Human & Experimental Toxicology最新文献

Doxorubicin (DOX) is a widely used chemotherapy drug that can cause significant cardiotoxicity, limiting its clinical application. This study aimed to investigate the potential protective effects of topiramate (TPM) and spirulina (SP), either alone or in combination, in preventing DOX-induced cardiotoxicity. Adult Sprague Dawley rats were divided into five groups, including a normal control group and groups receiving DOX alone, DOX with TPM, DOX with SP, or DOX with a combination of TPM and SP. Cardiotoxicity was induced by administering DOX intraperitoneally at a cumulative dose of 16 mg/kg over 4 weeks. TPM and/or SP administration started 1 week before DOX treatment and continued for 35 days. Body weight, serum markers of cardiac damage, oxidative stress and inflammatory parameters were assessed. Histopathological and immunohistochemical examinations were performed on cardiac tissues. Results showed that TPM and SP monotherapy led to significant improvements in serum levels of cardiac markers, decreased oxidative stress, reduced fibrosis-related growth factor levels, increased antioxidant levels, and improved histopathological features. SP demonstrated more prominent effects in comparison to TPM, and the combination of TPM and SP exhibited even more pronounced effects. In conclusion, TPM and SP, either alone or in combination, hold promise as therapeutic interventions for mitigating DOX-induced cardiotoxicity.

Background: Nasopharyngeal carcinoma (NPC) is cancer with high mortality and poor prognosis. Circular RNAs (circRNAs) have been identified in a wide variety of cancers. But the functional mechanism of circ_000285 in NPC remains unclear.

Purpose: To decipher the biological function and molecular mechanism of circ_000285 in NPC.

Methods: Quantitative PCR (RT-qPCR) was applied for detecting the expression of circ_0000285, miR-1278, and FNDC3B. Western blot was used to measure the protein levels of Fibronectin type III domain containing 3B (FNDC3B), Bcl2 associated X (Bax), and B cell leukemia/lymphoma 2 (Bcl2). Cell proliferation, migration, and invasion were analyzed by colony formation, 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays. Cell apoptosis was detected by flow cytometry assays. ELISA assay was used to analyze Caspase-3 activity. Bioinformatics was used to predict, and the target relationship between miR-1278 and circ_0000285 or FNDC3B was verified by luciferase reporter assay. Tumor xenograft models were established to examine how circ_0000285 functions during the mediation of NPC tumor growth in vivo.

Results: Increased circ_0000285 and FNDC3B expressions, and a decreased miR-1278 expression were observed in NPC tissues and cell lines. Knockdown of circ_0000285 inhibited NPC cell proliferation, migration, invasion, and while promoting NPC cell apoptosis in vitro. Circ_0000285 knockdown-mediated anti-tumor effects in NPC cells could be largely reversed by silencing of miR-1278 or overexpression of FNDC3B. Circ_0000285 could up-regulate FNDC3B expression by sponging miR-1278 in NPC cells. Knockdown of circ_0000285 could inhibit tumor growth in vivo.

Conclusion: Circ_0000285 upregulates FNDC3B expression by adsorbing miR-1278 to promote NPC development.

Objectives: The study aimed to examine long-term survival of patients with acute paraquat poisoning using computed tomography (CT) images and spirometry.

Methods: A total of 36 patients with long-term survival after paraquat poisoning were followed-up and divided into mild (11 patients), moderate (17 patients), and severe (8 patients) paraquat poisoning groups. Differences among the groups were compared using clinical indicators, such as peripheral capillary oxygen saturation, arterial partial pressure of oxygen and 6-min walk test (6-MWT), chest CT, spirometry, and serum immunoglobulin E (IgE).

Results: The 6-MWT distance was significantly shorter in the severe paraquat poisoning group than that in the mild and moderate paraquat poisoning groups. In the mild paraquat poisoning group, CT revealed no obvious lung injury, and spirometry showed normal lung function in most patients. In moderate or severe paraquat poisoning group, CT images showed fibrotic lesions as cord-like high-density shadows, reticulations, and honeycombs. In addition, other pulmonary changes, including bronchiectasis, increased lung transparency, and pulmonary bullae, were discovered. In moderate or severe paraquat poisoning group, obvious obstructive ventilation dysfunction with slight restrictive and diffuse impairment were observed in some patients, with positive bronchial relaxation test and high serum IgE level.

Conclusion: In the long-term follow-up, patients with severe paraquat poisoning showed the lowest exercise endurance. In moderate or severe paraquat poisoning group, CT images revealed diversified changes, not only dynamic evolution of pulmonary fibrosis process, but also signs of bronchiectasis, and chronic obstructive pulmonary disease. Some patients with moderate or severe paraquat poisoning developed obstructive ventilatory dysfunction with airway hyperresponsiveness.

Cadmium (Cd) is a toxic heavy metal, exposure to which leads to adverse health effects including chronic kidney damage. Tremendous efforts have been explored in identifying safe chelating agents for removing accumulated Cd from kidney, but with limited success owing to their associated side effects and the ineffectiveness in eliminating Cd. A newly developed chelating agent, sodium (S)-2-(dithiocarboxylato((2S,3 R,4R,5 R)-2,3,4,5,6-pentahydroxyhexyl) amino)-4(methylthio)butanoate (GMDTC), has been shown to effectively mobilize Cd from kidney. However, the mechanism(s) of removal are unclear, while it has been hypothesized that renal glucose transporters potentially play key roles mainly because GMDTC contains an open chain glucose moiety. To test this hypothesis, we utilized the CRISPR/Cas9 technology and human kidney tubule HK-2 cells, and constructed sodium-dependent glucose transporter 2 (SGLT2) or glucose transporter 2 (GLUT2) gene knockout cell lines. Our data showed that GMDTC's ability in removing Cd from HK-2 cells was significantly reduced both in GLUT2^-/- or SGLT2^-/- cells, with a removal ratio reduced from 28.28% in the parental HK-2 cells to 7.37% in GLUT2^-/- cells and 14.6% in SGLT2^-/- cells. Similarly, knocking out the GLUT2 or SGLT2 led to a compromised protective effect of GMDTC in reducing cytotoxicity of HK-2 cells. This observation was further observed in animal studies, in which the inhibition of GLUT2 transporter by phloretin treatment resulted in reduced efficiency of GMDTC in removing Cd from the kidney. Altogether, our results show that GMDTC is safe and highly efficient in removing Cd from the cells, and this effect is mediated by renal glucose transporters.

Arsenic is a prevalent environmental pollutant that targets the nervous system of living beings. Recent studies indicated that microglial injury could contribute to neuroinflammation and is associated with neuronal damage. Nevertheless, the neurotoxic mechanism underlying the arsenic-induced microglial injury requires additional research. This study explores whether cathepsin B promotes microglia cell damage caused by NaAsO₂. Through CCK-8 assay and Annexin V-FITC and PI staining, we discovered that NaAsO₂ induced apoptosis in BV2 cells (a microglia cell line). NaAsO₂ was verified to increase mitochondrial membrane permeabilization (MMP) and promote the generation of reactive oxygen species (ROS) through JC-1 staining and DCFDA assay, respectively. Mechanically, NaAsO₂ was indicated to increase the expression of cathepsin B, which could stimulate pro-apoptotic molecule Bid into the activated form, tBid, and increase lysosomal membrane permeabilization by Immunofluorescence and Western blot assessment. Subsequently, apoptotic signaling downstream of increased mitochondrial membrane permeabilization was activated, promoting caspase activation and microglial apoptosis. Cathepsin B inhibitor CA074-Me could mitigate the damage of microglial. In general, we found that NaAsO₂ induced microglia apoptosis and depended on the role of the cathepsin B-mediated lysosomal-mitochondrial apoptosis pathway. Our findings provided new insight into NaAsO₂-induced neurological damage.

Acute lung injury (ALI) is a heterogeneous pulmonary illness that is fast developing and has a high fatality rate. The current investigation set out to interpret the convergence of oxidative stress, inflammatory cytokines, TNF-α, snail, vimentin, e-cadherin, and NF-kB activation in ALI pathology. The outcome of assays of oxidative stress, ELISA, and western blot showed the declined of CAT, SOD, GPx, IL-1β, TNF-α, and upregulation of TGF-β, smad2/3, smad4, NF-kB, snail, and vimentin, concurrently with downregulation of e-cadherin expression in lung tissues as well as BALF in LPS-injected rats. The photomicrographs of the lungs marked severe congestion, infiltration of cytokines, and thickening of the alveolar walls. Pretreatments of ergothioneine after LPS-induced ALI, inhibited EMT-induction by blocking TGF-β, smad2/3, smad4, snail, vimentin, NF-kB, and inflammatory cytokines, and increased the expression of E-cadherin and antioxidant levels in a dose-dependent manner. These events helped to restore lung histoarchitecture and reduce acute lung injury. The present findings suggest that ergothioneine at 100 mg/kg is as effective as febuxostat (reference drug). The study concluded that ergothioneine may be replaced with febuxostat as a treatment option for ALI owing to its side effects after clinical trials for pharmaceutical purposes.

The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for many cancers with little known in osteosarcoma. This study evaluated the efficacy of eFT508, a highly selective inhibitor of MNK1/2, as single drug alone and in combination with paclitaxel in preclinical models of osteosarcoma. EFT508 is active against multiple osteosarcoma cell lines via inhibiting growth, survival and migration. It also demonstrates anti-osteosarcoma selectivity with much less toxicity on normal osteoblastic than osteosarcoma cells. Consistent with in vitro findings, eFT508 at non-toxic dose significantly arrested tumor growth in mice throughout the whole duration of treatment. Mechanistically, eEFT508 is highly effective in blocking eIF4E phosphorylation and eIF4E-mediated protein translation. Combination index shows that eFT508 and paclitaxel is synergistic in osteosarcoma cells. Our findings highlight the therapeutic value of MNK1/2 inhibition and suggest eFT508 as a promising candidate for the treatment of osteosarcoma.

Treatment strategies encompass synchronization of more than one therapy with specific dependence on zeroing side effects of natural products that might represent a niche in the continuous struggle against cancer. Thus, this study aimed at assessing the role of Withania somnifera; WS (Ashwagandha) in forcing MCF7 or MDA-MB 231 irradiated breast cancer cells to outweigh the route of programmed cell death. We check to what extent SIRT1-BCL2/Bax signaling pathway was interrelated to form apoptotic cancer cells. MDA or MCF7 cells are categorized into four groups: gp1, Control (C): MDA-MB-231 or MCF7 cells not treated with WS or exposed to γ-rays, gp2 (WS): cells challenged with WS for MDA-MB-231 or MCF7 cells respectively, gp3: irradiated (R) MDA-MB-231 or MCF7 cells exposed to γ-rays (4 Gy; one shot) and gp4 WS and irradiated (WS + R): cells challenged with WS as in gp2 and exposed to gamma rays as in gp3. The results revealed that, WS established IC₅₀ equivalent to 4897.8 μg/ml in MDA-MB-231 cells or equivalent to 3801.9 μg/ml in MCF7 cells. The flowcytometric analysis (Annexin V and cell cycle) showed that WS induces apoptosis at pre-G phase and induces cell arrest at G2/M and preG1 phases for MDA-MB-231 and at the preG1 for MCF7 cells. Furthermore, the WS + R group of cells (MDA-MB-231 and MCF7) showed significant increases in the expression of SIRT1, and BCL2 and a decrease in BAX compared with WS or R group. It could be concluded that WS has an anti-proliferative action on MDA-MB-231 and MCF7 cells because of its capability to enhance apoptosis.

Except for clinical value, borneol is routinely used in food and cosmetics with seldom safety evaluation. To investigate its hepatoxicity, we exposed 3 dpf (days post fertilization) larval zebrafish to borneol at a gradient of concentrations (200-500 μM) for 3 days. Herein, our results revealed that high doses of borneol (300-500 μM) caused liver size decrease or lateral lobe absence. Borneol also seriously disturbed the hepatic protein metabolism presented with the increased activity of alanine aminotransferase (ALT) and lipid metabolism shown with the increased level of triglycerides (TG) and total cholesterol (TC). The lipid accumulation (oil red staining) was detected as well. Additionally, significant upregulation of genes was detected that related to oxidative stress, lipid anabolism, endoplasmic reticulum stress (ERS), and autophagy. Conversely, the lipid metabolism-related genes were markedly downregulated. Moreover, the changes in the superoxide dismutase activity and the level of glutathione and malondialdehyde raised the likelihood of lipid peroxidation. The outcomes indicated the involvement of oxidative stress, ERS, lipid metabolism, and autophagy in borneol-induced lipid metabolic disorder and hepatic injury. This study will provide a more comprehensive understanding of borneol hepatoxicity and the theoretical basis for the safe use of this compound.