Toxicology and applied pharmacology最新文献

In the current study, we dosed didecyldimethylammonium chloride (DDAC) in mice by pharyngeal aspiration for 28 days or 90 days (weekly) and tried to elucidate the relationship between lamellar body formation and the lesions. When exposed for 28 days (0, 5, 10, 50, and 100 μg/head), all the mice in the 50 and 100 μg/head groups died since Day 2 after the third dosing (Day 16 after the first dosing). Edema, necrosis of bronchiolar and alveolar epithelium, and fibrinous exudate were observed in the lungs of all the dead mice, and chronic inflammatory lesions were observed in the lung tissues of alive mice. When dosed with DDAC of 0, 1, 4, and 8 μg/head for 13 weeks, the total number of pulmonary cells and the pulmonary levels of pro- and anti-inflammatory cytokines significantly increased, and chronic inflammatory lesions were detected with the production of collagen, collagen fibers, and lamellar body-like structures. Swelling of the nuclear envelope and nucleoplasmic components and generation of lipid droplets were also notably observed in the lung tissues of DDAC (8 μg/head)-treated mice. Furthermore, transcriptomic analysis performed using human bronchial epithelial cells showed that DDAC affected the expression of DNA damage, ER stress, lipid metabolism, and transcription regulation-related genes at 6 h after treatment, as it did 24 h treatment and that early growth response factor 1 gene was added to a list of the most up-regulated genes. Meanwhile, cytokines that are associated with the pathology of chronic lung diseases (IL-11, IL-24, and TGF-β) were slightly increased in the lung of DDAC-treated mice, and only the pulmonary level of CCL-2, but not CXCL-1 and CCL-3, increased in both sexes of mice. More importantly, the GM-CSF level increased dose-dependently in the lungs of both sexes of mice exposed to DDAC. Considering that the wound-healing process can take several weeks to complete, we suggest that DDAC-induced pulmonary fibrosis may be attributable to disruption of the wound-healing process due to continuous exposure to DDAC. We also hypothesize that the formation of lamellar bodies may be attributable to lysosomal accumulation of phospholipids separated from the destroyed lung tissue membrane.

Cadmium (Cd) is among the top seven most hazardous environmental contaminants. Minimal risk levels for daily exposure have been established, such as no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL). Chronic exposure to Cd, at both NOAEL and LOAEL doses, causes toxicity in diverse tissues. However, Cd toxicity in adipose tissue, an endocrine and metabolic organ, remains relatively understudied. We aimed to investigate the potentially toxic effects of chronic Cd exposure (at NOAEL and LOAEL doses) on epidydimal adipose tissue of adult male Wistar rats. Ninety male Wistar rats were divided into three groups (n = 30): Control Cd-free, NOAEL, and LOAEL that received CdCl₂ in drinking water for 15 days to 5 months. We evaluated over time zoometry, serum and adipose Cd concentration, redox balance, GLUT4 and Nrf2 expression, histology, leptin, adiponectin, adipose insulin resistance index, free fatty acids, and glucose tolerance. The higher dose group showed a more pronounced and sustained increase in serum and adipose tissue of Cd concentration. Zoometry was similarly affected in both Cd-exposed groups with adipocyte hypertrophy. The redox balance was maintained due to the augmenting of Nrf2 expression. Leptin concentration augmented, while adiponectin diminished. Adipose insulin resistance increased simultaneously to lipolysis and glucose intolerance despite high GLUT4 expression. In conclusion, this study provides strong evidence that chronic Cd exposure, even at minimal risk levels (LOAEL and NOAEL doses), has toxic effects, disrupting the function of epididymal adipose tissue and contributing to metabolic disorders.

Purpose: The impaired function of islet β-cell is associated with the pathogenesis of type 2 diabetes mellitus (T2DM). γ-glutamylcysteine (γ-GC), an immediate precursor of glutathione (GSH), has antioxidant and neuroprotective functions. Its level has been reported to be down-regulated in hyperglycemia. However, whether γ-GC has a protective effect on islet β-cell dysfunction remains elusive. Recently, we explore the molecular mechanism by which γ-GC protects islet β-cell from glucolipotoxicity-induced dysfunction.

Methods: In vivo mice models and in vitro cell models were established to examine the therapeutic effects and molecular mechanisms of γ-GC.

Results: db mice develop impaired glucose-stimulated insulin secretion (GSIS) due to reduced islet number and damaged islet microstructure. Serious oxidative damage, apoptosis and lipid accumulation are also observed in β-cell stimulated by glucolipotoxicity. Mechanistic studies suggest that glucolipotoxicity inhibits PDX-1 nuclear translocation by inducing endoplasmic reticulum (ER) stress, which leads to impaired insulin (INS) secretion in β-cell. Nevertheless, γ-GC as an inhibitor of ER stress can alleviate the damage of islet microstructure in db mice. Importantly, γ-GC promotes INS gene expression and GSIS through driving nuclear translocation of PDX-1, thereby enhancing intracellular INS content. Moreover, treatment with γ-GC can also mitigate oxidative damage, apoptosis and lipid accumulation of β-cell, resulting in ameliorating islet β-cell dysfunction induced by glucolipotoxicity.

Conclusion: Our results support the use of γ-GC as an inhibitor of ER stress for prevention and treatment of T2DM in the future.

Acute kidney injury (AKI) is one of the most important indications of severe clinical symptoms in patients with diquat poisoning and is closely related to poor prognosis. However, current studies have rarely focused on early warnings of diquat-related AKI, which is not conducive to the treatment of patients with early clinical diquat poisoning. In this study, untargeted plasma metabolomics was employed to reveal the differences between diquat-poisoned patients with and without AKI, as well as between patients and healthy volunteers. The results showed that 48 metabolites were significantly changed in the patients, among which 3-hydroxybutyrylcarnitine, SAICAR, dodecanoic acid, and tetrahydrofolyl-[Glu](2) could be used to effectively differentiate the above three groups. Based on the ratios of the first two metabolites and the ratios of the last two metabolites, a decision tree model for the early warning of diquat-induced AKI was established with an accuracy rate of 88.7 %. This model provides great support for accurate clinical diagnosis and intervention regarding the AKI risk of diquat-exposed patients.

Diabetic gastroparesis (DGP), a prevalent complication of diabetes, is characterized by delayed gastric emptying and inflammation. The dorsal motor nucleus of the vagus (DMV) plays a crucial role in modulating gastric function via the vagus nerve. Neuregulin 1 (NRG1), which is present in the DMV and influences the autonomic nervous system, has an unclear role in DGP. This study aimed to investigate the expression of NRG1 in the DMV of Zucker diabetic fatty (ZDF) rats and to evaluate the impact of centrally administered NRG1 on gastric motility and inflammation, as well as the underlying mechanisms. Our findings revealed a decrease in NRG1 and choline acetyltransferase (ChAT) expression in the DMV of ZDF rats, corresponding to weakened gastric motility. Microinjection of AAV-NRG1 (overexpressed NRG1 by means of an adeno-associated viral vector delivery of NRG1) into the DMV enhanced gastric motility and increased vagal nerve discharge frequency. Moreover, AAV-NRG1 upregulated acetylcholine (Ach) and α7 nicotinic acetylcholine receptor (α7nAChR) expression in the gastric body, mitigating gastric inflammation. The beneficial effects of AAV-NRG1 were partially reversed by vagotomy or α7nAChR antagonism. These findings provide novel evidence that NRG1 in the DMV can stimulate Ach release and activate α7nAChRs, thereby reducing inflammation and restoring gastric motility via the vagus nerve. This implicates the NRG1 as a potential therapeutic target for DGP.

Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.

Chemotherapeutic medication-induced systemic toxicity makes cancer treatment less effective. Thus, the need for drug repurposing, which aids in the development of safe and efficient cancer therapies, is urgent. The primary goal of this research was to assess desloratadine hepatoprotective abilities and its capacity to attenuate TLR4/MyD88/NF-κB inflammatory pathway in hepatocellular carcinoma (HCC) induced by thioacetamide (TAA). Male Sprague Dawely rats received TAA injections (200 mg/kg, i.p., 2 times/week) for 16 weeks. To confirm the development of HCC, liver function biomarkers and histopathological analysis were evaluated. Desloratadine (5 mg/kg, p.o.) was administered to rats in 2 treatment groups; HCC + DES 1 group received desloratadine with TAA for 1 month from week 13-16, HCC + DES 2 group received desloratadine with TAA for 2 months from week 9-16. Chronic TAA administration resulted in considerable overexpression of the profibrogenic cytokine TGF-β and elevation in protein expression of NF-κB besides levels of TLR4, MyD88, TRAF6, TAK1 and IL-1β. Desloratadine administration showed a significant improvement in liver function tests, as well as an increase in tissue antioxidant enzymes and an improvement in the liver's histopathological features. Collectively, desloratadine through modulating TLR4/MyD88/TRAF6/TAK1/NF-κB and acting as an antioxidant, is a promising treatment for HCC induced by TAA.

Cenobamate (CNB) is a novel anti-seizure medication with significant efficacy in treating epilepsy. However, in clinical trials, the most common adverse reactions observed in patients are central nervous system (CNS) symptoms. In animal studies, administration of CNB during pregnancy or lactation has been associated with adverse effects on neurodevelopment in offspring. To optimize the clinical use of CNB, we investigated the neurotoxicity of different concentrations of CNB (10, 20, 40, 80, and 160 μM) on zebrafish embryos. Following exposure, zebrafish embryos exhibited abnormal phenotypes such as shortened body length, impaired yolk sac absorption, and decreased heart rate. Behavioral experiments showed that CNB caused abnormal movements such as decreased spontaneous tail curling frequency, shortened total movement distance, and reduced average movement speed. We also found that CNB leads to increased acetylcholinesterase (AChE) activity levels in zebrafish embryos, along with differential expression of neurodevelopment-related genes such as nestin, gfap, synapsin IIa, and gap43. In summary, our research findings indicated that CNB may induce developmental and neurotoxic effects in zebrafish embryos by altering neurotransmitter systems and the expression of neurodevelopmental genes, thereby influencing behavior. This study will provide information for the clinical use of CNB, aiming to benefit more epilepsy patients through its appropriate administration.

Age-related macular degeneration (AMD) is a representative age-related ophthalmic disease, and the pathogenesis of AMD remains unclear. This research intended to determine whether epigallocatechin gallate (EGCG) could alleviate the progression of AMD and the possible mechanism. We constructed three groups of mice (young, aged, and EGCG), and HE and TUNEL staining of retinal tissues was performed to observe the structural changes in the retinal pigment epithelial (RPE) layer and the level of apoptosis, respectively. Through RNA-Sequencing analysis of retinal tissues and by RT-qPCR, GO, KEGG, and literature analyses, we identified cytoplasmic fragile X mental retardation 1-interacting protein 2 (CYFIP2) as a possible effector gene for EGCG action and validated its role by immunofluorescent and western blotting experiments. The CCK-8 and Hoechst 33342 apoptosis assays, and western blotting and qRT-PCR assays showed that EGCG reduced hydrogen peroxide (H₂O₂)-induced apoptosis in adult human RPE (ARPE-19) cells, and the expression of Cyfip2 was changed accordingly. RNA interference analysis indicated that Cyfip2 knockdown alleviated H₂O₂-induced ARPE apoptosis, while its overexpression weakened EGCG's protective effect. Western blot analysis showed that Cyfip2 mediated the anti-apoptotic effect of EGCG by modulating the level of protein kinase B (Akt) phosphorylation in ARPE cells, and the activation level of phosphorylated AKT (p-AKT Ser473) in retinal tissue of the EGCG-fed group was higher than that of the aged group. Taken together, this study suggests that EGCG plays a protective role in the development of AMD and the apoptosis of ARPE cells through the Cyfip2/AKT pathway.

A frequently utilized plasticizer is di-(2-ethylhexyl) phthalate (DEHP), considered a ubiquitous contaminant in the environment and reported to have severe impacts on animals. Although it disrupts the female reproductive system in mammals, little is known about how it effects on fish reproduction. The reproductive parameters of female adult koi carp (Cyprinus carpio) were investigated in this study subjected to environmentally relevant exposure of DEHP (1, 10 and 100 μg/L). After 60 days experiment, significantly lower GSI was recorded in females of 10 and 100 μg/L DEHP-exposed groups. The examination of ovarian histology showed defective histoarchitecture, which included the existence of atretic oocytes, the emergence of intra-oocyte vacuoles as well as necrosis. The groups exposed to DEHP (10 and 100 μg/L) showed significant decreases in fecundity and ova-diameter values. Significant changes in the biochemical (total protein, glucose and cholesterol) and ionic (sodium, potassium, calcium and magnesium) composition were noticed in the ovarian fluid of exposed groups. The groups treated with DEHP showed higher levels of 11-ketotestosterone along with reduced levels of 17β-estradiol. Using real-time PCR, the mRNA expression of several genes linked to reproduction, such as Fshr, Lhr, Ar, Erα and Erβ were assessed and observed that there was a concentration-dependent alternation. The pairing of exposed females with untreated males significantly lowered the rates of fertilization, hatching and larval survival. In summary, the results of this investigation validated that exposure to DEHP in a nominal concentration could potentially reduce the reproductive health of female fish.