Chlorpyrifos-induced suppression of the antioxidative defense system leads to cytotoxicity and genotoxicity in macrophages.

Chlorpyrifos, widely used for pest control, is known to have various harmful effects, although its toxic effects in macrophages and the mechanisms underlying its toxicity remain unclear. The present study investigated the toxic effects of chlorypyrifos in a macrophage cell line. Here, we found that chlorpyrifos induced cytotoxicity and genotoxicity in RAW264.7 macrophages. Moreover, chlorpyrifos induced intracellular ROS production, subsequently leading to lipid peroxidation. Chlorpyrifos reduced the activation of antioxidative enzymes including superoxide dismutase, catalase, and glutathione peroxidase. Chlorpyrifos upregulated HO-1 expression and activated the Keap1-Nrf2 pathway, as indicated by enhanced Nrf2 phosphorylation and Keap1 degradation. Chlorpyrifos exerted effects on the following in a dose-dependent manner: cytotoxicity, genotoxicity, lipid peroxidation, intracellular ROS production, antioxidative enzyme activity reduction, HO-1 expression, Nrf2 phosphorylation, and Keap1 degradation. Notably, N-acetyl-L-cysteine successfully inhibited chlorpyrifos-induced intracellular ROS generation, cytotoxicity, and genotoxicity. Thus, chlorpyrifos may induce cytotoxicity and genotoxicity by promoting intracellular ROS production and suppressing the antioxidative defense system activation in macrophages.

Vascular endothelial dysfunction induced by 3-bromofluoranthene via MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

A unique circ_0067716/EIF4A3 double-negative feedback loop impacts malignant transformation of human bronchial epithelial cells induced by benzo(a)pyrene.

Benzo(a)pyrene as a pervasive environmental contaminant is characterized by its substantial genotoxicity, and epidemiological investigations have established a correlation between benzo(a)pyrene exposure and the susceptibility to human lung cancer. Notably, much research has focused on the link between epigenetic alterations and lung cancer induced by chemicals, although circRNAs are also emerging as relevant contributors to the carcinogenic process of benzo(a)pyrene. In this study, we identified circ_0067716 as being significantly upregulated in response to stress injury and downregulated during malignant transformation induced by benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) in human bronchial epithelial cells. The observed differential expression of circ_0067716 in cells treated with BPDE for varying durations suggests a strong correlation between this circRNA and BPDE exposure. The tissue samples of lung cancer patients also suggest that a lower circ_0067716 expression is associated with BPDE-DNA adduct levels. Remarkably, we demonstrate that EIF4A3, located in the nucleus, interacts with the flanking sequences of circ_0067716 and inhibits its biogenesis. Conversely, circ_0067716 is capable of sequestering EIF4A3 in the cytoplasm, thereby preventing its translocation into the nucleus. EIF4A3 and circ_0067716 can form a double-negative feedback loop that could be affected by BPDE. During the initial phase of BPDE exposure, the expression of circ_0067716 was increased in response to stress injury, resulting in cell apoptosis through the involvement of miR-324-5p/DRAM1/BAX axis. Subsequently, as cellular adaptation progressed, long-term induction due to BPDE exposure led to an elevated EIF4A3 and a reduced circ_0067716 expression, which facilitated the proliferation of cells by stabilizing the PI3K/AKT pathway. Thus, our current study describes the effects of circ_0067716 on the genotoxicity and carcinogenesis induced by benzo(a)pyrene and puts forwards to the possible regulatory mechanism on the occurrence of smoking-related lung cancer, providing a unique insight based on epigenetics.

PS-MPs or their co-exposure with cadmium impair male reproductive function through the miR-199a-5p/HIF-1α-mediated ferroptosis pathway.

Microplastics (MPs) and cadmium (Cd) exist extensively in ambient environments and probably influence negatively on human health. However, the potential reproductive toxicity of MPs or MPs + Cd remains unknown. This study was aimed to observe the reproductive changes of male mice treated orally for 35 days with PS-MPs (100 mg/kg), CdCl2 (5 mg/kg) and PS-MPs plus CdCl2 mixture. We found that subchronic exposure to PS-MPs damaged mouse testicular tissue structure, reduced sperm quality and testosterone levels. Moreover, the reproductive toxicity in 0.1 µm group was stronger than 1 µm group, and mixture group was more severe than single particle size ones. Meanwhile, co-exposure of PS-MPs and Cd exacerbated reproductive injury in male mice, with an ascending toxicity of Cd, 1 µm + Cd, 0.1 µm + Cd, and 0.1+1 µm + Cd. In addition, we discovered that the testicular damage induced by PS-MPs or PS-MPs + Cd was associated with interfering the miR-199a-5p/HIF-1α/ferroptosis pathway. Promisingly, these findings will shed new light on how PS-MPs and PS-MPs + Cd damage male reproductive function.

Aluminum exposure induces central nervous system impairment via activating NLRP3-medicated pyroptosis pathway.

PURPOSE: Aluminum is an environmental toxicant whose long-term exposure is closely associated with nervous system impairment. This study mainly investigated neurological impairment induced by subchronic aluminum exposure via activating NLRP3-medicated pyroptosis pathway. METHODS: In vivo, Kunming mice were exposed to AlCl3 (30.3 mg/kg, 101 mg/kg and 303 mg/kg) via drinking water for 3 months, and administered with Rsv (100 mg/kg) by gavage for 1 month. Cognitive impairment was assessed by Morris water maze test, and pathological injury was detected via H&E staining. BBB integrity, pyroptosis and neuroinflammation were evaluated through western blotting and immunofluorescence methods. In vitro, BV2 microglia was treated with AlCl3 (0.5 mM, 1 mM and 2 mM) to sensitize pyroptosis pathway. The protein interaction was verified by co-immunoprecipitation, and neuronal damage was estimated via a conditioned medium co-culture system with BV2 and TH22 cells. RESULTS: Our results showed that AlCl3 induced mice memory disorder, BBB destruction, and pathological injury. Besides, aluminum caused glial activation, sensitized DDX3X-NLRP3 pyroptosis pathway, released cytokines IL-1ß and IL-18, initiating neuroinflammation. BV2 microglia treated with AlCl3 emerged hyperactivation and pyroptotic death, and Ddx3x knockdown inhibited pyroptosis signaling pathway. DDX3X acted as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome and G3BP1 stress granules. Furthermore, aluminum-activated microglia had an adverse effect on co-cultured neurons and destroyed nervous system homeostasis. CONCLUSION: Aluminum exposure could induce pyroptosis and neurotoxicity. DDX3X determined live or die via selectively regulating pro-survival stress granules or pro-death NLRP3 inflammasome. Excessive activation of microglia might damage neurons and aggravate nerve injury.

Active peptides with hypoglycemic effect obtained from hemp (Cannabis sativa L) protein through identification, molecular docking, and virtual screening.

Hemp (Cannabis sativa L) seeds are rich in proteins of high nutritional value, which makes the study of beneficial properties of hemp seed proteins and peptides, such as hypotensive and hypoglycemic effects, increasingly attractive. The present results confirm the good processability and stability of the hemp protein hydrolysate obtained by enzymatic hydrolysis of non-dehulled hemp seed meal (NDHM). Six peptides with potential hypoglycemic activity were obtained by ethanol-graded precipitation, Nano LC-Q-Orbitrap-MS/MS mass spectrometry, and computerized virtual screening. Further, validation experiments for in vitro synthesis showed that TGLGR, SPVI, FY, and FR exhibited good α-glucosidase inhibitory activity, respectively. Animal experiments showed that the hemp protein peptides modulated blood glucose and blood lipids in hyperglycemic rats. These results indicate that hemp protein peptides can reduce blood glucose levels in hyperglycemic rats, suggesting that hemp proteins may be a promising natural source for the prevention and treatment of hyperglycemia.

Cigarette smoke triggers calcium overload in mouse hippocampal neurons via the ΔFOSB-CACNA2D1 axis to impair cognitive performance.

A growing body of evidence shows that cigarette smoking impairs cognitive performance. The 'Calcium Hypothesis' theory of neuronopathies reveals a critical role of aberrant calcium signaling in compromised cognitive functions. However, the underlying implications of abnormalities in calcium signaling in the neurotoxicity induced by cigarette smoke (CS) have not yet been identified. CACNA2D1, an important auxiliary subunit involved in the composition of voltage-gated calcium channels (VGCCs), was reported to affect the calcium signaling in neurons by facilitating VGCCs-mediated Ca2+ influx. ΔFOSB, an alternatively-spliced product of the Fosb gene, is an activity-dependent transcription factor induced robustly in the brain in response to environmental stimuli such as CS. Interestingly, our preliminary bioinformatics analysis revealed a significant co-expression between ΔFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the ΔFOSB-CACNA2D1 axis in response to CS exposure might cause dysregulation of calcium homeostasis in hippocampal neurons via VGCCs-mediated Ca2+ influx, thereby contributing to cognitive deficits. To this end, the present study established a CS-induced mouse model of hippocampus-dependent cognitive impairment, in which the activation of the ΔFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, ΔFOSB knockdown-/overexpression-mediated inactivation/activation of the ΔFOSB-CACNA2D1 axis interdicted/mimicked CS-induced dysregulation of calcium homeostasis followed by severe cellular damage in HT22 mouse hippocampal neurons. Mechanistically speaking, a further ChIP-qPCR assay confirmed the physical interaction between transcription factor ΔFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by ΔFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention.

Bisphenol A and Di(2-Ethylhexyl) Phthalate promote pulmonary carcinoma in female rats via estrogen receptor beta: In vivo and in silico analysis.

The prevalence of lung cancer in women currently merits our attentions. However, cigarette exposure alone does not tell the whole story that lung cancer is more prevalent among non-smoking women. Since female lung cancer is closely linked to estrogen levels, many of endocrine disrupting chemicals (EDCs), as the substances similar to estrogen, affect hormone levels and become a potential risk of female lung cancer. Additionally, the combined toxicity of EDCs in daily environment has only been discussed on a limited scale. Consequently, this study explored the cancer-promoting effect of two representative substances of EDCs namely Bisphenol A (BPA) and Di(2-Ethylhexyl) Phthalate (DEHP) after their exposure alone or in combination, using a rat pulmonary tumor model published previously, combining bioinformatics analysis based on The Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas (TCGA) databases. It demonstrated that BPA and DEHP enhanced the promotion of pulmonary tumor in female rats, either alone or in combination. Mechanistically, BPA and DEHP mainly directly bound and activated ESR2 protein, phosphorylated CREB protein, activated HDAC6 transcriptionally, induced the production of the proto-oncogene c-MYC, and accelerated the formation of pulmonary tumor in female rats. Remarkably, BPA, rather than DEHP, exhibited a much more critical effect in female lung cancer. Additionally, the transcription factor ESR2 was most affected in carcinogenesis, causing genetic disruption. Furthermore, the TCGA database revealed that ESR2 could enhance the promotion and progression of non-small cell lung cancer in females via activating the WNT/ß-catenin pathway. Finally, our findings demonstrated that BPA and DEHP could enhance the promotion of pulmonary carcinoma via ESR2 in female rats and provide a potential and valuable insight into the causes and prevention of lung cancer in non-smoking women due to EDCs exposure.

Aluminum induces neuroinflammation via P2X7 receptor activating NLRP3 inflammasome pathway.

INTRODUCTION: Aluminum is everywhere in nature and is a recognized neurotoxicant closely associated with various neurodegenerative diseases. Neuroinflammation occurs in the early stage of neurodegenerative diseases, but the underlying mechanism by which aluminum induces neuroinflammation remains unclear. MATERIAL AND METHODS: A 3-month subchronic aluminum exposure mouse model was established by drinking water containing aluminum chloride (AlCl3). Microglia BV2 cells and hippocampal neuron HT22 cells were treated with AlCl3 in vitro. BBG and YC-1 were used as intervention agents. RESULTS: Aluminum could activate microglia and increase the level of extracellular ATP, stimulate P2X7 receptor, HIF-1α, activate NLRP3 inflammasome and CASP-1, release more cytokine IL-1ß, and induce an inflammatory response in nerve cells. There was a mutual regulatory relationship between P2X7 and HIF-1α at mRNA and protein levels. The co-culture system of BV2-HT22 cells observed that conditioned medium from microglia treated with aluminum could aggravate neuronal morphological damage, inflammatory response and death. While BBG and YC-1 intervention could rescue these injuries to some extent. CONCLUSION: The P2X7-NLRP3 pathway was involved in aluminum-induced neuroinflammation and injury. P2X7 and HIF-1α might mutually regulate and promote the progression of neuroinflammation, both BBG and YC-1 could relieve it.

Lanthanum Chloride Induces Axon Abnormality Through LKB1-MARK2 and LKB1-STK25-GM130 Signaling Pathways.

Lanthanum (La) is a natural rare-earth element that can damage the central nervous system and impair learning and memory. However, its neurotoxic mechanism remains unclear. In this study, adult female rats were divided into 4 groups and given distilled water solution containing 0%, 0.125%, 0.25%, and 0.5% LaCl3, respectively, and this was done from conception to the end of the location. Their offspring rats were used to establish animal models to investigate LaCl3 neurotoxicity. Primary neurons cultured in vitro were treated with LaCl3 and infected with LKB1 overexpression lentivirus. The results showed that LaCl3 exposure resulted in abnormal axons in the hippocampus and primary cultured neurons. LaCl3 reduced the expression of LKB1, p-LKB1, STRAD and MO25 proteins, and directly or indirectly affected the expression of LKB1, leading to decreased activity of LKB1-MARK2 and LKB1-STK25-GM130 pathways. This study indicated that LaCl3 exposure could interfere with the normal effects of LKB1 in the brain and downregulate LKB1-MARK2 and LKB1-STK25-GM130 signaling pathways, resulting in abnormal axon in offspring rats.

Transcription factor SP1 and oncoprotein PPP1R13L regulate nicotine-induced epithelial-mesenchymal transition in lung adenocarcinoma via a feedback loop.

Tobacco remains the most common environmental carcinogen leading to the occurrence and development of lung cancer. Nicotine, a tumor promoter in cigarette smoke, has been shown to induce epithelial-mesenchymal transition (EMT), a cellular program required for the invasion and metastasis in tumor cells. Specificity Protein 1 (SP1) is a well-characterized transcription factor that can regulate the EMT process via transcriptionally activating E-cadherin expression. Protein Phosphatase 1 Regulatory Subunit 13 Like (PPP1R13L) is a newly identified oncoprotein previously reported to inhibit the transcriptional activity of SP1 via a direct protein-protein interaction. To reveal the underlying implication of the interconnections between PPP1R13L and SP1 in the nicotine-induced EMT process, the present study established an EMT cell model of lung cancer using 1 µM of nicotine, a dose close to human exposure, in which an alternate fluctuation in the expression of PPP1R13L and SP1 was captured. Subsequently, the direct inhibition of SP1 by PPP1R13L was demonstrated to be a critical mechanism underlying the involvement of PPP1R13L in the nicotine-induced EMT process. More interestingly, SP1 was further shown to transcriptionally activate PPP1R13L expression in a feedback manner. In addition, PPP1R13L and SP1 expression was found to be closely associated with the clinicopathological characteristics of lung cancer patients. Here we proposed a novel feedback regulation mechanism, in which SP1 may transcriptionally activate the PPP1R13L gene expression in the early stage of lung cancer to promote tumor growth, while the accumulation of PPP1R13L drives tumor invasion and metastasis by direct repression of SP1. Thus, this unique feedback loop between PPP1R13L and SP1 may play a vital role in chemical carcinogenesis and serve as a potential intervention target for lung cancer progression attributable to cigarette smoking.

Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice.

Long-term exposure to environmental aluminum was found to be related to the occurrence and development of neurodegenerative diseases. Energy metabolism disorders, one of the pathological features of neurodegenerative diseases, may occur in the early stage of the disease and are of potential intervention significance. Here, sub-chronic aluminum exposure mouse model was established, and metformin was used to intervene. We found that sub-chronic aluminum exposure decreased the protein levels of phosphorylation AMPK (p-AMPK), glucose transporter 1 (GLUT1) and GLUT3, taking charge of glucose uptake in the brain, reduced the levels of lactate shuttle-related proteins monocarboxylate transporter 4 (MCT4) and MCT2, as well as lactate content in the cerebral cortex, while increased hypoxia-inducible factor-1α (HIF-1α) level to drive downstream pyruvate dehydrogenase kinase 1 (PDK1) expression, thereby inhibiting pyruvate dehydrogenase (PDH) activity, and ultimately led to ATP depletion, neuronal death, and cognitive dysfunction. However, metformin could rescue these injuries. Thus, it came to a conclusion that aluminum could damage glucose uptake, interfere with astrocyte-neuron lactate shuttle (ANLS), interrupt the balance in energy metabolism, and resulting in cognitive function, while metformin has a neuroprotective effect against the disorder of energy metabolism caused by aluminum in mice.

Association of Permanent Vascular Access Dysfunction with Subsequent Risk of Cardiovascular Disease: A Population-Based Cohort Study.

A functional permanent vascular access (VA) is required to perform a successful hemodialysis procedure. Hemodialysis VA dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. Cardiovascular disease (CVD) is the leading cause of death in patients receiving chronic hemodialysis. Information about CVD associated with hemodialysis VA dysfunction is unclear. We analyzed the association between dialysis VA dysfunction and the risk of developing CVD in hemodialysis patients. This nationwide population-based cohort study was conducted using data from the National Health Insurance Research Database in Taiwan. One million subjects were sampled from 23 million beneficiaries and data was collected from 2000 to 2013. Patients with end-stage renal disease who had received permanent VA construction and hemodialysis and were aged at least 20 years old from 2000 to 2007 were included in the study population. The primary outcome was CVD, as defined by ICD-9-CM codes 410-414 and 430-437. A total of 197 individuals with permanent VA dysfunction were selected as the test group, and 100 individuals with non-permanent VA dysfunction were selected as the control group. Compared with the control group, the adjusted hazard ratio of CVD for the VA dysfunction group was 3.05 (95% CI: 1.14-8.20). A Kaplan-Meier analysis revealed that the cumulative incidence of CVD was higher in the permanent VA dysfunction group than in the comparison group. Permanent VA dysfunction is significantly associated with an increased risk of subsequent CVD.

Corn embryo ameliorates cognitive dysfunction and anxiety-like behaviors in D-galactose-induced aging rats via attenuating oxidative stress, apoptosis and up-regulating neurotrophic factors.

Aging is the primary cause of neurodegenerative diseases, which are mainly characterized by cognitive decline and neuropsychiatric symptoms. Corn embryo, an important component of corn kernels, contains plenty of essential nutrients and bioactive compounds. However, corn embryo is often removed in the process of refining corn. To reveal potential biological benefits of corn embryo, the present study investigated the intervention effects of corn embryo on age-related cognitive decline and neuropsychiatric symptoms. Ninety male Wistar rats were randomly divided into six groups: Control, Corn embryo, Aging model, Low-, Medium- and High-dose intervention group. Aging models induced by an intraperitoneal injection of 60 mg/kg D-galactose plus a gavage of 200 mg/kg aluminum chloride were intervened with a gavage of 0.3, 0.6 or 1 g/kg corn embryo while the Control and Corn embryo groups received saline and 0.6 g/kg corn embryo respectively. Morris water maze and open field test were performed to assess cognitive abilities and anxiety-like behaviors. Brain biochemical parameters including the malondialdehyde, glutathione, glutathione sulfhydryl transferase and γ-glutamylcysteine synthetase were detected to evaluate oxidative stress levels. The mRNA expression of brain-derived neurotrophic factor was determined to estimate neurotrophic factor levels. Besides, histopathological alterations were visualized by hematoxylin-eosin staining and neuronal apoptosis levels were measured by the immunohistochemical staining of Bax and Bcl-2. Ultimately, the mimetic aging rats showed significant cognitive impairment (n = 15, P < 0.01) and anxiety-like behaviors (n = 15, P < 0.01), increased oxidative stress (n = 5, P < 0.001), neurodegeneration (n = 5, P < 0.001) and apoptosis (n = 5, P < 0.01) and reduced neurotrophic factors (n = 5, P = 0.074) in the brain. However, corn embryo effectively prevented the above undesirable neurobehavioral alterations via attenuating oxidative stress (n = 5, P < 0.01), neurodegeneration (n = 5, P < 0.001) and apoptosis (n = 5, P < 0.01) and increasing the levels of neurotrophic factors (n = 5, P < 0.001), suggesting its strong neuroprotective effects.

Resveratrol alleviates aluminum-induced intestinal barrier dysfunction in mice.

BACKGROUND: Aluminum is mainly exposed to the general population through food and water, and is absorbed into the systemic circulation through intestine, which in turn damages the intestinal barrier. METHODS: The mice model of subchronic exposure to aluminum chloride (AlCl3 ) was established via oral. Tail suspension test was used to detect depressive behavior. H&E staining was performed to assess pathological intestinal injury. Intestinal permeability was estimated by exogenous Evans blue content. The level of inflammatory cytokines and tight junction protein were assessed via ELISA and western blotting. Simultaneously, resveratrol (Rsv, an agonist of Sirt1) was evaluated the protective role against intestinal barrier injuries caused by aluminum exposure. RESULTS: Our results showed that AlCl3 induced depressive-like behavior, intestinal pathological damage and intestinal barrier permeability, resulting in intestinal barrier dysfunction. Besides, aluminum induced the expression of inflammatory cytokines, which further triggered IRF8-MMP9-mediated downregulation of tight junction proteins including CLD1, OCLD and ZO-1. After Rsv treatment, SIRT1 expression was increased, depressive symptom was improved, pathological injury was reduced, inflammatory reaction was alleviated, and intestinal barrier function restored. CONCLUSION: Our findings revealed that aluminum exposure induced intestinal barrier dysfunction by IRF8-MMP9 signaling pathway. Rsv alleviated these injuries via activating SIRT1.

Lanthanum Impairs Learning and Memory by Activating Microglia in the Hippocampus of Mice.

Lanthanum can induce neurotoxicity and impair cognitive function; therefore, research on the mechanism by which the ability to learning and memory is decreased by lanthanum is vitally important for protecting health. Microglia are a type of neuroglia located throughout the brain and spinal cord that play an important role in the central nervous system. When overactive, these cells can cause the excessive production of inflammatory cytokines that can damage neighboring neurons. The purpose of this study was to explore the effect of lanthanum in the form of lanthanum chloride (LaCl3) on learning and the memory of mice and determine whether there is a relationship between hippocampal neurons or learning and memory damage and excessive production of inflammatory cytokines. Four groups of pregnant Chinese Kun Ming mice were exposed to 0, 18, 36, or 72 mM LaCl3 in their drinking water during lactation. The offspring were then exposed to LaCl3 in the breast milk at birth until weaning and then exposed to these concentrations in their drinking water for 2 months after weaning. The results showed that LaCl3 impaired learning and memory in mice and injured their neurons, activated the microglia, and significantly overregulated the mRNA and protein expression of tumor necrosis factor alpha, interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein-1, and nitric oxide in the hippocampus. The results of this study suggest that lanthanum can impair learning and memory in mice, possibly by over-activating the microglia.

Lanthanum decreased VAPB-PTPP51, BAP31-FIS1, and MFN2-MFN1 expression of mitochondria-associated membranes and induced abnormal autophagy in rat hippocampus.

Lanthanum is one of REEs documented to have neurotoxicity that led to learning and memory ability impairments. However, the mechanisms underlying La-induced neurotoxicity remain largely unexplored. Autophagy is a self-balancing and self-renewal process that degrades damaged organelles and macromolecules through lysosomal pathway. Importantly, appropriate autophagy levels have protective effects against harmful stress, while excessive autophagy has been demonstrated to be implicated in neurological diseases. ER is close to mitochondria at specific sites with a reported distance of 10-30 nm. The functional domains between the two organelles, called MAM, have been associated with autophagosome synthesis. In this study, the pregnant Wistar rats were randomly divided into four groups and given distilled water solution containing 0%, 0.125%, 0.25%, and 0.5% LaCl3 for drinking during gestation and lactation. The pups were exposed to LaCl3 via the maternal placenta and three-week lactation. Experimental results showed that LaCl3 decreased spatial learning and memory ability of offspring rats, decreased tethering protein complexes expression of MAM, damaged MAM structure, up-regulated NOX4 expression which led to active ROS-AMPK-mTOR signaling pathway. Our findings suggest that decreased spatial learning and memory ability induced by LaCl3 may be related to the abnormally autophagy regulated by tethering protein complexes of MAM.

Bisphenol A drives di(2-ethylhexyl) phthalate promoting thyroid tumorigenesis via regulating HDAC6/PTEN and c-MYC signaling.

Bisphenol A (BPA) and di-(2-ethylhcxyl) phthalate (DEHP) are exist widespread in the environment and produce adverse effect to human as environmental disruptors (EDCs). Epidemiological studies have found that the exposure of DEHP and BPA could increase the susceptibility to thyroid diseases including thyroid cancer and benign thyroid nodules. Due to the existence of multiple pollutants in our daily life, the mixed toxic effects of exposure and their interrelationships may distinguish from the exposure to a single chemical, so it is of great significance to explore the mixed toxic effect of DEHP and BPA co-exposure. Thyroid, as one of the target organs of EDCs, is prone to tumor occurrence, however, whether the mixture of BPA and DEHP will affect the occurrence of thyroid cancer is still obscure. We aim to investigate the effect of single or combined exposure to BPA and DEHP on the occurrence of thyroid cancer. An animal model of exposure to BPA and DEHP was firstly established to evaluate their effect on DMD-induced thyroid cancer. Additionally, human thyroid cancer cells BCPAP and thyroid cells Nthy-ori3-1 were used to further clarify some possible mechanisms of BPA and MEHP, the main metabolite of DEHP. Consequently, we found that BPA alone could increase the incidence of thyroid tumors in female rats compared with DEHP, and DEHP enhanced the effect of BPA on cancer promotion. BPA alone and in combination with DEHP mainly induced the expression of HDAC6, inhibited tumor suppressor gene PTEN upregulated the expression of oncogene c-MYC, and eventually elevate the susceptibility to thyroid tumors. Mechanistically, BPA alone and in combination with MEHP could significantly induce the proliferation of BCPAP cells depending on HDAC6, which could modulate H3K9ac to inhibit PTEN, activate AKT signaling pathway, and simultaneously upregulate the expression of c-MYC. Interestingly, we found that BPA alone and in combination with MEHP could significantly induce the proliferation of Nthy-ori3-1 cells independent on HDAC6 via activating ERK signaling pathway. Taken together, these findings not only provide new evidence of the promoting effect of BPA and DEHP on thyroid cancer but also discusses some possible mechanisms underlying these effects.

Neochlorogenic Acid Attenuates Hepatic Lipid Accumulation and Inflammation via Regulating miR-34a In Vitro.

Neochlorogenic acid (5-Caffeoylquinic acid; 5-CQA), a major phenolic compound isolated from mulberry leaves, possesses anti-oxidative and anti-inflammatory effects. Although it modulates lipid metabolism, the molecular mechanism is unknown. Using an in-vitro model of nonalcoholic fatty liver disease (NAFLD) in which oleic acid (OA) induced lipid accumulation in HepG2 cells, we evaluated the alleviation effect of 5-CQA. We observed that 5-CQA improved OA-induced intracellular lipid accumulation by downregulating sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) expression, which regulates the fatty acid synthesis, as well as SREBP2 and HMG-CoA reductases (HMG-CoR) expressions, which regulate cholesterol synthesis. Treatment with 5-CQA also increased the expression of fatty acid ß-oxidation enzymes. Remarkably, 5-CQA attenuated OA-induced miR-34a expression. A transfection assay with an miR-34a mimic or miR-34a inhibitor revealed that miR-34a suppressed Moreover, Sirtuin 1 (SIRT1) expression and inactivated 5' adenosine monophosphate-activated protein kinase (AMPK). Our results suggest that 5-CQA alleviates lipid accumulation by downregulating miR-34a, leading to activation of the SIRT1/AMPK pathway.