Small extracellular vesicles-derived from 3d cultured human nasal mucosal mesenchymal stem cells during differentiation to dopaminergic progenitors promote neural damage repair via miR-494-3p after manganese exposed mice.

Manganese (Mn) exposure is a common environmental risk factor for Parkinson's disease (PD), with pathogenic mechanisms associated with dopaminergic neuron damage and neuroinflammation. Mesenchymal stem cells (MSCs)-derived small extracellular vesicles (sEVs) have emerged as a novel therapeutic approach for neural damage repair. The functional sEVs released from MSCs when they are induced into dopaminergic progenitors may have a better repair effect on neural injury. Therefore, we collected sEVs obtained from primary human nasal mucosal mesenchymal stem cells (hnmMSC-sEVs) or cells in the process of dopaminergic progenitor cell differentiation (da-hnmMSC-sEVs), which were cultured in a 3D dynamic system, and observed their repair effects and mechanisms of Mn-induced neural damage by intranasal administration of sEVs. In Mn-exposed mice, sEVs could reach the site of brain injury after intranasal administration, da-hnmMSC enhanced the repair effects of sEVs in neural damage and behavioral competence, as evidenced by restoration of motor dysfunction, enhanced neurogenesis, decreased microglia activation, up-regulation of anti-inflammatory factors, and down-regulation of pro-inflammatory factors. The transcriptomics of hnmMSC-sEVs and da-hnmMSC-sEVs revealed that miRNAs, especially miR-494-3p in sEVs were involved in neuroprotective and anti-inflammatory effects. Overexpression of miR-494-3p in sEVs inhibited Mn-induced inflammation and neural injury, and its repair mechanism might be related to the down-regulation of CMPK2 and NLRP3 in vitro experiments. Thus, intranasal delivery of da-hnmMSC-sEVs is an effective strategy for the treatment of neural injury repair.

Ribonuclease A-polymer conjugates via in situ growth for cancer treatment.

Efficient delivery of therapeutic proteins is a critical aspect for protein-based cancer treatment. Herein, an in situ growth approach was employed to prepare ribonuclease A (RNase A)-polymer conjugates by incorporating a cationic polymer, poly(N,N'-dimethylamino-2-ethyl methacrylate) (P(DMAEMA)), and a hydrophobic polymer, poly(N-isopropylacrylamide) (P(NIPAM)), through atom transfer radical polymerization (ATRP). The synthesized RNase A-polymer conjugates (namely R-P(D-b-N)) could preserve the integrity of RNase A and exhibit a unique combination of cationic and hydrophobic properties, leading to enhanced intracellular delivery efficiency. The successful delivery of RNase A by R-P(D-b-N) conjugates effectively triggered the cell apoptosis through the mitochondria-dependent signaling pathway to achieve the anti-proliferative response. Additionally, the conjugates could inhibit cell migration and thus possess the potential for the suppression of tumor metastasis. Overall, our findings highlight that the introduction of cationic and hydrophobic moieties via ATRP provides a versatile platform for the intracellular delivery of therapeutic proteins, offering a new avenue for treating diverse diseases.

Systematic review and integrated analysis of prognostic gene signatures for prostate cancer patients.

Prostate cancer (PC) is one of the most common cancers in men and becoming the second leading cause of cancer fatalities. At present, the lack of effective strategies for prognosis of PC patients is still a problem to be solved. Therefore, it is significant to identify potential gene signatures for PC patients' prognosis. Here, we summarized 71 different prognostic gene signatures for PC and concluded 3 strategies for signature construction after extensive investigation. In addition, 14 genes frequently appeared in 71 different gene signatures, which enriched in mitotic and cell cycle. This review provides extensive understanding and integrated analysis of current prognostic signatures of PC, which may help researchers to construct gene signatures of PC and guide future clinical treatment.

Fluorinated polyamidoamine dendrimer-mediated miR-23b delivery for the treatment of experimental rheumatoid arthritis in rats.

In rheumatoid arthritis (RA), insufficient apoptosis of macrophages and excessive generation of pro-inflammatory cytokines are intimately connected, accelerating the development of disease. Here, a fluorinated polyamidoamine dendrimer (FP) is used to deliver miR-23b to reduce inflammation by triggering the apoptosis of as well as inhibiting the inflammatory response in macrophages. Following the intravenous injection of FP/miR-23b nanoparticles in experimental RA models, the nanoparticles show therapeutic efficacy with inhibition of inflammatory response, reduced bone and cartilage erosion, suppression of synoviocyte infiltration and the recovery of mobility. Moreover, the nanoparticles accumulate in the inflamed joint and are non-specifically captured by synoviocytes, leading to the restoration of miR-23b expression in the synovium. The miR-23b nanoparticles target Tab2, Tab3 and Ikka to regulate the activation of NF-κB pathway in the hyperplastic synovium, thereby promoting anti-inflammatory and anti-proliferative responses. Additionally, the intravenous administration of FP/miR-23b nanoparticles do not induce obvious systemic toxicity. Overall, our work demonstrates that the combination of apoptosis induction and inflammatory inhibition could be a promising approach in the treatment of RA and possibly other autoimmune diseases.

Glutathione-functionalized magnetic thioether-COFs for the simultaneous capture of urinary exosomes and enrichment of exosomal glycosylated and phosphorylated peptides.

Exosomes play an irreplaceable role in physiological and pathological processes, and the study of proteomics (especially protein post-translational modifications, PTMs) in exosomes can reveal the pathogenesis of diseases and screen therapeutic disease targets. The separation and enrichment process is an essential step in mass spectroscopy-based exosomal PTMs studies to reduce sample complexity and ionization-suppression effects. Herein, we designed a novel magnetic zwitterionic material, namely glutathione-functionalized thioether covalent organic frameworks (Fe3O4@Thio-COF@Au@GSH), possessing fast magnetic responsiveness, regular porosity, and a suitable surface area. Thanks to the hydrophilicity and charge-switchable feature of GSH, for the first time, both the capture of exosomes from biological fluids and enrichment of the inherent glycoproteins/phosphoproteins in the exosomes were achieved with the same material. Furthermore, the high enrichment capacity was validated by theoretical calculations. The low detection limits (0.2/0.4 fmol for HRP/ß-casein), high selectivity (1 : 1000 for HRP/ß-casein : BSA molar ratio), and high exosomal glycoproteomics/phosphoproteomics profiling capability proved the feasibility of the developed method. This work provides a new heuristic strategy to solve the problems of exosomal capture and glycoproteins/phosphoproteins pretreatment in exosomal proteomics.

Exposure to the real ambient air pollutants alters the composition of nasal mucosa bacteria in the rat model.

Studies have indicated that ambient pollutant exposure correlates with nasal disease, in which nasal mucosa microbiota play a crucial role. However, the association between exposure to real-ambient air pollutants and the composition of nasal mucosa microbiota has not been well studied. This study aimed to explore the composition of nasal mucosa microbiota after exposure to real-ambient air pollutants with a special system. We monitored PM2.5, O3, etc. in the system and confirmed PM2.5 and O3 were the main pollutants. SD rats were exposed to the system for 16 weeks in summer or 22 weeks in autumn-winter. The concentrations of PM2.5 were 24.00 µg/m3 in the Summer stage and 22.21 µg/m3 in the autumn-winter stage. The O3 concentrations were 25.46 and 13.55 µg/m3, respectively. Exposure altered bacterial beta diversity in the summer stage. There were 4 and 3 different bacteria at the king, order, family and genus levels between the two groups at the two stages, respectively. The abundance of opportunistic pathogens changed, Pseudomonas decreased in summer stage, and Bifidobacterium increased in the autumn-winter stage. The influence of the season on the nasal mucosa microbiota was analyzed. The alpha diversity of the autumn-winter stage was higher than that of the summer stage. LEfSe analysis revealed 34 differential bacterial taxa at the king, order, family and genus level in the two control groups and 31 of the two exposure groups, which were not the same as the bacteria between the control groups and exposure groups. We found that PM2.5 combined with O3 exposure was associated with the composition of the nasal mucosa microbiota and the abundance of opportunistic pathogens, in which season likely impacted the microbiota.

Reduced mitochondrial DNA copy number in occupational workers from brominated flame retardants manufacturing plants.

Decabrominated diphenyl ether (BDE-209) and its substitute decabromodiphenyl ethane (DBDPE) are two flame retardants that have similar structure and are widely used in various industrial products. The accumulation and potential toxicity of them to human health have already aroused attention, and some research showed that they may affect mitochondrial function. Therefore, this study focused on the population with high exposure to brominated flame retardants (BFRs) and the related changes in mtDNA copy number (mtDNAcn) in whole blood. 334 blood samples were collected from three groups of people in Shandong Province, including 42 BDE-209 occupational exposure workers from the BDE-209 manufacturing plant, 131 DBDPE occupational exposure workers from the DBDPE manufacturing plant, and 161 non-BFRs occupational exposure residents from the BFRs contaminated area. We measured the levels of BDE-209, DBDPE in serum sample, and the mtDNAcn in whole blood sample and analyzed these data by multiple linear regression. The average concentrations of BDE-209, DBDPE and ∑(BDE-209 + DBDPE) in BDE-209 occupational workers were 3510, 639 and 4600 ng/g lw, respectively; the average concentrations of BDE-209, DBDPE and ∑(BDE-209 + DBDPE) in DBDPE occupational workers were 229, 4040 and 4470 ng/g lw, respectively; the average concentrations of BDE-209, DBDPE and ∑(BDE-209 + DBDPE) in non-BFRs occupational exposure residents were 66.3, 45.7 and 137 ng/g lw, respectively. The relative mtDNAcn was 0.823 in BDE-209 occupational workers, 0.845 in DBDPE occupational workers and 0.989 in non-BFRs occupational exposure residents. A 10-fold increase in BDE-209, DBDPE concentrations was separately associated with a 0.068 and 0.063 decrease in mtDNAcn. Therefore, our study implied that BFRs may affect mitochondrial function. As increasing BFRs exposure has emerged in recent years, the relationship between BFRs exposure and mitochondrial function needs further study.

N-Isopropylacrylamide-modified polyethylenimine-mediated miR-29a delivery to inhibit the proliferation and migration of lung cancer cells.

MicroRNAs have been identified as a promising tool in cancer gene therapy, and an efficient and safe gene carrier was significantly required in the clinical application of miRNAs. Herein, a polyethylenimine (PEI) derivative, N-isopropylacrylamide-modified PEI (namely PEN), was constructed through Michael addition and then employed as a carrier for miR-29a transfection. The carrier PEN has been demonstrated to possess favorable ability to condense miR-29a into stable nanoparticles and protect miR-29a against the nuclease degradation, using agarose gel retardation assay. Meanwhile, PEN exhibited excellent efficiency in miR-29a transfection demonstrated by flow cytometry and confocal laser scanning microscope. Further, the PEN-mediated miR-29a transfection could achieve an obvious anti-proliferative effect owing to the activation of cell apoptosis and the cell cycle arrest at G1 phase, using human lung adenocarcinoma cell line A549 as a model. In addition, PEN/miR-29a nanoparticles could suppress the migration and invasion of cancer cells measured by wound healing and Transwell migration assays. Overall, the PEN-mediated miR-29a transfection could be potentially employed as a useful approach to achieve cancer gene therapy.

Knockdown of long non­coding RNA AK094629 attenuates the interleukin­1ß induced expression of interleukin­6 in synovium­derived mesenchymal stem cells from the temporomandibular joint.

Interleukin (IL)­1ß is a key promotor in the pathogenesis of temporomandibular joint osteoarthritis. Differentiation of stem cells to cartilage is a crucial repair mechanism of articular cartilage damage, and IL­1ß has been reported to impede the differentiation by upregulating the secretion of IL­6, an important inflammatory factor. Long non­coding RNAs (lncRNAs) regulate a number of physiological and pathological processes, but whether lncRNA AK094629 contributes to the IL­1ß mediated induction of inflammation remains unclear. Therefore, the aim of the present study was to investigate the effect of AK094629 on IL­1ß­induced IL­6 expression in synovial­derived mesenchymal stem cells (SMSCs) of the temporomandibular joints. The results of the present study demonstrated that the expression of AK094629 in the synovial tissue of patients with osteoarthritis was positively correlated with IL­1ß. In addition, IL­1ß upregulated the expression of AK094629 in the SMSCs in vitro, and AK094629 knockdown inhibited the IL­1ß mediated upregulation of IL­6. The present study also demonstrated that AK094629 knockdown downregulated the expression of the mitogen­activated protein kinase kinase kinase 4 (MAP3K4), which is upregulated by IL­1ß, whereas knockdown of MAP3K4 did not affect the expression of AK094629, but reversed the upregulation of IL­6 in SMSCs. In conclusion, AK094629 knockdown attenuated the expression of IL­1ß­regulated IL­6 in the SMSCs of the temporomandibular joint by inhibiting MAP3K4. Therefore, AK094629 may be a potential novel therapeutic target for the treatment of temporomandibular joint osteoarthritis.

Pyrroloquinoline Quinine and LY294002 Changed Cell Cycle and Apoptosis by Regulating PI3K-AKT-GSK3ß Pathway in SH-SY5Y Cells.

To verify the role of PI3K-AKT-GSK3ß pathway during manganese (Mn)-induced cell death, apoptosis, related indicators were investigated. SH-SY5Y cells were directly exposed to different concentrations of MnCl2. Then, cell viability, apoptosis, necrosis rate, and cell cycle were detected by MTT, FITC Annexin V Apoptosis Detection Kit with PI and PI staining. Then, in two intervention groups, cells were preconditioned with agonist (PQQ) and suppressant (LY294002). The cell viability decreased with a dose-response relationship (p < 0.05), while apoptosis and necrosis increased (p < 0.05). The ratio of G0/G1 and G2/M also decreased, but the percentage of S phase increased (p < 0.05). During above process, PI3K-AKT-GSK3ß pathway was involved by regulating the expression of PI3K, AKT, p-AKT, and GSK3ß (p < 0.05). For further research, cell cycle and apoptosis were detected pretreatment with PQQ and LY294002 before Mn exposure. The result showed cell ability, apoptosis, and necrosis rate changed obviously compared with non-pretreated group (p < 0.05). The variance of G0/G1 and G2/M ratio and percentage of S phase were also different, especially in 2.0 mM (p < 0.05). Mn can cause apoptosis and necrosis, varying cell cycle of SH-SY5Y cells, which could be changed by PQQ and LY294002 by regulating PI3K-AKT-GSK3ß pathway.

Suberoylanilide Hydroxamic Acid Attenuates Interleukin-1ß-Induced Interleukin-6 Upregulation by Inhibiting the Microtubule Affinity-Regulating Kinase 4/Nuclear Factor-κB Pathway in Synovium-Derived Mesenchymal Stem Cells from the Temporomandibular Joint.

Synovium-derived mesenchymal stem cells (SMSCs) can migrate to the site of destroyed condylar cartilage and differentiate into chondrocytes to repair temporomandibular joint (TMJ) damage. Interleukin (IL)-1ß-induced IL-6 secretion has been shown to inhibit the chondrogenic potential of SMSCs. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) has recently been shown to be closely related to the inflammation induced by IL-1ß. However, the relationship between SAHA and IL-6 secretion induced by IL-1ß in SMSCs remains unclear. In this study, we evaluated the relationships between IL-1ß and IL-6 in synovial specimens from patients with TMD and in model rats with osteoarthritis (OA). We found that IL-1ß and IL-6 were positively correlated and that IL-6 expression in SMSCs increased with IL-1ß stimulation in vitro. Moreover, microtubule affinity-regulating kinase 4 (MARK4) was significantly upregulated in IL-1ß-stimulated SMSCs and in the synovium of rats with OA. MARK4 knockdown inhibited IL-6 secretion and nuclear factor (NF)-κB pathway activation in IL-1ß-stimulated SMSCs. SAHA attenuated IL-6 secretion in IL-1ß-induced SMSCs through NF-κB pathway inhibition, and MARK4 was also downregulated in SAHA-treated SMSCs. However, inhibition of the NF-κB pathway did not suppress MARK4 expression. Thus, these results showed that SAHA attenuated IL-6 secretion in IL-1ß-induced SMSCs through inhibition of the MARK4/NF-κB pathway.

Bifunctional Magnetic Supramolecular-Organic Framework: A Nanoprobe for Simultaneous Enrichment of Glycosylated and Phosphorylated Peptides.

Protein glycosylation and phosphorylation are two important protein post-translational modifications. Mass spectrometry (MS) has been proved to be a powerful technique in comprehensive characterization of protein glycosylation and phosphorylation; however, the complexity of biological matrices and weak ionization efficiency bring a big challenge. Capturing glycopeptides and phosphopeptides from complicated biological samples is indispensable before MS determinations. In this study, a bifunctional gallium ion immobilized magnetic pertriflated pillar[5]arene supramolecular-organic framework (magOTfP5SOF-Ga3+) was designed for the one-step simultaneous enrichment of glycopeptides and phosphopeptides. Thanks to the abundant sulfonic acid groups, the material owns strong hydrophilicity and leads to hydrophilic interaction chromatography for glycopeptides enrichment. Simultaneously, the high loading amount of gallium ion provides immobilized metal ion affinity for phosphopeptides enrichment. The established platform possesses quick magnetic response performance, high sensitivity (detection limits as low as 0.1 fmol and 0.05 fmol for glycopeptides and phosphopeptides, respectively), and good reusability. In addition, the method was applied to the determination of glycopeptides and phosphopeptides in clinical specimens, cell lysates, and mouse liver tissue samples, demonstrating its highly sensitive and specific glycoproteomics and phosphorproteomics analysis in complex biosamples.

Investigation of the impact of PM2.5 on the ciliary motion of human nasal epithelial cells.

Nasal epithelium provides a physical barrier to potentially harmful stimuli. Cilia, which is on the apical side of the human nasal epithelial cells (HNEpCs), plays a critical role in removing inhaled harmful matter. Ciliary beat frequency (CBF) and ciliary beat pattern (CBP) are the two important indicators for ciliary beat function. However, impacts of the fine particulate matter (PM2.5) on CBF and CBP are still unknown. We aimed to evaluate the impact of PM2.5 on the ciliary beat function of the HNEpCs and its potential mechanisms. After exposed to PM2.5 for 12 h, cilia of HNEpCs were in disordered arrangement. The ciliary coverage rate was decreased after PM2.5 exposure of a series of concentration, while the proportion of basal cells was continuously increased and could be observed on the apical side of the HNEpCs which is hardly be observed without PM2.5 exposure. PM2.5 increased the CBF after 12 h exposure, while 24 h exposure increased the CBF at the relative lower dosage groups and then made a decrease at relative higher dosage groups. CBF were classified into two different types, which had different changes following PM2.5 exposure. CBP showed significant changes characterized as the increased dyskinesia index. Total levels of cellular ATP and the mitochondrial membrane potential were decreased following 12 h exposure of PM2.5, while no change was found in O2 consumption. In conclusion, PM2.5 impact the ciliary beat function of HNEpCs, and the mitochondrial dysfunction might play an important role in it.

Overexpression of miR-138-5p suppresses MnCl2 -induced autophagy by targeting SIRT1 in SH-SY5Y cells.

The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1.

Nano-Scaled Zeolitic Imidazole Framework-8 as an Efficient Carrier for the Intracellular Delivery of RNase A in Cancer Treatment.

BACKGROUND: Zeolitic imidazole framework-8 (ZIF-8) as an emerging platform has exhibited great potential in the protein delivery owing to its tunable chemical functionality. MATERIALS AND METHODS: ZIF-8 was employed as a carrier for the encapsulation and intracellular delivery of RNase A, aimed to achieve a rapid release of proteins in an acidic environment. The intracellular uptake of RNase A was studied by confocal laser scanning microscopy (CLSM), and the inhibition of cell proliferation after the delivery of RNase A was evaluated by MTT assay, Live/Dead staining, and TUNEL cell apoptosis analysis, using human lung adenocarcinoma cell line A549 as a model. The biocompatibility of RNase A@ZIF-8 nanoparticles was systematically detected through the hemolysis and cytotoxicity assay. RESULTS: The RNase A@ZIF-8 nanoparticles constructed by biomimetic mineralization could not only facilitate the encapsulation of protein molecules (protein loading: 13.4%) but also maintain the enzymatic activity and stability of RNase A. The CLSM images showed that RNase A@ZIF-8 nanoparticles could efficiently improve the intracellular uptake of RNase A. Moreover, RNase A@ZIF-8 nanoparticles could obviously inhibit the cell proliferation through the induction of cell apoptosis, with 31.3% of cell death at an RNase A concentration of 10 µg/mL. Finally, RNase A@ZIF-8 nanoparticles were elucidated to possess excellent biocompatibility, with hemolysis of <5% using the same concentration of RNase A@ZIF-8. CONCLUSION: ZIF-8 could be used as an effective carrier to deliver the therapeutic protein RNase A into the cytosol, which will be beneficial for improving the efficacy of cancer treatment.

HDAC10 upregulation contributes to interleukin 1ß-mediated inflammatory activation of synovium-derived mesenchymal stem cells in temporomandibular joint.

Histone deacetylases (HDACs) are important in chronic inflammation, and inflammatory responses affect synovium-derived mesenchymal stem cell (SMSC) function in temporomandibular joint repair. However, the effect of HDACs on SMSC inflammatory activation remains unclear. In this study, temporomandibular joint fibroblast-like synoviocytes obtained from osteoarthritis patients met the minimal mesenchymal stem cell criteria. Interleukin 1ß (IL-1ß) upregulated IL-6 and IL-8 expression in SMSCs through nuclear factor-κB (NF-κB) pathway activation. IL-6 and IL-8 upregulation were blocked by broad-acting HDAC inhibitors SAHA and LBH589. MC1568 alleviated IL-1ß activation of SMSCs, whereas CI994 and FK228 produced a minimal or opposite effect in vitro. We also found HDAC10 was highly associated with localized IL-1ß expression in vivo and in vitro. HDAC10 knockdown alleviated IL-1ß-mediated SMSC activation and blocked NF-κB pathway activation. Conversely, HDAC10 overexpression promoted IL-6 and IL-8 expression and IL-1ß-mediated NF-κB pathway activation. In conclusion, HDAC10 upregulation contributed to IL-1ß-mediated inflammatory activation of SMSCs, indicating that HDAC10 may be a novel therapeutic target.

Disruption of thyroid hormone levels by decabrominated diphenyl ethers (BDE-209) in occupational workers from a deca-BDE manufacturing plant.

While there is some evidence that exposure to decabrominated diphenyl ethers (BDE-209) affects thyroid function, the results obtained to date have been inconsistent. No studies have been performed on workers in deca-BDE manufacturing who had a high level of exposure to BDE-209 and relatively little exposure to other contaminants. In the present study, the relationship between BDE-209 exposure and thyroid hormone in occupational workers from a deca-BDE manufacturing plant was investigated. The serum and urine levels of polybrominated diphenyl ethers (PBDEs) and serum thyroid hormones were measured in 72 workers recruited from the deca-BDE manufacturing plant. The associations between their thyroid hormone levels and their exposure to BDE-209 were examined using multiple linear regression models. Serum concentrations of BDE-209 ranged from 67.4 to 109,000 ng/g lipid weight (lw), with a median of 3420 ng/g lw, contributing to 93.1% of the total PBDEs. The concentration of BDE-209 in urine was highly correlated with that in the serum (r2 = 0.440, p < 0.001), indicating that urine may be a good non-invasive biomonitoring medium of BDE-209 body burden in occupational workers. BDE-209 in the serum was significantly and positively correlated with total thyroxine (tT4, r = 0.270, p = 0.029) and marginally and positively correlated with total triiodothyronine (tT3, r = 0.232, p = 0.061) in all occupational workers after adjusting for gender, age, BMI, and occupational exposure duration. A 10-fold increase in the serum BDE-209 concentration was associated with an increase in tT4 (8.63 nmol/L) [95% confidence interval (CI): 0.930-16.3] and tT3 (0.106 nmol/L) [95% confidence interval (CI): -0.005-0.219], corresponding to the increase of 7.8% in tT4 level and 5.4% in tT3 level. Associations between urine BDE-209 levels and thyroid hormones were similar to the results for the serum levels. These findings offer new evidence for proving the thyroid disrupting effects of BDE-209, impacting the direction of hyperthyroidism.

SIRT1 exhibits antioxidative effects in HT22 cells induced by tert-butyl alcohol.

Tertiary butyl alcohol (TBA) is a principal metabolite of methyl tertiary-butyl ether (MTBE), a common pollutant worldwide in the ground or underground water, which is found to produce nervous system damage. Nevertheless, few data regarding the effects of TBA has been reported. Studies indicated that oxidative stress plays a pivotal role in MTBE neurotoxic mechanism. Sirtuin 1 (SIRT1) has been reported to exert a neuroprotective effect on various neurologic diseases via resistance to oxidative stress by deacetylating its substrates. In this study, we examined levels of oxidative stress after exposure to TBA for 6 h in HT22 cells and HT22 cells with SIRT1 silencing (transfected with SIRT1 siRNA) or high expression (preconditioned with agonists SRT1720). We found that TBA activated oxidative stress by increasing generation of intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and Oxidized glutathione (GSSG), and decreasing contents of superoxide dismutase (SOD) and glutathione reductase (GSH). In additional, levels of TBA-induced oxidative stress were aggravated when SIRT1 silenced but alleviated when SIRT1 enhanced. Our study indicated that SIRT1 mitigated oxidative stress induced by TBA.