Toxicology Research最新文献

[This corrects the article DOI: 10.1093/toxres/tfae138.].

Nitrogen mustard (NM) belongs to vesicant agents. Blisters are one of the important characteristics of NM skin damage. It is urgent to further elucidate the mechanism and develop effective countermeasures for the skin damage induced by NM. The endoplasmic reticulum (ER) is an important intracellular organelle, playing an important role in maintaining cellular homeostasis. In this study, we explored the role of endoplasmic reticulum stress (ERS) and the protective effect of asiatic acid (AA) in the HaCaT cells induced by NM. It was found that the key regulatory proteins of ERS, such as glucose regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol requiring enzyme 1 (IRE1), Phospho-IRE1 (pIRE1), and TNF receptor associated factor 2 (TRAF2) were increased respectively in HaCaT cells exposed to NM compared with those of the control group, showing an increasing trend with the increase of NM exposure concentration and exposure time. Additionally, the protein expression of Caspase-3 and the Cleaved-Caspase-3 was also increased by NM in HaCaT cells, resulting in the apoptosis of HaCaT cells. Meanwhile, the content of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was also increased in HaCaT cells exposed to NM. Further study showed that AA pretreatment could decrease the protein expression of GRP78, XBP1 and IRE1, pIRE1, TRAF2, Caspase-3, and Cleaved-Caspase-3. And moreover, AA also could reduce the content of TNF-α and IL-6. Overall, the present study showed that AA played an important protective effect in HaCaT cells exposed to NM through the inhibition of the ERS-induced apoptosis and inflammatory response.

In this study, we aimed to investigate the effects of chronic benzene exposure on the self-renewal capacity of C57BL/6 bone marrow HSPCs. Twenty-four male C57BL/6 mice were randomly divided into two groups: the control group and the benzene-exposed group. Mice in the benzene-exposed group inhaled 1,000 mg/m³ (308 ppm; conversion factor: 20 °C, 101 kPa, 1 ppm = 3.25 mg/m³) benzene for 32 weeks and the control group mice inhaled clean air. The peripheral blood hematological alterations were monitored every two weeks. Competitive bone marrow transplantation was performed to assess the self-renewal capacity of bone marrow HSPCs and the donor cell chimerism was quantified through flow cytometry. By the fourth week of benzene exposure, significant reductions in leukocytes, erythrocytes, and hemoglobin levels (P < 0.05) were observed, suggesting the development of benzene poisoning in mice. In the B6.SJL recipient mice, the chimerism ratio of bone marrow cells from C57BL/6 donors exposed to benzene for 20 weeks significantly decreased after transplantation (16 weeks post-transplant: 52.58% ± 17.38% in controls vs. 3.89% ± 1.96% in the benzene group, P < 0.05). Furthermore, the chimerism ratio in recipients of 32-week benzene-exposed donors approached zero by week 84 post-transplant, suggesting a loss of self-renewal capacity in bone marrow HSPCs due to benzene exposure. The study concludes that bone marrow suppression and the diminished self-renewal ability of C57BL/6 bone marrow HSPCs may lead to bone marrow failure in mice, contributing to the potential occurrence of MDS.

Neurodegenerative diseases (NDs), including Alzheimer's and Parkinson's, are marked by progressive neuronal loss, driven largely by oxidative stress and apoptosis. Developing neuroprotective strategies to counteract these processes is critical for managing such disorders. This study explores the neuroprotective effects of pimecrolimus, a calcineurin inhibitor, in mitigating hydrogen peroxide (H₂O₂)-induced cytotoxicity in neuron-like differentiated SH-SY5Y (d-SH-SY5Y) cells. The investigation focuses on apoptosis modulation, cell viability, and molecular docking interactions with apoptotic proteins. SH-SY5Y cells were differentiated with retinoic acid and treated with H₂O₂ (250 μM) alone or in combination with pimecrolimus (0.01, 0.1, and 1 μM) for 24 h. Cell viability was assessed using lactate dehydrogenase (LDH) assays. Additionally, malondialdehyde (MDA) levels were measured to assess oxidative stress in SH-SY5Y cells following the treatment conditions. Molecular docking analyses evaluated pimecrolimus' interactions with bax, bcl-2, caspase-3 and caspase-8 proteins, using Venetoclax as a positive control. Apoptosis-related protein levels were analyzed via ELISA, qRT-PCR, and immunofluorescence staining (cleaved caspase-3 and DAPI). Molecular docking showed strong binding of pimecrolimus to bax, bcl-2, caspase-3 and caspase-8, with comparable binding energies to Venetoclax. LDH and MDA assays demonstrated significant reductions in H₂O₂-induced cytotoxicity with pimecrolimus. ELISA and qRT-PCR revealed that H₂O₂ increased pro-apoptotic bax, caspase-3 and caspase-8 levels while decreasing anti-apoptotic bcl-2 levels. Pimecrolimus co-treatment reversed these effects in a dose-dependent manner. Immunofluorescence confirmed reduced apoptosis and cell death with pimecrolimus. Pimecrolimus effectively mitigates oxidative stress and apoptosis in H₂O₂-treated d-SH-SY5Y cells. These findings suggest its potential as a neuroprotective agent for managing (NDs).

Adapalene is a third-generation synthetic retinoid that has been approved by the FDA as a dermatological drug was recently repurposed for its potential anti-cancer effects. Here, its anti-cancer potential was determined in human gastric adenocarcinoma cell lines. Adapalene did not show significant cytotoxicity toward AGS and MKN-45 cells, but displayed synergistic or additive effects in inhibiting cell growth and increasing apoptosis in MKN-45 cells, but not AGS cells, when combined with 5-FU, cisplatin, docetaxel, or doxorubicin. Co-treatment with adapalene plus docetaxel or doxorubicin increased DNA damage and S-phase arrest without affecting the expression levels of HR23A/B, XPC, or Rad51. In MKN-45 cells exposed to docetaxel or doxorubicin, adapalene co-treatment downregulated Aurora A and upregulated p21, potentially contributing to its ability to enhance DNA damage and cell cycle dysregulation, and increased reactive oxygen species (ROS) accumulation, which may potentiate the cytotoxicity of the anti-cancer agents. Our present results reveal that adapalene is not cytotoxic towards MKN-45 gastric cancer cells when applied alone, but can synergistically enhance the sensitivity of these cells to conventional chemotherapeutic drugs. Further investigations are warranted to fully elucidate the mechanisms underlying the synergistic effects of adapalene and identify markers that could, given the heterogeneity of gastric cancers, identify patients who are likely to benefit from adapalene co-treatment.

The study investigated the effects of Heracleum persicum L. extract (HPE) on oxidative damage caused by mercuric chloride (HgCl₂) in rat testes. Sixty male Wistar rats were divided into six groups: a sham group, a HgCl₂ group, three groups receiving HgCl₂ with HPE at doses of 250, 500, and 750 mg/kg, and a control group treated with 750 mg/kg HPE alone over 50 days. HgCl₂ was administered intraperitoneally for the first 10 days, followed by HPE gavage for 40 days. On day 51, hormone levels (testosterone, FSH, LH), nitric oxide levels, antioxidant enzyme activity, and pro-inflammatory cytokines were measured. Testicular tissue was analyzed for thiobarbituric acid reactive substances, ferric reducing capacity, thiol levels, and stereological indicators of seminiferous tubules. The study also examined the p53/Cas-3/Bax/Bcl-2 apoptotic pathway. LC-ESI/MS and SEM-EDS analysis detected 25 substances and 14 mineral elements. HgCl₂ exposure significantly reduced LH, T, and FSH levels, while HPE improved these hormones, especially at higher doses. Inflammatory cytokines were elevated due to HgCl₂, but HPE reduced (P < 0.05) these levels and enhanced (P < 0.05) antioxidant enzyme activity, indicating protective effects against oxidative stress. Testicular analysis showed significant (P < 0.05) damage from HgCl₂, but HPE preserved tissue integrity and improved parameters. Weight measurements indicated that HgCl₂ reduced (P < 0.05) body and reproductive weights, while HPE restored these weights. HPE also counteracted apoptotic changes, highlighting its potential as a therapeutic agent against HgCl₂-induced damage.

Hexabromocyclododecane (HBCD), a brominated flame retardant, is linked to various health implications, including prostate cancer. This study explored the molecular mechanisms and potential biomarkers associated with HBCD exposure using data from the Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas (TCGA). A total of 7,147 differentially expressed genes (DEGs) and 46 differentially expressed miRNAs were identified, with significant enrichment in cancer-related pathways and xenobiotic metabolism. Protein-protein interaction (PPI) network construction and enrichment analyses revealed four hub genes: DNAJC12, PKMYT1, RRM2, and SLC12A5. These genes displayed notable expression changes in response to HBCD exposure and were strongly correlated with survival outcomes in prostate cancer patients, as demonstrated by Cox regression and ROC curve analyses. Additionally, miRNA correlation analyses indicated robust positive associations, highlighting a coordinated regulatory network. Experimental expression analyses on HBCD-treated cell lines further validated these findings. This study sheds light on the significant impact of HBCD on gene and miRNA expression in prostate cancer, emphasizing the potential of the identified hub genes and miRNAs as prognostic biomarkers and therapeutic targets. By elucidating the pathways and regulatory networks influenced by HBCD, the findings provide a foundation for developing strategies to mitigate its carcinogenic effects and improve outcomes for prostate cancer patients.

Sepsis rapidly contributed to multiorgan failure, most typically damaging the cardiovascular system, and there were no effective treatments. Dexmedetomidine (Dex) has good therapeutic effects on sepsis-induced organ injury. Our work aimed to probe the pharmacological effects of Dex on ferroptosis in sepsis-associated myocardial injury (S-MI) and define underlying mechanism of action. Cardiomyocytes were exposed to lipopolysaccharide (LPS) for mimicking S-MI model in vitro. The septic mice were constructed by cecum ligation and puncture operation. The mRNA and protein expressions were assessed using quantitative real-time polymerase chain reaction or western blot. Cell survival was determined by cell counting kit-8, lactic dehydrogenase release, and flow cytometry assays. 2',7'-Dichlorodihydrofluorescein diacetate staining measured cellular reactive oxygen species level. The secretion levels of inflammatory cytokines, ferroptosis-related indicators were analyzed by enzyme-linked immunosorbent assay. The N6-methyladenosine (m⁶A) modification level of protein arginine methyltransferase 5 (PRMT5) mRNA was examined by methylated RNA binding protein immunoprecipitation (Me-RIP) assay. The interaction between methyltransferase like 3 (METTL3)/fat mass and obesity-associated protein (FTO) and PRMT5 was analyzed by RNA immunoprecipitation assay. Dex treatment alleviated LPS-induced cardiomyocyte injury and ferroptosis, while these effects of Dex were reversed by Erastin treatment. Mechanically, Dex ameliorated PRMT5 expression in LPS-induced cardiomyocytes by regulating METTL3/FTO catalyzed m⁶A modification on PRMT5 mRNA. Rescue experiments confirmed that PRMT5 overexpression abolished Dex-mediated inhibitory roles on LPS-induced cardiomyocyte injury and ferroptosis. Moreover, Dex administration alleviated inflammation, ferroptosis, and myocardial injury in septic mice. Taken together, Dex repressed PMRT5 expression in a m⁶A-dependent manner, thus lightening LPS-triggered ferroptosis to alleviate cardiomyocyte injury.

Sevoflurane is a commonly utilized inhalational anesthetic in surgical settings. Nevertheless, sevoflurane has been demonstrated to possess neurotoxic properties. The objective was to examine the neuroprotective function of long non-coding RNA prostate androgen-regulated transcript 1 (PART1) in sevoflurane-induced neurotoxicity and to elucidate its potential mechanism. The level of PART1 was quantified by RT-qPCR. The proliferation and apoptosis of HT22 cells were evaluated through CCK-8 assay and flow cytometry, respectively. To assess the protein level of IL-6, IL-1β, and TNF-α, ELISA was conducted. The levels of malondialdehyde, nitrite, and reduced glutathione along with the activity of superoxide dismutase were determined to evaluate oxidative stress. Verification of the targeting relationship between miR-16-5p and PART1 was performed using the dual-luciferase reporter assay. The Morris water maze test was used to assess the impact of PART1 on sevoflurane-induced learning and cognitive function in rats. PART1 levels were decreased in sevoflurane-treated HT22 cells and rats. PART1 suppressed sevoflurane-induced apoptosis and attenuated its inhibitory effect on cell proliferation. PART1 mitigated sevoflurane-induced inflammatory response and oxidative stress in HT22 cells through the regulation of miR-16-5p. PART1 suppressed oxidative damage and inflammatory response leading to improvement of learning and cognitive function in rats subjected to sevoflurane exposure. PART1 has the potential to regulate the sevoflurane-induced inflammatory response and oxidative stress via miR-16-5p, which in turn improves learning and cognitive function. Consequently, PART1 may be a promising therapeutic target for sevoflurane-induced neurotoxicity.