Melatonin restores hepatic lipid metabolic homeostasis disrupted by blue light at night in high-fat diet-fed mice.

Artificial light at night (ALAN) is an emerging environmental pollutant that threatens public health. Recently, ALAN has been identified as a risk factor for obesity; however, the role of ALAN and its light wavelength in hepatic lipid metabolic homeostasis remains undetermined. We showed that chronic dim (~5 lx) ALAN (dLAN) exposure significantly promoted hepatic lipid accumulation in obese or diabetic mice, with the most severe effect of blue light and little effect of green or red light. These metabolic phenotypes were attributed to blue rather than green or red dLAN interfering with hepatic lipid metabolism, especially lipogenesis and lipolysis. Further studies found that blue dLAN disrupted hepatic lipogenesis and lipolysis processes by inhibiting hepatic REV-ERBs. Mechanistically, feeding behavior mediated the regulation of dLAN on hepatic REV-ERBs. In addition, different effects of light wavelengths at night on liver REV-ERBs depended on the activation of the corticosterone (CORT)/glucocorticoid receptor (GR) axis. Blue dLAN could activate the CORT/GR axis significantly while other wavelengths could not. Notably, we demonstrated that exogenous melatonin could effectively inhibit hepatic lipid accumulation and restore the hepatic GR/REV-ERBs axis disrupted by blue dLAN. These findings demonstrate that dLAN promotes hepatic lipid accumulation in mice via a short-wavelength-dependent manner, and exogenous melatonin is a potential therapeutic approach. This study strengthens the relationship between ALAN and hepatic lipid metabolism and provides insights into directing ambient light.

Copper exposure induces mitochondrial dysfunction and hepatotoxicity via the induction of oxidative stress and PERK/ATF4 -mediated endoplasmic reticulum stress.

Copper is an essential trace element, and excessive exposure could result in hepatoxicity, however, the underlying molecular mechanisms remain incompletely understood. The present study is aimed to investigate the molecular mechanisms of copper sulfate (CuSO4) exposure-induced hepatoxicity both in vivo and in vitro. In vitro, HepG2 and L02 cells were exposed to various doses of CuSO4 for 24 h. Cell viability, ROS production, oxidative stress biomarkers, mitochondrial functions, ultrastructure, intracellular calcium (Ca2+) concentration, and the expression of proteins related to mitochondrial apoptosis and endoplasmic reticulum (ER) stress were assessed. In vivo, C57BL/6 mice were treated with CuSO4 at doses of 10 and 30 mg/kg BW/day and co-treated with 4-PBA at 100 mg/kg BW/day for 35 days. Subsequently, liver function, histopathological features, and protein expression were evaluated. Results found that exposure to CuSO4 at concentrations of 100-400 µM for 24 h significantly decreased the viabilities of HepG2 and L02 cells and it was in a dose-dependent manner. Additionally, CuSO4 exposure induced significant oxidative stress and mitochondrial dysfunction in HepG2 cells, which were partially ameliorated by the antioxidant N-acetylcysteine (NAC). Furthermore, CuSO4 exposure prominently triggered ER stress, as evidenced by the upregulation of GRP94, GRP78, phosphorylated forms of PERK and eIF2α, and CHOP proteins in livers of mice and HepG2 cells. NAC treatment significantly inhibited CuSO4 exposure -induced ER stress in HepG2 cells. Pharmacological inhibition of ER stress through co-treatment with 4-PBA and the PERK inhibitor GSK2606414, as well as genetic knockdown of ATF4, partially mitigated CuSO4-induced cytotoxicity in HepG2 cells by reducing mitochondrial dysfunction and inhibiting the mitochondrial apoptotic pathway. Moreover, 4-PBA treatment significantly attenuated CuSO4-induced caspase activation and hepatoxicity in mice. In conclusion, these results reveal that CuSO4-induced hepatotoxicity involves mitochondrial dysfunction and ER stress by activating oxidative stress induction and PERK/ATF4 pathway.

Lycopene as a Therapeutic Agent against Aflatoxin B1-Related Toxicity: Mechanistic Insights and Future Directions.

Aflatoxin (AFT) contamination poses a significant global public health and safety concern, prompting widespread apprehension. Of the various AFTs, aflatoxin B1 (AFB1) stands out for its pronounced toxicity and its association with a spectrum of chronic ailments, including cardiovascular disease, neurodegenerative disorders, and cancer. Lycopene, a lipid-soluble natural carotenoid, has emerged as a potential mitigator of the deleterious effects induced by AFB1 exposure, spanning cardiac injury, hepatotoxicity, nephrotoxicity, intestinal damage, and reproductive impairment. This protective mechanism operates by reducing oxidative stress, inflammation, and lipid peroxidation, and activating the mitochondrial apoptotic pathway, facilitating the activation of mitochondrial biogenesis, the endogenous antioxidant system, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (KEAP1) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) pathways, as well as regulating the activities of cytochrome P450 (CYP450) enzymes. This review provides an overview of the protective effects of lycopene against AFB1 exposure-induced toxicity and the underlying molecular mechanisms. Furthermore, it explores the safety profile and potential clinical applications of lycopene. The present review underscores lycopene's potential as a promising detoxification agent against AFB1 exposure, with the intent to stimulate further research and practical utilization in this domain.

Paeoniflorin recued hepatotoxicity under zinc oxide nanoparticles exposure via regulation on gut-liver axis and reversal of pyroptosis.

The risks of Zinc oxide nanoparticles (ZnO NPs) applications in biological medicine, food processing industry, agricultural production and the biotoxicity brought by environmental invasion of ZnO NPs both gradually troubled the public due to the lack of research on detoxification strategies. TFEB-regulated autophagy-pyroptosis pathways were found as the crux of the hepatotoxicity induced by ZnO NPs in our latest study. Here, our study served as a connecting link between preceding toxic target and the following protection mechanism of Paeoniflorin (PF). According to a combined analysis of network pharmacology/molecular docking-intestinal microbiota-metabolomics first developed in our study, PF alleviated the hepatotoxicity of ZnO NPs from multiple aspects. The hepatic inflammatory injury and hepatocyte pyroptosis in mice liver exposed to ZnO NPs was significantly inhibited by PF. And the intestinal microbiota disorder and liver metabolic disturbance were rescued. The targets predicted by bioinformatics and the signal trend in subacute toxicological model exhibited the protectiveness of PF related to the SIRT1-mTOR-TFEB pathway. These evidences clarified multiple protective mechanisms of PF which provided a novel detoxification approach against ZnO NPs, and further provided a strategy for the medicinal value development of PF.

Nootkatone Supplementation Attenuates Carbon Tetrachloride Exposure-Induced Nephrotoxicity in Mice.

Nootkatone (NKT), a major ingredient of Alpinia oxyphylla, exhibited potential nephroprotective effects; however, the precise molecular mechanisms remain poorly understood. This study aimed to study the nephroprotective effects of NKT and the underlying mechanisms in a mouse model. Our results showed that NKT pretreatment at the doses of 5, 10, and 20 mg/kg per day for 7 days significantly attenuates carbon tetrachloride (CCl4)-induced increases of serum BUN and CRE and kidney pathology injury. NKT pretreatment also markedly inhibited oxidative stress, inflammatory response, and the activation of caspases-9 and -3 in kidneys of mice exposed to CCl4. Meanwhile, NKT pretreatment downregulated the expression of NOX4, IL-1ß, IL-6, and TNF-α proteins and NO levels in the kidney tissues. Moreover, NKT pretreatment upregulated the expression of Nrf2 and HO-1 mRNAs, and downregulated the expression of NF-κB, IL-1ß, IL-6, TNF-α, and iNOS mRNAs in the kidneys of mice, compared to those in the CCl4 alone treatment group. In conclusion, our results reveal that NKT supplementation could protect against CCl4 exposure-induced oxidative stress and inflammatory response in the kidneys by inhibiting NOX4 and NF-κB pathways and activating the Nrf2/HO-1 pathway. Our current study highlights the therapeutic application of NKT for kidney diseases.

Identification, Fine Mapping and Application of Quantitative Trait Loci for Grain Shape Using Single-Segment Substitution Lines in Rice (Oryza sativa L.).

Quantitative trait loci (QTLs) and HQTL (heterosis QTLs) for grain shape are two major genetic factors of grain yield and quality in rice (Oryza sativa L.). Although many QTLs for grain shape have been reported, only a few are applied in production. In this study, 54 QTLs for grain shape were detected on 10 chromosomes using 33 SSSLs (single-segment substitution lines) and methods of statistical genetics. Among these, 23 exhibited significant positive additive genetic effects, including some novel QTLs, among which qTGW4-(1,2), qTGW10-2, and qTGW10-3 were three QTLs newly found in this study and should be paid more attention. Moreover, 26 HQTLs for grain shape were probed. Eighteen of these exhibited significant positive dominant genetic effects. Thirty-three QTLs for grain shape were further mapped using linkage analysis. Most of the QTLs for grain shape produced pleiotropic effects, which simultaneously controlled multiple appearance traits of grain shape. Linkage mapping of the F2 population derived from sub-single-segment substitution lines further narrowed the interval harbouring qTGW10-3 to 75.124 kb between PSM169 and RM25753. The candidate gene was identified and could be applied to breeding applications by molecular marker-assisted selection. These identified QTLs for grain shape will offer additional insights for improving grain yield and quality in rice breeding.

Oxidative stress-related canonical pyroptosis pathway, as a target of liver toxicity triggered by zinc oxide nanoparticles.

Zinc oxide nanoparticles (ZnO NPs) have been widely used in the fields of daily necessities, clinical diagnosis, drug delivery and agricultural production. The improper use of ZnO NPs could pose a risk to ecological environment and public health. Liver has been known as a critical toxic target of ZnO NPs. However, the question whether ZnO NPs lead to hepatocyte death through pyroptosis has not been answered yet, and the effect of oxidative stress on ZnO NPs-induced pyroptosis remains a mystery. We revealed that ZnO NPs disrupted zinc homeostasis and induced oxidative stress impairment in rat liver. Meanwhile, ZnO NPs triggered the assembly of NLRP3-ASC-Caspase-1 inflammatory complex and pyroptosis in both rat liver and HepG2 cells, further causing the activation of GSDMD, promoting the leakage of inflammatory cytokines including IL-1ß and IL-18. Importantly, the inhibition of oxidative stress was found to provide protection against pyroptosis in hepatocyte exposed to ZnO NPs. We identified a novel mechanism of liver damage induced by ZnO NPs, demonstrating the activation of canonical Caspase-1-dependent pyroptosis pathway and clarifying the protection of antioxidation against pyroptosis damage. Our discovery provided a support for risk assessment of ZnO NPs and target exploration for clinical treatment related to pyroptosis.

Involvement of the inhibition of mitochondrial apoptotic, p53, NF-κB pathways and the activation of Nrf2/HO-1 pathway in the protective effects of curcumin against copper sulfate-induced nephrotoxicity in mice.

Chronic copper exposure could cause potential nephrotoxicity and effective therapy strategies are limited. This study investigated the protective effects of curcumin on copper sulfate (CuSO4)-induced renal damage in a mouse model and the underlying molecular mechanisms. Mice were administrated orally with CuSO4 (100 mg/kg per day) in combination with or without curcumin (50, 100 or 200 mg/kg per day, orally) for 28 days. Results showed that curcumin supplementation significantly reduce the Cu accumulation in the kidney tissues of mice and improved CuSO4-induced renal dysfunction. Furthermore, curcumin supplantation also significantly ameliorated Cu exposure-induced oxidative stress and tubular necrosis in the kidneys of mice. Moreover, compared to the CuSO4 alone group, curcumin supplementation at 200 mg/kg per day significantly decreased CuSO4-induced the expression of p53, Bax, IL-1ß, IL-6, and TNF-α proteins, levels of NF-κB mRNA, levels of caspases-9 and - 3 activities, and cell apoptosis, and significantly increased the levels of Nrf2 and HO-1 mRNAs in the kidney tissues. In conclusion, for the first time, our results reveal that curcumin could trigger the inhibition of oxidative stress, mitochondrial apoptotic, p53, and NF-κB pathways and the activation of Nrf2/HO-1 pathway to ameliorate Cu overload-induced nephrotoxicity in a mouse model. Our study highlights that curcumin supplementation may be a promising treatment strategy for treating copper overload-caused nephrotoxicity.

Acute, chronic, and genotoxic studies on the protopine total alkaloids of the Macleaya cordata (willd.) R. Br. in rodents.

The protopine alkaloids are widely distributed within the opium poppy family and have a wide range of pharmacological effects. MPTA is a product of the protopine total alkaloids extracted from the Macleaya cordata (Willd.) R. Br. Previously, we reported good anti-inflammatory activity of MPTA as well as oral acute and sub-chronic toxicity studies in rats. In order to perform a systematic toxicological safety assessment of MPTA, oral acute toxicity, genotoxicity (bone marrow cell chromosome aberration test, sperm abnormality test, bone marrow cell micronucleus test, and rat teratogenicity test), and chronic toxicity in mice were performed in this study. In the oral acute toxicity test, the LD50 in ICR mice was 481.99 mg/kg, with 95% confidence limits ranging from 404.27 to 574.70 mg/kg. All three mutagenicity tests tested negative in the range of 60.25-241.00 mg/kg. The results of the teratogenicity test in rats showed no reproductive or embryonic developmental toxicity at only 7.53 mg/kg, which can be considered as a no observed effect level (NOEL) for the teratogenicity test. Therefore, MPTA is safe for use at the doses tested, but attention should be paid to the potential risk to pregnant animals and the safety evaluation and toxicity mechanisms in target animals should be further investigated.

Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications.

One of the most significant classes of mycotoxins, aflatoxins (AFTs), can cause a variety of detrimental outcomes, including cancer, hepatitis, aberrant mutations, and reproductive issues. Among the 21 identified AFTs, aflatoxin B1 (AFB1) is the most harmful to humans and animals. The mechanisms of AFB1-induced toxicity are connected to the generation of excess reactive oxygen species (ROS), upregulation of CYP450 activities, oxidative stress, lipid peroxidation, apoptosis, mitochondrial dysfunction, autophagy, necrosis, and inflammatory response. Several signaling pathways, including p53, PI3K/Akt/mTOR, Nrf2/ARE, NF-κB, NLRP3, MAPKs, and Wnt/ß-catenin have been shown to contribute to AFB1-mediated toxic effects in mammalian cells. Curcumin, a natural product with multiple therapeutic activities (e.g., anti-inflammatory, antioxidant, anticancer, and immunoregulation activities), could revise AFB1-induced harmful effects by targeting these pathways. Therefore, the potential therapeutic use of curcumin against AFB1-related side effects and the underlying molecular mechanisms are summarized. This review, in our opinion, advances significant knowledge, sparks larger discussions, and drives additional improvements in the hazardous examination of AFTs and detoxifying the application of curcumin.

Chelerythrine-Induced Apoptotic Cell Death in HepG2 Cells Involves the Inhibition of Akt Pathway and the Activation of Oxidative Stress and Mitochondrial Apoptotic Pathway.

Chelerythrine (CHE) is a majorly harmful isoquinoline alkaloid ingredient in Chelidonium majus that could trigger potential hepatotoxicity, but the pivotal molecular mechanisms remain largely unknown. In the present study, CHE-induced cytotoxicity and the underlying toxic mechanisms were investigated using human HepG2 cells in vitro. Data showed that CHE treatment (at 1.25-10 µM)-induced cytotoxicity in HepG2 cells is dose-dependent. CHE treatment increased the production of ROS and induced oxidative stress in HepG2 cells. Additionally, CHE treatment triggered the loss of mitochondrial membrane potential, decreased the expression of mitochondrial complexes, upregulated the expression of Bax, CytC, and cleaved-PARP1 proteins and the activities of caspase-9 and caspase-3, and downregulated the expression of Bcl-XL, and HO-1 proteins, finally resulting in cell apoptosis. N-acetylcysteine supplementation significantly inhibited CHE-induced ROS production and apoptosis. Furthermore, CHE treatment significantly downregulated the expression of phosphorylation (p)-Akt (Ser473), p-mTOR (Ser2448), and p-AMPK (Thr172) proteins in HepG2 cells. Pharmacology inhibition of Akt promoted CHE-induced the downregulation of HO-1 protein, caspase activation, and apoptosis. In conclusion, CHE-induced cytotoxicity may involve the inhibition of Akt pathway and the activation of oxidative stress-mediated mitochondrial apoptotic pathway in HepG2 cells. This study sheds new insights into understanding the toxic mechanisms and health risks of CHE.

Preclinical safety evaluation of Macleaya Cordata extract: A re-assessment of general toxicity and genotoxicity properties in rodents.

Macleaya cordata extract (MCE) is widely used for its diverse pharmacological actions and beneficial effects on farm animals. Modern pharmacological studies have shown that it has anti-inflammatory, anti-cancer, and anti-bacterial activities, and is gradually becoming a long-term additive veterinary drug used to improve animal intestinal health and growth performance. Although some evidence points to the DNA mutagenic potential of sanguinarine (SAN), a major component of MCE, there is a lack of sufficient basic toxicological information on the oral route, posing a potential safety risk for human consumption of food of animal origin. In this study, we assessed the acute oral toxicity, repeated 90-day oral toxicity and 180-day chronic toxicity of MCE in rats and mice and re-evaluated the genotoxicity of MCE using a standard combined in vivo and ex vivo assay. In the oral acute toxicity test, the LD50 for MCE in rats and mice was 1,564.55 mg/kg (95% confidence interval 1,386.97-1,764.95 mg/kg) and 1,024.33 mg/kg (95% confidence interval 964.27-1,087.30 mg/kg), respectively. The dose range tested had no significant effect on hematology, clinical chemistry, and histopathological findings in rodents in the long-term toxicity assessment. The results of the bacterial reverse mutation, sperm abnormality and micronucleus test showed negative results and lack of mutagenicity and teratogenicity; the results of the rat teratogenicity test showed no significant reproductive or embryotoxicity. The results indicate that MCE was safe in the dose range tested in this preclinical safety assessment. This study provides data to support the further development of maximum residue limits (MRLs) for MCE.

The Flow-Induced Degradation and Vascular Cellular Response Study of Magnesium-Based Materials.

Magnesium (Mg)-based materials are considered as potential materials for biodegradable vascular stents, and some Mg-based stents have obtained regulatory approval. However, the development and application of Mg-based stents are still restricted by the rapid degradation rate of Mg and its alloys. In order to screen out the desirable Mg-based materials for stents, the degradation behavior still needs further systematic study, especially the degradation behavior under the action of near-physiological fluid. Currently, the commonly used Mg-based vascular stent materials include pure Mg, AZ31, and WE43. In this study, we systematically evaluated their corrosion behaviors in a dynamic environment and studied the effect of their degradation products on the behavior of vascular cells. The results revealed that the corrosion rate of different Mg-based materials was related to the composition of the elements. The dynamic environment accelerated the corrosion of Mg-based materials. All the same, AZ31 still shows good corrosion resistance. The effect of corrosive products on vascular cells was beneficial to re-endothelialization and inhibition of smooth muscle cell proliferation at the implantation site of vascular stent materials.

T-2 Toxin Induces Apoptotic Cell Death and Protective Autophagy in Mouse Microglia BV2 Cells.

T-2 toxin exposure could cause neurotoxicity; however, the precise molecular mechanisms remain unclear. In the present study, we investigated T-2 toxin-induced cytotoxicity and underlying molecular mechanisms using a mouse microglia BV2 cell line. The results show that T-2 toxin treatment-induced cytotoxicity of BV2 cells was dose- and time-dependent. Compared to the control, T-2 toxin treatment at 1.25-5 ng/mL significantly increased reactive oxygen species (ROS) production and triggered oxidative stress. T-2 toxin treatment also caused mitochondrial dysfunction in BV2 cells, which was evidenced by decreased mitochondrial transmembrane potential, upregulated expression of Bax protein, and decreased expression of Bcl-2 protein. Meanwhile, T-2 toxin treatment upregulated the expression of cleaved-caspase-3, cleaved-PARP-1 proteins, and downregulated the expression of HO-1 and nuclear Nrf2 proteins, finally inducing cell apoptosis in BV2 cells. N-acetylcysteine (NAC) supplementation significantly attenuated T-2 toxin-induced cytotoxicity. Moreover, T-2 toxin treatment activated autophagy and upregulated autophagy flux, and the inhibition of autophagy significantly promoted T-2 toxin-induced cell apoptosis. Taken together, our results reveal that T-2 toxin-induced cytotoxicity in BV2 cells involves the production of ROS, the activation of the mitochondrial apoptotic pathway, and the inhibition of the Nrf2/HO-1 pathway. Our study offers new insight into the underlying molecular mechanisms in T-2 toxin-mediated neurotoxicity.

Safety assessment of marigold flavonoids from marigold inflorescence residue.

ETHNOPHARMACOLOGICAL RELEVANCE: Marigold flavonoids, extracted from marigold (Tagetes erecta L.) inflorescence residues, have attracted significant attention with respect to antioxidant, anti-inflammatory and chelating properties. However, the toxicity of marigold flavonoids have not yet been fully investigated. AIM OF THE STUDY: The main purpose of this study was to assess the safety of marigold flavonoids extracted from Marigold (Tagetes erecta L.) in order to provide information on its nonclinical safety. Thus, the acute oral toxicity, in vitro Ames test, sperm aberration study, bone marrow micronucleus test, subchronic oral toxicity test, and teratogenic potential were carried out in rats or mice. MATERIALS AND METHODS: For an acute oral toxicity test, SD rats and ICR mice (male and female, n = 5) orally received a single dose of 5000 mg/kg marigold flavonoids. Evaluation of marigold flavonoids genotoxic potential with a battery of tests, including an in vitro bacterial reverse mutation test using four mutant strains of Salmonella typhimurium (TA97、TA98、TA100、TA102), an sperm aberration test and an in vivo micronucleus test using bone marrow cells ICR mice that were orally administered marigold flavonoids, an subchronic oral toxicity study and teratogenic test employing male and female SD rats that were orally administered marigold flavonoids. All animals tests were completed in accordance with GB 15193 for toxicity tests. RESULTS: In the acute oral toxicity test, marigold flavonoids given at the dose of 5000 mg/kg body weight for 14 days didn't produce any abnormal clinical symptoms or mortality in SD rats and ICR mice (both sex, n = 5). There was no evidence of genotoxicity of marigold flavonoids based on the results of the in vitro bacterial reverse mutation test (up to 1250 µg/plate), the sperm aberration test (up to 5000 mg/kg body weight), the in vivo micronucleus test (up to 5000 mg/kg body weight), the subchronic oral toxicity study (up to 10 g/kg feed dose) and the teratogenic test (up to 1250 mg/kg body weight). CONCLUSIONS: We found that marigold flavonoids are safe with regard to acute toxicity in rats or mice as well as genotoxicity such as mutagenesis or clastogenesis under the present experimental conditions. These results might support the safety of marigold flavonoids as a potential therapeutic material for the traditional use of herbal medicines and for the further development of novel antioxidant.

Lethality of Zinc Oxide Nanoparticles Surpasses Conventional Zinc Oxide via Oxidative Stress, Mitochondrial Damage and Calcium Overload: A Comparative Hepatotoxicity Study.

Zinc oxide nanoparticles (ZnO NPs) with high bioavailability and excellent physicochemical properties are gradually becoming commonplace as a substitute for conventional ZnO materials. The present study aimed to investigate the hepatotoxicity mechanism of ZnO NPs and traditional non-nano ZnO particles, both in vivo and in vitro, and identify the differences in their toxic effects. The results showed that the extent and conditions of zinc ion release from ZnO NPs were inconsistent with those of ZnO. The RNA-seq results revealed that the expression quantity of differentially expressed genes (DEGs) and differentially expressed transcripts (DETs) affected by ZnO NPs was more than in ZnO, and the overall differences in genes or transcripts in the ZnO NPs group were more pronounced than in the ZnO group. Furthermore, the cell inactivation, oxidative stress, mitochondrial damage, and intracellular calcium overload induced by ZnO NPs were more serious than ZnO in HepG2 cells. Moreover, compared with traditional ZnO, the rat liver damage induced by ZnO NPs was more significant, with evidence of higher AST and ALT levels, weaker antioxidant capacity, and more serious histopathological damage (p < 0.05). In summary, the hepatotoxicity of ZnO NPs was more serious than that of conventional ZnO, which is helpful to understand the hepatotoxicity mechanism of Zn compounds in different states and improve the risk assessment of novel nano ZnO products in a variety of applications.

Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy.

Ivermectin (IVM) could cause potential neurotoxicity; however, the precise molecular mechanisms remain unclear. This study explores the cytotoxicity of IVM in human neuroblastoma (SH-SY5Y) cells and the underlying molecular mechanisms. The results show that IVM treatment (2.5-15 µM) for 24 h could induce dose-dependent cell death in SH-SY5Y cells. Compared to the control, IVM treatment significantly promoted the production of ROS, mitochondrial dysfunction, and cell apoptosis. IVM treatment also promoted mitophagy and autophagy, which were charactered by the decreased expression of phosphorylation (p)-Akt and p-mTOR proteins, increased expression of LC3II, Beclin1, ATG5, PINK, and Pakin1 proteins and autophagosome formation. N-acetylcysteine treatment significantly inhibited the IVM-induced production of ROS and cell death in SH-SY5Y cells. Autophagy inhibitor (e.g., 3-methyladenine) treatment significantly inhibited IVM-induced autophagy, oxidative stress, and cell apoptosis. Taken together, our results reveal that IVM could induce autophagy and apoptotic cell death in SH-SY5Y cells, which involved the production of ROS, activation of mitochondrial pathway, and inhibition of Akt/mTOR pathway. Autophagy inhibition improved IVM-induced oxidative stress and apoptotic cell death in SH-SY5Y cells. This current study provides new insights into understanding the molecular mechanism of IVM-induced neurotoxicity and facilitates the discovery of potential neuroprotective agents.

Safety assessment of MPTA: An oral acute and 90-day sub-chronic toxicity study in Sprague-Dawley rats.

MPTA is a novel extract product derived from Macleaya cordata (Willd.) R. Br., which has good anti-inflammatory and antioxidant activity. The aim of this study was to investigate the acute oral toxicity and 90-day sub-chronic oral toxicity of MPTA. In the acute toxicity study, 50 SD rats of both sexes were randomly divided into 5 groups and dosed in a gradient from 197.53 mg/kg to 1000.00 mg/kg bw. Toxic effects were observed up to 14 days and LD50 was calculated. In a subchronic toxicity test, male and female SD rats were orally dosed repeatedly with 96.40, 19.28, 3.86 mg/kg bw of MPTA for 90 days. In addition, a control group was set up in the subchronic study. The acute toxicity test showed that the oral LD50 of MPTA was 481.99 mg/kg with a 95% confidence interval of 404.24-574.70 mg/kg. MPTA did not appear to induce toxic effects in the longer term in terms of food and water consumption, weight gain, haematological and clinical biochemical parameters and pathological examination. The first data on the potential toxicity of MPTA was provided to highlight the safety of short-term to longer-term oral administration of MPTA, and the experimental results yield and establish a NOEAL of 96.40 mg/kg/d for MPTA.

Colistin-induced pulmonary toxicity involves the activation of NOX4/TGF-ß/mtROS pathway and the inhibition of Akt/mTOR pathway.

Colistin therapy can cause pulmonary toxicity, however, our understanding of the underlying molecular mechanism remains incomplete. This study aimed to investigate the molecular mechanism of colistin-induced pulmonary toxicity in vitro and in vivo. Our results showed that intraperitoneal colistin treatment significantly increased the expression of TGF-ß and NOX4 protein and mRNA, then triggers oxidative stress, mitochondrial dysfunction, and apoptosis in the lung tissue of mice and A549 cells. Moreover, colistin treatment significantly increased levels of mitochondrial ROS (mtROS) and autophagy flux in A549 cells. Inhibition of NOX4 protected A549 cells against colistin-induced mtROS and apoptosis. Colistin treatment also down-regulated the expression of p-Akt and p-mTOR proteins (all P < 0.05 or 0.01) in lung tissues of mice or A549 cells. Inhibition of autophagy or Akt pathways by chloroquine (CQ), 3-Methyladenine (3-MA) or LY294002 promoted colistin-induced mitochondrial damage, and caspase-dependent cellular apoptosis. Whereas, activation of autophagy by rapamycin pretreatment of A549 cells partly abolished colistin-induced cytotoxicity, mitochondrial dysfunction, and apoptosis. This is first study to show that colistin-induced pulmonary toxicity involves the activation of TGF-ß/NOX4/mtROS pathway and the inhibition of Akt/mTOR pathway in lung tissues of mice and highlights the key protective role of autophagy activation.

Food-Origin Mycotoxin-Induced Neurotoxicity: Intend to Break the Rules of Neuroglia Cells.

Mycotoxins are key risk factors in human food and animal feed. Most of food-origin mycotoxins could easily enter the organism and evoke systemic toxic effects, such as aflatoxin B1 (AFB1), ochratoxin A (OTA), T-2 toxin, deoxynivalenol (DON), zearalenone (ZEN), fumonisin B1 (FB1), and 3-nitropropionic acid (3-NPA). For the last decade, the researches have provided much evidences in vivo and in vitro that the brain is an important target organ on mycotoxin-mediated neurotoxic phenomenon and neurodegenerative diseases. As is known to all, glial cells are the best regulator and defender of neurons, and a few evaluations about the effects of mycotoxins on glial cells such as astrocytes or microglia have been conducted. The fact that mycotoxin contamination may be a key factor in neurotoxicity and glial dysfunction is exactly the reason why we reviewed the activation, oxidative stress, and mitochondrial function changes of glial cells under mycotoxin infection and summarized the mycotoxin-mediated glial cell proliferation disorders, death pathways, and inflammatory responses. The purpose of this paper is to analyze various pathways in which common food-derived mycotoxins can induce glial toxicity and provide a novel perspective for future research on the neurodegenerative diseases.