Human & experimental toxicology最新文献

{"title":"LncRNA-NEAT1 facilitates autophagy to boost pemetrexed resistance in lung adenocarcinoma via the mir-379-3p/HIF1A pathway.","authors":"Wei Hu, Wenjun Cao, Jiheng Liu","doi":"10.1177/09603271241292169","DOIUrl":"https://doi.org/10.1177/09603271241292169","url":null,"abstract":"<p><strong>Background: </strong>As a primary chemotherapeutic agent for lung adenocarcinoma (LUAD), pemetrexed (PEM) faces the challenge of resistance development in cancer cells due to its chronic use, which compromises its therapeutic benefits. LncRNA-NEAT1, implicated in the promotion of cancer, is a key player in LUAD. The objective of this study is to explore the contribution of lncRNA-NEAT1 to PEM resistance in LUAD and to dissect the molecular mechanisms involved.</p><p><strong>Method: </strong>The expression levels of lncRNA-NEAT1 in LUAD tissues and cells were deciphered using the TCGA database and qRT-PCR. To delve into the functional implications of lncRNA-NEAT1, we engineered plasmids to modulate its expression levels in PEM-resistant A549 cells. PEM resistance in the modified cells was then quantitatively assessed via a panel of assays including cell counting kit-8 (CCK-8), and colony formation, and flow cytometry. To predict the interaction sites between lncRNA-NEAT1 and miR-379-3p, along with the miR-379-3p and hypoxia-inducible factor (HIF1A), we referred to the StarBase and TargetScan databases. The interplay between these RNA molecules was further characterized by RNA immunoprecipitation (RIP) and dual-luciferase reporter assays, while the expression of autophagy-related proteins LC3I, LC3II, and Beclin1 was profiled using western blot (WB).</p><p><strong>Results: </strong>Abundant lncRNA-NEAT1 expression was observed in LUAD tissues and cell lines. Its depletion resulted in impeded growth of A549/PEM cells, enhanced apoptotic rates, and a lowered threshold for PEM to exert a half-maximal inhibitory effect. The interplay between lncRNA-NEAT1 and miR-379-3p, as evidenced by dual-luciferase reporter assays, RIP, and qRT-PCR, led to the upregulation of HIF1A. WB and CCK-8 outcomes illustrated that the autophagy and PEM resistance were compromised when HIF1A expression was curtailed by miR-379-3p mimics in A549/PEM cells. The restoration of these effects was observed upon lncRNA-NEAT1-mediated downregulation of miR-379-3p.</p><p><strong>Conclusion: </strong>Our study illuminates the role of lncRNA-NEAT1 in LUAD, where it mediates resistance to PEM through the activation of autophagy via the miR-379-3p/HIF1A axis. This work paves the way for new therapeutic strategies for managing PEM resistance in LUAD patients.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"43 ","pages":"9603271241292169"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of safety through mutagenicity and subchronic toxicity studies with black pepper extract preparation.","authors":"Lee Chae, Sungwon Lee, Swetha Mahadevan, Mark R Bauter, Colleen Wojenski, Kristin Robertson, Brian Premkumar, Brinda Mahadevan","doi":"10.1177/09603271241298531","DOIUrl":"https://doi.org/10.1177/09603271241298531","url":null,"abstract":"<p><strong>Introduction: </strong>Black pepper (<i>Piper nigrum</i>) is a rich source of natural and bioactive components such as N-trans-feruloyltyramine (NFT). In this paper, we discuss the results of the subchronic toxicity and mutagenicity studies conducted to understand the potential for adverse effects if any, of Black Pepper Extract Preparation (BPE).</p><p><strong>Methods: </strong>To evaluate mutagenicity, an Ames test was conducted with BPE in the presence and absence of S9 metabolic activation. Long-term safety was inferred through a 90-day subchronic toxicology study using adult rats. Dose levels were selected with expected human intake levels of NFT (120 mg/kg/day), with an acceptable safety factor, for preclinical safety and tolerability. Sprague Dawley rats were fed diets targeting dietary intakes (doses) of 0, 125, 350, or 700 mg/kg/day of BPE for 90 days, an NFT dose level equivalent to 68, 190, and 380 mg/kg/day.</p><p><strong>Results: </strong>In vitro Ames test up to 5000 µg/plate with and without S9 metabolic activation showed no BPE-related increases in revertant colony numbers and was non-mutagenic. There were no BPE-related changes in viability, clinical signs, body weight, food consumption, and organ weights. BPE dietary administration did not induce any treatment-related changes in hematology, clinical chemistry, other macroscopic or microscopic endpoints.</p><p><strong>Discussion and conclusion: </strong>The highest dose tested with BPE (700 mg/kg/day) was the no-observed-adverse-effect level (NOAEL) that revealed no adverse effects. Based on toxicological endpoints evaluated, this NOAEL for BPE corresponded to a human equivalent NFT dose level of 380 mg/kg/day, dependent upon a (∼50%) concentration of NFT in BPE.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"43 ","pages":"9603271241298531"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver and ovarian toxicities boosted by bisphenol and gamma radiation in female albino rats.","authors":"Asmaa A Hassan, Sherein S Abdelgayed, Somaya Z Mansour","doi":"10.1177/09603271231219264","DOIUrl":"10.1177/09603271231219264","url":null,"abstract":"<p><p>Bisphenol A (BPA), a carbon-based synthetic polymer compound, was newly classified as an environmental toxicant and an endocrine-disrupting chemical leading to abnormalities in cell proliferation, apoptosis, or migration that contributes to cancer development and progression. This study aims to evaluate the effect of the elevation of γ- radiation dose and BPA on the liver and ovaries of female rats. In this study, eighty female albino rats (130-150 g) were used in this work. Rats in this experiment received BPA in ethanol (50 mg/kg b. wt.) for 30 days, day after day, and in the irradiated groups, animals were administered BPA and then exposed to γ- radiation in doses (2, 4, and 6 Gy) one shot dose. Several members of the cytochrome family were examined. Exposure to γ-radiation and BPA showed an increase in cytochrome P450 and b5 fold change. Further, BPA and γ-radiation activate α and β estrogen receptors and also downregulate aromatase (CYT19) fold change. The current results also revealed that BPA and/or γ-radiation regulate the protein expression of the PI3K/Akt signaling pathway. The steroidogenic acute regulatory protein (StAR) appeared to be targeted by BPA and γ-radiation and its relative expression was elevated significantly by raising the γ-radiation dose. In conclusion, exposure to BPA, an endocrine-disrupting chemical, leads to marked toxicity. Additionally, toxicity is heightened by increasing the γ-radiation dose, either alone or in combination with BPA.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"43 ","pages":"9603271231219264"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rg5 induces NSCLC cell apoptosis and autophagy through PI3K/Akt/mTOR signaling pathway.","authors":"Caidie Zhang, Yan Jin","doi":"10.1177/09603271241229140","DOIUrl":"10.1177/09603271241229140","url":null,"abstract":"<p><strong>Objective: </strong>Ginsenoside Rg5 (Rg5) is a minor ginsenoside of ginseng and has a strong anti-tumor potential. This study focused on deciphering the function of Rg5 in non-small cell lung cancer (NSCLC) and investigating its related mechanism.</p><p><strong>Methods: </strong>After treating human NSCLC cell lines (H1650 and A549) and bronchial epithelial cells (BEAS-2B) with increasing concentration of Rg5, cell viability was examined using methyl thiazolyl tetrazolium (MTT) assay. NSCLC cell proliferation and apoptosis were evaluated by colony formation assay and flow cytometry, respectively. The levels of proteins associated with cell cycle progression, cell apoptosis, and autophagy as well as the key markers in the PI3K/Akt/mTOR pathway were measured using western blot. A xenograft nude mouse model was established to explore the function of Rg5 <i>in vivo</i>.</p><p><strong>Results: </strong>NSCLC cell viability was dose- and time-dependently suppressed after Rg5 treatment. Rg5 restrained NSCLC cell proliferation by inducing G2/M phase arrest via regulation of cell cycle-related genes including p21, cyclin B1, and Cdc2. Additionally, Rg5 promoted caspase-dependent apoptosis in NSCLC cells by regulating the intrinsic mitochondrial signaling pathway. Rg5 induced autophagy via the regulation of autophagy-related proteins. The <i>in vivo</i> experiments revealed the inhibitory impact of Rg5 on xenograft growth. Rg5 also inactivated the PI3K/Akt/mTOR signaling pathway in NSCLC cells and mouse tumors.</p><p><strong>Conclusion: </strong>Rg5 induced autophagy and caspase-dependent apoptosis in NSCLC cells by inhibiting the PI3K/Akt/mTOR signaling pathway, suggesting that Rg5 might become a promising and novel anti-tumor agent for the clinical treatment of NSCLC patients.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"43 ","pages":"9603271241229140"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subchronic oral toxicity assessment of <i>Bacillus velezensis</i> strain BV379 in sprague-dawley rats.","authors":"Mark R Bauter, Laura M Brutscher, Laurie C Dolan, Jessica L Spears","doi":"10.1177/09603271241278977","DOIUrl":"https://doi.org/10.1177/09603271241278977","url":null,"abstract":"<p><strong>Introduction: </strong>The spore-forming bacterial species <i>Bacillus velezensis</i> is commonly utilized in feed for livestock and aquaculture. In recent years, there has been increased interest in introducing <i>B</i>. <i>velezensis</i> into human supplements and food. Before it can be safely administered in humans, the safety of each <i>B</i>. <i>velezensis</i> strain needs to be established. The objective of this study was to evaluate the in vivo safety of <i>Bacillus velezensis</i> strain BV379 by high-dose oral administration to rats in a 28-day subchronic toxicity study.</p><p><strong>Methods: </strong>In this study, 80 animals were assigned to four groups: vehicle control, 1 × 10¹⁰, 4 × 10¹⁰, or 10 × 10¹⁰ CFU/kg bw/day by gavage. The following toxicological assessments were performed: ophthalmological examinations; observations for viability, signs of gross toxicity, and behavioral changes; in-life parameters, including body weight and food consumption; urinalysis, hematology, clinical chemistry, and coagulation assessments; macroscopic and microscopic tissue assessments; and bacterial enumeration in selected tissues.</p><p><strong>Results: </strong>Under the conditions of this study, no adverse clinical endpoints were attributed to the administration of <i>Bacillus velezensis</i> strain BV379, which was well-tolerated up to the highest dose of 10 × 10¹⁰ CFU/kg bw/day.</p><p><strong>Conclusion: </strong>These results support the in vivo pre-clinical safety of <i>Bacillus velezensis</i> strain BV379 for use in food and supplements.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"43 ","pages":"9603271241278977"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MG132 inhibits proliferation and induces apoptosis of acute lymphoblastic leukemia via Akt/FOXO3a/Bim pathway.","authors":"Zhong Fan, Wen-Hao Lin, Cong Liang, Yu Li, Chun-Jin Peng, Jie-Si Luo, Wen-Yan Tang, Li-Min Zheng, Dan-Ping Huang, Zhi-Yong Ke, Li-Na Wang, Xiao-Li Zhang, Li-Bin Huang","doi":"10.1177/09603271241303030","DOIUrl":"https://doi.org/10.1177/09603271241303030","url":null,"abstract":"<p><strong>Background: </strong>Acute lymphoblastic leukemia (ALL) is one of the most common pediatric cancers, characterized by the malignant proliferation of leukemic cells. Despite advancements in treatment, the prognosis for refractory and relapsed ALL remains poor, underscoring the need for novel therapeutic targets and approaches.</p><p><strong>Methods: </strong>To investigate the anti-leukemic properties of MG132, MTS assays were employed to assess cell viability, and flow cytometry was used to evaluate apoptosis. Mechanistic studies, including qRT-PCR, Western blotting, and lentivirus-mediated FOXO3a knockdown, were conducted to explore MG132's effects on the Akt/FOXO3a/Bim signaling pathway. A xenograft mouse model was utilized to validate the in vivo efficacy of MG132 in suppressing tumor growth.</p><p><strong>Results: </strong>MG132 inhibited cell proliferation and induced apoptosis in both ALL cell lines and primary cells in a concentration-dependent manner. Mechanistic studies revealed that MG132 promoted FOXO3a nuclear localization by suppressing Akt phosphorylation and preventing FOXO3a degradation, leading to increased Bim expression. Furthermore, FOXO3a knockdown significantly reduced MG132's anti-proliferative effects. In vivo, MG132 markedly inhibited tumor growth in the xenograft model.</p><p><strong>Conclusion: </strong>These findings suggest that MG132 exerts potent anti-leukemic effects through modulation of the Akt/FOXO3a/Bim axis, offering a promising therapeutic avenue for treating ALL.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"43 ","pages":"9603271241303030"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Problems with the effectiveness of L-carnitine and paraffin oil in acute aluminum phosphide poisoning.","authors":"Maryam Zaare Nahandi,&nbsp;Ali Banagozar Mohammadi","doi":"10.1177/09603271231210974","DOIUrl":"10.1177/09603271231210974","url":null,"abstract":"","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"42 ","pages":"9603271231210974"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50164248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ozone in the adjunct medical treatment. The round personality of a molecule with hormetic properties.","authors":"Salvatore Chirumbolo, Umberto Tirelli, Marianno Franzini, Sergio Pandolfi, Giovanni Ricevuti, Francesco Vaiano, Luigi Valdenassi","doi":"10.1177/09603271231218926","DOIUrl":"https://doi.org/10.1177/09603271231218926","url":null,"abstract":"<p><p>Ozone, an allotrope of oxygen, is enjoying an increasing interest in the setting and management of the medical adjunct treatment, which is called, maybe too simplistically, \"ozone therapy\". Ozone is not a medicine, so the word therapy does not properly fit this gaseous molecule. Like many natural compounds, for example plant flavonoids, even ozone interacts with aryl hydrocarbon receptors (AhRs) and, at low doses, it works according to the paradoxical mechanism of hormesis, involving mitochondria (mitohormesis). Ozone, in the hormetic range, exerts cell protective functions via the Nrf2-mediated activation of the anti-oxidant system, then leading to anti-inflammatory effects, also via the triggering of low doses of 4-HNE. Moreover, its interaction with plasma and lipids forms reactive oxygen species (ROS) and lipoperoxides (LPOs), generally called ozonides, which are enabled to rule the major molecular actions of ozone in the cell. Ozone behaves as a bioregulator, by activating a wide population of reactive intermediates, which usually target mitochondria and their turnover/biogenesis, often leading to a pleiotropic spectrum of actions and behaving as a tuner of the fundamental mechanisms of survival in the cell. In this sense, ozone can be considered a novelty in the medical sciences and in the clinical approach to pharmacology and medical therapy, due to its ability to target complex regulatory systems and not simple receptors.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"42 ","pages":"9603271231218926"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138814278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice: \"Long noncoding RNA SNHG14 regulates ox-LDL-induced atherosclerosis cell proliferation and apoptosis by targeting miR-186-5p/WIPF2 axis\".","authors":"","doi":"10.1177/09603271231215964","DOIUrl":"https://doi.org/10.1177/09603271231215964","url":null,"abstract":"","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"42 ","pages":"9603271231215964"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138814393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue.","authors":"Xiaocheng Liu, Guojuan Li, Jing Zhong, Ouyan Rang, Guifang Ou, Xinru Qin, Yonghong Tang, Mu Wang","doi":"10.1177/09603271231217992","DOIUrl":"10.1177/09603271231217992","url":null,"abstract":"<p><p><b>Background</b>: Adipose tissue is a dynamic endocrine organ that plays a key role in regulating metabolic homeostasis. Previous studies confirmed that bisphenol A (BPA) or fructose can interfere with the function of adipose tissue. Nonetheless, knowledge on how exposure to BPA and fructose impacts energy metabolism in adipose tissue remains limited.<b>Purpose</b>: To determine impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue.<b>Method</b>: 57 energy metabolic intermediates in adipose tissue and 7 adipocytokines in serum from Sprague Dawley rats were examined after combined exposure to two levels of BPA (lower dose: 0.25, and higher dose: 25 μg/kg every other day) and 5% fructose for 6 months.<b>Results</b>: combined exposure to lower-dose BPA and fructose significantly increased omentin-1, pyruvic acid, adenosine triphosphate (ATP), adenosine monophosphate (AMP), inosine monophosphate (IMP), inosine, and l-lactate; however, these parameters were not significantly affected by higher-dose BPA combined with fructose. Interestingly, the level of succinate (an intermediate of the citric acid cycle) increased dose-dependently in adipose tissue, and the level of apelin 13 (a versatile adipocytokine) decreased dose-dependently in serum after combined exposure to BPA and fructose. Phosphoenolpyruvic acid, phenyl-lactate, and ornithine were significantly correlated with asprosin, omentin-1, apelin, apelin 13, and adiponectin, while l-tyrosine was significantly correlated with irisin and a-FABP under combined exposure to BPA and fructose.<b>Conclusions</b>: these findings indicated that lower-dose BPA combined with fructose could amplify the impact on glycolysis, energy storage, and purine nucleotide biosynthesis in adipose tissue, and adipocytokines, such as omentin-1 and apelin 13, may be related to metabolic interference induced by BPA and fructose exposure.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":"42 ","pages":"9603271231217992"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138292640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}