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Dibromoacetic acid (DBA) is one of haloacetic acids, often as a by-product of disinfection in drinking water. DBA is a multiple-organ carcinogen in rodent animals, but little research on its hepatotoxicity has been conducted and its mechanism has not been elucidated. In this study, we found that DBA could induce obvious hepatotoxcity in Balb/c mice as indicated by histological changes, increasing serum level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and accumulation of hepatic glycogen, after the mice were administered DBA at doses of 1.25, 5, and 20 mg/kg body weight for 28 days via oral gavage. In mechanism study, DBA induced oxidative stress as evidenced by increasing the level of malondialdehyde (MDA), reactive oxygen species (ROS) in the liver, advanced oxidative protein products (AOPPs) in the serum, and decreasing the level of glutathione (GSH) in the liver. DBA induced inflammation in the liver of the mice which is supported by increasing the production of tumor necrosis factor- α (TNF- α ) and the mRNA levels of TNF- α , interleukin-6 (IL-6), interleukin-1 β (IL-1 β ), and nuclear factor κ B (NF- κ B) in the liver. DBA also upregulated the protein levels of Toll-like receptor (TLR) 4, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), inhibitor of nuclear factor κ B alpha (I κ B- α ), nuclear factor κ B p65 (NF- κ B p65), and the phosphoralation of P38 mitogen-activated protein kinase (P38MAPK) and c-Jun N-terminal kinase (JNK). Conclusion . DBA could induce hepatotoxicity in mice by oral exposure; the mechanism is related to oxidative stress, inflammation, and Toll-like receptor 4 signaling pathway activation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Tingting Gong et al.)

Diisodecyl phthalate (DIDP) is commonly used as a plasticizer in industrial and consumer products, however, its toxicity remains unclear. This study investigated the possible involvement of oxidative stress in DIDP-induced liver and kidney toxicity. Liver function and kidney function, tissue lesions, oxidative stress biomarkers, inflammatory mediators and apoptosis factors were investigated in this study. The results showed that oral exposure to DIDP induced a marked increase in lever of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urinary nitrogen (UREA) and creatinine (CREA), decrease in albumin (ALB) level, as well as causing hepatic and renal histopathological change. Investigation of the role of oxidative stress pathways showed that DBP exposure could lead to a significant increase in levels of reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB), while a decrease in glutathione (GSH) levels were observed. Administration of vitamin E to DIDP-treated mice restored these biochemical parameters to within normal levels, and resulted in less damage to livers and kidneys. Overall, these results suggest that the oxidative stress pathway is involved in DIDP-induced toxicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dibromoacetic acid (DBA) exsits in drinking water as a by-product of disinfection as a result of chlorination or ozonation processes. Hippocampus and pre-frontal cortex are the key structures in memory formation and weanling babies are more sensitive to environmental toxicant than adults, so this study was conducted to evaluate the potential neurotoxicity effects of DBA exposure when administered intragastrically for 4 weeks to weanling Sprague-Dawley rats, at concentration of 0, 20, 50, 125 mg/kg via the neurobehavioral and neurochemical effects. Results indicated that animals weight gain and food consumption were not significantly affected by DBA. However, morris water maze test showed varying degrees of changes between control and high-dose group. Additionally, the level of malondialdehyde (MDA) and generation of reactive oxygen species (ROS) in the hippocampus and pre-frontal cortex of rats increased significantly. The activities of total superoxide dismutase (SOD) and the glutathione (GSH) content in the hippocampus and pre-frontal cortex of rats decreased significantly after treatment with DBA. Treatment with DBA increased the protein and mRNA expression of Iba-1, NF-κB, TNF-α, IL-6, IL-1β and HO-1 in the hippocampus and pre-frontal cortex of rats. These data suggested that DBA had a toxic influence on the hippocampus and pre-frontal cortex of rats, and that the mechanism of toxicity might be associated with the neuroinflammation response and oxidative stress.

Introduction: Ovarian aging is characterized by a gradual decline in quantity and quality of oocytes and lower chance of fertility. Better understanding the genetic modulation during ovarian aging can further address available treatment options for aging-related ovarian diseases and fertility preservation. Methods: A novel technique spatial transcriptomics (ST) was used to investigate the spatial transcriptome features of rat ovaries. Transcriptomes from ST spots in the young and aged ovaries were clustered using differentially expressed genes. These data were analyzed to determine the spatial organization of age-induced heterogeneity and potential mechanisms underlying ovarian aging. Results: In this study, ST technology was applied to profile the comprehensive spatial imaging in young and aged rat ovary. Fifteen ovarian cell clusters with distinct gene-expression signatures were identified. The gene expression dynamics of granulosa cell clusters revealed three sub-types with sequential developmental stages. Aged ovary showed a significant decrease in the number of granulosa cells from the antral follicle. Besides, a remarkable rearrangement of interstitial gland cells was detected in aging ovary. Further analysis of aging-associated transcriptional changes revealed that the disturbance of oxidative pathway was a crucial factor in ovarian aging. Conclusions: This study firstly described an aging-related spatial transcriptome changes in ovary and identified the potential targets for prevention of ovarian aging. These data may provide the basis for further investigations of the diagnosis and treatment of aging-related ovarian disorders. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effects of leaf extract from Lithocarpus polystachyus Rehd. on type II diabetes mellitus (T2DM) and the active ingredients of this effect. In addition, this study determined, for the first time, the underlying molecular and pharmacological mechanisms of the extracts on hyperglycemia using long-term double high diet-fed and streptozotocin (STZ) induced type II diabetic mice. In the present study, leaf extract, phloridzin and trilobatin were assessed in vivo (gavage) and in vitro (non-invasive micro-test technique, NMT) in experimental T2DM mice. The biochemical parameters were measured including blood glucose and blood lipid level, liver biochemical indexes, and hepatic glycogen. The relative expression of glycometabolism-related genes was detected. The effect of leaf extracts on physiological glucose flux in liver tissue from control and T2DM mice was also investigated. Body weight of experimental T2DM mice increased significantly after the first week, but stabilized over the subsequent three weeks; body weight of all other groups did not change during the four weeks’ study. After four weeks, all treatment groups decreased blood glucose, and treatment with leaf extract had numerous positive effects: a) promoted in glucose uptake in liver, b) increased synthesis of liver glycogen, c) reduced oxidative stress, d) up-regulation of glucokinase (GK), glucose transporter 2 (GLUT2), insulin receptor (IR) and insulin receptor substrate (IRS) expression in liver, e) down-regulation of glucose-6-phosphatase (G-6-P) expression, and f) ameliorated blood lipid levels. Both treatment with trilobatin or phloridzin accelerated liver glycogen synthesis, decreased oxidative stress and increased expression of GK. IRS and phosphoenolpyruvate carboxykinase (PEPCK) were both up-regulated after treatment with trilobatin. Expression of GLUT2, PEPCK and G-6-P were also increased in liver tissue after treatment with phloridzin. Our data indicate that leaf extract from L. polystachyus Rehd. has a preferable hypoglycemic effects than trilobatin or phloridzin alone. Leaf extract significantly increased glucose uptake and hepatic glycogen synthesis while also inducing a decline of hepatic gluconeogenesis and oxidative stress in T2DM mice. From this study, we draw conclusions that L. polystachyus promoted glycogen synthesis in T2DM mice, and that the active compounds were not only the trilobatin or phloridzin. [ABSTRACT FROM AUTHOR]

There is evidence of an association between exposure to ambient fine particulate matter (PM2.5) and female ovarian dysfunction in adults. However, it is not fully clear whether maternal exposure to PM2.5 negatively affects the ovarian function in offspring. The size of primordial follicle pool, definitely assembled during fetal life, determines ovarian reserve and ovarian function. In this study, female C57BL/6 mice were exposed to either ambient PM2.5 (mean daily concentration 49 µg/m3) or filtered air through a whole-body exposure system for 4 weeks before mating, and remained exposed until postpartum. We found that maternal exposure to PM2.5 reduces the initial size of primordial follicle pool and impairs its development in offspring mice. The number of primordial follicles and total follicles was decreased in PM2.5-exposed offspring mice on postnatal day 3 (PND3) and postnatal day 7 (PND7). Maternal PM2.5 exposure promoted the activation of primordial follicles and upregulated the level of p-AKT in offspring mice, accelerating the depletion of primordial follicle pool. While LY294002, a specific inhibitor of PI3K, reversed the overactivation of primordial follicles induced by PM2.5. Besides, maternal PM2.5 exposure induced follicular atresia and granulosa cell apoptosis, increased the accumulation of lipid peroxidation products 4-HNE, and elevated the expression of oxidative stress-related genes and p-p65, p-IκBα in offspring mice. While N-acetylcysteine (NAC) pretreatment abolished the increases of apoptosis, reactive oxygen species (ROS), p-p65 and p-IκBα levels in ovarian granulosa COV434 cells induced by PM2.5 exposure. These findings reveal that maternal exposure to PM2.5 decreases the initial size of primordial follicle pool, and impairs ovarian follicular development in offspring mice. Our data suggest that this involves the activation of the PI3K/AKT/FoxO3a pathway and the ROS-dependent NF-κB pathway. Our study implicates a link between maternal PM2.5 exposure and ovarian reserve in offspring, and improves our understanding of the effects of PM2.5 on reproductive health. [Display omitted] • Maternal PM2.5 exposure reduces ovarian reserve. • Maternal PM2.5 exposure accelerates primordial follicle activation through the PI3K/AKT/FoxO3a pathway. • Maternal PM2.5 exposure induces follicular atresia through ROS-dependent NF-κB pathway. [ABSTRACT FROM AUTHOR]

Carbon tetrachloride (CCL 4) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL 4 is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL 4 on ovarian function has not been reported. In this study, we found that the mice treated with CCL 4 showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17β-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1β, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL 4 group. In the CCL 4 treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL 4 could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL 4 inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL 4 exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis. [Display omitted] • CCL 4 exposure decreased the number of healthy follicle and caused ovarian endocrine dysfunction. • CCL 4 -induced oxidative stress and inflammatory response led to ovarian fibrosis. • CCL 4 exposure blocked oocytes development and maturation. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of tanshinone II A ( Tan II A) on the intermittent high glucose (IHG)- induced oxidative stress and apoptosis of Schwann cells (SCs) in suckling rat. Methods Cultured SCs of newborn suckling rats were randomized into several groups including control (con, 5.6 mmol/L glucose), stable high glucose (HG, 50 mmol/L glucose), IHG (5.6 and 50.0 mmol/L glucoseper 8 h alternative), osmotic control, ALA (500 µmol/L) and IHG in the presence of 0.1, 1.0, 10.0 µmol/L Tan II A. Apoptosis rate, oxidative stress level, expression of apoptosis related proteins and the mRNA in the cells were detected. Results (1) The percentages of apoptotic cells exposed to HG ((34.57± 2.45)%) and IHG ((40.17±2.33)%) were significantly higher than that in control group ((4.74±0.26)%). Furthermore, apoptosis rate of IHG was much higher than that of HG (t=3.70,P<0.01). (2) ROS and 8-OHdG levels increased significantly in the IHG group compared with those in control and HG groups (F=73.44, 194.21, P<0.01). IHG exposure up-regulated expression of bax protein and mRNA (F=66.78, 126.69, both P<0.01), while down-regulating expression of bcl-2 protein and mRNA (F=151.88,54.99,both P<0.01). In addition, IHG increased activities of caspase-3 and (poly(ADP-ribose) polymerase, PARP) (129% ,18% , 139% ,56% ,all P<0.01). (3) Treatment with 1.0 µmol/L and 10.0 µmol/L of Tan IIA inhibited IHG-enhanced ROS production and 8-OHdG levels (t=3.50-6.47,P<0.05). Bax protein and mRNA (t=3.59-5.39,P<0.01), PARP and caspase-3 activation (42%,61%,13%,34%,all P<0.01), and SC apoptosis (t= 12.39, 21.26, P<0.01)were decreased with Tan µ A, too. Conclusions Tan µ A decreases IHG-induced apoptosis via reducing oxidative stressin SCs of newborn suckling rats. [ABSTRACT FROM AUTHOR]

Embryonic exposure to environmental chemicals may result in specific chronic diseases in adulthood. Parabens, a type of environmental endocrine disruptors widely used in pharmaceuticals and cosmetics, have been shown to cause a decline in women's reproductive function. However, whether exposure to parabens during pregnancy also negatively affect the ovarian function of the female offspring in adulthood remains unclear. This study aims to investigate the effects of prenatal propylparaben (PrP) exposure on the ovarian function of adult mice aged 46 weeks, which is equivalent to the age of 40 years in women. Pregnant ICR mice were intraperitoneally injected with human-relevant doses of PrP (i.e., 0, 7.5, 90, and 450 mg/kg/day) during the fetal sex determination period—from embryonic day E7.5 to E13.5. Our results revealed that ovarian aging was accelerated in PrP-exposed mice at 46 weeks, with altered regularity of the estrous cycle, decreased serum estrogen (E2) and progesterone (P4) levels, reduced size of the primordial follicle pool, and increased number of atretic follicles. It was found that prenatal exposure to human-relevant doses of PrP exacerbated ovarian oxidative stress, inflammation, and fibrosis, which promoted follicular atresia by activating the mitochondrial apoptosis pathway. To compensate, the depletion of primordial follicles was also accelerated by activating the PI3K/AKT/mTOR signaling pathway in PrP-exposed mice. Moreover, PrP induced hypermethylation of CpG sites in the promoter region of Cyp11a1 (a 17.16–64.28% increase) partly led to the disrupted steroidogenesis, and the altered methylation levels of imprinted genes H19 and Peg3 may also contribute to the phenotypes observed. These remarkable findings highlight the embryonic origin of ovarian aging and suggest that a reduced use of PrP during pregnancy should be advocated. [Display omitted] •Prenatal PrP exposure decreased steroidogenesis and the ovarian reserve of adult mice. •Oxidative stress-induced inflammation and fibrosis promoted follicle atresia. •The hypermethylation of Cyp11a1 decreased its expression level in PrP-exposed mice. •Changed methylation level of H19 and Peg3 contributed to PrP-induced ovarian aging. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) presents profound ramifications for patients, leading to diminished motor and sensory capabilities distal to the lesion site. Once SCI occurs, it not only causes great physical and psychological problems for patients but also imposes a heavy economic burden. Ezrin is involved in various cellular processes, including signal transduction, cell death, inflammation, chemotherapy resistance and the stress response. However, whether Ezrin regulates functional repair after SCI and its underlying mechanism has not been elucidated. Here, our results showed that there is a marked augmentation of Ezrin levels within neurons and Ezrin inhibition markedly diminished glial scarring and bolstered functional recuperation after SCI. RNA sequencing indicated the potential involvement of pyroptosis, oxidative stress and autophagy in the enhancement of functional recovery upon reduced Ezrin expression. Moreover, the inhibition of Ezrin expression curtailed pyroptosis and oxidative stress by amplifying autophagy. Our studies further demonstrated that Ezrin inhibition promoted autophagy by increasing TFEB activity via the Akt-TRPML1-calcineurin pathway. Finally, we concluded that inhibiting Ezrin expression alleviates pyroptosis and oxidative stress by enhancing TFEB-driven autophagy, thereby promoting functional recovery after SCI, which may be a promising therapeutic target for SCI treatment. [Display omitted] • Ezrin inhibition promotes functional recovery after spinal cord injury. • Ezrin inhibition promotes autophagy to suppress oxidative stress and pyroptosis in spinal cord injury. • The effects following Ezrin inhibition are mediated by promoting activation of TFEB in spinal cord injury. • Ezrin regulates TFEB through the TRPML1-calcineurin signaling pathway in spinal cord injury. [ABSTRACT FROM AUTHOR]

Introduction: Dichloroacetic acid (DCA), a by‐product of disinfection in drinking water, is a multiple organ carcinogen in humans and animals. Still, little research on its neurotoxicity and its underlying mechanism has not been elucidated. Methods: Sprague Dawley rats were intragastrically treated with DCA at 10, 30, 90 mg/kg body weight from pregnancy till delivery. At eight weeks of age of pups, we assessed cognitive performance using the standard behavioral tests. And the hippocampus structure and ultrastructure were evaluated using light and electron microscope. The oxidative stress indicators and neuroinflammation factors were measured with the corresponding kits. The mRNA and protein of synaptic factors were detected using RT‐PCR and Western blot. Results: The results indicated that maternal weight gain and offspring birthweight were not significantly affected by DCA. However, behavioral tests, including morris water maze and step down, showed varying degrees of changes in DCA‐treated pups. Additionally, we found significant differences in hippocampal neurons by histomorphological observation. Biochemical analysis results indicated superoxide dismutase (SOD) and catalase (CAT) activities, as well as reactive oxygen species (ROS), nitric oxide (NO), and reduced glutathione (GSH) levels, were affected by DCA accompanying with DNA damage. Moreover, the results showed that the neuroinflammation factors (TNF‐α, IL‐6, IL‐1β) in DCA treatment groups increased significantly compared with the control pups. And we also found that DCA treatment caused a differential modulation of proteins (BDNF, cAMP‐response element‐binding protein1 (CREB1), p‐CREB1, postsynaptic density‐95 (PSD‐95), synapsin I, p‐synapsin I), and mRNA (BDNF, PSD‐95). Conclusions: Taken together, these results above showed that oxidative stress, neuroinflammation response, and weakened synaptic plasticity in pups hippocampus induced by fetal exposure to DCA could damage the function of memory and cognition in the adulthood. [ABSTRACT FROM AUTHOR]

Abstract Diisodecyl phthalate (DIDP) is a new type of phthalate used in the coating of pharmaceutical pills and in plastic food wrappers. This research was conducted to investigate whether DIDP could cause learning and memory impairment in mice, using formaldehyde (FA) to construct a positive control. Behavioral analysis showed that oral administration of 15 mg kg−1·d−1 DIDP combined with inhalation of 1 mg m−3 FA led to learning and memory impairment in mice. Histopathological observations of the brain showed that the pathological alterations in the hippocampi. Detection of testosterone (T) and estradiol (E2) levels in the brain and serum showed that E2 levels were associated with learning and memory disorders. Reactive oxygen species (ROS), reduced glutathione (GSH), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OH-dG) revealed the increased oxidative stress levels. Detection of caspase-3, NF-κB, the phosphorylated cAMP response-element binding protein (p-CREB) and the brain derived neurotrophic factor (BDNF) showed that the protective effect mediated by BDNF, is reduced. However, some of these effects were blocked by the administration of Vitmin E (VitE, 100 mg kg−1·d−1) or 17β-estradiol (17β-E2, 100 μg kg−1). These data suggest that DIDP may aggravate the FA-exposure-induced learning and memory impairment in mice, and that 17β-E2 could be utilized to avoid these adverse effects. Graphical abstract Image 1 Highlights • DIDP aggravates the FA-exposure-impaired learning and memory via oxidative stress. • DIDP causes learning and memory disabilities in mice by abnormal estradiol levels. • 17β-E2 could be utilized to avoid DIDP-induced learning and memory impairment. [ABSTRACT FROM AUTHOR]

Bone marrow mesenchymal stem cells (BMSCs) therapy for tissue repair is limited by low survival of cells transplanted in the recipient sites after spinal cord injury (SCI). Here, we investigated the effects of a calpain inhibitor (MDL28170) on BMSCs survival by a rat model of spinal cord injury in vitro and in vivo. Conditioned medium from hypoxia injured VSC4.1 motor neurons (Hypoxia-CM) were collected to mimic the micro-environment of injured spinal cord. Tunicamycin was also applied to induce endoplasmic reticulum (ER) stress in BMSCs. The CCK-8 assay, LDH leakage assay and flow cytometer assay demonstrated that MDL28170 could enhance BMSCs survival in response to Hypoxia-CM and tunicamycin. Moreover, MDL28170 significantly enhanced GFP-positive BMSCs survival in vivo after transplantation into the contused spinal cord of SCI rats. The protective effects of MDL28170 on BMSCs survival may inhibit the activation of calpain and the downstream ER stress-induced apoptosis. The present results suggested for the first time that MDL28170 with BMSCs transplant helped to rescue cells in injured spinal cord by modulating the ER stress-induced apoptosis. The calpain inhibitor, MDL28170 may have the promising new strategies for promoting the survival of transplanted BMSCs on cell-based regenerative medicine. [ABSTRACT FROM AUTHOR]