As3MT via consuming SAM is involved in arsenic-induced nonalcoholic fatty liver disease by blocking m6A-mediated miR-142-5p maturation.

Arsenic, a common environmental hazard, is a risk factor for nonalcoholic fatty liver disease (NAFLD). However, the mechanism remains unclear. Here, we found that chronic exposure to environmental-related doses of arsenic disturbed fatty acid and methionine metabolism in mice, caused liver steatosis, increased arsenic (3) methyltransferase (As3MT), sterol regulatory element binding protein 1 (SREBP1) and lipogenic gene levels, and decreased N6-methyladenosine (m6A) and S-adenosylmethionine (SAM) levels. Mechanistically, arsenic blocks m6A-mediated miR-142-5p maturation by consuming SAM via As3MT. miR-142-5p was involved in arsenic-induced cellular lipid accumulation by targeting SREBP1. SAM supplementation or As3MT deficiency blocked arsenic-induced lipid accumulation by promoting the maturation of miR-142-5p. Moreover, in mice, folic acid (FA) and vitamin B12 (VB12) supplementation blocked arsenic-induced lipid accumulation by restoring SAM levels. Arsenic-exposed heterozygous As3MT mice showed low liver lipid accumulation. Our study demonstrates that SAM consumption caused by arsenic, through As3MT, blocks m6A-mediated miR-142-5p maturation, thereby elevating the levels of SREBP1 and lipogenic genes, leading to NAFLD, which provides a new mechanism and biological insights into the therapy of NAFLD induced by environmental factors.

Oxidative injury induced by drinking water disinfection by-products dibromoacetonitrile and dichloroacetonitrile in mouse hippocampal neuronal cells: The protective effect of N-acetyl-L-cysteine.

Dibromoacetonitrile (DBAN) and dichloroacetonitrile (DCAN) are haloacetonitriles (HANs) produced as by-products of chloramine disinfection of drinking water and can cause neurotoxicity. The molecular pathways leading to HAN-induced neuronal cell death remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of oxidation reactions. We explored the role of the sequestosome 1 (p62)-Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway in DBAN- and DCAN-induced mouse hippocampal neuronal (HT22) cell injury. DBAN and DCAN reduced cell viability, increased lactate dehydrogenase release rate, and promoted apoptosis. Over the same treatment time, DBAN at lower concentrations caused cell injury, suggesting that DBAN is more cytotoxic than DCAN. DBAN and DCAN triggered oxidative stress by reducing intracellular glutathione and increasing reactive oxygen species concentrations. DBAN and DCAN activated the Nrf2 pathway. Furthermore, Nrf2 inhibitors (all-trans retinoic acid) attenuated DBAN- and DCAN-induced toxicity, whereas Nrf2 activators (tert-Butylhydroquinone) achieved the opposite effect. This indicates that activation of the Nrf2 pathway mediates DBAN- and DCAN-induced cell injury. Notably, the expression of p62, a noncanonical pathway that mediates Nrf2 activation, increased, whereas the expression of Keap1, another regulator of Nrf2, decreased. We noted that high p62 expression activated the Nrf2 pathway, and p62 was regulated through Nrf2, forming a positive feedback loop. N-acetyl-L-cysteine, a mercaptan substance, protected against DBAN- and DCAN-induced toxicity and inhibited the Nrf2 pathway. In summary, Nrf2 pathway inhibition and mercaptan supplementation prevent DBAN- and DCAN-induced HT22 cell injury, accordingly, targeting them is a potential approach to preventing HAN-induced neurotoxicity.

Ginseng Stem-and-Leaf Saponin (GSLS)-Enhanced Protective Immune Responses Induced by Toxoplasma gondii Heat Shocked Protein 70 (HSP70) Against Toxoplasmosis in Mice.

Toxoplasma gondii is an obligate intracellular protozoan parasite and is able to infect birds and mammals including humans. In order to find effective antigen-adjuvant combinations that can boost the immunogenicity and protection of antigen vaccines against toxoplasmosis, we examined the protective efficacy in mice immunized with recombinant protein HSP70 when co-administered with ginseng stem-and-leaf saponins (GSLS) isolated from Panax ginseng . All immunized mice produced significantly high levels of specific antibodies against rTgHSP70, and splenocytes from mice presented strong proliferative immune responses. Vaccinated mice displayed a significantly increased percentage of CD4+ and CD8+ T cells, indicating a strong immune response was triggered. The cellular and humoral immune responses were enhanced, which could be reflected of the increased mRNA levels of IFN-γ and IL-4, respectively. Immunization with rTgHSP70 and GSLS prolonged survival time of the treated mice compared to the controls, which died within 6 days after challenge with the virulent T. gondii RH strain. Our data demonstrate that by addition with GSLS, rTgHSP70 induced a strong immune response and provided partial protection against T. gondii ; therefore GSLS could be used as a promising vaccine adjuvant against acute toxoplasmosis.

Mushroom tyrosinase inhibitors from mung bean (Vigna radiatae L.) extracts.

A seventy percent ethanol from mung bean (Vigna radiatae L.) was extracted further with CH(2)Cl(2), EtOAc and n-BuOH to afford four fractions: CH(2)Cl(2)-soluble, EtOAc-soluble, n-BuOH-soluble and residual extract fractions. When using l-3,4-dihydroxyphenylalanine as the substrate for mushroom tyrosinase, the EtOAc-soluble fractions showed the highest inhibitory activity. Two pure flavonoid compounds, vitexin and isovitexin, were isolated (using the enzyme assay-guided fractionation method) from the EtOAc-soluble fractions. Vitexin and isovitexin showed high inhibitory activities, with IC(50) values of 6.3 and 5.6 mg/ml, respectively. This is the first study on the active compositions of azuki beans against mushroom tyrosinase.

A determination of potential α-glucosidase inhibitors from Azuki Beans (Vigna angularis).

A 70% ethanol extract from azuki beans (Vigna angularis) was extracted further with CH(2)Cl(2), EtOAc and n-BuOH to afford four fractions: CH(2)Cl(2)-soluble, EtOAc-soluble, n-BuOH-soluble and residual extract fractions. The EtOAc-soluble fractions showed the highest α-glucosidase inhibitory activity. Two pure flavonoid compounds, vitexin and isovitexin, were isolated (using the enzyme assay-guide fractionation method) from the EtOAc-soluble fractions. We further evaluated the interaction between the flavonoid compounds and α-glucosidase by fluorescence spectroscopy. Vitexin and isovitexin showed high inhibitory activities, with IC(50) values of 0.4 mg·mL(-1) and 4.8 mg·mL(-1), respectively. This is the first study of the active compositions of azuki beans against α-glucosidase.