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Keiko Taguchi,Thomas W. Kensler 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.3
Liver plays essential roles in the metabolismof many endogenous chemicals and exogenous toxicants. Mechanistic studies in liver have been at the forefront ofefforts to probe the roles of bioactivation and detoxicationof environmental toxins and toxicants in hepatotoxicity. Moreover, idiosyncratic hepatoxicity remains a key barrierin the clinical development of drugs. The now vast Nrf2 fieldemerged in part from biochemical and molecular studies onchemical inducers of hepatic detoxication enzymes and subsequentcharacterization of the modulation of drug/toxicantinduced hepatotoxicities in mice through disruption of eitherNrf2 or Keap1 genes. In general, loss of Nrf2 increases thesensitivity to such toxic chemicals, highlighting a centralrole of this transcription factor and its downstream targetgenes as a modifier to chemical stress. In this review, wesummarize the impact of Nrf2 on the toxicology of multiplehepatotoxicants, and discuss efforts to utilize the Nrf2response in predictive toxicology.
Cytoprotection Against Oxidative Damage by Nrf2-regulated Genes
Kwak, Mi-Kyoung,Kensler, Thomas W. Korean Society of ToxicologyKorea Environmental Mu 2007 Toxicological Research Vol.23 No.3
Chronic oxidative stress produced by exposure to environmental chemicals or pathophysiological states can lead animals to aging, carcinogenesis and degenerative diseases. Indirect antioxidative mechanisms, in which natural or synthetic agents are used to coordinately induce the expression of cellular antioxidant capacity, have been shown to protect cells and organisms from oxidative damages. Electrophile and free radical detoxifying enzymes, which were originally identified as the products of genes induced by cancer chemopreventive agents, are members of this protective system. The NFE2 family transcription factor Nrf2 was found to govern expression of these detoxifying enzymes, and screening for Nrf2-regulated genes has identified many gene categories involved in maintaining cellular redox potential and protection from oxidative damage as Nrf2 downstream genes. Further, studies using Nrf2-deficient mice revealed that these mutant mice showed more susceptible phenotypes towards exposure to environmental chemicals/carcinogens and in oxidative stress related disease models. With the finding that cancer chemopreventive efficacy of indirect antioxidants (enzyme inducers) is lost in the absence of Nrf2, a central role of Nrf2 in the antioxidative protective system has been firmly established. Promising results from cancer prevention clinical trials using enzyme inducers propose that pharmacological interventions that modulate Nrf2 can be an effective strategy to protect tissues from oxidative damage.
Cytoprotection Against Oxidative Damage by Nrf2-regulated Genes
Mi-Kyoung Kwak,Thomas W. Kensler 한국독성학회 2007 Toxicological Research Vol.23 No.3
Chronic oxidative stress produced by exposure to environmental chemicals or pathophysiological states can lead animals to aging, carcinogenesis and degenerative diseases. Indirect antioxidative mechanisms, in which natural or synthetic agents are used to coordinately induce the expression of cellular antioxidant capacity, have been shown to protect cells and organisms from oxidative damages. Electrophile and free radical detoxifying enzymes, which were originally identified as the products of genes induced by cancer chemopreventive agents, are members of this protective system. The NFE2 family transcription factor Nrf2 was found to govern expression of these detoxifying enzymes, and screening for Nrf2-regulated genes has identified many gene categories involved in maintaining cellular redox potential and protection from oxidative damage as Nrf2 downstream genes. Further, studies using nrf2-deficient mice revealed that these mutant mice showed more susceptible phenotypes towards exposure to environmental chemicals/carcinogens and in oxidative stress related disease models. With the finding that cancer chemopreventive efficacy of indirect antioxidants (enzyme inducers) is lost in the absence of Nrf2, a central role of Nrf2 in the antioxidative protective system has been firmly established. Promising results from cancer prevention clinical trials using enzyme inducers propose that pharmacological interventions that modulate Nrf2 can be an effective strategy to protect tissues from oxidative damage.
Lung Cancer in a Rural Area of China: Rapid Rise in Incidence and Poor Improvement in Survival
Yang, Juan,Zhu, Jian,Zhang, Yong-Hui,Chen, Yong-Sheng,Ding, Lu-Lu,Kensler, Thomas W,Chen, Jian-Guo Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.16
Background: Lung cancer has been a major health problem in developed countries for several decades, and has emerged recently as the leading cause of cancer death in many developing countries. The incidence of lung cancer appears to be increasing more rapidly in rural than in urban areas of China. This paper presents the trends of lung cancer incidence and survival derived from a 40-year population-based cancer monitoring program in a rural area, Qidong, China. Materials and Methods: The Qidong cancer registration data of 1972-2011 were used to calculate the crude rate, age-standardized rate by Chinese population (CASR) and by world population (WASR), birth cohort rates, and other descriptive features. Active and passive methods were used to construct the data set, with a deadline of the latest follow-up of April 30, 2012. Results: The total number of lung cancer cases was 15,340, accounting for 16.5% of all sites combined. The crude incidence rate, CASR and WASR of this cancer were 34.1, 15.7 and 25.4 per 100,000, respectively. Males had higher crude rates than females (49.7 vs 19.0). Rapidly increasing trends were found in annual percent change resulting in lung cancer being a number one cancer site after year 2010 in Qidong. Birth cohort analysis showed incidence rates have increased for all age groups over 24 years old. The 5 year observed survival rates were 3.55% in 1973-1977, 3.92 in 1983-1987, 3.69% in 1993-1997, and 6.32% in 2003-2007. Males experienced poorer survival than did females. Conclusions: Lung cancer has become a major cancer-related health problem in this rural area. The rapid increases in incidence likely result from an increased cigarette smoking rate and evolving environmental risk factors. Lung cancer survival, while showing some improvement in prognosis, still remains well below that observed in the developed areas of the world.