Human & Experimental Toxicology

Yang, Juan; Peng, Shuping; Zhang, Keqiang

doi: 10.1177/09603271221135064pmid: 36366750

Increasing studies indicate that cholesterol plays an important role in drug resistance. ARL4C is implicated in the export and import of cholesterol, therefore this study aimed to explore the effect of ARL4C on the resistance of ovarian cancer (OVC) to Carboplatin. This study collected OVC tissue samples from patients who are sensitive or resistant to carboplatin, and established Carboplatin-resistant OVC cell lines, OVCAR3(R) and SKOV3(R) using OVCAR3 and SKOV3. High throughput sequencing was conducted to find genes that regulated by ARL4C. Cholesterol esterification was performed to evaluate the transport of cholesterol from Lysosome (LY) to Endoplasmic reticulum (ER). The fluorescence of LC3-GFP-mRFP was used to evaluate the function of autophagy flux. As indicated by PCR, western blot and Immunohistochemistry, ARL4C was increased in the Carboplatin-resistant OVC tissues and cells. Knockdown of ARL4C attenuated the resistance of OVCAR3(R) and SKOV3(R) to Carboplatin. By suppressing Notch signal, ARL4C knockdown inhibited the transcriptional function of RBP-Jκ and RBP-Jκ-induced H3K4Me3, which collectively reduced OSBPL5 expression. OSBPL5 deficiency inhibited the transport of cholesterol from LYs to ER, which led to the accumulation of cholesterol in LYs and the dysfunction of autophagy. In summary, ARL4C knockdown attenuated the resistance of OVC to Carboplatin by disrupting cholesterol transport and autophagy. This study revealed a promising target to attenuate the resistance of OVC to Carboplatin and elucidated the potential mechanism.

Sadighara, P; Abedini, A; Zirak, M-R; Salehi, A; Darbandi Azar, S; Mirzaei, G; Vakili Saatloo, N

doi: 10.1177/09603271221133538pmid: 36321261

Styrene is widely used in industrial applications. Inhalation exposure occurs in the industry. Some studies indicated that serum prolactin concentrations increased after exposure to styrene, while other studies found no change. In this systematic review, the search was done with the keywords styrene and prolactin in the PubMed, Science Direct, Web of Science and Scopus databases, regardless of the publication period. 118 studies were obtained and only seven articles were finally selected according to exclusion and inclusion criteria. The effect of styrene on prolactin secretion was selected in both human and animal studies. The increased response was seen in inhalation exposures. Subcutaneous exposure has no significant effect on prolactin levels. The observed responses were both dose-dependent and gender-dependent. Changes in serum prolactin were more frequent in women compared to exposed men. Dopamine depletion was not observed in all studies, so more tests on laboratory animals are necessary to clarify the possible mechanism.

Refaie, Marwa M.M.; El-Hussieny, Maram; Abdel-Hakeem, Elshymaa A.; Fawzy, Michael A; Mahmoud Abd El Rahman, Eman Shaaban; Shehata, Sayed

doi: 10.1177/09603271221136209pmid: 36270296

Purpose: Doxorubicin (DOX) is a widely used chemotherapeutic agent complicated with cardiotoxic adverse effects. Up till now, there are no researches discussing the role of vinpocetine (VIN) in DOX cardiotoxicity. Thus, the aim of our work was to study this effect and explore the different involved mechanisms.Methods: 50 male Wistar albino rats were subjected to DOX toxicity via administration of single i.p. Dose (15 mg/kg) on the 4th day with or without co-administration of VIN (10, 20, 30 mg/kg/day) orally for 5 days. Results: Our data revealed that VIN succeeded in protecting the heart against DOX induced damage as manifested by significant decrease of cardiac enzymes, hypoxia inducible factor alpha (HIF-1α), vascular endothelial growth factor-A (VEGF-A), tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and caspase3 levels. Furthermore, VIN given group showed marked improvement of the histopathological changes of cardiac injury, total antioxidant capacity (TAC), elevation of reduced glutathione (GSH), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT-1). Conclusion: We concluded that VIN could ameliorate DOX induced cardiac damage and this effect may be attributed to modulation of HIF/VEGF signaling pathway, up-regulation of cGMP/cAMP/SIRT pathway, inhibition of phosphodiesterase enzyme, besides its anti-apoptotic, anti-inflammatory, and anti-oxidant properties.

Khan, A; Feulefack, J; Sergi, CM

doi: 10.1177/09603271221136211pmid: 36289056

BackgroundThere are hereditary types of nephroblastoma or Wilms’ tumor associated with exposure of the germ cells of either parent to harmful environmental factors. Some studies have examined the exposure of compounds used pesticides and herbicides as a risk factor for Wilms’ tumor.MethodsA systematic review and meta-analysis were carried out on case-control studies to establish the potential link between exposure to these organic molecules and Wilms’ tumor occurrence in children rigorously. We examined the monographs on some organo-phosphate insecticides and herbicides issued by the International Association for the Research on Cancer (IARC) under the auspices of the World Health Organization (WHO). PUBMED, SCOPUS, and Google Scholar studies (1960–2021) were identified and systematically reviewed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Subgroup analyses were conducted after stratification for occupational versus residential exposure and before birth (prenatal) vs. after birth (postnatal) exposure. In addition, we revised the monographs on chemical compounds issued recently by the IARC/WHO.ResultsOur findings seem to consolidate that parental pesticide exposure during the preconception or pregnancy period is correlated with an increased occurrence risk for Wilms’ tumor. We confirm the validity of the WHO essays on certain organophosphate herbicides and insecticides, which support these compounds, may be highly relevant in future cancer prevention policies.ConclusionParental exposure to pesticides, particularly in household settings, is poorly emphasized in our society. There is a strong association between these organophosphate compounds and pediatric cancer. Public health agencies may need to take stronger action than in the past.

Esmat, Marwa A; Osman, Ahmed; Hassan, Rasha E; Hagag, Sanaa A; El-maghraby, Tarek K

doi: 10.1177/09603271221136205pmid: 36270770

The therapeutic efficacy of cisplatin (CIS) is limited owing to its hepatotoxic side effects. The current study aimed to investigate the protective impact of ferulic acid (FA) and low-doses of γ-irradiation (LDR) against CIS-prompted hepatotoxicity in rats. Adult male Swiss albino rats were divided into eight groups: untreated group; FA, LDR, and CIS treated groups; and combinations of one or more of the above treatments. Post-treatment analyses included measuring redox markers like SOD and CAT activity, NO free radical content, and lipid peroxidation in liver tissue. Serum aminotransferase activities were also determined. Additionally, gene transcript levels of liver NF-ҡB-P65, caspase-1, COX-2, and IL-1β were quantified. Moreover, immunohistochemistry for caspase-3 and histopathological examinations were estimated in liver tissue. Our findings revealed increased levels of oxidative stress along with a significant reduction in anti-oxidative responses and a significant increase in serum aminotransferase activities in the CIS-intoxicated group. A similar increase was also observed in COX-2 and IL-1β transcript levels and caspase-3 enzyme activity, besides a decrease in transcript levels of NF-ҡB-p65 and caspase-1, indicating an overall inflammatory trend and an increase in the apoptotic shift. The co-administration of FA and/or treatment with LDR has ameliorated the hepatotoxic effect induced by CIS. The histopathological investigation of liver tissues confirmed this ameliorating action of these adjuvant therapies against CIS toxicity. In conclusion, it is plausible to suggest that the hepatoprotective effects of co-administration of FA and/or LDR against CIS-induced hepatotoxicity are attributed to the possession of anti-oxidative, anti-inflammatory, and anti-apoptotic capabilities.

Zhang, Di; Zheng, Jiaming; Qiu, Guobin; Niu, Tongjuan; Gong, Yuneng; Cui, Sheng

doi: 10.1177/09603271221135033pmid: 36310519

Carbon tetrachloride (CCl4) is a widely used hepatotoxin for the studies of liver fibrosis and cirrhosis, and taurine has function to abate liver fibrosis induced by CCl4. But the interacting mechanisms between taurine and CCl4 in liver are still largely unknown. These made us to hypothesize that CCl4 may induce liver fibrosis by affecting the expressions of taurine biosynthetic enzymes and taurine synthesis. We thus assayed the expressions of hepatic cysteine dioxygenase (CDO), cysteine sulfonate acid decarboxylase (CSAD) and taurine transporter (TauT) in the progression of mouse liver fibrosis induced by CCl4. The results demonstrated that CCl4 treatment markedly decreased hepatic CSAD, CDO expressions, and taurine levels in hepatic tissue, although TauT expression did not exhibit significant decline. It was contrasting that hepatic α-SMA, serum AST, ALT, ALP kept increasing, which were accompanied by the pathological characters of liver, whereas taurine supplement attenuated the progression of liver fibrosis induced by CCl4. These results demonstrate that CCl4 may induce liver fibrosis by inhibiting hepatic CSAD and CDO expressions and taurine synthesis, which are crucial for our understanding the mechanisms of liver fibrosis induced by CCl4, and also potential for establishing therapeutic strategies of liver fibrosis and related diseases.

Öztürk, Mehmet Evren; Yirün, Anıl; Erdemli-Köse, Selinay Başak; Balcı-Özyurt, Aylin; Çakır, Deniz Arca; Oral, Didem; Erkekoğlu, Pınar

doi: 10.1177/09603271221136206pmid: 36411272

In this study, we aimed to evaluate possible toxic effects of thimerosal, aluminum and combination of thimerosal and aluminum in SH-SY5Y cells. Inhibitory concentrations were determined by MTT assay; reactive oxygen species (ROS) were determined by a fluorometric kit and antioxidant/oxidant parameters were measured by spectrophotometric kits. Nuclear factor erythroid 2-associated factor 2 (Nrf2), norepinephrine (NE), dopamine transporter (DAT) and dopamine beta β-hydroxylase (DBH) levels were measured by sandwich ELISA kits while 8-hydroxy deoxyguanosine (8-OHdG) and dopamine levels were determined by competitive ELISA kits. Thimerosal (1.15 μM) and aluminum (362 μM) were applied to cells at inhibitory concentrations 20 (IC20s) for 24 h. ROS increased significantly in cells aluminum- and aluminum+thimerosal-treated cells. Glutathione levels decreased in aluminum group while total antioxidant capacity and protein oxidation levels increased significantly in aluminum and aluminum+thimerosal groups. Lipid peroxidation increased significantly in groups treated with aluminum and aluminum+thimerosal. Nrf2 levels and DNA damage were significantly higher in all groups while dopamine levels significantly increased in cells treated with thimerosal and aluminum+thimerosal, DAT levels were found to be higher in all experimental groups compared to the control. These findings showed that both thimerosal and aluminum can change oxidant/antioxidant status, cause DNA damage, alter dopamine and DAT levels. Changes seen in cells treated with combined exposure to aluminum and thimerosal are more pronounced. Special care should be taken while vaccinating sensitive populations and safer alternatives for aluminum and thimerosal should used.

Chu, Jing; Jiang, Yi; Zhou, Wenyu; Zhang, Jialei; Li, Hong; Yu, Yang; Yu, Yonghao

doi: 10.1177/09603271221133547pmid: 36214461

Sepsis-associated encephalopathy (SAE) is a cognitive impairment caused by sepsis, associated with increased morbidity and death. And acetaminophen (APAP) is a promising therapeutic medicine for SAE treatment. This research was designed to determine whether APAP alleviates SAE by attenuating ferroptosis and mediating the glutathione peroxidase (GPX4) pathway. The cecal ligation and puncture (CLP) approach was used to establish septic mouse models. The survival rates for 7 days were determined. The Morris water maze (MWM) was utilized to assess cognitive function. Hematoxylin and eosin (HE) staining identified histopathologic alterations in hippocampal tissue. Mitochondrial damage was discovered in hippocampal tissue using transmission electron microscopy (TEM). The reactive oxygen (ROS) levels in hippocampal tissue were measured using commercial assays. Septic cell models were produced using HT22 cells grown with 1 μg/ml lipopolysaccharide (LPS). ROS were quantified using immunofluorescence. Ferroptosis-related protein expression levels in hippocampal tissue and HT22 cells were measured using western blotting. To evaluate the iron content of hippocampal tissue and HT22 cells, commercial kits were employed. According to the findings, APAP improved survival rates, lowered hippocampal and mitochondrial damage, and improve cognitive impairment. In both animal and cell studies, APAP reduced iron content, ROS, glutamate antiporter (xCT), 4-hydroxy-2-nonenal (4-HNE) levels but increased GPX4 expression. However, RSL3, a GPX4 inhibitor that acts as a ferroptosis activator, decreased the protective properties of APAP in vitro. Our findings suggest that APAP reduces sepsis-induced cognitive impairment by reducing ferroptosis, which is mediated by the GPX4 signaling pathway.

Xie, Yi; Zhang, Jin; Zhang, Min; Jiang, Li

doi: 10.1177/09603271221136208pmid: 36289015

Angiotensin II (AngII) is involved in the pathogenesis of hypertensive artery remodeling by inducing a phenotypic switch in vascular smooth muscle cells [Gly14]-Humanin (HNG), a humanin analogue, exerts potent cytoprotective effects both in vitro and in vivo. This study aimed to investigate the effects of HNG on an AngII-induced phenotypic switch in VSMCs and the potential mechanisms underlying these effects. The roles of [Gly14]-Humanin in AngII-stimulated VSMCs proliferation and migration was detected by CCK-8 assay, Cell cycle analysis, wound healing assay, trsnswell assay and western blot. The mechanism by which [Gly14]-Humanin regulates VSMC phenotypic switch was determined by intracellular oxidative stress detection, transcriptomic analysis and qRT-PCR. The results showed that HNG inhibited AngII-induced VSMC proliferation and migration and maintained a stable VSMC contractile phenotype. In addition, HNG reduced the level of AngII-induced oxidative stress in vascular smooth muscle cells. This process could be accomplished by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity. In conclusion, the results suggested that HNG ameliorated intracellular oxidative stress by inhibiting NAD(P)H oxidase activity, thereby suppressing the AngII-induced VSMC phenotype switch. Thus, HNG is a potential drug to ameliorate artery remodeling in hypertension.