Two-polarized roles of transcription factor FOSB in lung cancer progression and prognosis: dependent on p53 status.

BACKGROUND: Activator protein-1 (AP-1) represents a transcription factor family that has garnered growing attention for its extensive involvement in tumor biology. However, the roles of the AP-1 family in the evolution of lung cancer remain poorly characterized. FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB), a classic AP-1 family member, was previously reported to play bewilderingly two-polarized roles in non-small cell lung cancer (NSCLC) as an enigmatic double-edged sword, for which the reasons and significance warrant further elucidation. METHODS AND RESULTS: Based on the bioinformatics analysis of a large NSCLC cohort from the TCGA database, our current work found the well-known tumor suppressor gene TP53 served as a key code to decipher the two sides of FOSB - its expression indicated a positive prognosis in NSCLC patients harboring wild-type TP53 while a negative one in those harboring mutant TP53. By constructing a panel of syngeneically derived NSCLC cells expressing p53 in different statuses, the radically opposite prognostic effects of FOSB expression in NSCLC population were validated, with the TP53-R248Q mutation site emerging as particularly meaningful. Transcriptome sequencing showed that FOSB overexpression elicited diversifying transcriptomic landscapes across NSCLC cells with varying genetic backgrounds of TP53 and, combined with the validation by RT-qPCR, PREX1 (TP53-Null), IGFBP5 (TP53-WT), AKR1C3, and ALDH3A1 (TP53-R248Q) were respectively identified as p53-dependent transcriptional targets of FOSB. Subsequently, the heterogenous impacts of FOSB on the tumor biology in NSCLC cells via the above selective transcriptional targets were confirmed in vitro and in vivo. Mechanistic investigations revealed that wild-type or mutant p53 might guide FOSB to recognize and bind to distinct promoter sequences via protein-protein interactions to transcriptionally activate specific target genes, thereby creating disparate influences on the progression and prognosis in NSCLC. CONCLUSIONS: FOSB expression holds promise as a novel prognostic biomarker for NSCLC in combination with a given genetic background of TP53, and the unique interactions between FOSB and p53 may serve as underlying intervention targets for NSCLC.

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.

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.

Effect of Clamping Compression on the Mechanical Performance of a Carbon Paper Gas Diffusion Layer in Polymer Electrolyte Membrane Fuel Cells.

During all the assembly stages of a polymer electrolyte membrane fuel cell (PEMFC) stack, gas diffusion layers (GDLs) endure clamping loads in the through-plane direction several times. Under such complicated assembly conditions, GDLs have to deform with the changes in structure, surface roughness, pore size, etc. A comprehensive understanding of the compressive performance of GDLs at different clamping phases is crucial to the assembly process improvement of PEMFCs. Two typical clamping compression was designed and performed to get close to the actual assembly conditions of PEMFCs. The results indicate that the initial clamping compression and the magnitude of the maximum clamping load have great impacts on the segmented compressive properties of GDLs. The nonlinear compressive performance of the GDL is mainly attributed to the unique microstructural information. The rough surface morphology contributes to the initial compressive characteristics where the big strain along with the small stress occurs, and the irreversible failures such as carbon fiber breakages and adhesive failures between fibers and binders account for the hysteresis between different compression stages. Importantly, it is found that the clamping compression hardly influences the small pore distribution below 175 µm but affects the large pore distribution over 200 µm.

Blood uptake and urine excretion of nano- and micro-plastics after a single exposure.

Nano- and micro-plastic (NMP) pollution has emerged as a global issue; however, uptake in the blood is controversial. Also, there is no evidence that NMPs are excreted via urine. This study was designed to clarify the time course of NMPs absorption in blood and the excretion in urine. Male mice received a single administration of fluorescent polystyrene (PS) beads (100-nm and 3-µm) via tail vein injection, gavage, or pulmonary perfusion. Blood and urine samples were measured 0.5, 1, 2, and 4 h after exposure by confocal laser scanning microscope (CLSM). Transmission electron microscopy (TEM) was performed to corroborate the findings. Fluorescence particles were detected in both blood and urine from the 100-nm and 3-µm PS-treated groups after exposure. In the 3-µm PS treated group, particles with corresponding diameters were detected after intravenous injection and pulmonary perfusion, and particles with a diameter <3 µm were detected in blood samples after gavage. The fluorescent signal in urine was particularly weak and the size was <3 µm. Significant time course changes in fluorescence intensity were demonstrated in blood and urine (P < 0.05) after intravenous injection and pulmonary perfusion in the 100-nm PS-treated group. By contrast, significant changes were detected in the urine (P < 0.05), but not the blood, after gavage. TEM confirmed the presence of particles with corresponding diameters in blood samples; however, the excretion in urine was difficult to confirm for nano-plastics (NPs) and micro-plastics (MPs) because all particles with diameters of approximately 100 nm and 3 µm had irregular shapes and no clear boundaries. Our findings revealed that both NPs and MPs enter the blood circulation through digestive and respiratory pathways. Both 100-nm and 3-µm NMPs may be excreted through urine, but further evidence is needed. The physical and chemical properties of MPs may be impacted by digestive processes in vivo.

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.

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.

Aluminum induced intestinal dysfunction via mechanical, immune, chemical and biological barriers.

Aluminum is the most abundant metal element in the Earth's crust, which exists naturally in the form of aluminum compounds. Aluminum is mainly absorbed through the gastrointestinal tract, which varies with different aluminum compounds. During this process, aluminum could induce the disruption of intestinal mucosa barrier. However, its underlying mechanism has not been elucidated yet. Previous studies have reported that aluminum can firstly promote the apoptosis of intestinal epithelial cells, destroy the structure of tight-junction proteins, and increase the intestinal permeability, injuring the mechanical barrier of gut. Also, it can induce the activation of immune cells to secrete inflammatory factors, and trigger immune responses, interfering with immune barrier. Moreover, aluminum treatment can regulate intestinal composition and bio-enzyme activity, impairing the function of chemical barrier. In addition, aluminum accumulation can induce an imbalance of the intestinal flora, inhibit the growth of beneficial bacteria, and promote the proliferation of harmful bacteria, which ultimately disrupting biological barrier. Collectively, aluminum may do extensive damage to intestinal barrier function covering mechanical barrier, immune barrier, chemical barrier and biological barrier.

Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway.

INTRODUCTION: Aluminum is a kind of chemical contaminants in food which can induce neurotoxicity. Aluminum exposure is closely related to neurodegenerative diseases (ND), in which neuroinflammation might involve. However, the molecular mechanism of aluminum-induced neuroinflammation through pyroptosis is not fully clarified yet. MATERIAL AND METHODS: The mice model of subacute exposure to aluminum chloride (AlCl3) was established. BV2 microglia cells was treated with AlCl3 in vitro. Resveratrol (Rsv) was adopted as intervention agent. RESULTS: Our results showed that aluminum induced cognitive impairment, destroying blood brain barrier (BBB), and causing nerve injury in mice. Meanwhile, aluminum could stimulate nucleotide oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome assembly and activate caspase-1 (CASP1), inducing gasdermin D (GSDMD)-mediated pyroptosis signaling, releasing cytokines IL-1ß and IL-18, further promoting the activation of glial cells to magnify neuroinflammatory response. Moreover, DEAD-box helicase 3 X-linked (DDX3X) and stress granule RasGAP SH3-domain-binding protein 1 (G3BP1) both participated in neuroinflammation induced by aluminum. When co-treated with Rsv, these injuries were alleviated to some extent. CONCLUSION: Aluminum exposure could induce nerve cell pyroptosis and neuroinflammation by DDX3X-NLRP3 inflammasome signaling pathway, which could be rescued via Rsv activating sirtuin 1 (SIRT1).

Lanthanum chloride induces autophagy in primary cultured rat cortical neurons through Akt/mTOR and AMPK/mTOR signaling pathways.

Autophagy is a lysosome dependent degradation pathway occurring in eukaryotic cells. Autophagy ensures balance and survival mechanism of cells during harmful stress. Excessive or weak autophagy leads to abnormal function and death in some cases. Lanthanum (La), a rare earth element (REE), damages the central nervous system (CNS) and promotes learning and memory dysfunction. However, underlying mechanism has not been fully elucidated. La induces oxidative stress, inhibits Nrf2/ARE and Akt/mTOR signaling pathways, and activates JNK/c-Jun and JNK/Foxo signaling pathways, resulting in abnormal induction of autophagy in rat hippocampus. In addition, La activates PINK1- Parkin signaling pathway and induces mitochondrial autophagy. However, the relationship between La and autophagy in rat neurons at the cellular level has not been explored previously. The aim of this study was to explore adverse effects of La. Primary culture of rat neurons were exposed to 0 mmol/L, 0.025 mmol/L, 0.05 mmol/L and 0.1 mmol/L lanthanum chloride (LaCl3). The results showed that La upregulates p-AMPK, inhibits levels of p-Akt and p-mTOR, increases levels of autophagy related proteins (Beclin1 and LC3B-II), and downregulates expression of p-Bcl-2 and p62. Upstream and downstream intervention agents of autophagy were used to detect autophagy flux to verify accuracy of our results. Electron microscopy results showed significant increase in the number of autophagosomes in LaCl3 exposed groups. These findings imply that LaCl3 inhibits Akt/mTOR signaling pathway and activates AMPK/mTOR signaling pathway, resulting in abnormal autophagy in primary cultured rat cortical neurons. In addition, LaCl3 induces neuronal damage through excessive autophagy.

Benzo[a]pyrene diol epoxide-induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1-derived circular RNA in pulmonary squamous cell carcinoma.

ERCC1 is a gene for repairing DNA damage whose function is related to carcinogenic-induced tumorigenesis and the effectiveness of platinum therapies. Circular RNAs (circRNAs) are products of posttranscriptional regulation with pleiotropic effects on the pathogenesis of lung cancer. We aim to identify that specific circRNAs derived from ERCC1 can regulate key biological processes involved in the development of lung cancer. We performed bioinformatics analysis, in vitro experiments, and analyzed clinical samples, to determine the biological features of a certain ERCC1-derived circRNA termed as hsa_circ_0051488 in benzo[a]pyrene diol epoxide-induced malignant transformed cell and lung cancer cell. The well-established model of transformed cells provided an ideal platform for analyzing the molecular characteristics of this circRNA in the malignant transformation of lung epithelial cell, which supports that hsa_circ_0051488 functions in the onset and growth of lung squamous cell carcinoma (LUSC). Further analysis indicates that the absence of hsa_circ_0051488 promoted the proliferation of cells with the malignant phenotype. Extensive experiments confirm that hsa_circ_0051488 is present in the cytoplasm and functioned as a competing endogenous RNA. In particular, hsa_circ_0051488 binds to mir-6717-5p, thereby modulating the expression of SATB2 gene, a lung cancer suppressor. Furthermore, our in silico experiments indicate that SATB2 can inhibit multiple tumor pathways and its expression positively correlated with the tumor suppressor gene CRMP1. These findings suggest a possible regulatory mechanism of hsa_circ_0051488 in LUSC, and that the newly discovered hsa_circ_0051488/miR-6717-5p/SATB2 axis may be a potential route for therapeutic intervention of LUSC.