Toxicology Research最新文献

Background: Cyclophosphamide (CP) is an anticancer drug; however, clinical utilization of CP is limited, resulting from its considerable toxicities. This research was performed to explore the protective effects of Chlorogenic acid (CGA) on reproductive damage induced by CP in mice.

Methods: Blood samples were collected for analysis of hormone content subsequently; semen samples were evaluated for quality, and testis samples were used for histopathological evaluation and analysis of oxidative stress biomarkers, protein and gene expression levels of steroid regulatory factors, and steroid synthase.

Results: The results noted that CGA increased serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) activity; increased SOD, GPx, and GSH oxidative stress levels in testis tissue; and decreased MDA content in testis tissue. Testicular cells in the CGA treatment group gradually returned to normal morphology, and CYP11A1 and CYP17A1 levels increased after CGA treatment. The mRNA levels of CYP11A1, CYP17A1, StAR, 3β-HSD, and 17β-HSD were significantly raised in the CGA dose group. In the test dose range, CGA can improve sperm quality, quantitative abnormality, and serum T synthesis disorder caused by CP. This mechanism may be correlated with the inhibition of oxidative stress and antioxidation levels.

Conclusions: Therefore, CGA has a protective impact on testicular injuries arising from CP in mice.

The Threshold of Toxicological Concern (TTC) is a very well-established concept in applied toxicology, and has become a key tool for the pragmatic human health risk assessment of data-poor chemicals. Within the pharmaceutical sector, regulatory guidance on genotoxins defaults to a TTC of 1.5 μg/day equating to a maximum lifetime cancer risk of 1 in 100,000. Higher doses for drug products where exposures are intermittent or otherwise "less-than-lifetime" (LTL) are also considered tolerable. This also allows substance-specific lifetime Acceptable Intakes (AIs) for known genotoxic carcinogens to be scaled up for shorter durations. The default TTCs for assessing LTL exposures build in conservatism such that there is deviation from strict linearity. However, close to the boundaries between LTL categories there can be such a difference in the default tolerable intakes that a health risk assessment can yield conflicting results. We have presented a theoretical case study based on our recent work that illustrates this apparent "cliff-edge." The total acceptable cumulative dose over a 56-day treatment is - in absolute terms - one third of that allowed over 28 days, despite the maximum cancer risk of the longer exposure being an order of magnitude higher. Our analysis suggests the need for careful consideration of what might represent tolerable exposures in the region of the category limits, rather than simply adopting the hardline default. Where a potential patient exposure is found to be above a default value, there is real value in refining the cancer risk estimates using the Lifetime Cumulative Dose approach.

Many mechanisms are thought to play a role in the pathogenesis of the COVID-19 pandemic, which started in 2019 and affected the whole world. It has been claimed that a deficiency in the immune system can significantly affect the severity of COVID-19 disease. It is important that the levels of essential elements and vitamin D are at certain levels for the healthy functioning of the immune system. Therefore, in this study, it was aimed to evaluate immunotoxicity biomarkers (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10, interferon (IFN)-γ, monocyte chemotactic protein-1 (MCP-1)), vitamin D, and essential element levels in COVID-19 patients in Turkey. According to the results of the study, it was found that the magnesium (Mg), zinc (Zn), and selenium (Se) levels decreased as the severity of the disease worsened, while the iron (Fe), and copper (Cu) levels were similar to the mild group and the control group, and the levels decreased as the disease worsened. It has also been found that vitamin D levels decrease as the severity of the disease worsens. Compared to the control group, TNF-α, MCP-1, and IFN-γ levels were found to decrease as the severity of the disease worsened. Also, it was observed that there was a significant relationship between essential metal levels and disease progression in most of the patient groups.

Introduction: This review article gives an overview of the biogenic synthesis of metal nanoparticles (mNPs) while using Litchi chinensis extract as a reducing and stabilizing agent. The subtropical fruit tree i.e lychee contains phytochemicals such as flavonoids, terpenoids, and polyphenolic compounds which act as reducing agents and convert the metal ions into metal atoms that coagulate to form mNPs.

Methodology: Different methodologies adopted for the synthesis of lychee extract and its use in the fabrication of mNPs under different reaction conditions such as solvent, extract amount, temperature, and pH of the medium have also been discussed critically in detail.

Techniques: Different techniques such as FTIR, UV-visible, XRD, SEM, EDX, and TEM adopted for the analysis of biogenic synthesis of mNPs have also been discussed in detail. Applications of mNPs: Applications of these prepared mNPs in various fields due to their antimicrobial, antiinflammatory, anticancer, and catalytic activities have also been described in detail.

Human exposure to mycotoxins through food involve a mixture of compounds, which can be harmful to human health. The Fusarium fungal species are known to produce zearalenone (ZEN), a non-steroidal estrogenic mycotoxin, and its metabolite alpha-zearalenol (α-ZEL), both of which possess endocrine-disruptive properties. Given their potential harm to human health through food exposure, investigating the combined effects of ZEN and α-ZEL becomes crucial. Hence, the combined impact of ZEN and α-ZEL study hold significant importance. This in vitro study delves into the critical area, examining their combined impact on the proliferation and metabolic profile of endometrial cancer Ishikawa cells via sulforhodamine, clonogenic, proliferating cell nuclear antigen (PCNA) and liquid chromatography-high resolution mass spectrometry (LC-HRMS) based untargeted metabolomics. Low concentrations of ZEN (25 nm), α-ZEL (10 nm), or a combination of both were observed to significantly enhance cell proliferation of Ishikawa cells, as evidenced by PCNA immunostaining, immunoblotting as well and clonogenic assays. The metabolomics revealed the perturbations in glycerophospholipid metabolism, nicotinate and nicotinamide metabolism and phenylalanine, tyrosine, tryptophan biosynthesis provides valuable insights into potential mechanism by which these mycotoxins may facilitate cell proliferation. However, further investigations are warranted to comprehensively understand the implications of these findings and their possible implications for human health.

Detoxification is one of the most important liver functions. Therefore, liver is the front line of defense when the biosystem faces drug overdose, toxins, and anything that may cause harm. Some famous antibiotics are known for their side effects on liver; one of them is amoxicillin, AM. This work has investigated the toxic effect of amoxicillin on rat's liver with overdose (90 mg/kg) and has studied the ameliorative role of protective and therapeutic Ashwagandha seeds extract (ASE) at doses (100, 200, and 300 mg/kg) against this toxicity. To achieve this work, the authors used two modalities; the first is liver histopathology to figure out the amoxicillin and ASE effects and to detect the sensitivity of another modality; the electric modulus, and its related thermodynamic parameters of liver tissue. Histopathological examination showed that the role of therapeutic ASE in reducing amoxicillin (AM) toxicity was more effective than the protective one. Also, most dielectric and thermodynamic results achieved the same result. Histopathology confirmed the liver injury by amoxicillin and the partial repair by the biosystem using ASE. Moreover, electric modulus, related dielectric parameters, and their thermodynamic state functions showed different changes in their values under the effect of amoxicillin. Using ASE helped the biosystem to restore these changes near their control values.

Objective: Bisphenol A (BPA) is a ubiquitous pollutant worldwide and 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is considered a major active metabolite of BPA with a wide range of potent toxicological properties. However, its adverse outcome pathway (AOP) on the hepatic and renal system has not yet been explored.

Methods: Hence, the current study evaluated its effect on cell survival, oxidative stress, and apoptosis. In addition, the influence of signalling pathways on cytotoxicity and ROS generating enzymes (NOX2 and XO) on oxidative stress was explored by siRNA knockdown experiments. Further, its molecular interaction with SOD, CAT, and HSA (molecular docking and dynamics) was evaluated and validated with spectroscopy (fluorescence and FTIR) based methods.

Results: The outcome indicates that MBP exposure dose dependently increased the cytotoxic response, oxidative stress, and apoptosis in both hepatocytes and kidney cells. Further, MAPK signalling pathways and oxidative stress influenced the overall cytotoxic response in both cells. In addition, the stimulatory (NOX2 and XO) and inhibitory (SOD and CAT) effects of MBP were observed, along with a robust interaction with HSA.

Conclusions: The overall observation illustrates that MBP exposure adversely impacts hepatic and renal cells through oxidative stress and relevant molecular pathways which may connect the missing links during risk assessment of BPA.

The search for novel therapeutic agents to treat breast cancer has compelled the development of fusion proteins that synergize the functional benefits of different bioactive peptides. Leptulipin, derived from scorpion venom, exhibits antitumor properties. On the other hand, p28, a peptide from the bacterial protein azurin, enhances cell penetration. The current study investigated the design and computational evaluation of a Leptulipin-p28 fusion protein for breast cancer treatment. The amino acid sequences of Leptulipin and p28 were joined via a rigid linker to maintain structural and functional integrity. Secondary and tertiary structure predictions were performed using online servers of GOR-IV and I-TASSER. Physicochemical properties and solubility were analyzed using ProtParam and Protein-Sol. Validation and quality assessment of the fusion protein were confirmed through Rampage and ERRAT2. Finally, the fusion protein was docked with 2 receptors (VEGFR and Cadherin) and docked complexes were simulated on GROMACS. The Leptulipin-p28 fusion protein exhibited a stable structure exhibiting a high quality score of 92 on ERRAT and Ramachandran plot analysis highlighting 76.3% of residues in the favorable region. Docking studies with VEGFR and Cadherin receptors followed by 100 ns simulations on GROMACS showed stable complex formation. Molecular dynamics simulations confirmed the stability and robust interaction of the fusion protein-receptor complexes over time. The computational analysis indicates that the Leptulipin-p28 fusion protein holds promise as a multitarget therapeutic agent in breast cancer. The current findings warrant further investigation through in vitro and in vivo studies to validate the current outcomes.

Objective: Non-small-cell lung cancer (NSCLC) is a leading attributor to cancer deaths. High HDAC10 and low microRNA (miR)-223-5p levels have been observed in NSCLC. But their roles remain elusive. This study illustrated their roles in NSCLC cell ferroptosis and the mechanism.

Methods: HDAC10, miR-223-5p, and solute carrier family 7 member 11 (SLC7A11) levels in cells were determined by RT-qPCR. Iron ion content, reactive oxygen species (ROS), and glutathione (GSH) levels were tested using reagent kits, and levels of SLC7A11 and Acyl-CoA synthesis long chain family (ACSL4) were examined using Western blot. Chromatin immunoprecision was performed to analyze the enrichment of HDAC10 and acetylated lysine 9 of histone H3 (H3K9ac) on the miR-223-5p promoter. The targeted binding of miR-223-5p and SLC7A11 was analyzed by dual-luciferase assay. Joint experiments were designed to identify the role of miR-223-5p/SLC7A11 axis in HDAC10-regulated ferroptosis in NSCLC cells.

Results: HDAC10 was highly expressed in NSCLC cells. Silencing HDAC10 significantly reduced GSH and SLC7A11 levels, upregulated iron ion content, ROS levels, and ACSL4 expression, promoting cell ferroptosis. Mechanically, HDAC10 inhibited miR-223-5p expression through H3K9ac deacetylation of the miR-223-5p promoter, thereby targeting SLC7A11. The joint experimental results showed that overexpression of SLC7A11 or downregulation of miR-223-5p alleviated the promoting effect of silencing HDAC10 on ferroptosis in NSCLC cells.

Conclusion: HDAC10 inhibits miR-223-5p expression through H3K9ac deacetylation of the miR-223-5p promoter, thereby promoting SLC7A11 expression and inhibiting ferroptosis in NSCLC cells.

Background: MSA-2, as an oral molecule for activating STING signaling pathway to cure the tumor entering clinical trials. The toxicity of MSA-2 has aroused wide concern, especially the reproductive toxicity can not be ignored.

Objectives: We synthesized the STING agonist (MSA-2) and its derivative manganese-MSA-2 (MSA-2-Mn) and investigated the reproductive toxicity.

Methods: We evaluated the reproductive effects of MSA-2 and MSA-2-Mn in female mice under the administration alone and on the reproductive system of male mice in the presence or absence of combined radiation.

Results: Results suggested that MSA-2 and MSA-2-Mn have negligible reproductive toxicity in healthy adults. Conclusions: This provides new ideas to enhance the efficacy of immunotherapy, as well as favorable evidence for future systemic dosing in patients of reproductive age and clinical trials of immunotherapy.