[Effects and mechanisms of negative air ions on blood pressure, oxidative stress and inflammation levels in SHR rats].

OBJECTIVE: To investigate the effects and possible mechanisms of negative air ions(NAIs) on blood pressure, oxidative stress, and inflammatory status in spontaneous hypertension rats(SHR). METHODS: A total of 60 SHR(half male and half female) were randomly divided into one-month and three-month groups, 30 rats per groups, based on the duration of the intervention. Each group was further randomized into three groups based on the daily intervention time: SHR control group, 2 h NAIs-SHR group, and 6 h NAIs-SHR group, 10 rats per groups. In addition, 20 Wistar Kyoto(WKY)(half male and half female), were randomized into one-month WKY group and three-month WKY group, 10 rats per groups, based on the intervention time. The 2 h NAIs-SHR group and 6 h NAIs-SHR group were exposed to an environment with NAIs concentrations of 4.5×10~4-5×10~4 cm~3 per day for 2 h and 6 h. The WKY group and SHR group were exposed to normal air on a daily basis. Blood pressure of rats in each group was measured every three days, while weight was measured once a week. After sacrificing the rats in the first month and the third month of rearing, wet weight of the organs was weighed. The enzyme linked immunosorbent assay(ELISA) was used to detect 8-hydroxylated deoxyguanosine(8-OHdG), interleukin-6(IL-6), interleukin-8(IL-8), tumor necrosis factor-α(TNF-α), nitric oxide(NO) and endothelin-1(ET-1) levels. Reactive oxygen species(ROS) detection kit was used to detect ROS level. Malondialdehyde(MDA) and superoxide dismutase(SOD), glutathione(GSH) and glutathione disulfide(GSSG) were measured by colorimetric analysis. HE staining was conducted to observe the histopathological morphological changes of the thoracic aorta in each group, and Western blot was conducted to detect the thoracic aortap38 mitogen-activated protein kinase(p38 MAPK), extracellular signal-regulated kinases(ERK), c-Jun n-terminal kinase(JNK), c-fos proteins, c-jun proteins and their phosphorylated proteins level. RESULTS: The weight of WKY male mice in the same week age group was higher than that of SHR control group, and there was no significant difference in the weight between the other groups. The coefficient of heart in SHR control group(4.66±0.48) was higher than that in WKY group(3.73±0.15)(P<0.05), while there were no significant differences in the coefficients of brain, kidney, liver and spleen among the groups. Blood pressure in WKY group at the same age was lower than that in SHR group, and blood pressure in SHR control group at 2-5 and 8-11 weeks was higher than that in 2 h NAIs-SHR and 6 h NAIs-SHR groups(P<0.05). HE staining showed that the internal, middle and external membranes of thoracic aorta in 2 h NAIs-SHR group and 6 h NAIs-SHR group were improved to varying degrees compared with those in SHR control group, including disordered internal membrane structure, thickened middle membrane and broken external membrane. In terms of oxidative stress levels, compared with the SHR control group, the ROS(0.66%±0.17%, 0.49%±0.32%) and 8-OHdG((48.29±8.00) ng/mL, (33.13±14.67)ng/mL) levels were lower in the 6 h NAIs-SHR group(P<0.05), while the GSH/GSSG ratio was higher in the one-month 6 h NAIs-SHR group(10.08±4.93). Compared with the 2 h NAIs-SHR group, the ROS level(0.99%±0.19%) was lower in the 6 h NAIs-SHR group(P<0.05). In terms of inflammatory factor levels, compared with the SHR control group, the IL-8 levels((160.44±56.54) ng/L, (145.77±38.39) ng/L) were lower in the 6 h NAIs-SHR group(P<0.05), while the ET-1 level((249.55±16.98) ng/L) was higher in the one-month WKY group. There was no significant difference in NO levels among the groups. The relative expression of p-p38 protein in the thoracic aorta of rats in the one-month SHR control group was lower than that in the WKY group(P<0.05). The relative expression of p-p38 and p-c-fos proteins in the thoracic aorta of rats at three-months was higher in the SHR control group than in the 2 h NAIs-SHR and 6 h NAIs-SHR groups(P<0.05). CONCLUSION: The intervention of NAIs at a concentration of 4.5×10~4-5×10~4/cm~3 may regulate the partial oxidation and inflammatory state of SHR rats through the ROS/MAPK/AP1 signaling pathway, thereby reducing their blood pressure level.

Detection of Sarcocystis albifronsi, Eimeria alpacae, and Cystoisospora felis in Eurasian lynx (Lynx lynx) in northwestern China.

Eurasian lynx (Lynx lynx) is widely distributed in various habitats in Asia and Europe, and it may harbor multiple pathogens. Currently, the information on protozoan infection in Eurasian lynx is scarce. In this study, we performed nested polymerase chain reaction (nPCR) analysis to detect intestinal protozoan infection in three dead Eurasian lynxes, in northwestern China. Three dead Eurasian lynxes, an adult female (#1), an adult male (#2), and a cub male (#3), were sampled in West Junggar Mountain, the northwestern region of Xinjiang Uyghur Autonomous Region. The intestine samples were analyzed using nPCR. We used primers targeting the cytochrome C oxidase subunit I gene (COI) for detection of Sarcocystis and Eimeria species and targeting the small subunit 18 S ribosomal RNA gene (18S rRNA) for detection of Cystoisospora species. The nPCR-positive products were sequenced, aligned, and phylogenetically analyzed. Three intestinal protozoa, Sarcocystis albifronsi, Eimeria alpacae, and Cystoisospora felis, were found in three Eurasian lynxes. The intestine sample of Eurasian lynx #2 was detected with S. albifronsi and E. alpacae. In addition, C. felis was only found in the intestine sample of Eurasian lynx #3. To the best of our knowledge, S. albifronsi and E. alpacae were detected in Eurasian lynx for the first time. In addition, C. felis was firstly found in Eurasian lynx in China. These findings extend our knowledge of the geographical distribution and host range of intestinal protozoa.

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.

Contriving a novel of CHB therapeutic vaccine based on IgV_CTLA-4 and L protein via immunoinformatics approach.

Chronic infection induced by immune tolerance to hepatitis B virus (HBV) is one of the most common causes of hepatic cirrhosis and hepatoma. Fortunately, the application of therapeutic vaccine can not only reverse HBV-tolerance, but also serve a potentially effective therapeutic strategy for treating chronic hepatitis B (CHB). However, the clinical effect of the currently developed CHB therapeutic vaccine is not optimistic due to the weak immunogenicity. Given that the human leukocyte antigen CTLA-4 owns strong binding ability to the surface B7 molecules (CD80 and CD86) of antigen presenting cell (APCs), the immunoglobulin variable region of CTLA-4 (IgV_CTLA-4) was fused with the L protein of HBV to contrive a novel therapeutic vaccine (V_C4HBL) for CHB in this study. We found that the addition of IgV_CTLA-4 did not interfere with the formation of L protein T cell and B cell epitopes after analysis by means of immunoinformatics approaches. Meanwhile, we also found that the IgV_CTLA-4 had strong binding force to B7 molecules through molecular docking and molecular dynamics (MD) simulation. Notably, our vaccine V_C4HBL showed good immunogenicity and antigenicity by in vitro and in vivo experiments. Therefore, the V_C4HBL is promising to again effectively activate the cellular and humoral immunity of CHB patients, and provides a potentially effective therapeutic strategy for the treatment of CHB in the future.Communicated by Ramaswamy H. Sarma.

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.

Biomechanical comparison of the new cross-locking intramedullary nail with tension band wiring for transverse olecranon fractures.

BACKGROUND: In the treatment of transverse olecranon fractures, complicated tension band wiring (TBW) has high rates of re-operations. Besides, plate fixation (PF) and TBW both have large surgical incisions and soft-tissue irritation. Therefore, the new cross-locking intramedullary nail (CIN) with easy handling and minimally invasive features is significantly advantageous. The goal of this study was to biomechanically compare CIN with TBW for fixing transverse olecranon fracture. METHODS: The transverse olecranon fracture models were created with 15 fresh-frozen cadaveric ulnae which were randomly divided into 3 groups: one group for TBW fixation, another for CIN fixation with 1 conical locking screw (CIN-1), and the last for CIN fixation with 3 conical locking screws (CIN-3). The stiffness, cyclic stability, and failure strength of the fixed fracture models were compared after the corresponding experimental tests. RESULTS: The failure strength of TBW, CIN-1 and CIN-3 were (313.38±27.68) N, (528.56±53.58) N and (871.04±94.95) N. There was a significant difference between them. However, as for dynamic stability and stiffness, CIN-3 was higher and TBW was lower, with no significant differences between the groups. CONCLUSION: The biomechanical properties of CIN were superior to those of TBW, and CIN was more stable and solid for fixing transverse olecranon fracture, of which CIN-3 was the strongest.

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.

A miR-15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum-based chemotherapy.

Platinum-based chemotherapy is regarded as a preferential curative-intent option for non-small cell lung cancer (NSCLC), while the acquired drug resistance has become a major obstacle that limits its clinical application. Since the repair efficiency of tumour cells to platinum-DNA adducts plays a crucial role in chemotherapy resistance, we aimed to explore whether several meaningful polymorphisms of DNA repair genes were associated with the benefits of platinum-based chemotherapy in NSCLC patients. Firstly, six single nucleotide polymorphisms (SNPs) located in the 3'untranslated region (3'UTR) of three DNA repair genes were detected in 246 NSCLC patients receiving platinum-based chemotherapy and analysed the correlation of these candidate SNPs with the overall survival. Cox proportional hazard model showed that NSCLC patients carrying ERCC1 rs3212986 AA genotype had a shorter overall survival compared to those with CC. Mechanistically, we performed tumour chemosensitivity assay to observe the convincing linkage of rs3212986 polymorphism with ERCC1 expression and cisplatin sensitivity. The subsequent in vitro experiments identified that rs3212986 polymorphism altered the post-transcriptional regulation of ERCC1 via affecting the binding of miR-15a, and further changed the sensitivity to platinum analogue. It reminded that patients carrying ERCC1 rs3212986 CC homozygote were expected to respond better to platinum-based chemotherapy due to a lower expression of ERCC1. Compared with previous studies, our current comprehensive study suggested that rs3212986, a 3'UTR polymorphism in ERCC1, might have clinical relevance in predicting the prognosis of NSCLC patients receiving platinum-based chemotherapy.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China.

BACKGROUND: Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse. AIM: To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China. METHODS: We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model. RESULTS: In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (P < 0.001). Among 242 enrolled AILD patients, the prevalence rates of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and PBC-AIH overlap syndrome (PBC/AIH) were 50.8%, 28.5% and 12.0%, respectively. In ACLF patients, the proportions of PBC, AIH and PBC/AIH were 41.2%, 29.4% and 20.6%. 28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF. The etiology of AILD had no significant impact on 28-d, 90-d or 365-d LT-free mortality in patients with cirrhosis and AD in both univariate and multivariate analysis. Total bilirubin (TB), hepatic encephalopathy (HE) and blood urea nitrogen (BUN) were independent risk factors for 90-d LT-free mortality in multivariate analysis. The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio. CONCLUSION: AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.

Design for a Multicentre Prospective Cohort for the Assessment of Platelet Function in Patients with Hepatitis-B-Virus-Related Acute-on-Chronic Liver Failure.

Background: Acute-on-chronic liver failure (ACLF) has high short-term mortality and lacks sufficient medical therapy. Available algorithms are unable to precisely predict short-term outcomes or safely stratify patients with ACLF as emergent liver transplantation candidates. Therefore, a personalized prognostic tool is urgently needed. Purpose: Platelet function and its clinical significance in ACLF patients with chronic hepatitis B virus (HBV) infection have not been investigated. This study aimed to assess changes in platelet function using thromboelastography (TEG) and platelet mapping (TEG-PM) in HBV-related ACLF patients. Methods: Chronic liver disease patients with acute decompensation or acute hepatic injury were recruited. The derivation cohort enrolled HBV-related patients at Nanfang Hospital. HBV-related and non-HBV-related patients were both enrolled in internal and external validation cohorts at seven university hospitals. TEG and TEG-PM were performed at baseline in the derivation cohort and baseline, day 7, and day 14 in the validation cohorts. The primary outcome was all-cause 28-day mortality. Status check and new-onset complications were recorded during the 3-month follow-up, but status check will extend to 5 years. Conclusion and Future Plans: In this study, 586 participants were enrolled, including 100 in derivation cohort, 133 in internal validation cohort, and 353 in external validation cohort. Biomaterials, including plasma, serum, urine, and some explanted liver tissues, were collected from these patients. A 3-month follow-up with survival status was completed. The baseline characteristics indicated that 51% of the patients had adenosine diphosphate (ADP)-hyporesponsive circulating platelets. The prognostic potential of platelet function will be explored in the derivation cohort (HBV-related ACLF patients) and further substantiated in the validation cohorts (HBV-related and non-HBV-related ACLF patients). Biosamples are currently used to explore the underlying mechanisms related to ADP-hyporesponsive platelets. The ongoing proteomic and metabolic analyses will provide new insights into the pathogenesis of extrahepatic organ failures in ACLF patients.

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.

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.

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.

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.

Glomus Tumors of the Distal Phalanx: A Retrospective Review of Clinical Diagnosis and Treatment.

Glomus tumors (GTs) are rare and typically occur in distal digital bones, with a majority of cases comprising benign vascular tumors. The current study retrospectively reviewed 10 cases of GTs treated by the authors between January 2009 and December 2016. In 9 cases, the GTs were subungual; 1 case was periungual. The affected fingers included 2 thumbs, 3 index fingers, 3 middle fingers, and 2 little fingers. The GTs showed characteristic signs and symptoms. All patients underwent tumor excision. Pathological examination found a thin layer of fibrous membrane surrounding the excised tumor body, which contained small vessels surrounded by multilayered tumor cells. No recurrence was seen during follow-up. The results of this study suggested the following: (1) whole tumor excision is key to preventing GT recurrence; and (2) in case of considerable phalangeal cortex erosion, K-wire fixation followed by autogenous bone grafting can produce satisfactory outcomes, although accurate evidence-based indications for this management need to be established. [Orthopedics. 2022;45(2):e101-e106.].

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.