Chiral assemblies of pinwheel superlattices on substrates.

The unique topology and physics of chiral superlattices make their self-assembly from nanoparticles highly sought after yet challenging in regard to (meta)materials1-3. Here we show that tetrahedral gold nanoparticles can transform from a perovskite-like, low-density phase with corner-to-corner connections into pinwheel assemblies with corner-to-edge connections and denser packing. Whereas corner-sharing assemblies are achiral, pinwheel superlattices become strongly mirror asymmetric on solid substrates as demonstrated by chirality measures. Liquid-phase transmission electron microscopy and computational models show that van der Waals and electrostatic interactions between nanoparticles control thermodynamic equilibrium. Variable corner-to-edge connections among tetrahedra enable fine-tuning of chirality. The domains of the bilayer superlattices show strong chiroptical activity as identified by photon-induced near-field electron microscopy and finite-difference time-domain simulations. The simplicity and versatility of substrate-supported chiral superlattices facilitate the manufacture of metastructured coatings with unusual optical, mechanical and electronic characteristics.

Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS: We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS: We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS: This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer.

PURPOSE: To explore the association of clinicopathologic and molecular factors with the occurrence of positive margins after first surgery in breast cancer. METHODS: The clinical and RNA-Seq data for 951 (75 positive and 876 negative margins) primary breast cancer patients from The Cancer Genome Atlas (TCGA) were used. The role of each clinicopathologic factor for margin prediction and also their impact on survival were evaluated using logistic regression, Fisher's exact test, and Cox proportional hazards regression models. In addition, differential expression analysis on a matched dataset (71 positive and 71 negative margins) was performed using Deseq2 and LASSO regression. RESULTS: Association studies showed that higher stage, larger tumor size (T), positive lymph nodes (N), and presence of distant metastasis (M) significantly contributed (p ≤ 0.05) to positive surgical margins. In case of surgery, lumpectomy was significantly associated with positive margin compared to mastectomy. Moreover, PAM50 Luminal A subtype had higher chance of positive margin resection compared to Basal-like subtype. Survival models demonstrated that positive margin status along with higher stage, higher TNM, and negative hormone receptor status was significant for disease progression. We also found that margin status might be a surrogate of tumor stage. In addition, 29 genes that could be potential positive margin predictors and 8 pathways were identified from molecular data analysis. CONCLUSION: The occurrence of positive margins after surgery was associated with various clinical factors, similar to the findings reported in earlier studies. In addition, we found that the PAM50 intrinsic subtype Luminal A has more chance of obtaining positive margins compared to Basal type. As the first effort to pursue molecular understanding of the margin status, a gene panel of 29 genes including 17 protein-coding genes was also identified for potential prediction of the margin status which needs to be validated using a larger sample set.

Targeting Diverse Wounds and Scars: Recent Innovative Bio-design of Microneedle Patch for Comprehensive Management.

Wounds and the subsequent formation of scars constitute a unified and complex phased process. Effective treatment is crucial; however, the diverse therapeutic approaches for different wounds and scars, as well as varying treatment needs at different stages, present significant challenges in selecting appropriate interventions. Microneedle patch (MNP), as a novel minimally invasive transdermal drug delivery system, has the potential for integrated and programmed treatment of various diseases and has shown promising applications in different types of wounds and scars. In this comprehensive review, the latest applications and biotechnological innovations of MNPs in these fields are thoroughly explored, summarizing their powerful abilities to accelerate healing, inhibit scar formation, and manage related symptoms. Moreover, potential applications in various scenarios are discussed. Additionally, the side effects, manufacturing processes, and material selection to explore the clinical translational potential are investigated. This groundwork can provide a theoretical basis and serve as a catalyst for future innovations in the pursuit of favorable therapeutic options for skin tissue regeneration.

Integrin CD11b Negatively Regulates B Cell Receptor Signaling to Shape Humoral Response during Immunization and Autoimmunity.

Our previous work has revealed the ability of CD11b to regulate BCR signaling and control autoimmune disease in mice. However, how CD11b regulates the immune response under normal conditions remains unknown. Through the use of a CD11b knockout model on a nonautoimmune background, we demonstrated that CD11b-deficient mice have an elevated Ag-specific humoral response on immunization. Deletion of CD11b resulted in elevated low-affinity and high-affinity IgG Ab and increases in Ag-specific germinal center B cells and plasma cells (PCs). Examination of BCR signaling in CD11b-deficient mice revealed defects in association of negative regulators pLyn and CD22 with the BCR, but increases in colocalizations between positive regulator pSyk and BCR after stimulation. Using a CD11b-reporter mouse model, we identified multiple novel CD11b-expressing B cell subsets that are dynamically altered during immunization. Subsequent experiments using a cell-specific CD11b deletion model revealed this effect to be B cell intrinsic and not altered by myeloid cell CD11b expression. Importantly, CD11b expression on PCs also impacts on BCR repertoire selection and diversity in autoimmunity. These studies describe a novel role for CD11b in regulation of the healthy humoral response and autoimmunity, and reveal previously unknown populations of CD11b-expressing B cell subsets, suggesting a complex function for CD11b in B cells during development and activation.

Characterization of chemical constituents in Huangqi Guizhi Wuwu decoction using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Huangqi Guizhi Wuwu decoction (HGWWD) is a classic traditional Chinese medicine prescription for the treatment of ischemic stroke, etc. However, the material basis of its efficacy remains unclear, seriously affecting drug development and clinical applications. In the present study, an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry method was developed to separate and identify the chemical components of HGWWD. A total of 81 compounds were identified and tentatively characterized. Eight compounds were accurately identified by comparing the retention time and mass spectrometry data with those of reference substances, the remaining compounds were characterized by comparing the mass spectrometry data and reference information. Based on the results of compound attribution, 35 compounds were from Astragali Radix, six compounds were from Cinnamomi Ramulus, 23 compounds were from Paeoniae Radix Alba, eight compounds were from Zingiberis Rhizoma Recens and nine compounds were from Jujubae Fructus. The results showed that monoterpenoids, flavonoids, organic acids, triterpenes, amino acids, gingerols, alkaloids, and glycosides were the main chemical components of HGWWD. This analytical method is suitable for characterizing the chemical constituents of HGWWD, and the results provide important information for elucidating its pharmacodynamic material basis and mechanism of action.

Flexible and Wearable Strain-Temperature Sensors Based on Chitosan/Ink Sponges.

A simple and economic strategy to construct a chitosan-ink carbon nanoparticle sponge sensor was proposed by freeze-drying of chitosan and Chinese ink mixture solution. The microstructure and physical properties of the composite sponges with different ratios are characterized. The interfacial compatibility of chitosan and carbon nanoparticles in ink is satisfied, and the mechanical property and porosity of chitosan was increased by the incorporation of carbon nanoparticles. Due to excellent conductivity and good photothermal conversion effect of the carbon nanoparticles in ink, the constructed flexible sponge sensor has satisfactory strain and temperature sensing performance and high sensitivity (133.05 ms). In addition, these sensors can be successfully applied to monitor the large joint movement of the human body and the movement of muscle groups near the esophagus. Dual functionally integrated sponge sensors show great potential for strain and temperature detection in real time. The prepared chitosan-ink carbon nanoparticle composite shows promising applications in wearable smart sensors.

A MSALL quantitative method for the determination of Poloxamer 188 in rat plasma by UHPLC-Q-TOF/MS and its application to pharmacokinetic study.

Poloxamer (PL)188 is a commonly used pharmaceutical excipient with unique physicochemical properties. In this study, an MSALL quantitative method for the determination of PL188 in rat plasma by UHPLC-Q-TOF/MS was developed and validated. PL188 was analyzed on PLRP-S reversed-phase column (50 × 4.6 mm, 8 µm, 1,000 Å) with mobile phase 0.1% formic acid-water and 0.1% formic acid in acetonitrile-isopropanol (2:3, v/v). The liner range was 0.1-10.0 µg/ml. A pharmacokinetic study was performed on rats at a dose of 5 mg/kg by intravenous injection. The pharmacokinetic parameters of intravenous injection were as follows: half-life was 2.0 ± 1.1 h, volume of distribution was 5.1 ± 3.2 L/kg, area under the concentration-time curve was 3.0 ± 0.6 µg/L h and clearance was 1.7 ± 0.3 L/h/kg. The results indicated that PL188 could be rapidly distributed to tissues with a high clearance rate. This study can provide a good reference for the further study of PL188.

Gut microbiota mediated the toxicity of high concentration of dietary nitrite in C57BL/6 mice.

Growing evidence indicates that exposure to high levels of nitrite for a prolonged time has adverse health effects. Although gut microbiota is responsible for the transformation of nitrite in the gut, the evidence concerning whether gut microbiota mediates the toxicity of nitrite is still lacking. The present study addressed the long-term effects of dietary nitrite on male C57BL/6 mice and employed fecal microbiota transplantation (FMT) to reveal whether gut microbiota mediated the effects of nitrite. Furthermore, the effect of azoxymethane (AOM) on gut microbiota was detected for mice drinking normal or nitrite-containing water. High nitrite had toxic effects on C57BL/6 mice. Meanwhile, high nitrite induced skin lesions in mice, accompanied with increased serum ALT, colon IL-6, TNF-α, and MDA levels, together with decreased serum Cr, colon sIgA, and T-AOC levels. After fecal microbiota was transplanted into the normal mice, the nitrite-regulated gut microbiota could also induce skin lesions, coupled with reduced serum Cr, and increased colon MDA. The high dose of nitrite caused the upregulations of Alistipes, Prevotella, and Ruminococcus, which could be transplanted into normal mice through FMT. Inversely, gut microbiota from normal mice reduced the effects of nitrite on serum ALT and Cr, together with colon sIgA and MDA. Gut microbiota from normal mice could also upregulate metabolic genes and downregulate stress genes in the nitrite-treated mice. It might due to the upregulation of Akkermansia and Parabacteroides caused by FMT from normal water-treated mice to nitrite-treated mice. In addition, AOM exhibited to be more toxic to the colon in the nitrite-treated mice in comparison with normal water-treated mice, and it might be due to the expression of Hspa1a and Hspa1b in the colon. Interestingly, gut microbiota was more influenced by AOM in the normal water-treated mice than the nitrite-treated mice. Overall, these data demonstrated that gut microbiota mediated the toxicity of a high concentration of dietary nitrite.

Upregulation of SNTB1 correlates with poor prognosis and promotes cell growth by negative regulating PKN2 in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most highly malignant tumors and has a complicated pathogenesis. A preliminary study identified syntrophin beta 1 (SNTB1) as a potential oncogene in CRC. However, the clinical significance, biological function, and underlying mechanisms of SNTB1 in CRC remain largely unknown. Thus, the present study aimed to investigate the role of SNTB1 in CRC. METHODS: The expression profile of SNTB1 in CRC samples was evaluated by database analysis, cDNA array, tissue microarray, quantitative real-time PCR (qPCR), and immunohistochemistry. SNTB1 expression in human CRC cells was silenced using short hairpin RNAs (shRNA)/small interfering RNAs (siRNA) and its mRNA and protein levels were assessed by qPCR and/or western blotting. Cell viability, survival, cell cycle, and apoptosis were determined by the CCK-8 assay, colony formation, and flow cytometry assays, respectively. A xenograft nude mouse model of CRC was established to validate the roles of SNTB1 in vivo. Immunohistochemistry and TUNEL staining were used to determine the expression of SNTB1, PCNA, and cell apoptosis in tissue samples. Isobaric tag for relative and absolute quantification (iTRAQ) was used to analyze the differentially expressed proteins after knockdown of SNTB1 in CRC cells. Silence of protein kinase N2 (PKN2) using si-PNK2 was performed for rescue experiments. RESULTS: SNTB1 expression was increased in CRC tissues compared with adjacent noncancerous tissues and the increased SNTB1 expression was associated with shorter overall survival of CRC patients. Silencing of SNTB1 suppressed cell viability and survival, induced cell cycle arrest and apoptosis in vitro, and inhibited the growth of CRC cells in vivo. Further elucidation of the regulation of STNB1 on CRC growth by iTRAQ analysis identified 210 up-regulated and 55 down-regulated proteins in CRC cells after SNTB knockdown. A PPI network analysis identified PKN2 as a hub protein and was up-regulated in CRC cells after SNTB1 knockdown. Western-blot analysis further confirmed that SNTB1 knockdown significantly up-regulated PKN2 protein expression in CRC cells and decreased the phosphorylation of both ERK1/2 and AKT. Moreover, rescue experiments indicated that PKN2 knockdown significantly rescued SNTB1 knockdown-mediated decrease in cell viability, survival, and increase of cell cycle arrest at G0/G1 phase and apoptosis of CRC cells. CONCLUSIONS: These findings indicate that SNTB1 is overexpressed in CRC. Elevated SNTB1 levels are correlated with shorter patient survival. Importantly, SNTB1 promotes tumor growth and progression of CRC, possibly by reducing the expression of PKN2 and activating the ERK and AKT signaling pathway. Our study highlights the potential of SNTB1 as a new prognostic factor and therapeutic target for CRC.

The high expression of miR-564 in patients with systemic lupus erythematosus promotes differentiation and maturation of DC cells by negatively regulating TP53 expression in vitro.

BACKGROUND: miRNA is involved in the occurrence and progression of systemic lupus erythematosus (SLE), but the regulatory effect of miRNA on dendritic cells in SLE patients is still unclear. MATERIAL AND METHODS: Bioinformatics methods were used to analyze the differentially expressed miRNA and its target genes in SLE patients. In vitro experiments were conducted to explore the effects and mechanisms of differentially expressed miRNAs in SLE patients on the differentiation and maturation of monocyte-derived dendritic cells. RESULTS: Bioinformatics analysis showed that miR-564 was up-regulated in SLE patients, and TP53 was the core target gene of miR-564. The expression level of miR-564 showed a rising trend during the differentiation and maturation of monocytes into Mo-DC cells. The differentiation, maturation and proliferation of Mo-DC cells were significantly inhibited by transfection with miR-564 antagomir. The expression of TP53 is negatively regulated by miR-564. In rescue experiments, the proliferation and migration of DC cells were significantly restored by co-transfection of miR-564 antagomir and TP53 si-RNA. CONCLUSION: Highly expressed miR-564 promotes the maturation, proliferation of Mo-DC cells by negatively regulating the expression of TP53.

Lifestyle is associated with thyroid function in subclinical hypothyroidism: a cross-sectional study.

BACKGROUND: Few studies have focused on the association between lifestyle and subclinical hypothyroidism (SCH). The purpose of this study was to investigate the association between lifestyle and thyroid function in SCH. METHODS: This study was a part of a community-based and cross-sectional study, the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 159 participants with SCH (81 males and 78 females) and 159 euthyroid (87 males and 72 females) participants without any missing data were included in the analysis. General information and lifestyle information including sleep, exercise, diet and smoking habits of the participants was collected by questionnaire and Pittsburgh sleep quality index scale (PSQI) was collected. Thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TgAb) and urine iodine concentration (UIC) were tested. Thyroid homeostasis parameter thyroid' s secretory capacity (SPINA-GT), Jostel's TSH index (TSHI), thyrotroph T4 sensitivity index (TTSI) were calculated. Logistic regression and multiple linear regression were performed to assess associations. RESULTS: Compared with euthyroid subjects, patients with SCH were more likely to have poor overall sleep quality (15.1 vs.25.8 %, P = 0.018) and l less likely to stay up late on weekdays (54.7 vs. 23.9 % P < 0.001). In SCH group, exercise was the influencing factor of TSH (ß= -0.224, P = 0.004), thyroid secretory capacity (ß = 0.244, P = 0.006) and thyrotropin resistance (ß = 0.206, P = 0.009). Iodine excess was the influencing factor of thyroid secretory capacity (ß = 0.209, P = 0.001) and pituitary thyroid stimulating function (ß = 0.167, P = 0.034). Smoking was the influencing factor of pituitary thyroid stimulating function (ß = 0.161, P = 0.040). Staying up late on weekends was the influencing factor of thyroid secretory capacity (ß = 0.151, P = 0.047). After adjusting for possible confounders, logistic regression showed that those with poor overall sleep quality assessed by PSQI and iodine excess had an increased risk of SCH (OR 2.159, 95 %CI 1.186-3.928, P = 0.012 and OR 2.119, 95 %CI 1.008-4.456, P = 0.048, respectively). CONCLUSIONS: Lifestyle including sleep, smoking, diet and exercise was closely related to thyroid function especially thyroid homeostasis in SCH.

Understanding the hepatoxicity of inorganic mercury through guts: Perturbance to gut microbiota, alteration of gut-liver axis related metabolites and damage to gut integrity.

Mercury (Hg) brings adverse effects to the environment and human beings and inorganic mercury (IHg) is a typical hepatic toxin. This work studied the impacts of IHg on gut microbes and metabolome together with its damage to liver and gut in rats through gut microbiome, metabolomics and metallomics. Sprague Dawley (SD) rats were orally exposed to 0.4 µg/mL IHg and sacrificed after 24 h. It was found that IHg perturbed greatly on the gut microbiota, such as increased pathogenic bacteria like G. bacillus. In addition, IHg also changed gut-liver axis related metabolites, which was confirmed by the secretion of a large number of inflammatory factors in both the gut and the liver. The changed gut-liver axis related metabolites correlated well to the changes of gut microbiome. In all, besides the direct deposition in liver of Hg, the perturbance to gut microbiome and alteration of gut-liver axis related metabolites by IHg also contributed to its hepatoxicity, which provides new insights about the hepatoxicity of chemicals. The strategy applied in this work may also be used to understand the hepatoxicity of other chemicals.

Tissue Distribution Study of Poloxamer188 in Rats by Ultra-High-Performance Liquid Chromatography Quadrupole Time of Flight/Mass Spectrometry with MSALL-Based Approach.

Poloxamer188 (PL188), as one of the most commonly used pharmaceutical excipients, has unique physicochemical properties and good biocompatibility, and so is playing an increasingly extensive role in the field of medicine. Currently, there are few studies on the tissue distribution of PL188 in vivo. In this study, the LC-MS method based on MSALL technique of quadrupole time of flight mass spectrometry for absolute quantitative analysis of poloxamer 188 in biological substrates was established for the first time. The tissue distribution of poloxamer188 in SD rats were studied using the established quantitative analysis method. To explore the distribution of PL188 in organs and tissues, PL188 was administered via rat tail vein at a dose of 5 mg/kg. Eight kinds of tissues including heart, liver, spleen, lung, kidney, stomach, muscle and brain of rats were collected at 0.25 h, 1 h and 4 h after administration. Tissue distributions showed the highest level was observed in kidney, then in stomach, which indicated PL188 mainly bioaccumulated in the kidney. This study can provide references for the further study of PL188.

Polymeric Ligand-Mediated Regioselective Bonding of Plasmonic Nanoplates and Nanospheres.

Nanoparticle (NP) clusters are attractive for many applications, but controllable and regioselective assembly of clusters remains challenging. This communication reports a strategy to precisely assemble Ag nanoplates (NP-As) and Au nanospheres (NP-Bs) grafted with copolymer ligands into defined ABx clusters with controlled coordination number (x) and orientation of the NPs. The directional bonding of shaped NPs relies on the stoichiometric reaction of complementary reactive groups on copolymer ligands. The x value of NP clusters can be tuned from 1 to 4 by varying the number ratio of reactive groups on single NP-Bs to NP-As. The regioselective bonding of nanospheres to the edge or face of a central nanoplate is governed by the steric hindrance of copolymeric ligands on the nanoplate. The clusters exhibit distinctive plasmonic properties that are dependent on the bonding modes of NPs. This study paves a route to fabricating nanostructures with high precision and complexity for applications in plasmonics, catalysis, and sensing.

Acute oral methylmercury exposure perturbs the gut microbiome and alters gut-brain axis related metabolites in rats.

Environmental pollutants like methylmercury (MeHg) can bring devastating neurotoxicity to animals and human beings. Gut microbiota has been found to demethylate MeHg and promote the excretion of Hg through feces. However, the impacts of MeHg on gut microbiota and metabolites related to gut-brain interactions were less studied in mammals. The object of this study was to investigate the impacts of acute MeHg exposure on gut microbiome and metabolites together with its impact on gut integrity and related biological responses in rats. Rats were exposed to MeHg through oral administration and were sacrificed after 24 h 16 S rRNA gene sequencing was used to study the perturbance to gut microbiome and liquid chromatography mass spectrometry (LC-MS) was used for metabolomics profiling. It was found that gut was one of the target tissues of MeHg. MeHg induce the changes of intestinal microbial community structure and induce the regulating neuron activity change of intestinal neurotransmitters and metabolites on intestinal neurotransmitters and metabolites regulating the neuron activity. This was supported by the increased BDNF level. These findings may suggest a potential new mechanism regarding the neurotoxicity of MeHg. The protocols used in this study may also be applied to understand the neurotoxicity of other environmental neurotoxins like Pb, Mn, polychlorinated biphenyls, and pesticides, etc and to screen the neurotoxicity of emerging environmental contaminants.

Chronic exercise buffers the cognitive dysfunction and decreases the susceptibility to seizures in PTZ-treated rats.

Epilepsy is a serious neurological disorder posing a severe burden to our society. Cognitive deficits are very common comorbidities of epilepsy. It is known that enhanced cognition has been demonstrated as an indicator for successful treatment of epilepsy. Physical exercise shows a positive consequence on cognition in healthy individuals and improves health and life conditions in people with epilepsy. However, there is no direct evidence to determine the role and the potential mechanism of physical exercise on the cognitive impairment and the relationship of susceptibility to seizures. The goal of the current investigation was to explore whether sustained physical exercise improves the cognitive dysfunction and simultaneously decreases the susceptibility to seizures in rats with epilepsy. Rats were treated with pentylenetetrazole (PTZ) (35 mg/kg, i.p. [intraperitoneally]) for 36 days to induce chronic epilepsy. During the induction period, rats were exposed to voluntary wheel running or forced swimming 30 min prior to each PTZ injection from the 16th day. The cognition of rats was evaluated by object recognition test and passive avoidance test. The susceptibility to seizures was evaluated by seizure frequency and duration. The levels of synaptic-related proteins including PSD95 (postsynaptic density 95), Synapsin, GluA1, and BDNF (brain-derived neurotrophic factor) were measured to evaluate the hippocampal synaptic plasticity. Furthermore, the GAD67 (glutamic acid decarboxylase) levels and GABA (γ-aminobutyric acid)ergic function in PTZ-treated rats were also determined. Finally, antagonist of GABAAR (GABAA receptors) bicuculline was used to explore the reversal effects of physical activity on seizures and cognition. The results showed that rats subjected to voluntary wheel running or forced swimming showed a significant reduction of seizure frequency and duration in PTZ-treated group relative to rats without running or swimming. In addition, both running and swimming improved cognitive function as measured by enhanced performance in object recognition test and passive avoidance test. Furthermore, the reduced levels of synaptic-related proteins and GABAergic function were reversed by exercise compared with rats without exercise. Moreover, antagonism of hippocampal CA3 (cornu ammonis 3) GABAergic neurons blocks the reversal effects of physical activity on seizures and cognition in PTZ-treated rats. These data showed that chronic physical exercise reduced the frequency of seizures and improved the cognitive function in a rat model of chronic epilepsy through normalization of CA3 synaptic plasticity and GABAergic function. Our findings suggest that chronic physical exercise has beneficial effects on controlling seizure through enhancement of cognition and highlights the possibility to translate into reduced seizure recurrence in people with epilepsy.

Selenium modulated gut flora and promoted decomposition of methylmercury in methylmercury-poisoned rats.

INTRODUCTION: Selenium plays important roles in antagonizing the toxicity of methylmercury. The underlying mechanism for the antagonism between Se and MeHg is still not fully understood. OBJECTIVE: The role of gut flora against the toxicity of environmental contaminants is receiving more and more attention. The objective of this study was to investigate the role of Se against MeHg-poisoning in the modulation of gut flora and the decomposition of MeHg. METHODS: MeHg-poisoned rats were treated with sodium selenite every other day for 90 days. Fecal samples were collected on Day 8, 30, 60 and 90. Gut flora in feces was determined using 16S rRNA gene profiling, and the concentrations of Se and total mercury (THg) were measured by ICP-MS, and the concentration of MeHg was measured by CVAFS. RESULTS: Gut flora at both the ranks of phylum and genus in the MeHg-poisoned rats after Se treatment was modulated towards that in the control group, suggesting the restoration of the profile of gut flora. Increased THg was found in fecal samples after Se treatment on day 30. The percentage of MeHg (of total mercury) in the MeHg-poisoned group was in the range of 81-105% while it was 65-84% in the Se treatment group on different days, suggesting the increased decomposition of MeHg in MeHg-poisoned rats after Se treatment. CONCLUSIONS: This study suggests that MeHg poisoning damaged the abundance of gut flora and decreased their capacity for the decomposition of MeHg. After Se treatment, the abundance of gut flora was partially restored and the decomposition and excretion of MeHg was enhanced. These findings suggest that the modulation of gut flora may be one way to promote the health status in MeHg-poisoned rats and possibly in human beings.

Nanoelemental selenium alleviated the mercury load and promoted the formation of high-molecular-weight mercury- and selenium-containing proteins in serum samples from methylmercury-poisoned rats.

Selenite (Se4+) has been found to counteract the neurotoxicity of methylmercury (MeHg) in MeHg-poisoned rats. However, Se4+ has narrow range between its toxic and beneficial effects. Nanoelemental selenium (SeNPs) was found to be less toxic than other forms of Se such as Se4+. In this study, the effects of SeNPs on the load of mercury (Hg) in rats were investigated. Hyphenated technique based on size-exclusion chromatography coupled with UV and inductively coupled plasma mass spectrometry (SEC-ICP-MS) detection and synchrotron radiation X-ray fluorescence spectroscopy (SR-XRF) were used to analyze the Hg-Se-containing proteins in the serum from MeHg-poisoned rats. The Hg-Se-containing fractions monitored by UV and ICP-MS were further characterized by MALDI-TOF-MS. Elevated serum Hg and Se levels were found in MeHg-poisoned rats after SeNPs treatment. Three main Hg-containing bands with molecular weights (MWs) of 25, 62 and 140 kDa were detected in the control samples. Treatment with SeNPs increased the Hg content in proteins at 62 and 170 kDa and decreased the Hg content at 25 kDa. The fraction with 25 kDa was assigned to metallothioneins (MTs), and fractions with 40 and 75 kDa were assigned to albumin. This study showed that the low-toxicity SeNPs could reduce the Hg load in the tissues and promote the formation of high molecular weight Hg- and Se-containing proteins in MeHg-poisoned rats.

Intestinal Methylation and Demethylation of Mercury.

Mercury (Hg) is a global pollutant, which is linked with different diseases. The methylation of Hg and demethylation of methylmercury (MeHg) in the environment were extensively studied and summarized; however, the transformation of Hg in the intestine is less presented. In this review, the research progress and the perspectives on the intestinal transformation of Hg were discussed. Studies found that MeHg could be formed when exposed to inorganic Hg by the gut microbiota in aquatic organisms, terrestrial invertebrates, and mammals, etc. hgcAB genes could be used as indicators for predicting Hg methylation potential. In vitro studies using fecal specimen, intestinal contents, and the isolated intestinal microbes confirmed the intestinal demethylation of MeHg. The investigation on the effects of Hg exposure to the abundance and diversity of intestinal microbes and their metabolites could shed light on the mechanism of the toxicity of Hg, especially the neurotoxicity of MeHg, which deserves further study.