Cervical cancer is the fourth most common gynecological malignancy affecting the health of women worldwide and the second most common cause of cancer-related mortality among women in developing regions. Thus, the development of effective chemotherapeutic drugs for the treatment of cervical cancer has become an important issue in the medical field. The application of natural products for the prevention and treatment of various diseases, particularly cancer, has always attracted widespread attention. In the present study, a library of natural products composed of 78 single compounds was screened and it was found that digitoxin exhibited the highest cytotoxicity against HeLa cervical cancer cells with an IC 50 value of 28 nM at 48 h. Furthermore, digitoxin exhibited extensive antitumor activities in a variety of malignant cell lines, including the lung cancer cell line, A549, the hepatoma cell line, MHCC97H, and the colon cancer cell line, HCT116. Mechanistically, digitoxin caused DNA double-stranded breaks (DSBs), inhibited the cell cycle at the G 2 /M phase via the ataxia telangiectasia mutated serine/threonine kinase (ATM)/ATM and Rad3-related serine/threonine kinase (ATR)-checkpoint kinase (CHK1)/checkpoint kinase 2 (CHK2)-Cdc25C pathway and ultimately triggered mitochondrial apoptosis, which was characterized by the disruption of Bax/Bcl-2, the release of cytochrome c and the sequential activation of caspases and poly(ADP-ribose) polymerase (PARP). In addition, the in vivo anticancer effect of digitoxin was confirmed in HeLa cell xenotransplantation models. On the whole, the findings of the present study demonstrate the efficacy of digitoxin against cervical cancer in vivo and elucidate its molecular mechanisms, including DSBs, cell cycle arrest and mitochondrial apoptosis. These results will contribute to the development of digitoxin as a chemotherapeutic agent in the treatment of cervical cancer.
For the partially linear varying-coefficient model when the parametric covariates are measured with additive errors, the estimator of the error variance is defined based on residuals of the model. At the same time, we construct Jackknife estimator as well as Jackknife empirical likelihood statistic of the error variance. Under both the response variables and their associated covariates form a stationary 伪-mixing sequence, we prove that the proposed estimators and Jackknife empirical likelihood statistic are asymptotic normality and asymptotic 蠂 2 distribution, respectively. Numerical simulations are carried out to assess the performance of the proposed method.
Difficult or even non-healing diabetic foot ulcers (DFU) are a global medical challenge. Although current treatments such as debridement, offloading, and infection control have resulted in partial improvement in DFU, the incidence, amputation, and mortality rates of DFU remain high. Therefore, there is an urgent need to find new or more effective drugs. Numerous studies have shown that oxidative stress plays an important role in the pathophysiology of DFU. The nuclear factor erythroid 2-related factor (Nrf2) signaling pathway and the advanced glycated end products (AGEs)-receptor for advanced glycation endproducts (RAGE), protein kinase C (PKC), polyol and hexosamine biochemical pathways play critical roles in the regulation of oxidative stress in the body. Targeting these pathways to restore redox balance can control and alleviate the occurrence and development of DFU. Natural biologics are a major source of potential drugs for these relevant targets, and their antioxidant potential has been extensively demonstrated. Here, we discussed the pathophysiological mechanism of oxidative stress in DFU, and identifiled natural biologics targeting these pathways to accelerate DFU healing, in order to provide a new or potential direction for clinical treatment, nursing and related basic research of DFU.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations鈥揷itations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.