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TBBPA bis(2-hydroxyethyl) ether (TBBPA-DHEE) pollution in the environment has raised serious public health concerns due to its potential neuroendocrine-disrupting effects. The neuroendocrine-disrupting effects of TBBPA-DHEE on marine spices, on the other hand, have received little attention. The behavioral, neuroendocrine-disrupting, and possible reproductive toxicity of TBBPA-DHEE were assessed in sexual developing zebrafish treated for 40 days by examining locomotor activity, Gonadotrophin releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, and quantifying gene expression. In addition, transcriptome profiling was carried out to explore the possible mechanisms. According to our findings, TBBPA-DHEE treated zebrafish showed altered locomotor activity, a potential neuroendocrine-disrupting effect via the toxic effect on the hypothalamus and pituitary gland, which is evident in decreased levels of GnRH, FSH, and LH, according to our findings. The transcriptomic profiling reveals that a total of 216 DEGs were detected (5 upregulated and 211 down-regulated). Transcriptomic analysis shows that TBBPA-DHEE exposure caused decreased transcript levels of genes (cyp11a1, ccna1, ccnb2, ccnb1, cpeb1b, wee2) involved in cell cycle oocyte meiosis, progesterone mediated oocyte maturation, and ovarian steroidogenesis, which are known reproduction-related pathways. Overall, these findings add to our understanding of the impact of TBBPA-DHEE and biomonitoring in the maritime environment.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance (IR) and has attracted worldwide attention due to its high prevalence. As a typical persistent organic pollutant, decabromodiphenyl ether (BDE-209) has been detected in food and human samples, and the concentration trends increase year by year. In addition, it has been proved to have the potential to increase the risk of IR, but it is rarely reported whether it could aggravate IR in T2DM. Therefore, in this study, the IR-BRL (buffalo rat liver cells with IR) model was applied to study the metabolism toxicity and susceptibility of BDE-209. Results showed that BDE-209 could inhibit glucose absorption and increase the levels of serum total cholesterol (TC) and triglyceride (TG), ultimately leading to the disorder of glucolipid metabolism in IR-BRL cells. Besides, it also could cause cell damage by increasing the levels of aspartate transaminase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) in cells. Moreover, its potential mechanisms were to: (1) affect the transport of glucose, synthesis of glycogen and fatty acid via IRS-1/GLUT4 and IRS-1/PI3K/AKT/GSK-3β pathways; (2) impact the proliferation and differentiation by regulating the expression of Mek1/2, Erk1/2, and mTOR proteins and genes. Furthermore, susceptibility analysis showed that there was a significant synergism interaction between IR and BDE-209, which suggested that IR-BRL cells were more susceptible to the metabolism toxicity induced by BDE-209.

In the present study, the neurotoxicity and mechanisms of di-(2-ethylhexyl) phthalate (DEHP) exposure on pubertal normal (P-normal) and pubertal type 2 diabetes mellitus (P-T2DM) mice were investigated by typical neurobehavioral methods and transcriptome analysis. Pubertal male ICR mice were orally exposed to DEHP (0.18, 1.8, 18 and 180 mg/kg/d) for 3 weeks. In Open field test, DEHP significantly increased the time in central area staying and decreased the total distance and clockwise (CW) rotation of P-normal and P-T2DM mice. Morris water maze showed that DEHP significantly increased the latency in locating platform and decreased the original platform quadrant and residence time in target quadrant of P-normal and P-T2DM mice. Transcriptome analysis results revealed the effects of DEHP exposure on neural signaling pathway including biogenic amines neurotransmitters, nerve receptors, neurobiological processes, etc. Enzyme-linked immunosorbent assay (ELISA) and western blotting results showed that DEHP significantly decreased the contents of 5-HT, cAMP, GABA and Ca2+, the levels of CREB, phosphorylation of PKA, ERK1/2 and CREB, increased the levels of CaM and phosphorylation of CaMKII in P-normal and P-T2DM mice. Factorial analysis results showed that P-T2DM mice were more sensitive than those of P-normal mice. The potential neurotoxicity mechanism of DEHP may be synergistically mediated by the cAMP-PKA-ERK1/2-CREB signaling and the Ca2+ signaling pathway.

In this study, the immature mice were taken to assess the potential neurological toxicity of lead (Pb) and di (n-butyl) phthalates (DBP) combination exposure. Mouse administration with DBP combination with Pb exhibited longer escape latency and lower average number of crossing of the platform. Pb content in the tissues was increased, especially in the brain, after Pb exposure as compared to those without Pb exposure. The alterations of oxidative damages in tissues (MDA and SOD) and biochemical indicators in the brain (AChE, TNOS, and iNOS) were observed, as well as the synergistic effect of joint exposure. Expressions of apoptosis-related protein (bax/bcl-2 ratio and caspase-3) were significantly increased in the hippocampus, while the bcl-2 was remarkably decreased and no significant differences were observed on the bax. The results suggested that the possible mechanisms for the learning and memory ability impairments were as follows: Firstly, the combination exposure induced the occurrence of lipid peroxidation in the brain, leading to damage to the brain cells. Secondly, it destroyed the normal metabolic balance of ACh, causing nerve damage in mice. Thirdly, it induced apoptosis in mouse hippocampal cells. The overall findings revealed that Pb and DBP co-exposure greatly influenced the developmental nervous system and accompanied with synergistic toxic effect.

Tetrabromobisphenol A bis (2-hydroxyethyl ether) (TBBPA-DHEE) is a derivative of Tetrabromobisphenol A (TBBPA) used as an intermediate flame retardant in engineering polymers. The mechanism of neurodevelopmental toxicity of TBBPA-DHEE remains unclear due to limited toxicological data. We performed behavioral and transcriptomic analyses to assess the neurodevelopmental effects of TBBPA-DHEE on developing zebrafish and potential toxicity mechanisms. Our result shows that exposure to TBBPA-DHEE significantly increased mortality, deformity rate, and reduction in hatch rate, hatchability, and body length relative to the DMSO control. The behavior analysis indicates that TBBPA-DHEE significantly reduced the spontaneous movement of larva compared to the control. The TSH and GH levels were significantly reduced in all the exposure groups in a concentration-dependent manner relative to the DMSO control. TBBPA-DHEE exhibited a significant reduction in locomotor activity across all the exposure groups in the light/dark locomotion test. The transcriptomic analysis result shows that 579 genes were differentially expressed. KEGG analysis shows the enrichment of complement cascade, JAK-STAT signaling pathway, cytokine-cytokine interaction, and phototransduction pathway resulting in a change in mRNA expression of their genes. These observed changes in developmental endpoints, hormonal level, and alteration in mRNA expression of component genes involved in neurodevelopmental pathways could be part of the possible mechanism of the observed toxic effects of TBBPA-DHEE exposure on zebrafish. This study could reveal the possible neurodevelopmental toxicity of TBBPA-DHEE to aquatic species, which could help uncover the health implications of emerging environmental contaminants.

Tetrabromobisphenol A bis(2-hydroxyetyl) ether (TBBPA-DHEE) is among the main derivatives of Tetrabromobisphenol A (TBBPA). Result from previous study showed that TBBPA-DHEE can cause neurotoxicity in rat. In this study, zebrafish larvae were used for evaluation of TBBPA-DHEE-induced developmental toxicity, apoptosis, oxidative stress and the potential molecular mechanisms of action. Our result showed that TBBPA-DHEE exposure caused a significant concentration-dependent developmental toxicity endpoints like death rate, malformation rate, growth rate. TBBPA-DHEE altered locomotor and enzymes activities of larvae and caused apoptosis within the brain indicating the potential TBBPA-DHEE-induced cardiac, brain impairment in the zebrafish larvae. Our transcriptomic analysis shows that 691 genes were differentially expressed (DEGs) (539 upregulated, 152 downregulated). The KEGG and GO enrichment pathway analysis shows that the DEGs were involved in development, immunity, enzyme activity. Our study provides novel evidence on the neurodevelopmental toxicity and toxicity mechanism of TBBPA-DHEE which are vital for assessment of the environmental toxicity and risk assessment of the chemical.

Diabetes mellitus is a common endocrine metabolic disorder, and previous studies have shown that diabetics are more sensitive to the toxic environmental contaminants. Acrylamide (ACR) is both an industrially multipurpose compound and a common endogenous food contaminant to which people are frequently exposed and at high risk. However, the toxicity of ACR on diabetes hasn't attracted much attention. In this study, both healthy mice and diabetic mice received ACR administration orally to investigate the ACR-induced metabolic toxicity, mechanism and susceptibility to ACR toxicity in adult diabetic male mice. The results showed that ACR significantly increased FBG level and decreased bodyweight, serum lipid and liver lipid biomarkers (TC, TG, LDL-C, HDL-C) levels as well as expression of lipid and glucose metabolism-related genes in diabetic mice, indicating that ACR can exacerbate metabolic disorders of glucose and lipid in diabetic male mice. Moreover, ACR exposure significantly increased levels of MDA and COX-2), decreased GSH level and antioxidant enzyme activity (SOD, GSH-PX and CAT) by downregulating expression of Nrf2 and Keap1 in diabetic mice. Factorial analysis showed ACR had a more significant disturbance in diabetic mice compared with healthy mice. Our results indicated that ACR exposure can cause oxidative stress and inflammatory damage, which can exacerbate abnormal glucose and lipid metabolism. This work helps to elucidate the effects and underlying mechanisms of ACR-induced metabolic toxicity in adults with diabetes.

As a typical persistent organic pollutant, decabromodiphenyl ether (BDE-209) is associated with various health risks, especially on immune system, which is sensitive to environmental pollutants. In addition, there is a problem of multi-index estimation and lack of comprehensive evaluation in immune toxicity study. In this study, the immunotoxicity of BDE-209 was systematically estimated from the aspects of immunopathology, humoral immunity, cellular immunity and non-specific immunity, etc., and integrated biomarker responses (IBR) combined with principal component analysis was applied to comprehensively evaluate the immunotoxicity of BDE-209 and its self-recovery after discontinuation. Results showed that BDE-209 exposure could cause immunotoxicity. This response seems to depend on (1) atrophying immune organs (thymus and spleen), hepatomegaly accompanied by increasing aspartate aminotransferase and oxidative stress;(2) changing humoral (immunoglobulins) and cellular (lymphocyte proliferation and cytokine secretion) immunity indices; (3) altering related expressions of genes, and further leading to imbalance of Th1/Th2 (Th, helper T cell). Integrated biomarker responses (IBR) companied with principal component analysis selected five biomarkers (mRNA expression of GATA-3, malondialdehyde level in thymus, count of white blood cell, serum IgG and lipopolysaccharide-induced splenic lymphocyte proliferation) to clarify the immunotoxicity induced by BDE-209. Furthermore, IBR combined with factorial analysis revealed that the effect of BDE-209 could be dose-dependently reduced after withdrawal of BDE-209. Overall results suggested that BDE-209 has immunotoxicity on adult Balb/c mice, whereas this immunotoxicity could be reduced by the self-regulation of organisms to some extent.

Dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) have been reported to exhibit reproductive toxicity in vertebrates. However, the combined effect of DBP and DiBP on offspring of exposed parents remains unclear, especially for aquatic organisms such as fish. The aims of this study were to assess the effects of parental co-exposure to DBP and DiBP on early development of zebrafish offspring, and to explore the potential molecular mechanisms involved. The early developmental indicators and transcriptomic profiles of F1 larvae were examined after parental exposure to DBP, DiBP and their mixtures (Mix) for 30 days. Results showed that parental exposure to DBP and DiBP, alone or in combination, resulted in increased hatchability at 48 hpf and heart rate at 96 hpf, and increased the prevalence of malformations and mortality in F1 larvae. Generalized linear model (GLM) suggested an antagonistic interactive effect between DBP and DiBP on mortality and malformations of F1 larvae. The transcriptomic analysis revealed that the molecular mechanisms of parental co-exposure were different from those of either chemical alone. Disruption of molecular functions involved unfolded protein binding, E-box binding and photoreceptor activity in F1 larvae. These findings provide initial insights in the potential mechanism of action of parental co-exposure to DBP and DiBP.

To explore the comprehensive utilization of agricultural wastes, solid-state fermentation was applied to residues of Flammulina velutipes (F. velutipes) and vinegar for use in culturing earthworms. Fermentation technology and earthworm culture technology were optimized by response surface methodology in this study. The optimal fermentation product for earthworm culture was obtained under an inoculum amount of 7.5%, fermentation temperature of 25.6 °C, pH 7.7 and protein content of 18.23%. The optimum culture conditions were a culture density of 18.4 individuals/dm3, an initial pH of 7.2 and a fermentation temperature of 26.8 °C. The daily weight gain multiplier of earthworms was 0.0387 units, and it increased significantly compared with that of the unfermented and cow dung groups. The fermented product of F. velutipes and vinegar residues could be used to culture earthworms and improve the metabolism and antioxidant capacities of earthworms. This provides a new way to comprehensively utilize agricultural waste resources.

Tetrabromobisphenol S (TBBPS), an emerging brominated flame retardant (BFR) has been widely detected in the environment, and may potentially pose environmental risks. However, data on the occurrence and toxic effects of TBBPS are limited. Circadian rhythms govern multiple behavioral and physiological processes, and their disruption is closely associated with various pathological conditions. Little is known about the potential for TBBPS to perturb circadian rhythm networks or circadian-driven locomotor behavior. In the present study, behavior assays and gene expression analysis based on circadian rhythm pathways were designed to investigate the potential circadian rhythm impairments and subsequent adverse effects caused in 120 h post-fertilization (hpf) zebrafish larvae by TBBPS. The development of embryos was inhibited by TBBPS exposure even at concentrations below the maximal non-lethal concentration (MNLC, 3.47 mg/L). Our results indicated remarkable alterations in the expression of several key circadian rhythm genes due to TBBPS exposure. Compared to control, the expression of per1a, per1b, per3, cry2, and csnk1da was increased, while the expression of clocka, clockb, cry4, cry1ba, arntl1a, and cank1db was decreased. Significant alterations of the circadian rhythm network could be observed in the zebrafish embryos. TBBPS exposure also significantly affected the behavioral responses of larvae. Our findings suggest the circadian rhythm network could be a potential target of TBBPS. Further study is needed to explore whether the transcriptional alterations in circadian rhythm translate into physiological effects.

In this study, a Se-deficient mice model was successfully developed by feeding a Se-deficient diet (0.02 mg Se/kg diet) for 4 weeks, and Se supplementation by Se-polysaccharides (Se-GFP-22) was lasted for 4 weeks. The immunomodulatory activity and Se supplementation of Se-GFP-22 from Se-enriched G. frondosa was investigated. Results showed that Se-GFP-22 remarkably enhanced glutathione peroxidase (GSH-Px) and thioredoxin reductase (TrxR) activities in liver, kidney and plasma, and serum, liver, spleen and kidney Se levels of Se-deficient mice. Se-GFP-22 increased the thymus and spleen indices, phagocytic index, co-mitogenic (ConA- or LPS-stimulated) activities on splenocytes and DTH reaction. Se-GFP-22 caused significant increments in cytokine (IL-1β, TNF-α and IFN-γ) levels and Ig G, Ig A, Ig M and Ig E levels. Se-GFP-22 exhibited superior immunomodulatory effects than GFP-22. These findings indicated that Se-GFP-22 promote the protective effects against Se deficiency-induced immunosuppression and could be a potential immunomodulatory agent and a dietary Se-supplement.

To assess the immunomodulatory and antioxidant activities of a Se-polysaccharide from Se-enriched G. frondosa (Se-GFP-22), immunosuppressed mice models were generated by cyclophosphamide (CTX) administration and then treated with Se-GFP-22. Results showed that Se-GFP-22 could increase thymus and spleen indices, phagocytic index, co-mitogenic (ConA- or LPS-stimulated) activities on splenocytes, DTH reaction, serum hemolysin formation and immunoglobulin (Ig G, Ig A and Ig M) levels in CTX-treated mice. Se-GFP-22 significantly enhanced the antioxidant activity in CTX-treated mice, as shown by the evaluation of GSH-Px, SOD and CAT activities, as well as MDA levels in serum, liver and kidney. Se-GFP-22 strongly stimulated inflammatory cytokines (IL-2 and IFN-γ) and NO productions by up-regulating mRNA expressions of IL-2, IFN-γ and iNOS. Se-GFP-22 possessed the immunomodulatory activity by up-regulating various transcription factors (JNK, ERK, and p38) in MAPKs signaling pathways. This study suggested that Se-GFP-22 may provide an alternative strategy in lessening chemotherapy-induced immunosuppression.

Anthocyanins (ACNs) are naturally occurring components of human diet. Evidence has accumulated regarding the positive association of their intake with chronic disease. Because microbiota has been considered as a metabolic organ, the bacterial-dependent metabolisms of three types of ACNs from mulberry fruits (cyanidin-3-glucoside (C3G), cyanidin-3-rutinoside (C3R), delphinidin-3-rutinoside (D3R)) during a simulation of large intestine conditions were investigated. ACNs and metabolites were analysed and characterized by high performance liquid chromatography-electrospray ionization-mass spectrum (HPLC-ESI-MS/MS). C3G disappeared after 6h of metabolism, while C3R and D3R were no longer detected after 8h. The metabolism of C3G and C3R mainly resulted in the formation of protocatechuic, vanillic, and p-coumaric acids, as well as 2,4,6-trihydroxybenzaldehyde, while the main metabolites of D3R were gallic acid, syringic acid and 2,4,6-trihydroxybenzaldehyde. This research indicated that the intake of ACNs may result in the appearance of specific metabolites that exert a protective effect in the host physiology.

Anthocyanins (ANCs) are phytochemicals with several health effects and undergo significant degradation and subsequent biotransformation during complex metabolic processes. The aim of the present study was to determine the bioaccessibility and biotransformation of cyanidin-3-glucoside (C3G) during the simulated gastric-intestinal digestion in vitro and the metabolism in rats in vivo. Characterization of C3G and its metabolites was conducted by HPLC-ESI-MS/MS. After gastric-intestinal digestion, C3G was detected with a recovery of 88.31% in the gastric-digestive system, and a small amount of methylated-C3G occurred. In the intestinal-digestive system, C3G occurred with a recovery of 6.05%, and mainly decomposed into protocatechuic acid (PCA) and 2,4,6-trihydroxybenzaldehyde. The pharmacokinetic trial of C3G in rats showed rapid elimination in plasma. In tissues, C3G underwent rapid absorption and metabolism into phenolic acids or their derivatives. C3G and methylated-C3G passed through the blood–brain barrier and caused rapid distribution of C3G in the brain. Understanding the conversion of C3G and its metabolites helps in the future design of dietary interventions and the exploration of biological activities of ACNs.

The prevalence of adolescent type 2 diabetes mellitus (A-T2DM) is increasing year by year. Di-(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer, could exacerbate type 2 diabetes mellitus (T2DM). The study aimed to investigate the metabolic toxicity, susceptibility and mechanism of DEHP exposure to A-T2DM. DEHP was administered orally (0, 0.18, 1.8, 18, and 180 mg/kg/day) for 3 weeks to adolescent normal mice (A-normal mice) and established A-T2DM mice. The results of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) levels showed that the susceptibility of A-T2DM mice to DEHP exposure was more significant than that of A-normal mice. DEHP, interfering with glucose and lipid metabolism of A-normal and A-T2DM mice, caused the body weight increase of A-normal mice and decrease of A-T2DM mice. Besides, DEHP could cause more injury of cardiovascular, hepatic and renal function to A-T2DM mice than A-normal mice. Hepatic transcriptome analysis revealed that DEHP exposure interfered with the biological feedback adjustment of endocrine and metabolic system in A-T2DM mice and then led to the development of T2DM. According to the transcriptome results, insulin signaling transduction pathway was applied and researched by immunoassay. It was discovered that DEHP reduced insulin sensitivity and disturbed insulin signaling transduction, glucose utilization, lipid synthesis and protein synthesis. Collectively, DEHP could disturb the endocrine and metabolic functions and increase the insulin resistance in adolescent mice. Moreover, the adolescent T2DM mice are more sensitive to DEHP-induced endocrine and metabolic toxicity than the healthy adolescent mice.

Polychlorinated biphenyls (PCBs) would do serious damage to multiple systems, while coplanar polychlorinated biphenyls, the most toxic member of the family, has been widely taken into consideration. In this study, ICR mice were fed with different doses of PCB126 to explore the underlying molecular mechanisms on immunotoxicity. The results showed that PCB126 caused immunosuppression as evidenced by inhibiting the ratios of thymus and spleen weights, changing the organizational structure and decreasing levels and mRNA expression of TNF-α, IFN-γ and IL-2. PCB126 inhibited the SOD activity and spurred the accumulation of MDA in spleen and thymus. Meanwhile, it also disturbed the Nrf2 signaling pathway as evidenced by up-regulating the mRNA expression of Nrf2 and Keap1. Additionally, a remarkable reduction in the mRNA expression of AhR and enhancement in the mRNA expression of Cyp1 enzymes (Cyp1a1, Cyp1a2 and Cyp1b1) were observed, which increased the ROS levels. PCB126 could increase protein expression of Bax, Caspase-3, Caspase-8 and Caspase-9, while the protein expression of Bcl-2 was decreased. In summary, the results indicated that PCB126 modulated the AhR signaling pathway, which interacted with apoptosis and oxidative stress to induce immunotoxicity, enrich the immunotoxicological mechanisms of PCB126.

Di-(2-ethylhexyl) phthalate (DEHP), one of the most common plasticizers, is closely associated with a high prevalence of pubertal type 2 diabetes mellitus (T2DM). Numerous studies have indicated that DEHP-induced metabolic toxicity exhibits sex differences. In this study, the sex differences in the effect of DEHP on pubertal T2DM (P-T2DM) mice, the susceptibility of female P-T2DM mice to DEHP-induced metabolic toxicity, and the underlying mechanisms were investigated. DEHP exposure exacerbated metabolic disorders in female P-T2DM mice. Factorial analysis showed that female P-T2DM mice were more sensitive to DEHP exposure than female normal mice and male P-T2DM mice. It was determined by integrated biomarker response results that female P-T2DM mice had higher risks of developing T2DM, metabolic disorders, cardiovascular events and hepatotoxicity than male P-T2DM mice. Moreover, hepatic transcriptome analysis emphasized the effects of DEHP on the expression of oxidative injury- and metabolic function-related genes. Western blotting indicated that DEHP activated Jun-N-terminal kinase (JNK) and impaired insulin sensitivity in the liver, which were the main causes of DEHP-exacerbated metabolic abnormalities in P-T2DM mice. Our study revealed that compared with normal mice and male P-T2DM mice, female P-T2DM mice tend to suffer from increased DEHP-induced metabolic toxicity, which was primarily attributed to hepatotoxicity.

In our previous study, a polysaccharide was extracted from Schisandra Chinensis (Trucz.) Baill and found with anti-diabetic effects. The aim of this study was to investigate the anti-diabetic effects of the low weight molecular polysaccharide (SCPP11) purified from crude Schisandra polysaccharide and illustrate the underlying mechanism in buffalo rat liver cells. The insulin resistance model of BRL cells was established by incubating with insulin solution for 24h. The effects of SCPP11 on regulating related protein and mRNA expression in an insulin and AMPK signal pathway were investigated by western blot and RT-PCR analysis. SCPP11 showed no cytotoxicity to BRL cells and could improve the glucose consumption in BRL cells. SCPP11 increased the protein expression of Akt, p-AMPK and GLUT-4 in BRL cells. Moreover, SCPP11 could enhance the mRNA expression levels of IRS-1, PI3K, Akt, GLUT-4, AMPKα and PPAR-γ in BRL cells at the same time. In conclusion, SCPP11 possessed effects in improving glucose consumption by up-regulating the expression of GLUT-4 which might occur via insulin and AMPK signal pathway and could be a potential functional food to prevent and mitigate the insulin resistance condition.

The rational for the study was to review the literature on the toxicity and corresponding mechanisms associated with lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), individually and as mixtures, in the environment. Heavy metals are ubiquitous and generally persist in the environment, enabling them to biomagnify in the food chain. Living systems most often interact with a cocktail of heavy metals in the environment. Heavy metal exposure to biological systems may lead to oxidation stress which may induce DNA damage, protein modification, lipid peroxidation, and others. In this review, the major mechanism associated with toxicities of individual metals was the generation of reactive oxygen species (ROS). Additionally, toxicities were expressed through depletion of glutathione and bonding to sulfhydryl groups of proteins. Interestingly, a metal like Pb becomes toxic to organisms through the depletion of antioxidants while Cd indirectly generates ROS by its ability to replace iron and copper. ROS generated through exposure to arsenic were associated with many modes of action, and heavy metal mixtures were found to have varied effects on organisms. Many models based on concentration addition (CA) and independent action (IA) have been introduced to help predict toxicities and mechanisms associated with metal mixtures. An integrated model which combines CA and IA was further proposed for evaluating toxicities of non-interactive mixtures. In cases where there are molecular interactions, the toxicogenomic approach was used to predict toxicities. The high-throughput toxicogenomics combines studies in genetics, genome-scale expression, cell and tissue expression, metabolite profiling, and bioinformatics.

A polysaccharide termed Se-GP11 was extracted and purified from Se-enriched Grifola frondosa in our previous study. This study investigated the characterization, anti-tumor and immunomodulatory activity of Se-GP11. The results showed that Se-GP11 was composed of mannose, glucose and galactose with a molar ratio of 1:4.91:2.41. The weight-average molecular weight (Mw) and weight-average mean square radius (Rw) of Se-GP11 in 0.1M sodium chloride solution were 3.3×10(4)Da and 32.8 nm. Se-GP11 existed as a globular conformation with random coil structure. Se-GP11 had no anti-tumor activity against HepG-2 cells in vitro, and it significantly inhibited the growth of Heps tumor in vivo. Se-GP11 increased the relatively thymus and spleen weights as well as serum necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) levels. In addition, Se-GP11 promoted the phagocytosis and NO production of RAW264.7 as compared with that of the normal control group. The results revealed that the Se-GP11 may exhibit the anti-tumor through improving immunologic function of the tumor bearing mice.

Dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) are phthalate compounds frequently detected in the environment. Despite increasing awareness of their toxicity in human and animals, the male reproductive toxicity of their combined exposure remains elusive. The purposes of this study were to investigate whether combined exposure to DBP and DiBP could induce male reproductive toxicity, and to explore the potential toxicological mechanisms. Adult male zebrafish were exposed to DBP (11, 113 and 1133 μg L−1), DiBP (10, 103 and 1038 μg L−1) and their mixtures (Mix) (11 + 10, 113 + 103, 1133 + 1038 μg L−1) for 30 days, and their effects on plasma hormone secretion, testis histology and transcriptomics were examined. Highest concentrations of Mix exposure caused greater imbalance ratio of T/E2 and more severe structural damage to testis than single exposure. These effects were consistent with the testis transcriptome analysis for which 4570 genes were differentially expressed in Mix exposure, while 2795 and 1613 genes were differentially expressed in DBP and DiBP, respectively. KEGG pathway analysis showed that both single and combined exposure of DBP and DiBP could affect cytokine-cytokine receptor interaction. The difference was that combined exposure could also affect steroid hormone synthesis, extracellular matrix receptor interaction, retinol metabolism, and PPAR signaling pathways. These results demonstrated that combined exposure to DBP and DiBP could disrupt spermatogenesis and elicit male reproductive toxicity in zebrafish.

Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer which could be easily absorbed by humans and animals through various channels. It has been found that exposure to DEHP could increase the incidence of insulin resistance. In this study, therefore, the metabolism toxicity, susceptibility and mechanism of DEHP (5500 and 50,000 nM exposure for 24 h) on normal BRL cells (Buffalo Rat Liver cells) and BRL cells with insulin resistance induced by insulin were investigated. The results showed that DEHP could cause cell damage with ALT and AST activities and MDA levels increased, cell apoptosis with Caspase-3 levels increased and insulin resistance with IR-β levels decreased in BRL cells with resistance and normal BRL cells. Western-blot analysis and Q-PCR showed that the levels and gene expressions of insulin signaling proteins (IRS-1, GLUT4, GSK-3α, GSK-3β, PI3K, AKT, mTOR), cell signaling proteins (RAS, ERK1/2, MEK1/2, BAD, BAX, BCL-2) and immediate early genes in insulin resistance cells and normal cells were significantly altered by DEHP. DEHP significantly promoted serine phosphorylation of IRS-1. The insulin resistance cells in metabolism toxicity were more sensitive to DEHP than normal cells. Intervention with insulin could improve the metabolism toxicity and insulin resistance. The results indicated that DEHP exerted metabolic toxic effects and increased insulin resistance through interfering with glucose metabolism and insulin signaling transduction pathway. Moreover, the risks of DEHP-induced metabolic toxicity and insulin resistance in BRL cells with insulin resistance were higher than that of normal BRL cells.

Dioctyl phthalate (DOP) (200, 500, and 1000 mg kg-1 bw, i.g.), Pb (Ac)2 (50 mg L-1, p.o.), and NaAsO2 (10 mg L-1, p.o.) were administered individually and as mixtures to weanling male mice for 8 weeks. It was observed that Pb, As, and DOP exposure could significantly inhibit the growth and development of mice. Compared with the Pb, As, and Pb + As groups, the activities of iNOS and TNOS were significantly increased, the levels of AChE and SOD were significantly decreased, and the level of MDA was significantly increased in the Pb + DOP-H, As + DOP-H, and Pb + As + DOP-H groups. The factorial analysis shows that the iNOS, TNOS, and AChE present synergistic effects on Pb, As, and DOP. A significant increase of escape latency and a significant decrease of original platform quadrant stops were observed between Pb + As + DOP-H and Pb + As groups. The factorial analysis shows that there was a synergistic effect on Pb, As, and DOP. Compared with that of the control group, the expression levels of caspase-3 and Bax expression in Pb + As, DOP-H, Pb + DOP-H, As + DOP-H, and Pb + As + DOP-H groups were significantly increased in the hippocampus. The expression levels of Bcl-2 expression decreased significantly and the Bax/Bcl-2 ratio increased significantly. Pathological alterations on the hippocampus were found in exposed groups. This result shows that combined exposure of Pb, As, and DOP could induce neurotoxicity, of which possible mechanism is hippocampal neuronal apoptosis. Graphical abstract This study shows that there were three components with eigenvalues greater than 1, which together explained 89.40% of total variance. The first component (PC1) showed high loadings on B-SOD, L-SOD, B-MDA, L-MDA, K-MDA, iNOS, tNOS, and AChE and accounted for 46.55% of the total variance after Varimax rotation. PC2 accounted for 23.81% of the total variance with high loadings on B-As, L-As, K-As, and K-SOD, whereas PC3 showed high loadings on B-Pb, L-Pb, and K-Pb and accounted for 19.04% of the total variance.

GP11 had been reported to have effectively anti-tumor activity by improving the immune function in our previous study. To avoid drawbacks of the 5-Fu, GP11 in combination with 5-Fu was investigated in this study. The results demonstrated that such synergism displayed enhance the anti-tumor activity of 5-Fu. Additionally, a strength effect was also observed in regulating immune function of GP11 and 5-Fu simultaneous administration, such as enhancing serum interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) secretion, and increasing immune organs weights. Moreover, GP11 could improve the haematological and biochemical parameters deterioration, superoxide dismutase (SOD) activities reduction and malondialdehyde (MDA) levels enhancement in non-immune organs induced by 5-Fu. All these results illustrated that GP11 exhibited attenuated and synergized effect on 5-Fu by improving the immune function. It could be developed as an auxiliary preparation for chemotherapeutic drugs.

Previous study revealed that chromium malate improved the regulation of fasting blood glucose and insulin resistance in type 2 diabetic rats. In this study, the effect of chromium malate on anti-high-glucose and improve insulin resistance activities in L6 skeletal muscle cells with insulin resistance and its acting mechanism were investigated. Chromium malate showed direct anti-high-glucose activity in vitro. The glucose levels had a significant downward trend compared to chromium trichloride. Compared with model group, chromium malate could significantly promote the secretion levels of GLUT-4, Akt, Irs-1, PPARγ, PI3K and p38-MAPK, promote AMPKβ1 phosphorylation, and reduced the level of p-Irs-1 in L6 cells with insulin resistance. And the relate mRNA expression of chromium malate was significantly increased. Chromium malate is more effective at improving the related proteins and mRNA expression than those of chromium trichloride and chromium picolinate. Pretreatment with the specific p38MAPK inhibitor completely inhibited the GLUT-4 and Irs-1 proteins and mRNA expression induced by the chromium malate when compared with model group, but GLUT-4 and Irs-1 proteins and mRNA expression was partially inhibited after inhibiting p38MAPK/PI3K expression. The results suggested that chromium malate had a beneficial influence on the improvement of controlling glucose levels and insulin resistance in L6 cells with insulin resistance by regulating proteins production and genes expression in glucose uptake and insulin sensitivity signaling pathways. The signaling pathways of glucose uptake and insulin sensitivity. This study shown that chromium malate could significant increase in the production levels of GLUT-4, p-AMPKβ1, Akt, Irs-1, PPARγ, PI3K and p38-MAPK proteins and mRNA in L6 cells with insulin resistant. Pretreatment with the specific p38MAPK inhibitor completely inhibited the GLUT-4 and Irs-1 proteins and mRNA expression induced by the chromium malate compared to model group, but the proteins and mRNA were partially inhibited after inhibiting p38MAPK/PI3K. Therefore, chromium malate had beneficial influence on improvement of controlling glucose levels and insulin resistant in L6 cells by regulating proteins production and genes expression in glucose uptake and insulin sensitivity signaling pathways. The key proteins of glucose uptake and insulin sensitivity signaling pathways were p38MAPK, PI3K and PPARγ.

The structural characterization, antioxidant activity and protective effect against H

In our previous study, chromium malate is beneficial for type 2 diabetic rats in control glycometabolism and lipid metabolism. The present study was designed to observe the chronic toxicity, lipid metabolism, learning and memory ability, and related enzymes of chromium malate in rats during the year. The results showed that pathological, toxic, feces, and urine of chromium malate (at daily doses of 10.0, 15.0, and 20.0 μg Cr/kg bm) did not change measurably. Chromium malate (at daily doses of 15.0 and 20.0 μg Cr/kg bm) could significantly reduce the levels of total cholesterol (TC), LDL, and triglyceride (TG), and increase the level of HDL in male rats compared to control group and chromium picolinate group. Significant escalating trends of the escape latency and swimming speed (Morris water maze test), and the original platform quadrant stops, residence time, and swimming speed (Space exploration test) in male rats of chromium malate groups were obtained. The SOD, GSH-Px, and TChE activities of chromium malate (at daily doses of 15.0 and 20.0 μg Cr/kg bm) were enhanced significantly in male rats compared with those of the normal control group and chromium picolinate group. Glycometabolism and related enzymes had no significant changes compared to normal control group and chromium picolinate group. These results indicated that long-term chromium malate supplementation did not cause measurable toxicity at daily doses of 10.0, 15.0, and 20.0 μg Cr/kg bm and could improve dyslipidemia and learning and memory deficits.

Grifola frondosa has long been known and respected as a medically important fungus. This study investigated the characterization, antitumor and immunomodulatory activity of a polysaccharide named GP11 purified from G. frondosa. The results revealed that GP11 was composed of → 1)-D-Manp-(6 →,→ 1)-D-Glcp-(4 →,→ 1)-D-Galp-(6 → and → 2,3,6)-D-Glcp-(1 →, with branches attached at O-2,3 of 1,2,3,6-linked Glcp residues and terminal T-Glcp. GP11 exhibited indirect cytotoxic activity against HepG-2 cells in vitro, and it significantly inhibited the growth of Heps cells in vivo. GP11 increased the relative thymus and spleen weights as well as serum tumor necrosis factor-alpha and interleukin-2 levels. GP11 stimulated tumoricidal activity and the production of nitric oxide (NO), TNF-α and interleukin-1β, and it also stimulated the protein expression of iNOS and mRNA expression of iNOS and TNF-α. TLR-4 is a potential receptor for GP11-mediated macrophage activation. The results suggested that the antitumor activity of GP11 may be due to the improvement of immune functions through the TLR-4-mediated up-regulation of NO and TNF-α.

In this study, lead acetate solution and porcine cerebral hydrolysate peptides (PCHPs) were administered to developing mice. Porcine cerebral protein pretreated by ultrasound was hydrolyzed with alcalase, and 11 peptide fragments were obtained by Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of PCHPs. Our data showed that PCHPs significantly decreased Pb2+-induced spontaneous locomotor activity, latencies to reach the platform, and the time in target quadrant. It also decreased the accumulation of lead in the blood and brain of Pb2+-exposed developing mice. Co-administration of PCHPs and dimercaptosuccinic acid (DMSA) did not only reduce the accumulation of lead in blood but also increased the absorption of zinc and iron in Pb2+-exposed mice. Administration of PCHPs individually significantly enhanced hematopoietic parameters compared with the Pb2+-exposed group. PCHPs significantly reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but increased glutathione (GSH) content and anti-oxidant enzymes and nitric oxide synthase (NOS) activities in Pb2+-exposed brain. Our findings suggest that PCHPs have the ability to protect against Pb2+-exposed learning and memory deficits and oxidative damage.

A novel bioactive polysaccharide, GFP-22, was isolated from the fruit bodies of Grifola frondosa by anion-exchange and gel filtration chromatography. Structure of GFP-22 was investigated using gas chromatography–mass spectrometry (GC–MS), methylation, nuclear magnetic resonance (NMR), high-performance size exclusion chromatography-multi-angle laser light scattering-refractive index detector (HPSEC-MALLS-RI) and atomic force microscopy (AFM) analysis. The backbone of GFP-22 is composed of 1,4-β- d -Glcp, 1,3-β- d -Glcp, 1,6-α- d -Glcp, 1,6-α- d -Galp, 1,4,6-α- d -Manp and 1,3,6-α- d -Manp units. Molecular weight of GFP-22 is 2.72 × 104 Da. GFP-22 has a linear filamentous structure. The administration of GFP-22 could improve or reverse the CTX-induced immunosuppression, significantly enhance the spleen and thymus indices, spleen lymphocyte proliferation and cytokines production in splenocytes. These findings suggest that GFP-22 could be explored as a natural and potential immunomodulatory agent and as an alternative means of lessening chemotherapy-induced immunosuppression.

Previous study revealed that Se-GP11 could exhibited its antitumor activity by improving the immune functions. 5-Fu, as a chemotherapeutic drugs, can kill many immune cells in addition to tumor cells. Accordingly, the enhanced antitumor and reduced toxicity of Se-GP11 on 5-Fu were estimated in this study. The results demonstrated that Se-GP11 could evidently increase the antitumor activity of 5-Fu. Furthermore, Se-GP11 could enhance the immune functions during the tumor inhibition process of 5-Fu for increasing the cytokines secretion (IL-2 and TNF-α) and immune organs weights. In addition, Se-GP11 could reduce the toxicity of 5-Fu on liver by improving the hematological and biochemical parameters and up-regulating the SOD activities and down-regulating the MDA levels. Taken together, the results indicated that Se-GP11 may develop as an auxiliary preparation to chemical antitumor drugs.

Phthalate esters (PAEs), which are notable plasticizers, can be prolific contaminants in aquatic environments, and have been shown to induce reproductive toxicity. However, the studies concerning their toxicity towards aquatic species are based on individual chemicals, and the combined toxicity of PAEs to aquatic organisms remains unclear. The aim of this study was to explore the potential toxicity mechanisms associated with combined exposure to dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) in adult female zebrafish ovaries. Zebrafish were exposed to DBP, DiBP and their mixtures for 30 days, and their effects on ovarian histology, plasma sex hormones and ovarian transcriptomics were investigated. Plasma estradiol (E2) levels were significantly decreased by 38.9% in the DBP-1133 exposure group and 41.0% in the DiBP-1038 exposure group. The percentage of late/mature oocytes was also significantly decreased by 17.3% under DBP-1133 exposure and 16.2% under DiBP-1038 exposure, while that under combined exposure was not significantly affected. Nevertheless, transcriptome sequencing revealed 2564 differentially expressed genes (DEGs) in zebrafish ovaries after exposure to the mixtures. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were involved in the neuroactive ligand-receptor interaction, GnRH, progesterone-mediated oocyte maturation, oocyte meiosis and steroid hormone biosynthesis signaling pathways. These results revealed that combined exposure exerts potential reproductive toxicity at the molecular level.

Currently, there is limited information on the toxicity of low concentration of metal mixtures in the environment. Of particular interest is the effect of low levels of metal mixtures on neurodevelopment of aquatic organisms. This study reports the neurological gene expressions after exposing zebrafish embryos to low concentration toxic heavy metals, 120 h post fertilization (hpf). Embryos were exposed to low concentration individual and mixtures of lead (Pb), mercury (Hg), arsenic (As), and cadmium (Cd). Quantitative real-time PCR was used to assess gene expressions. The findings of this study confirmed that exposure to low concentration heavy metals upregulated N-methyl-D-aspartate (NMDA) receptor subunits NMDAR2A (NR2A), NMDAR2B (NR2B), and NMDAR2D (NR2D) and B cell lymphoma (Bcl-2) genes. NR2A genes were significantly upregulated by 90 and 74%, respectively, on exposure to Pb + As and Pb + Cd. NR2B genes were upregulated by 85.3, 68.6, 62.7, and 62.7% on exposure to As, Pb + Hg, Pb + As, and Pb + Cd, respectively. Exposure to As, Pb + Cd, and Pb + Hg + As significantly upregulated Bcl-2 genes by 2.01-, 1.84-, and 1.80-fold, respectively. NR1A and C-fos gene expressions were not significantly different from control. Upregulation of NMDAR subunits and Bcl-2 genes in this study was largely a counter measure against insults from exposure to low concentration heavy metals. Principal component analysis confirmed the influence of low concentration individual and mixtures of Pb, Hg, As, and Cd on gene expression of NMDAR subunits and Bcl-2. These data suggest that altered expression of NMDA receptor subunits and Bcl-2 genes may explain toxicity of low concentration individual and mixtures of Pb, Hg, As, and Cd.

Our previous study showed that chromium malate improved the composition of intestinal flora, glycometabolism, glycometabolism-related enzymes, and lipid metabolism in type 2 diabetes mellitus (T2DM) rats. The present study was designed to evaluate the effect of chromium malate with long-term supplementation on short chain fatty acid (SCFA) content in Sprague-Dawley rats. The samples were analyzed by gas chromatography with high linearity (R 2 ≥ 0.9995), low quantification limit (0.011-0.070 mM), and satisfactory recoveries. The method was simple and environmentally friendly. The acetic content in cecum of 3-month control group was significantly higher than that of 1-year control group. When compared with 1-year control group, chromium malate (at a dose of 20.0 μg Cr/kg bw) could significantly increase acetic, propionic, i-butyric butyric, butyric, i-valeric, valeric, and n-caproic levels. The acetic, propionic, i-butyric, valeric, and n-caproic contents of 1-year chromium malate group (at a dose of 20.0 μg Cr/kg bw) had a significant improvement when compared with 1-year chromium picolinate group. Acetic, propionic, and butyric contained approximately 91.65 % of the total SCFAs in 1-year group. The results indicated that the improvement of chromium malate on short chain fatty acid content change was better than that of chromium picolinate.

The chromium citrate complex [CrCIT] was synthesized and its structure was determined by infrared, UV-visible and atomic absorption spectroscopy, elemental and thermodynamic analysis. Anti-diabetic activity, oxidative DNA damage capacity and acute oral toxicity of [CrCIT] were investigated and compared with that of chromium trichloride hexahydrate. [CrCIT] was synthesized in a single step reaction by chelating chromium(III) with citric acid in aqueous solution. The molecular formula of [CrCIT] was inferred as CrC(6)H(5)O(7)·4H(2)O. The anti-diabetic activity of the complex [CrCIT] was assessed in alloxan-diabetic rats by daily oral gavage for 3 weeks. The biological activity results showed that the complex at the dose of 0.25-0.75 mg Cr/kg body weight could decrease the blood glucose level and increase liver glycogen level in alloxan-diabetic rats. [CrCIT] had more beneficial influences on the improvement of controlling blood glucose, serum lipid and liver glycogen levels compared with CrCl(3)·6H(2)O. Furthermore, [CrCIT] did not cause oxidative DNA damage under physiologically relevant conditions, and [CrCIT] did not produce any hazardous symptoms or deaths in acute oral toxicity test, showing the LD(50) value for female and male rats were higher than 15.1 g/kg body weight. The results suggested that [CrCIT] might represent a novel and proper chromium supplement with potential therapeutic value to control blood glucose in diabetes.

OBJECTIVES: In our preliminary study, chromium malate could decrease the blood glucose level in mice with diabetes and exhibits good benefits in treating glycometabolism and adipose metabolization obstacle in rats with type 2 diabetes. This study was aimed at assessing the pharmacokinetics and bioavailability of chromium malate and influence on trace metals absorption in rats. METHODS: BAPP 2.3 pharmacokinetic calculating program (China Pharmaceutical University Medicine Center) was used to calculate the pharmacokinetic parameters. Models of type 2 diabetic mellitus rats were applied to analyzed Ca, Mg, Fe, Cu, and Zn contents. RESULTS: The results showed that mean retention time (MRT) in chromium malate group was significantly prolonged and the area under the curve (AUC) and relative bioavailability of chromium malate (male) group were significant increase compared to chromium picolinate group. The serum Ca, Mg, Fe, Cu, and Zn contents in chromium malate (at doses of 15 and 20 μg Cr/kg bw) groups were significantly increased compared to control group, chromium trichloride group, and chromium picolinate group in type 2 diabetes mellitus rats. CONCLUSIONS: Those results indicated that chromium malate can significantly prolong MRT and increase AUC (male). Moreover, chromium malate is more effective at treating increased serum Ca, Mg, Fe, Cu, and Zn contents compared to chromium trichloride and chromium picolinate.

Concerns over the potential health effects of mixtures of low concentration heavy metals on living organisms keep growing by the day. However, the toxicity of low concentration metal mixtures on the immune system of fish species has rarely been investigated. In this study, the zebrafish model was employed to investigate the effect on innate immune and antioxidant-related gene expressions, on exposure to environmentally relevant concentrations of individual and mixtures of Pb (0.01 mg/L), Hg (0.001 mg/L), As (0.01 mg/L) and Cd (0.005 mg/L). Messenger-RNA (mRNA) levels of IL1β, TNF-α, IFNγ, Mx, Lyz, C3B and CXCL-Clc which are closely associated with the innate immune system were affected after exposing zebrafish embryos to metals for 120 h post fertilization (hpf). Individual and mixtures of metals exhibited different potentials to modulate innate-immune gene transcription. IL1β genes were significantly up regulated on exposure to Pb + As (2.01-fold) and inhibited on exposure to Pb + Hg + Cd (0.13-fold). TNF-α was significantly inhibited on exposure to As (0.40-fold) and Pb + As (0.32-fold) compared to control. Metal mixtures generally up regulated IFNγ compared to individual metals. Additionally, antioxidant genes were affected, as CAT and GPx gene expressions generally increased, whiles Mn-SOD and Zn/Cu-SOD reduced. Multivariate analysis showed that exposure to individual metals greatly influenced modulation of innate immune genes; whiles metal mixtures influenced antioxidant gene expressions. This suggests that beside oxidative stress, there may be other pathways influencing gene expressions of innate immune and antioxidant-related genes. Low concentration heavy metals also affect expression of development-related (wnt8a and vegf) genes. Altogether, the results of this study clearly demonstrate that low concentration individual and mixtures of metals in aquatic systems will greatly influence the immune system. It is indicative that mechanisms associated with toxicity of metal mixtures is complex, however, further studies to elucidate them are ongoing in our research laboratory.

The objective of this study was to evaluate the toxicity of individual and mixtures of di(n-butyl) phthalates (DBP) and their active metabolite monobutyl phthalate (MBP) and arsenic (As) on spatial cognition associated with hippocampal apoptosis in mice. Mice were exposed, individually or in combination, to DBP (50 mg/kg body weight, intragastrically), MBP (50 mg/kg body weight, intragastrically), and As (10 mg/L, per os) for 8 weeks. The Morris water maze test showed that mice exposed to DBP/MBP combined with As exhibited longer escape latencies and the lower average number of crossing the platform. The As content in the hippocampus after As exposure increased as compared to those without As exposure. In mice exposed to DBP/MBP combined with As, pathological alterations and oxidative damage to the hippocampus were found. Expression of apoptosis-related protein: Bax and caspase-3 were significantly increased in the hippocampus, while there was no significant change in expression of Bcl-2. The results suggested that DBP and MBP combined with As can induce spatial cognitive deficits through altering the expression of apoptosis-related protein and As played a critical role in cognition impairments. And the joint exposure has antagonistic effect.

Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the reproductive toxicity of chromium malate in Sprague-Dawley rats and then inspected the effect of chromium malate on glycometabolism, glycometabolism-related enzymes, and lipid metabolism. The results showed that no pathological, toxic feces and urine changes were observed in clinical signs of parental and fetal rats in chromium malate groups. The fasting blood glucose, serum insulin, insulin resistance index, C-peptide, hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels of chromium malate groups have no significant change compared with control group and chromium picolinate group. The serum and organ contents of Cr in chromium malate groups have no significant change when compared with control group. No measurable damage on liver, brain, kidney, and testis/uterus of chromium malate groups was found. No significant change in body mass, absolute and relative organ weights, and hematological and biochemical changes of rats were observed compared with the control and chromium picolinate groups. The results indicated that supplements with chromium malate does not cause obvious damage and has no obvious effect on glycometabolism, glycometabolism-related enzyme, and lipid metabolism on female and male rats. The results of this study suggested that chromium malate is safe for human consumption and has the potential for application as a functional food ingredient and dietary supplement.

Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the 90-day oral toxicity of chromium malate in Sprague-Dawley rats. The present study inspected the effect of chromium malate on glycometabolism, glycometabolism-related enzymes, lipid metabolism, and learning and memory ability in metabolically healthy Sprague-Dawley rats. The results showed that all rats survived and pathological, toxic, feces, and urine changes were not observed. Chromium malate did not cause measurable damage on liver, brain, and kidney. The fasting blood glucose, serum insulin, insulin resistance index, C-peptide, hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels of normal rats in chromium malate groups had no significant change when compared with control group and chromium picolinate group under physiologically relevant conditions. The serum and organ content of Cr in chromium malate groups had no significant change compared with control group. No significant changes were found in morris water maze test and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and true choline esterase (TChE) activity. The results indicated that supplementation with chromium malate did not cause measurable toxicity and has no obvious effect on glycometabolism and related enzymes, learning and memory ability, and related enzymes and lipid metabolism of female and male rats. The results of this study suggest that chromium malate is safe for human consumption.

Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the effect of chromium malate on glycometabolism, glycometabolism-related enzymes and lipid metabolism in type 2 diabetic rats. Our results showed that fasting blood glucose, serum insulin level, insulin resistance index and C-peptide level in the high dose group had a significant downward trend when compared with the model group, chromium picolinate group and chromium trichloride group. The hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, Glut4, phosphor-AMPKβ1 and Akt levels in the high dose group were significantly higher than those of the model, chromium picolinate and chromium trichloride groups. Chromium malate in a high dose group can significantly increase high density lipoprotein cholesterol level while decreasing the total cholesterol, low density lipoprotein cholesterol and triglyceride levels when compared with chromium picolinate and chromium trichloride. The serum chromium content in chromium malate and chromium picolinate group is significantly higher than that of the chromium trichloride group. The results indicated that the curative effects of chromium malate on glycometabolism, glycometabolism-related enzymes and lipid metabolism changes are better than those of chromium picolinate and chromium trichloride. Chromium malate contributes to glucose uptake and transport in order to improved glycometabolism and glycometabolism-related enzymes.

The deleterious effects of long term exposure to individual toxic metals in low doses are well documented. There is however, a paucity of information on interaction of low dose toxic metal mixtures with toxic and essential metals. This study reports on interactions between low dose mixtures of lead (Pb), mercury (Hg), arsenic (As) and cadmium (Cd) and toxic and essential metals. For 120d, six groups of forty mice each were exposed to metal mixtures, however, the control group was given distilled water. Exposure to Pb+Cd increased brain Pb by 479% in 30d, whiles Pb+Hg+As+Cd reduced liver Hg by 46.5%, but increased kidney As by 130% in 30d. Brain Cu, increased by 221% on Pb+Hg+As+Cd exposure, however, liver Ca reduced by 36.1% on Pb+Hg exposure in 60-d. Interactions within metal mixtures were largely synergistic. Principal component analysis (PCA) showed that low dose metal exposures influenced greatly levels of Hg (in brain and liver) and As (brain). The influence exerted on essential metals was highest in liver (PC1) followed by kidney (PC2) and brain (PC3). Exposure to low dose metal mixtures affected homeostasis of toxic and essential metals in tissues of mice.

This study reports on interactions between low dose toxic and essential metals. Low dose Pb (0.01 mg/L), Hg (0.001 mg/L), Cd (0.005 mg/L) and As (0.01 mg/L) were administered singly to four groups of 3-week old mice for 120 days. Pb exposure increased brain Mg and Cu by 55.5% and 266%, respectively. Increased brain Mg resulted from metabolic activity of brain to combat insults, whiles Cu overload was due to alteration and dysfunction of CTR1 and ATP7A molecules. Reduction of liver Ca by 56.0% and 31.6% (on exposure to As and Cd, respectively) resulted from inhibition of Ca-dependent ATPase in nuclei and endoplasmic reticulum through binding with thiol groups. Decreased kidney Mg, Ca and Fe was due to uptake of complexes of As and Cd with thiol groups from proximal tubular lumen. At considerably low doses, the study establishes that, toxic metals disturb the homeostasis of essential metals.

Previous study indicated that the refined polysaccharide from Schisandra could improve the CTX-induced inhibition of T and B lymphocytes proliferation. Accordingly, the enhanced antitumor and reduced toxicity effects of a low molecular weight purified polysaccharide from Schisandra (SCPP11) were investigated in 5-fluorouracil (5-Fu) treated Heps-bearing mice. The results revealed that the SCPP11 (oral administration) exhibited a significant enhanced effect of antitumor activity when combined with 5-Fu. Moreover, a increased effect was also observed in boosting immunity functions when the Heps-bearing mice receiving SCPP11 combination with 5-Fu administration, including increased in thymus indexes and enhancing serum IL-2 and TNF-α secretion. In addition, SCPP11 could ameliorate the hematological and biochemical parameters changes induced by 5-Fu to normal level, and reduce the formation of MDA and enhance the activities of SOD in liver to against 5-Fu induced free radical damage. The above results suggested that the SCPP11 combined with 5-Fu presented enhanced effects on antitumor activity and the SCPP11 could attenuate the 5-Fu-induced toxicity effect. It could serve as a new and promising adjuvant for chemotherapy drugs.

In this study, hyaluronic acid-selenium (HA-Se) nanoparticles as novel complexes were synthesized and their antitumor activities in vivo were investigated. The mice inoculated with Heps tumor were orally administered with HA-Se nanoparticles at 86.45 mg/kg (H) and 4.32 mg/kg (L) body weights as high and low doses respectively (2.20% selenium content in the HA-Se nanoparticles samples by ICP-AES) for 10 days. The transmission electron microscopy (TEM) results indicated that the HA-Se nanoparticles were spherical with mean size of 50-70 nm. The HA-Se nanoparticles could significantly reduce tumor weights at the tumor inhibition ratios of 46.92% (H) and 49.12% (L) respectively. However, in the 5-fluorouracil positive group (25 mg/kg), the tumor inhibition ratio was 61.71%. From the study, the HA-Se nanoparticles (4.32 mg/kg) significantly increased thymus and spleen relative weights, enhanced the activities of superoxide dismutase (SOD), reduced the formation of malondialdehyde (MDA) and the activities of aspartate transaminase, alanine transaminase and crea in Heps tumor mice. The results of the study indicated that the HA-Se nanoparticles are potential antitumor candidate for cancer treatment.

Chinese sturgeon (Acipenser sinensis), a rare species, is an important fishery resource in China. To save this species from overfishing, damming and pollution, artificial propagation has been developed rapidly in recent years. However, the cartilage from Chinese sturgeon, which contains an abundance of chondroitin sulfate (CS), is currently discarded as solid waste after consumption of the fish. The aim of this study was to investigate the extraction, purification and characterisation of CS from Chinese sturgeon cartilage.The optimal extraction parameters were a ratio of aqueous NaOH to cartilage powder of 9.2, a concentration of aqueous NaOH of 4.4% and an extraction time of 3.9 h. Under these optimal conditions the yield of crude CS from Chinese sturgeon cartilage was 26.51%, in agreement with the model prediction (26.54%). Purification by DEAE-52 cellulose and Sephadex G-100 column chromatography yielded a single fraction, CS-11. Its characterisation indicated that CS-11 was consistent with the polysaccharide backbone structure -4GlcAβ-3GalNβ- and was present in the form of chondroitin-4-sulfate and chondroitin-6-sulfate.The results of this study provide a basis for promoting the utilisation of Chinese sturgeon resources and are significant for the development and utilisation of CS from Chinese sturgeon cartilage in the food industry.

In order to obtain the additional benefit of anti-diabetic activity and protective effects of liver injury for diabetes, the anti-diabetic effect and acute oral toxicity of a combination of chromium(III) malate complex (Cr(2)(LMA)(3)) and propolis were assessed. The anti-diabetic activity of the combination of the Cr(2)LMA(3) and propolis was compared with Cr(2)(LMA)(3) and propolis alone in alloxan-induced diabetic mice by daily oral gavage for a period of 2 weeks. Acute oral toxicity of the combination of the Cr(2)LMA(3) and propolis was tested using ICR mice at the dose of 1.0-5.0 g/kg body mass by a single oral gavage and observed for a period of 2 weeks. The results of the anti-diabetic activity of the combination from the aspects of blood glucose level, liver glycogen level, and the activities of aspartate transaminase, alanine transaminase, and alkaline phosphatase indicated that the increased anti-diabetic activity and the protective efficacy of liver injury for diabetes were observed. In acute toxicity study, LD(50) (median lethal dose) value for the combination was greater than 5.0 g/kg body mass. The combination of Cr(2)LMA(3) and propolis might represent the nutritional supplement with potential therapeutic value to control blood glucose and exhibit protective efficacy of liver injury for diabetes and non-toxicity in acute toxicity.