Toxicology Research最新文献

Morphine is an analgesic in the opiate family, isolated from many plants. It can inhibit androgen biosynthesis by Leydig cells. Whether morphine directly inhibits androgen biosynthesis and underlying mechanism remains unclear. To investigate the influence of morphine on androgen secretion by rat immature Leydig cells (ILCs) and possible mechanism. Rat ILCs were treated with 0.5-50 μM morphine for 3 h in vitro. Morphine at ≥0.5 μM significantly reduced total androgen secretion. Morphine at 50 μM also compromised luteinizing hormone (LH, 10 mg/kg), 8Br-cAMP (1 mM), and 22R-hydroxycholesterol (20 μM) stimulated total androgen, androstanediol, and testosterone secretion, without affecting pregnenolone, progesterone, androstenedione mediated androgen secretion and testosterone and dihydrotestosterone mediated androstanediol secretion. Further analysis revealed that morphine at ≥0.5 μM downregulated Star expression and at ≥5 μM downregulated Cyp11a1 expression. Morphine also significantly reduced STAR (≥0.5 μM) and reduced CYP11A1 (≥5 μM) levels. 0.5 μM naloxone significantly antagonized morphine-mediated action. In conclusion, morphine might cause side effects by suppressing androgen biosynthesis via u opioid receptor.

Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPR^mt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPR^mt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPR^mt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPR^mt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPR^mt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPR^mt contributed to the recovery of mitochondrial function.

The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.

Objective: Radiation pneumonitis (RP) is the major adverse response of radiation therapy for thoracic malignant tumors, and there is a lack of effective interventions. The aim of this study was to investigate the radioprotective effect of Glycyrrhizin (GL) on RP and its potential mechanism.

Method: The body weight and lung weight of mice were monitored. HE staining was used to observe lung injury, and the expression of endoplasmic reticulum (ER) stress biomarkers and the activation of NLRP3 inflammasome were determined by Western blotting and immunohistochemistry. Flow cytometry was performed to check MLE-12 apoptosis. ER stress activator, Tunicamycin (Tuni), was used to verify the potential mechanism of GL. A systemic pharmacology explored the potential targets and pathways of GL.

Results: In this study, the lungs of irradiated mice showed significant pneumonic changes. In vivo and in vitro assay, NLRP3 inflammasome was significantly activated, the expression of ER stress biomarkers was elevated, flow cytometry confirms increased apoptosis in irradiated MLE-12 cells. GL inhibits the activation of NLRP3 inflammasome and ER stress pathways. Furthermore, systemic pharmacology revealed that the radioprotective effect of GL may be related to the MAPK signaling pathway.

Conclusion: In the present study, the results indicated that GL may regulate NLRP3 inflammasome through ER stress, thus exerting irradiation-protective effects on RP, and the ER stress pathway may be a potential target for RP treatment.

The safety of a rhamnogalacturonan-I-enriched pectin extract (G3P-01) from pumpkin (Cucurbita moschata var. Dickinson) was evaluated for use as an ingredient in food and dietary supplements. G3P-01 was tested in a battery of genetic toxicity studies including reverse mutagenicity and in vitro micronucleus assay. In addition, Sprague-Dawley rats were randomized and orally dosed with G3P-01 incorporated in animal diet at concentrations of 0, 9000, 18,000, and 36,000 ppm daily for 13-weeks (n=10/sex/group) in line with OECD guidelines (TG 408). The results of the in vitro bacterial reverse mutation assay and micronucleus assay in TK6 cells demonstrated a lack of genotoxicity. The 13-week oral toxicity study in Sprague-Dawley rats demonstrated that the test article, G3P-01 was well tolerated; there were no mortalities and no adverse effects on clinical, gross pathology, hematology, blood chemistry, and histological evaluation of the essential organs of the animals. The present study demonstrates that G3P-01 is non-genotoxic and is safe when ingested in diet at concentrations up to 36, 000 ppm. The subchronic no-observed-adverse-effect level (NOAEL) for G3P-01 was concluded to be 36,000 ppm, equivalent to 1,899 and 2,361 mg/kg/day for male and female rats respectively.

Background: A broad spectrum carbamate fungicide called carbendazim (Carb) is used to combat a number of different fungal diseases. One of the extensively utilized medicinal plants in oriental countries is Coriandrum sativum.

Aim: In the current study, the impact of C. sativum seeds extract (CSE) on albino rats' testicular toxicity caused by carbendazim was investigated.

Materials and methods: A total of 50 male albino rats were classified into 5 groups [Gp1, Control Gp; Gp2, Coriandrum Gp (CSE); Gp 3, carbendazim Gp (Carb); Gp 4, Co treated CSE with Carb (CSE + Carb); Gp 5, Post treated Carb with CSE (Carb + CSE)].

Results: Carb induced elevation in serum LH. FSH, testicular malondialdehyde (MDA), testicular nitric oxide (NO) markers and testicular injury and it reduced serum testosterone, testicular glutathione (GSH), testicular catalase and PCNA. Treatments of Carb with CSE (CSE + Carb and/or Carb + CSE) improved these parameters and reduced testicular toxicity with best results for Carb + CSE than CSE + Carb.

Conclusions: The above findings revealed that; Carb induced testicular toxicity and it supported the hypothesis that the antioxidant characteristics of one or more of CSE constituents can reduce the testicular toxicity of Carb.