.
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Autofagia/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Invasividad Neoplásica/patología , Material Particulado/efectos adversos , ARN Largo no Codificante/genética , Células A549 , Carcinogénesis/inducido químicamente , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Exposición a Riesgos Ambientales/efectos adversos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We aimed to investigate if short-term exposure to reduced particulate matter (PM) air pollution would affect respiratory function in healthy adults. We followed a cohort of 42 healthy participants from a community afflicted with severe PM air pollution to a substantially less polluted area for nine days. We measured daily airborne PM [with an aerodynamic diameter of less than 2.5 µm (PM2.5) and 10 µm (PM10)] and PM2.5 carbon component concentrations. Five repeated respiratory function measurements and fractional exhaled nitric oxide test were made for each participant. Associations between respiratory health and PM exposure were assessed using linear mixed models. Each 10 µg/m3 decrease in same-day PM2.5 was associated with small but consistent increase in the forced expiratory volume in 1 s (FEV1) (9.00 mL) and forced vital capacity (14.35 mL). Our observations indicate that respiratory health benefits can be achieved even after a short-term reduction of exposure to PM. Our results provide strong evidence for more rigorous air pollution controls for the health benefit of populations.
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Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/prevención & control , Exposición a Riesgos Ambientales , Material Particulado/análisis , Fenómenos Fisiológicos Respiratorios/efectos de los fármacos , China , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Estudios Prospectivos , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND: Epidemiologic studies suggest that variability in DNA damage from vinyl chloride monomer (VCM) may be partially mediated by genetic polymorphisms in DNA repair. This study aimed to corroborate these observations with controlled experiments in vitro using cell lines from individuals with differing DNA repair genotypes to determine damage following VCM metabolite exposure. METHODS: Matched pairs of lymphoblast cell lines (homozygous wild-type versus homozygous variant for either XRCC1 399 or XPD 751 polymorphism) were exposed to chloroacetaldehyde and analyzed by the cytokinesis-block micronucleus assay. RESULTS: All cell lines demonstrated a dose-response of increasing micronuclei with increasing exposure, but for both XRCC1 and XPD, the polymorphic cells peaked at higher micronucleus frequencies and declined at a slower rate to baseline than the wild-type cells. CONCLUSION: This supports the findings that XRCC1 and XPD polymorphisms may result in deficient DNA repair of VCM-induced genetic damage.
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Daño del ADN , Reparación del ADN/genética , Linfocitos/efectos de los fármacos , Cloruro de Vinilo/toxicidad , Línea Celular Transformada , Humanos , Técnicas In Vitro , Linfocitos/metabolismo , Pruebas de Micronúcleos , Polimorfismo GenéticoRESUMEN
OBJECTIVE: To evaluate the effects of polymorphisms in XRCC1 and APE1 genes on vinyl chloride (VC)-induced chromosomal damage in peripheral lymphocytes. METHODS: In this study, 317 workers occupationally exposed to VC were recruited from a factory in Shandong Province, China. The micronucleus (MN) frequency in peripheral lymphocytes was used as an indicator of chromosomal damage. Polymerase chain reaction-restriction fragment length polymorphism and created restriction site combined with restriction fragment length polymorphism were used to determine the five single nucleotide polymorphisms in XRCC1 and APE1 genes in the base excision repair pathway. The association of chromosomal damage with these polymorphisms and the haplotype of XRCC1 was analyzed using Poisson regression and PHASE 2.0.2. RESULTS: It was found that among the VC-exposed workers, individuals with XRCC1 polymorphisms (-77C/T, Arg194Trp, Arg280His, and Arg399Gln) had a significantly higher MN frequency than those with homozygous wild-type genotypes, with frequency ratios (FR) as follows, respectively: FR = 1.21, 95%CI: 1.05â¼1.39 (P < 0.05); FR = 1.14, 95%CI: 1.00â¼1.38 (P < 0.05); FR = 1.26, 95%CI: 1.11â¼1.44 (P < 0.05); FR = 1.23, 95%CI: 1.08â¼1.46 (P < 0.05). APE1 Asp148Glu was found of no significant relationship with MN frequency. Haplotype analysis of XRCC1 demonstrated that the MN frequencies in subjects with CTAA/CTAA and CCAA/CTAA were significantly higher than that in those with TCGG/TCGG (FR = 1.19, 95%CI: 1.02â¼1.32, P < 0.05; FR = 1.41, 95%CI: 1.02â¼1.87, P < 0.05). Furthermore, association was found between accumulated exposure to VC and XRCC1 polymorphisms (-77C/T, Arg194Trp, Arg280His, and Arg399Gln) after adjustment for age, sex, drinking, and smoking. CONCLUSION: VC can induce chromosomal damage even when the exposure level is lower than the national occupational health standard of China (PC-TWA: 10 mg/m(3)); the polymorphisms in XRCC1 and APE1 are associated with chromosomal damage induced by VC.
Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Proteínas de Unión al ADN/genética , Exposición Profesional/efectos adversos , Polimorfismo de Longitud del Fragmento de Restricción , Cloruro de Vinilo/envenenamiento , Adulto , Femenino , Haplotipos , Humanos , Masculino , Micronúcleos con Defecto Cromosómico , Persona de Mediana Edad , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Adulto JovenRESUMEN
OBJECTIVE: Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. RESEARCH DESIGN AND METHODS: DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. RESULTS: Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07-1.27]) and CVD (HR, 1.09 [95% CI, 1.03-1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90-1.09]; HR for CVD, 1.04 [95% CI, 0.98-1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. CONCLUSIONS: DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation.
Asunto(s)
Enfermedades Cardiovasculares , Colesterol en la Dieta , Humanos , Masculino , Femenino , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/epidemiología , Persona de Mediana Edad , Colesterol en la Dieta/efectos adversos , Colesterol en la Dieta/administración & dosificación , Diabetes Mellitus/genética , Diabetes Mellitus/epidemiología , Anciano , Adulto , Predisposición Genética a la Enfermedad , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Proteínas de Transporte de Membrana/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genéticaRESUMEN
BACKGROUND: To investigate whether and what lifestyle factors in later life modify the associations of early-life smoking behaviors and genetic susceptibility with type 2 diabetes (T2D). METHODS: In the UK Biobank, in utero tobacco exposure (n = 354,493) and age of smoking initiation (n = 353,557) were self-reported. A composite lifestyle score was calculated based on diet, physical activity, nicotine exposure, sleep duration, and BMI. Hazard ratio (HR) and absolute risk difference (ARD) were used to estimate the associations of early-life smoking behaviors and genetic risk with incident T2D, as well as the effect modification of the lifestyle score. RESULTS: During a median follow-up of 14.6 years, the HRs (95 % CIs) of T2D for in utero tobacco exposure, and smoking initiation in adulthood, adolescence, and childhood, compared with no smoking behavior, were 1.19 (1.16-1.23), 1.34 (1.29-1.39), 1.58 (1.53-1.64), 2.22 (2.11-2.32), respectively (P for trend<0.001). Early-life smoking behaviors and high genetic risk (vs no smoking behavior and low genetic risk) were associated with a 302%-593 % higher T2D risk (P for additive interaction<0.05). Compared to participants with early-life smoking behaviors, high genetic risk, and an unfavorable lifestyle, those who adhered to a favorable lifestyle had a lower T2D risk in all subgroups (HRs from 0.05 to 0.36 and ARD from -14.97 % to -9.51 %), with the highest ARD attributable to lifestyle in participants with early-life smoking behaviors and high genetic risk. CONCLUSIONS: The T2D risk associated with early-life smoking behaviors and genetic risk was modified by a favorable lifestyle.