Toxicological Research最新文献

{"title":"Integrated transcriptomic analysis of liver and kidney after 28 days of thioacetamide treatment in rats.","authors":"Hyoung-Yun Han, Se-Myo Park, Je-Won Ko, Jung-Hwa Oh, Sang Kyum Kim, Tae-Won Kim","doi":"10.1007/s43188-022-00156-y","DOIUrl":"10.1007/s43188-022-00156-y","url":null,"abstract":"<p><p>Thioacetamide (TAA) was developed as a pesticide; however, it was soon found to cause hepatic and renal toxicity. To evaluate target organ interactions during hepatotoxicity, we compared gene expression profiles in the liver and kidney after TAA treatment. Sprague-Dawley rats were treated daily with oral TAA and then sacrificed, and their tissues were evaluated for acute toxicity (30 and 100 mg/kg bw/day), 7-day (15 and 50 mg/kg bw/day), and 4-week repeated-dose toxicity (10 and 30 mg/kg). After the 4-week repeated toxicity study, total RNA was extracted from the liver and kidneys, and microarray analysis was performed. Differentially expressed genes were selected based on fold change and significance, and gene functions were analyzed using ingenuity pathway analysis. Microarray analysis showed that significantly regulated genes were involved in liver hyperplasia, renal tubule injury, and kidney failure in the TAA-treated group. Commonly regulated genes in the liver or kidney were associated with xenobiotic metabolism, lipid metabolism, and oxidative stress. We revealed changes in the molecular pathways of the target organs in response to TAA and provided information on candidate genes that can indicate TAA-induced toxicity. These results may help elucidate the underlying mechanisms of target organ interactions during TAA-induced hepatotoxicity.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-022-00156-y.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10050285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9242848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of 4-week inhalation exposure to titanium nitride on lungs of Sprague-Dawley rats.","authors":"Yong-Soon Kim, Eun-Sang Cho, Chan-Hyuck Park, Hyo-Geun Cha","doi":"10.1007/s43188-022-00162-0","DOIUrl":"10.1007/s43188-022-00162-0","url":null,"abstract":"<p><p>Titanium nitride (TiN) is a ceramic material with physical properties such as extreme hardness, high decomposition temperature, defect structure, and gold-yellow color. TiN is generally considered non-toxic and safe; however, hazards have not been identified, especially in workers after inhalation exposure. Here, we conducted a four-week inhalation toxicity study of TiN using a nose-only inhalation exposure system in Sprague-Dawley rats. Rats were exposed to TiN for 4 weeks (6 h a day, 5 days per week) at target concentrations of 45, 90, and 180 mg/m³. Clinical signs, mean body weight changes, hematology, blood biochemistry, necropsy, organ weight, bronchoalveolar lavage fluid analysis, and histopathological findings were observed. Analytical concentrations of the low, middle, and high-concentration groups were 45.55 ± 3.18 mg/m³, 90.69 ± 7.30 mg/m³, and 183.87 ± 15.21 mg/m³, respectively. The mass median aerodynamic diameter (MMAD) for the low, middle, and high-concentration groups were 1.44 ± 0.07 μm, 1.47 ± 0.18 μm, and 1.68 ± 0.16 μm, and the geometric standard deviation (GSD) was 2.24 ± 0.03, 2.31 ± 0.16, and 2.43 ± 0.11, respectively. No systemic adverse effects were observed after inhalation exposure to TiN; however, histopathological findings (increased phagocytic macrophages and alveolar/bronchiolar epithelial hyperplasia) and Bronchoalveolar Lavage Fluid (BALF) analysis (elevated lactate dehydrogenase and gamma-glutamyltransferase values) showed adverse effects on the lungs in the middle and high-concentration groups. Based on these results, the no observed adverse effect concentration (NOAEC) is suggested to be 45 mg/m³.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9194684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF4-activated parkin induction contributes to deferasirox-mediated cytoprotection in Parkinson's disease.","authors":"Sangwoo Ham, Ji Hun Kim, Heejeong Kim, Jeong-Yong Shin, Yunjong Lee","doi":"10.1007/s43188-022-00157-x","DOIUrl":"10.1007/s43188-022-00157-x","url":null,"abstract":"<p><p>The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD. Although repression of iron accumulation and oxidative stress in brains has been implicated in their marked neuroprotective potential, molecular mechanisms of iron chelator's neuroprotective function are largely unexplored. Here, we show that the iron chelator deferasirox provides cytoprotection against oxidative stress through enhancing parkin expression under basal conditions. Parkin expression is required for cytoprotection against oxidative stress in SH-SY5Y cells with deferasirox treatment as confirmed by abolished deferasirox's cytoprotective effect after parkin knockdown by shRNA. Similar to the previously reported parkin inducing compound diaminodiphenyl sulfone, deferasirox-mediated parkin expression was induced by activation of the PERK-ATF4 pathway, which is associated with and stimulated by mild endoplasmic reticulum stress. The translational potential of deferasirox for PD treatment was further evaluated in cultured mouse dopaminergic neurons. There was a robust ATF4 activation and parkin expression in response to deferasirox treatment in dopaminergic neurons under basal conditions. Consequently, the enhanced parkin expression by deferasirox provided substantial neuroprotection against 6-hydroxydopamine-induced oxidative stress. Taken together, our study results revealed a novel mechanism through which an iron chelator, deferasirox induces neuroprotection. Since parkin function in the brain is compromised in PD and during aging, maintenance of parkin expression through the iron chelator treatment could be beneficial by increasing dopaminergic neuronal survival.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10050497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9247913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Saline extract of <i>Portulaca elatior</i> leaves with photoprotective and antioxidant activities does not show acute oral and dermal toxicity in mice.","authors":"Suéllen Pedrosa da Silva, Clarice Barbosa Lucena da Costa, Anderson Felipe Soares de Freitas, José Dayvid Ferreira da Silva, Wêndeo Kennedy Costa, Wênio Sandoval Filho Lima da Silva, Janaina Carla Barbosa Machado, Sandra Maria Souza da Silva, Magda Rhayanny Assunção Ferreira, Luiz Alberto Lira Soares, Jacinto da Costa Silva Neto, Márcia Vanusa da Silva, Alisson Macário de Oliveira, Patrícia Maria Guedes Paiva, Thiago Henrique Napoleão","doi":"10.1007/s43188-022-00160-2","DOIUrl":"10.1007/s43188-022-00160-2","url":null,"abstract":"<p><p>The present study aimed to evaluate saline extracts from the leaves (LE) and stem (SE) of <i>Portulaca elatior</i> in relation to their phytochemical composition and photoprotective and antioxidant effects, as well as to evaluate the toxicity of the leaf extract. The extracts were characterized for protein concentration and phenol and flavonoid contents, as well as for thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) profiles. Total antioxidant capacity and DPPH and ABTS⁺ scavenging activities were determined. In the photoprotective activity assay, the sun protection factor (SPF) was calculated. The toxicity evaluation of LE included in vitro hemolytic assay and in vivo oral and dermal acute toxicity assays in Swiss mice. LE showed the highest protein, phenol, and flavonoid (8.79 mg/mL, 323.46 mg GAE/g, and 101.96 QE/g, respectively). TLC revealed the presence of flavonoids, reducing sugars, terpenes, and steroids in both extracts. In HPLC profiles, LE contained flavonoids, while SE contained flavonoids and ellagic tannins. The antioxidant activity assays showed the lowest IC₅₀ values ​(34.15-413.3 µg/mL) for LE, which presented relevant SPF (> 6) at 50 and 100 µg/mL. LE demonstrated low hemolytic capacity, and no signs of intoxication were observed in mice treated orally or topically at 1000 mg/kg. However, at 2000 mg/kg, an increase in the mean corpuscular volume of erythrocytes and a reduction in lymphocytes were observed; animals treated topically with 2000 mg/kg displayed scratching behavior during the first hour of observation and showed edema and erythema that regressed after six days. In conclusion, LE did not present acute oral or dermal toxicity in Swiss mice at a dose of 1000 mg/kg and showed slight toxicity in animals treated with 2000 mg/kg.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-022-00160-2.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10050472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9242849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid hydroperoxide-derived insulin resistance and its inhibition by pyridoxamine in skeletal muscle cells.","authors":"Seon Hwa Lee, Mizuki Tsutsui, Atsushi Matsunaga, Tomoyuki Oe","doi":"10.1007/s43188-022-00155-z","DOIUrl":"10.1007/s43188-022-00155-z","url":null,"abstract":"<p><p>Oxidative stress is strongly associated with the onset and/or progression of diabetes. Under conditions of oxidative stress, lipid hydroperoxides are decomposed to reactive aldehydes that have been reported to induce insulin resistance by modifying proteins involved in insulin signaling. Pyridoxamine (PM) can inhibit the formation of advanced glycation/lipoxidation end products by scavenging reactive carbonyl species. Thus, PM has emerged as a promising drug candidate for various chronic conditions, including diabetic complications. In this study, L6 skeletal muscle cells were treated with 4-oxo-2(<i>E</i>)-nonenal (ONE), one of the most abundant and reactive lipid-derived aldehydes. Cellular insulin resistance was assessed by measuring insulin-stimulated glucose uptake using 2-deoxyglucose. ONE induced a time- and dose-dependent decrease in glucose uptake. Liquid chromatography/electrospray ionization-mass spectrometry analysis of the reaction between ONE and insulin receptor substrate 1 (IRS1) lysate identified multiple modifications that could disturb the interaction between IRS1 and activated IR, leading to insulin resistance. Pretreatment of the cells with PM restored the ONE-induced decrease in glucose uptake. Concomitantly, the formation of PM-ONE adducts in cell culture medium was increased in a PM-dose dependent manner. PM can therefore prevent lipid hydroperoxide-derived insulin resistance by quenching ONE.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-022-00155-z.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10696111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory effects of <i>Athyrium yokoscense</i> extract via inhibition of the Erk1/2 and NF-κB pathways in bisphenol A-stimulated A549 cells.","authors":"Jung-Kyu Lee, Won Seok Choi, Jin Yong Song, Oh Seong Kwon, Yeon Jin Lee, Jong Seok Lee, Sarah Lee, Se Rin Choi, Choong Hwan Lee, Ji-Yun Lee","doi":"10.1007/s43188-022-00154-0","DOIUrl":"10.1007/s43188-022-00154-0","url":null,"abstract":"<p><p>Bisphenol A is an environmental endocrine disruptor that has similar functions to estrogen in humans. However, few studies have investigated pulmonary inflammation induced by BPA, and the effect of <i>Athyrium yokoscense</i> extract on this inflammatory response is unknown. In this study, we investigated this effect in A549 human alveolar epithelial cells. BPA at concentrations higher than 100 µM were cytotoxic to A549 cells at 24 and 48 h after treatment; however, AYE (100 µg/mL) had a protective effect against BPA-induced cytotoxicity. AYE also inhibited the generation of intracellular reactive oxygen species, expressions of cyclooxygenase-2 and extracellular signal-regulated kinase1/2 proteins, activities of phospholipase A₂, COX-2, nuclear factor kappa-light-chain-enhancer of activated B cells, and proinflammatory mediators including prostaglandin E₂, tumor necrosis factor-α, and interleukin-6 induced by BPA in A549 cells. This study demonstrated that BPA, which induces chronic lung disease, causes oxidative stress and inflammatory response in lung epithelial cell line, and found that AYE reduces BPA-induced oxidative stress and inflammatory response by down-regulating the Erk1/2 and NF-κB pathways.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9194686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Explanation of difenoconazole removal by chitosan with Langmuir adsorption isotherm and kinetic modeling.","authors":"Şükran Altun, Ali Eslem Kadak, Aygül Küçükgülmez, Osman Gülnaz, Mehmet Çelik","doi":"10.1007/s43188-022-00152-2","DOIUrl":"10.1007/s43188-022-00152-2","url":null,"abstract":"<p><p>In this study, the adsorption of toxic difenoconazole pesticide was investigated by using chitosan. In the first phase of the study, chitosan was extracted from deep-water pink shrimp (<i>Parapenaeus longirostris</i>) shells, by deacetylation of the chitin, which is separated and disposed of after meat extraction in processing facilities in Turkey. The deacetylation degree, molecular weight, viscosity, moisture, and crude-ash values of the extracted chitosan were determined. Chitosan, having a high deacetylation degree (90.21%), was used as the adsorbent. In the second phase of the study, the effects of pH, temperature, and pesticide concentration on the adsorption were investigated. The optimum pH level for pesticide adsorption was determined as 5. It was observed that the adsorption increases as the temperature increases. A rapid increase was observed within the first 5 min of the 60-minute adsorption process in difenoconazole concentrations of 5, 15, and 25 µg/L, and after 10 min, the adsorption rate was stable. The Langmuir isotherm parameters regarding the adsorption were determined as aL = 0.635, kL = 15.10, and the Q_max value was calculated as 23.77 mg/g. In the evaluation of overall study results, it was determined that the chitosan biopolymer is a suitable adsorbent for difenoconazole pesticide adsorption.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10696109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to China dust exacerbates testicular toxicity induced by cyclophosphamide in mice.","authors":"Woong-Il Kim, Je-Oh Lim, So-Won Pak, Se-Jin Lee, In-Sik Shin, Changjong Moon, Jeong-Doo Heo, Jong-Choon Kim","doi":"10.1007/s43188-022-00149-x","DOIUrl":"10.1007/s43188-022-00149-x","url":null,"abstract":"<p><p>This study investigated the potential effects of China dust (CD) exposure on cyclophosphamide (CP)-induced testicular toxicity in mice, focusing on spermatogenesis and oxidative damage. CP treatment reduced testicular and epididymal weight and sperm motility and enhanced sperm abnormality. Histopathological examination presented various morphological alterations in the testis, including increased exfoliation of spermatogenic cells, degeneration of early spermatogenic cells, vacuolation of Sertoli cells, a decreased number of spermatogonia/spermatocytes/spermatids, along with a high number of apoptotic cells. In addition, the testis exhibited reduced glutathione (GSH) levels and glutathione reductase (GR) activity and enhanced malondialdehyde (MDA) concentration. Meanwhile, CD exposure exacerbated testicular histopathological alterations induced by CP. CD exposure also aggravated oxidative damage by increasing the lipid peroxidative product MDA and decreasing GSH levels and antioxidant enzyme activities in the testis. These results suggest that CD exposure exacerbates CP-induced testicular toxicity in mice, which might be attributed to the induction of lipid peroxidation and reduced antioxidant activity.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10696108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of maternal cigarette smoke exposure on the progression of nonalcoholic steatohepatitis in offspring mice.","authors":"Daram Yang, Jong Won Kim, Hyuneui Jeong, Min Seok Kim, Chae Woong Lim, Kyuhong Lee, Bumseok Kim","doi":"10.1007/s43188-022-00153-1","DOIUrl":"10.1007/s43188-022-00153-1","url":null,"abstract":"<p><p>Cigarette smoke (CS) is a dominant carcinogenic agent in a variety of human cancers. CS exposure during pregnancy can adversely affect the fetus. Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of a metabolic disorder, and ranges from simple steatosis to cirrhosis leading to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a more severe phase of NAFLD. Recently, there is increasing apprehension about the CS-related chronic liver diseases. Therefore, we examined whether maternal CS exposure could affect the pathogenesis of NASH in offspring. Mainstream CS (MSCS) was exposed to pregnant C57BL/6 mice via nose-only inhalation for 2 h/day, 5 days/week for 2 weeks from day 6 to 17 of gestation at 0, 300, or 600 μg/L. Three-week-old male offspring mice were fed methionine and choline-supplemented (MCS) diet or methionine and choline-deficient including high-fat (MCDHF) diet for 6 weeks to induce NASH. Maternal MSCS exposure increased the severity of NASH by increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic total cholesterol (TC) and triglyceride (TG) levels, pro-inflammation, fibrosis, and steatosis in offspring mice. Especially, maternal MSCS exposure significantly downregulated the phosphorylation of AMP-activated protein kinase (AMPK) in MCDHF diet-fed offspring mice. Subsequently, the protein levels of sterol regulatory element-binding protein (SREBP)-1c and stearoyl-CoA desaturase-1 (SCD1) were upregulated by maternal MSCS exposure. In conclusion, maternal MSCS exposure exacerbates the progression of NASH by modulating lipogenesis on offspring mice.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-022-00153-1.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9194687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of synergistic apoptosis by tetramethoxystilbene and nutlin-3a in human cervical cancer cells.","authors":"Hong-Gyu An,&nbsp;Sangyun Shin,&nbsp;Boyoung Lee,&nbsp;Yeonju Kwon,&nbsp;Tae-Uk Kwon,&nbsp;Yeo-Jung Kwon,&nbsp;Young-Jin Chun","doi":"10.1007/s43188-022-00150-4","DOIUrl":"10.1007/s43188-022-00150-4","url":null,"abstract":"<p><p>2,4,3',5'-Tetramethoxystilbene (TMS) is a selective inhibitor of cytochrome P450 1B1 to block the conversion from estradiol to 4-OH-estradiol. Several studies suggested that TMS may act as a potent anti-cancer agent for hormone-related cancer including cervical cancer. Nutlin-3a is a cis-imidazoline analog that interferes with the interaction between mouse double minute 2 homolog (MDM2) and the tumor suppressor p53. The purpose of the study was to compare the cytotoxic effect of TMS and nutlin-3a treatment individually and in combination in HeLa cells. To assess the potential synergistic effects between TMS and nutlin-3a, low concentrations of TMS and nutlin-3a were simultaneously treated in HeLa cells. Based on cell viability, apoptosis assays, and the increase in cleaved caspase-3 and poly (ADP-ribose) polymerase cleavage, it was demonstrated that the combination with TMS and nutlin-3a exerts a synergistic effect on cancer cell death. Isobologram analysis of HeLa cells noted synergism between TMS and nutlin-3a. The combined treatment increased the expression of mitochondrial pro-apoptotic factors such as Bax and Bak, and decreased the expression of the XIAP. In addition, combination treatment significantly enhanced the translocation of AIF to the nucleus in HeLa cells. In conclusion, the results demonstrate that the combination of TMS and nutlin-3a induces synergistic apoptosis in HeLa cells, suggesting the possibility that this combination can be applied as a novel therapeutic strategy for cervical cancer.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9532473/pdf/43188_2022_Article_150.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40677049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}