RESUMEN
Non-small-cell lung cancer (NSCLC) is a major cause of worldwide cancer death, posing a challenge for effective treatment. Our previous findings showed that Chinese herbal medicine (CHM) QiDongNing (QDN) could upregulate the expression of p53 and trigger cell apoptosis in NSCLC. Here, our objective was to investigate the mechanisms of QDN-induced apoptosis enhancement. We chose A549 and NCI-H460 cells for validation in vitro, and LLC cells were applied to form a subcutaneous transplantation tumour model for validation in more depth. Our findings indicated that QDN inhibited multiple biological behaviours, including cell proliferation, cloning, migration, invasion and induction of apoptosis. We further discovered that QDN increased the pro-apoptotic BAX while inhibiting the anti-apoptotic Bcl2. QDN therapy led to a decline in adenosine triphosphate (ATP) and a rise in reactive oxygen species (ROS). Furthermore, QDN elevated the levels of the tumour suppressor p53 and the mitochondrial division factor DRP1 and FIS1, and decreased the mitochondrial fusion molecules MFN1, MFN2, and OPA1. The results were further verified by rescue experiments, the p53 inhibitor Pifithrin-α and the mitochondrial division inhibitor Mdivi1 partially inhibited QDN-induced apoptosis and mitochondrial dysfunction, whereas overexpression of p53 rather increased the efficacy of the therapy. Additionally, QDN inhibited tumour growth with acceptable safety in vivo. In conclusion, QDN induced apoptosis via triggering p53/DRP1-mediated mitochondrial fission in NSCLC cells.
Asunto(s)
Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Medicamentos Herbarios Chinos , Dinaminas , Neoplasias Pulmonares , Dinámicas Mitocondriales , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Células A549 , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Dinaminas/metabolismo , Dinaminas/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer with high morbidity and mortality rates. Due to the heterogeneity of LUAD, its characteristics remain poorly understood. Exploring the clinical and molecular characteristics of LUAD is challenging but vital for early diagnosis. METHODS: This observational and validation study enrolled 80 patients and 13 healthy controls. Nuclear and mtDNA-captured sequencings were performed. RESULTS: This study identified a spectrum of nuclear and mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with diagnosis. The correlation coefficient for somatic mutations in cfDNA and patient-matched tumor tissues was high in nuclear and mitochondrial genomes. The mutation number of highly mutated genes was evaluated, and the Least Absolute Shrinkage and Selection Operator (LASSO) established a diagnostic model. Receiver operating characteristic (ROC) curve analysis explored the diagnostic ability of the two panels. All models were verified in the testing cohort, and the mtDNA panel demonstrated excellent performance. This study identified somatic mutations in the nuclear and mitochondrial genomes, and detecting mutations in cfDNA displayed good diagnostic performance for early-stage LUAD. Moreover, detecting somatic mutations in the mitochondria may be a better tool for diagnosing early-stage LUAD. CONCLUSIONS: This study identified specific and sensitive diagnostic biomarkers for early-stage LUAD by focusing on nuclear and mitochondrial genome mutations. This also further developed an early-stage LUAD-specific mutation gene panel for clinical utility. This study established a foundation for further investigation of LUAD molecular pathogenesis.
Asunto(s)
Adenocarcinoma del Pulmón , Ácidos Nucleicos Libres de Células , Genoma Mitocondrial , Neoplasias Pulmonares , Humanos , Genoma Mitocondrial/genética , Detección Precoz del Cáncer , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , ADN Mitocondrial/genéticaRESUMEN
To investigate the efficacy and safety of olanzapine, aripiprazole, and risperidone in the treatment of mental and behavioral symptoms of Alzheimer's Disease. A retrospective analysis was performed on the clinical data of 126 patients with Alzheimer's Disease from February 2018 to February 2020. The patients were divided into group A (aripiprazole, n=44), group B (olanzapine, n=42) and group C (risperidone, n=40) based on the treatment method. Remarkably differences at different time points among the three groups were observed (P<0.05). Significant differences in the Positive and Negative Syndrome Scale scores of different time points and cross-group comparison among the three groups were detected (P<0.05). The time-point comparison of BEHAVE-AD scores among the three groups indicated a remarkable difference (P<0.05). After 4 weeks of treatment, the Positive and Negative Syndrome Scale and BEHAVE-AD scores of group A were lower than those of groups B and C (P<0.05). The total incidence of adverse reactions in group A was remarkably lower than in groups B and C (P<0.05). Olanzapine, aripiprazole and risperidone are effective in treating Alzheimer's disease and aripiprazole, with a better safety profile and fewer adverse reactions, is more suitable for elderly patients.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Aripiprazol/uso terapéutico , Olanzapina/uso terapéutico , Risperidona/uso terapéutico , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Antipsicóticos/efectos adversos , Aripiprazol/efectos adversos , Femenino , Humanos , Masculino , Olanzapina/efectos adversos , Estudios Retrospectivos , Risperidona/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: The Toll-like receptor 4(TLR4)/nuclear factor kappa B NF-κB inflammatory pathway contributes to secondary inflammation in many diseases including stroke. Moreover, the neuroprotective effect of splenectomy in stroke is supported by a vast body of experimental evidence. Nevertheless, the underlying mechanism(s) by which splenectomy enhance neuroprotection in stroke is still poorly understood. Our study aimed to investigate whether post-ischemic splenectomy modulate the TLR4/NF-κB inflammatory pathway in stroke. METHODS: Immunohistochemistry was used to evaluate the levels of TLR4 and NF-κB expression in brain areas (parietal lobe, hippocampus and striatum) of rats that underwent: MCAO-splenectomy surgery (MS ); MCAO surgery without splenectomy (MCAO control or MC); Sham MCAO and splenectomy surgery (sham control group or SC group respectively. Apoptosis in these areas was assessed by TUNEL detection technique. RESULTS: The levels of TLR4 and NF-κB expression were significantly reduced in splenectomized rats relative to the MS group (P<0.01). Additionally, the number of apoptotic cells in the ischemic hemisphere were significantly higher in both MCAO groups compared to the Sham group (P<0.05), between day 1 and day 7. An exception was observed in the striatum where the difference in apoptotic rate between the MS and sham group was not statistically significant at the same time points. Moreover, the variation apoptotic rate in different cerebral zone correlated to variation in TLR4 and NF-κB expression. CONCLUSION: In summary, our study provides further evidence of neuroprotective effect of splenectomy in ischemic stroke. Our results suggest that such an effect might be due to the inhibition of theTLR4/NF-κB inflammatory pathway.
Asunto(s)
Infarto de la Arteria Cerebral Media , FN-kappa B/metabolismo , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/prevención & control , Transducción de Señal/fisiología , Esplenectomía/métodos , Receptor Toll-Like 4/metabolismo , Análisis de Varianza , Animales , Encéfalo/metabolismo , Encéfalo/patología , Infarto Encefálico/prevención & control , Modelos Animales de Enfermedad , Etiquetado Corte-Fin in Situ , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/cirugía , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/prevención & control , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Resultado del TratamientoRESUMEN
Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. Recent studies have increasingly suggested that a high concentration of advanced glycation end products (AGEs) may be important in AD pathogenesis. However, the mechanisms and pathways involved remain unknown. The aim of this study was to explore whether the mechanism of the effect of AGEs on AßPC12 cells [PC12 cells treated with ßamyloid (Aß) peptide] was associated with oxidative stress; and to study whether inhibiting the activity of the receptor for AGE (RAGE) attenuated the toxic effect of AGEs and Aß on PC12 cells. Several PC12 cells were pretreated with Aß, and were then treated with different concentrations of AGEs. Other PC12 cells were treated with trypsin, a pancreatic protein enzyme and an inhibitor of RAGE, and were then treated with Aß and AGEs. Apoptosis was measured by flow cytometry (FCM) and cell viability was measured by MTT assay. RAGE and nuclear factorκB (NFκB) were measured by reverse transcription-polymerase chain reaction (RTPCR) assay. With an increase in AGE concentration, the viability of AßPC12 cells treated with AGEs decreased. However, the AßPC12 cell viability was greater in the trypsin group than in the nontrypsin group. Cell apoptosis rates and mRNA expression of RAGE and NFκB in AßPC12 cells treated with AGEs were significantly higher than in the AßPC12 cells. AGEs and Aß were neurotoxic, and RAGE triggered the neural cytotoxic role of AGEs in AßPC12 cells. The molecular mechanisms may be connected with the expression of NFκB and apoptosis mediated by RAGE. Inhibiting the activity of RAGE may mitigate the toxic effect of AGEs and Aß on neural cells.