Positive Association of Urinary Dimethylarsinic Acid (DMAV) with Serum 25(OH)D in Adults Living in an Area of Water-Borne Arsenicosis in Shanxi, China.

Limited studies have demonstrated that inorganic arsenic exposure is positively associated with serum vitamin D levels, although the correlation between urinary arsenic species and serum vitamin D has not been investigated in areas of water-borne arsenicosis. A cross-sectional study of 762 participants was conducted in Wenshui Country, Shanxi Province, a water-borne arsenicosis area. The results showed a positive relationship between urinary arsenic species (inorganic arsenic (iAs), methylarsonic acid (MMAV), dimethylarsinic acid (DMAV) and serum 25(OH)D. Log-binomial regression analysis indicated a 0.4% increase in the risk of vitamin D excess for every 1-unit increment in the Box-Cox transformed urinary DMAV after adjustment for covariates. After stratifying populations by inorganic arsenic methylation metabolic capacity, serum 25(OH)D levels in the populations with iAs% above the median and primary methylation index (PMI) below the median increased by 0.064 ng/mL (95% CI: 0.032 to 0.096) for every one-unit increase in the Box-Cox transformed total arsenic (tAs) levels. Serum 25(OH)D levels increased by 0.592 ng/mL (95% CI: 0.041 to 1.143) for every one-unit rise in the Box-Cox transformed iAs levels in people with skin hyperkeratosis. Overall, our findings support a positive relationship between urinary arsenic species and serum 25(OH)D. It was recommended that those residing in regions with water-borne arsenicosis should take moderate vitamin D supplements to avoid vitamin D poisoning.

Association between mtDNA haplogroups and skeletal fluorosis in Han population residing in drinking water endemic fluorosis area of northern China.

To investigate the association between mtDNA genetic information and the risk of SF, individuals were conducted in the drinking water endemic fluorosis area in northern China, sequenced the whole genome of mtDNA, identified the SNPs and SNVs, analyzed the haplogroups, and diagnosed SF, and then, the effect of mtDNA genetic information on the risk of SF was evaluated. We find that, D5 haplogroup and its specific SNPs reduced the risk, while the D4 haplogroup and its specific SNPs increased the risk of SF. The number of SNVs in coding regions of mitochondrial respiratory chain (MRC) is different between the controls and cases. This suggests that D5 haplogroup may play a protective role in the risk of SF, while the opposite is observed for the D4 haplogroup, this may relate to their specific SNPs. And SNVs that encode the MRC complex may also be associated with the risk of SF.

The disruption of blood-brain barrier induced by long-term arsenic exposure is associated with the increase of MMP-9 and MMP-2: The characteristics are similar to those caused by senescence.

Accumulating evidence suggests that Matrix metalloproteinase-9 (MMP-9) and -2 (MMP-2) are involved in the neuropathological processes by contributing to breaking the extracellular matrix and the tight junctions that constitute the blood-brain barrier (BBB). However, the influences of arsenic (As) on these two MMPs were inconsistent. In the cross-sectional study of 500 adults, serum MMP-2 and MMP-9 positively correlated with urine arsenic. And the positive correlation between urine tAs and serum MMP-9/2 was found in people older than 59 years. In vivo studies, we found that arsenic exposure or senescence might decrease number of neurons and neuritic density and increase serum and cortical MMP-9/2 levels. Furthermore, arsenic exposure or senescence could disrupt the tight junction of BBB and elevate MMP-9 and MMP-2 expression in the cerebral microvascular endothelium. The MMP-9 and MMP-2 are of particular interest when researching the link between arsenic exposure and nerve damage.

Association between arsenic (+3 oxidation state) methyltransferase gene polymorphisms and arsenic methylation capacity in rural residents of northern China: a cross-sectional study.

Arsenic is a toxic metal-like element. The toxic reaction of the body to arsenic is related to the ability of arsenic methylation metabolism. As the rate-limiting enzyme of arsenic methylation metabolism, the genetic single nucleotide polymorphisms (SNPs) of arsenic (+ 3 oxidation state) methyltransferase (AS3MT) gene are related to capacity of arsenic methylation. In this paper, we investigated the association of five SNPs (rs7085104, rs3740390, 3740393, rs10748835, and rs1046778) in AS3MT with arsenic methylation metabolizing using the data and samples from a cross-sectional case-control study of arsenic and Type 2 diabetes mellitus conducted in Shanxi, China. A total of 340 individuals were included in the study. Urinary total arsenic (tAs, µg/L) was detected by liquid chromatography-atomic fluorescence spectrometry (LC-AFS). According to "safety guidance value of urinary arsenic for population" as specified in WS/T665-2019 (China), participants were divided into the control group (tAs ≤ 32 µg/L, n = 172) and arsenic-exposed group (tAs > 32 µg/L, n = 168). iAs%, MMA%, and DMA% are as the indicator of arsenic methylation capacity. The genotypes of AS3MT SNPs were examined by Multiple PCR combined sequencing. Linear regression analysis showed that AG + GG genotype in rs7085104 was associated with decreased iAs% and increased DMA%. Moreover, AG + AA genotype in rs10748835 and TC + CC genotype in rs1046778 were associated with decreased iAs% and MMA% and increased DMA%. The interaction between rs7085104 and arsenic is associated with iAs% and DMA%. The interaction of rs3740390 and rs10748835 with arsenic is associated with iAs%. Haplotype CTAC (rs3740393-rs3740390-rs10748835-rs1046778) was associated with lower iAs% and higher DMA%, but this association disappeared after adjusting for age, gender, drink, smoking, BMI and tAs. Haplotype GCAC was associated with decreased MMA%. Our study provides additional support for revealing the factors influencing the metabolic capacity of arsenic methylation and might be helpful to identify the population susceptible to arsenic exposure through individualized screening in the future.

Effects of carnosic acid on arsenic-induced liver injury in mice: A comparative transcriptomics analysis.

BACKGROUND: Long-term chronic exposure to arsenic can cause different degrees of liver injury. Till date, its molecular mechanism has not meant fully elucidated. Evidence indicates that Carnosic acid (CA) has a protective role in arsenic-induced liver injury. This study aimed to reveal the potential targets and evaluate the potential effect of CA intervention at transcriptional level, and provide reference for the intervention of arsenic-induced liver injury. METHODS: Arsenic-induced liver injury and CA intervention models were established in C57BL/6 mice. RNA sequencing technique was carried out to obtain the differentially expressed gene (DEG) profiles. The common covariant DEGs between arsenic induction and CA intervention was screened by comparative transcriptomic analysis methods. QRT-PCR was used to verify the covariant DEGs. RESULTS: Transcriptome results showed that 220 DEGs were identified after arsenic induction. 267 DEGs were identified after CA intervention (|fold change| > 2.0 and adjusted P < 0.05). 42 covariant DEGs were discovered between the comparison of "AS vs Control" and "AS & CA vs AS". In addition, hub gene analysis revealed a total of 8 covariant DEGs (Ehhadh, Fgf21, Cyp2b10, Plin2, Aacs, Cyp7a1, Per2 and Mylip). The mRNA expressions of Fgf21 and Plin2 were significantly increased (P < 0.05) and the mRNA expressions of Cyp2b10, Cyp7a1, Per2 and Mylip were significantly decreased (P < 0.05) after arsenic induction. On the contrary, the changes of these DEGs were reversed after CA intervention. CONCLUSION: The present study would be helpful to understand the potential health effects of arsenic-induced liver injury and identify new potential targets, and provide a reference for the intervention of CA.

GSTM1 and GSTT1 Null Genotype Polymorphisms and Susceptibility to Arsenic Poisoning: a Meta-analysis.

The value of the glutathione S-transferase (GST) null genotype in patients with arsenic poisoning has been recognized, but the conclusions of previous studies remain inconsistent. The objective of this study was to evaluate the relationship between GST mu 1 (GSTM1) and GST theta 1 (GSTT1) null genotype polymorphisms and susceptibility to arsenic poisoning. PubMed, Medline, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, and WeiPu databases were systematically searched for publications up to March 31, 2020. The quality of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to estimate the relationship between GSTM1 and GSTT1 null genotype polymorphisms and arsenic poisoning. The meta-analysis was conducted using STATA 14.0 software. Nine articles with 3324 subjects were included in the meta-analysis. A significantly negative correlation was observed between the GSTM1 null genotype and susceptibility to arsenic poisoning (OR = 0.731; 95% CI: 0.536-0.999; P = 0.049; I2 = 70.5%). There was no significant correlation between the GSTT1 null genotype (OR = 1.009; 95% CI: 0.856-1.189; P = 0.915, I2 = 36.8%) and GSTM1-GSTT1 double null genotype (OR = 1.105; 95% CI: 0.670-1.822; P = 0.695; I2 = 64.7%) and the risk of arsenic poisoning. Egger's and Begg's tests indicated no publishing bias. Compared with controls, individuals with the GSTM1 null genotype were less susceptible to arsenic poisoning. The GSTT1 single null genotype and GSTM1-GSTT1 dual-null genotype were not associated with the risk of arsenic poisoning. The GSTM1 single null genotype may have potential as a genotoxic biomarker to identify individuals who are not prone to arsenic poisoning, and as a reference for guiding the prevention of arsenic poisoning.

Inhibitors of apoptosis proteins (IAPs) are associated with T-2 toxin-induced decreased collagen II in mouse chondrocytes in vitro.

T-2 toxin is considered an unavoidable pollutant, which contaminates food crops and stockpiled cereals, impairing the health of humans and animals due to its multi-organ toxicity. Studies have shown that T-2 toxin can cause articular cartilage damage; however, the underlying molecular mechanism is still unclear. Here, we investigated the possible mechanism of the following inhibitors of apoptosis proteins (IAPs) family members: NAIP, cIAP1, cIAP2, XIAP, and Survivin, and their involvement in T-2 toxin-induced mouse chondrocyte damage. In this study, mouse articular chondrocytes were isolated and cultured in vitro, and the chondrocytes were then treated with 0, 5, 10, and 20 ng/mL T-2 toxin. Firstly, the toxic effect of T-2 toxin on chondrocytes was determined. CCK-8 assay results showed that T-2 toxin induced a dose-dependent inhibition of chondrocyte viability. Transmission electron microscopy demonstrated that T-2 toxin caused morphological changes in chondrocyte endoplasmic reticulum and an increase in mitochondrial swelling. In addition, Annexin-V-FITC/PI staining and caspase 3 protein expression showed that T-2 toxin induced an increase in the apoptotic rate of chondrocytes. Secondly, it was found that T-2 toxin cause decreased expression of cellular and secreted Collagen II. Finally, we examined the expression of NAIP, cIAP1, cIAP2, XIAP, and Survivin in chondrocytes in the presence of T-2 toxin and their relationship with decreased Collagen II. The decrease in Collagen II was negatively correlated with the expression of cIAP1, cIAP2 and positively correlated with NAIP and Survivin mRNA level. Survivin mRNA level had a positive correlation with Collagen II as shown by partial correlation analysis. This study revealed the new role of IAPs in chondrocyte injury and provides new insights and clues into the mechanism of T-2 toxin-induced chondrocyte damage.

The Sphkl/SlP pathway regulates angiogenesis via NOS/NO synthesis following cerebral ischemia-reperfusion.

AIMS: Sphingosine kinase 1 (Sphk1) and the signaling molecule sphingosine-1-phosphate (S1P) are known to be key regulators of a variety of important biological processes, such as neovascularization. Nitric oxide (NO) is also known to play a role in vasoactive properties, whether Sphk1/S1P signaling is able to alter angiogenesis in the context of cerebral ischemia-reperfusion injury (IRI), and whether such activity is linked with NO production, however, remains uncertain. METHODS: We used immunofluorescence to detect the expression of Sphk1 and NOS in cerebral epithelial cells (EC) after IR or oxygen-glucose deprivation (OGDR). Western blotting was used to detect the Sphk1 and NOS protein levels in brain tissues or HBMECs. Adenovirus transfection was used to inhibit Sphk1 and NOS. An NO kit was used to detect NO contents in brain tissues and epithelial cells. Tube formation assays were conducted to measure angiogenesis. RESULTS: We determined that EC used in a model of cerebral IRI expressed Sphk1, and that inhibiting this expression led to decreased expression of two isoforms of NO synthase (eNOS and iNOS), as well as to decrease neovascularization density and NO production following injury. In HBMECs, knocking down Sphk1 markedly reduced NO production owing to reduced eNOS activity, and inhibiting eNOS directly similarly decreased NO production in a manner which could be reversed via exogenously treating cells with S1P. We further found that knocking down Sphk1 reduced HBMEC eNOS expression, in addition to decreasing the adhesion, migration, and tube formation abilities of these cells under OGDR conditions. CONCLUSIONS: Based on these results, we therefore postulate that Sphk1/S1P signaling is able to mediate angiogenesis following cerebral IRI via the regulation of eNOS activity and NO production. As such, targeting these pathways may potentially represent a novel means of improving patient prognosis in those suffering from cerebral IRI.

An enzyme-free electrochemical sandwich DNA assay based on the use of hybridization chain reaction and gold nanoparticles: application to the determination of the DNA of Helicobacter pylori.

An ultrasensitive enzyme-free electrochemical sandwich DNA biosensor is described for the detection of ssDNA oligonucleotides. A DNA sequence derived from the genom of Helicobacter pylori was selected as a model target DNA. The DNA assay was realized through catching target DNA on capture DNA immobilized gold electrode; then labeling the target DNA with reporter DNA (rpDNA) and initiator DNA (iDNA) co-modified gold nanoparticles (AuNPs). The high density of iDNAs serves as one of the amplification strategies. The iDNA triggers hybridization chain reaction (HCR) between two hairpins. This leads to the formation of a long dsDNA concatamer strand and represents one amplification strategy. The electrochemical probe [Ru(NH3)5L]2+, where L stands for 3-(2-phenanthren-9-ylvinyl)pyridine, intercalated into dsDNA chain. Multiple probe molecules intercalate into one dsDNA chain, serving as one amplification strategy. The electrode was subjected to differential pulse voltammetry for signal acquisition, and the oxidation peak current at -0.28 V was recorded. On each AuNP, 240 iDNA and 25 rpDNA molecules were immobilized. Successful execution of HCR at the DNA-modified AuNPs was confirmed by gel electrophoresis and hydrodynamic diameter measurements. Introduction of HCR significantly enhances the DNA detection signal intensity. The assay has two linear ranges of different slopes, one from 0.01 fM to 0.5 fM; and one from 1 fM to 100 fM. The detection limit is as low as 0.68 aM. Single mismatch DNA can be differentiated from the fully complementary DNA. Conceivably, this highly sensitive and selective assay provides a general method for detection of various kinds of DNA. Graphical abstractSchematic representation of the detection and the amplification principles of the electrochemical sandwich DNA assay. Purple curl: Captured DNA; Green curl: Reporter DNA; Orange curl: HCR initiator DNA; Yellow solid-circle: Gold nanoparticle; H1 and H2: Two hairpin DNA; [Ru(NH3)5L]2+: Signal probe.

A recyclable biointerface based on cross-linked branched DNA nanostructures for ultrasensitive nucleic acid detection.

The detection of specific nucleic acids is becoming increasingly important in the discovery of genetic diseases and clinical molecular diagnostics. Here we report a DNA nanostructure-based platform which enables a recyclable biointerface for ultra-sensitive detection of nucleic acid. We created a chemically cross-linked branched DNA nanostructure (CCLB-DNA) as the probe DNA to engineer the biointerfaces, thereby increasing probe distance, exposing more DNA probes from the interface into the solution phase, and thus enhancing the signal dramatically. In addition, DNA functionalized Fe3O4 nanoparticles were utilized for further signal amplification. The detection limit could go as low as 500 fM. Moreover, CCLB-DNA could endure denaturation conditions without disruption of duplex integrity; as a result, the recognition layer could be easily regenerated and the biointerface could be reused. Our CCLB-DNA represents an excellent prospect in the engineering of recyclable biointerface, which will be beneficial to many biosensing systems.

Engineering nanomaterials-based biosensors for food safety detection.

Food safety always remains a grand global challenge to human health, especially in developing countries. To solve food safety pertained problems, numerous strategies have been developed to detect biological and chemical contaminants in food. Among these approaches, nanomaterials-based biosensors provide opportunity to realize rapid, sensitive, efficient and portable detection, overcoming the restrictions and limitations of traditional methods such as complicated sample pretreatment, long detection time, and relying on expensive instruments and well-trained personnel. In this review article, we provide a cross-disciplinary perspective to review the progress of nanomaterials-based biosensors for the detection of food contaminants. The review article is organized by the category of food contaminants including pathogens/toxins, heavy metals, pesticides, veterinary drugs and illegal additives. In each category of food contaminant, the biosensing strategies are summarized including optical, colorimetric, fluorescent, electrochemical, and immune- biosensors; the relevant analytes, nanomaterials and biosensors are analyzed comprehensively. Future perspectives and challenges are also discussed briefly. We envision that our review could bridge the gap between the fields of food science and nanotechnology, providing implications for the scientists or engineers in both areas to collaborate and promote the development of nanomaterials-based biosensors for food safety detection.

[Preparation and quality evaluation of microcapsules of volatile oil from Ledum palustre].

OBJECTIVE: To study the preparation of microcapsules of volatile oil from Ledum palustre and its quality evaluation. METHODS: The microcapsules were prepared by complex coacervation with encapsulation efficiency as evaluation index, and the preparation was optimized by orthogonal experimental design. RESULTS: The optimum condition of microcapsules prepared was that 5% gelatin and gum arabic was material, with core material ratio of 1: 2; pH 4.0 and glutaraldehyde in an amount of 1.0 mL. The average encapsulation efficiency of microcapsules of volatile oil from Ledum palustre was 79.62%. Microcapsules was distributed evenly without adhesion through microscopic observation and more than 73% of the microcapsule size distribution between 10 - 14 microm. Microcapsules was spherical and the surface folded by using electron microscope scanning. The test solution and reference solution appeared same spot in the same location compared with the negative control solution. CONCLUSION: The preparation process is simple, stable and feasible.

Pharmacophore and molecular docking guided 3D-QSAR study of bacterial enoyl-ACP reductase (FabI) Inhibitors.

Enoyl acyl carrier protein (ACP) reductase (FabI) is a potential target for the development of antibacterial agents. Three-dimensional quantitative structure-activity relationships (3D-QSAR) for substituted formamides series of FabI inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore and molecular docking methods were used for construction of the molecular alignments. A training set of 36 compounds was performed to create the 3D-QSAR models and their external predictivity was proven using a test set of 11 compounds. Graphical interpretation of the results revealed important structural features of the formamides related to the active site of FabI. The results may be exploited for further optimization of the design of new potent FabI inhibitors.

Recent advance in the design of small molecular modulators of estrogen-related receptors.

The estrogen-related receptors (ERRs), comprising ERRα, ERRß and ERRγ, are the members of the nuclear receptor superfamily, which have been functionally implicated in estrogen signal pathway in various patterns. However, no natural ligand of ERRs has been identified to data, so identification of the synthetic modulators (inverse agonist and agonist) of ERRs would be highly effective in the treatment of estrogen-related pathologies, such as diabetes, breast cancer and osteoporosis. This review summarizes the structures and biological functions of ERR subtypes, and the progress in designing the small molecular modulators of ERRs as well as the detailed description of available co-crystal structures of the LBD of ERRs in three distinct states: unligand, inverse agonist bound, and agonist bound.