Green conversion of waste PET into magnetic Ni0·4Fe2·6O4/(Fe,Ni)@carbon nanostructure for adsorption and separation of dyes from aqueous media.

A nanostructured core-shell composite (Ni0·4Fe2·6O4/(Fe,Ni)@carbon, NFC) comprising magnetic nano-cores encapsulated with graphitic shells (≈80 wt%) is prepared by facile and clean mechanochemical-molten salt processing approach using waste PET; providing a specific surface area of 201.9 m2 g-1, well-developed mesopores, and ferromagnetic behavior characterized by the coercivity value of 149 Oe. NFC is utilized as a high-performance adsorbent for the removal of organic dyes from their aqueous solutions. Moreover, the magnetic performance of NFC enables the facile collection of the exhausted adsorbent out of the purified water. Performances of NFC for the removal of crystal violet dye (CV), methyl orange (MO) and rhodamine B (Rh B) from their aqueous solutions are systematically investigated under different environmental conditions including the adsorbent dosage and dye concentration, as well as the solution pH and temperature, where an impressive CV removal capacity of 201.6-243.8 mg g-1 is recorded for a wide pH range of 2-10. Mechanism and kinetics involved in the adsorption process are investigated by studying the adsorption isotherms and thermodynamics. The dye adsorption of the nanocomposite material is confirmed to follow the pseudo-second-order kinetic model combined with the Langmuir isotherm model, exhibiting an excellent spontaneous and exothermic monolayer adsorption capacity of around 153 mg g-1 (for MO) for the fresh adsorbent and around 89 mg g-1 after three adsorption-regeneration cycles.

Mechanism of thyroid hormone and its structurally similar contaminant bisphenol S exposure on retinoid metabolism in zebrafish larval eyes.

The photoreceptor necessitates the retinoids metabolism processes in visual cycle pathway to regenerate visual pigments and sustain vision. Bisphenol S (BPS), with similar structure of thyroid hormone (TH), was reported to impair the light-sensing function of zebrafish larvae via disturbing TH-thyroid hormone receptor ß (TRß) signaling pathway. However, it remains unknown whether TRß could modulate the toxicity of BPS on retinoid metabolism in visual cycle. This study showed that BPS diminished the optokinetic response of zebrafish larvae and had a stimulative effect on all-trans-retinoic acid (atRA) metabolism, like exogenous T3 exposure. By modulating CYP26A1 and TRß expression, it was found that CYP26A1 played a crucial role in catalyzing oxidative metabolism of atRA and retinoids regeneration in visual cycle, and TRß mediated cyp26a1 expression in zebrafish eyes. Similar with 10 nM T3 treatment, cyp26a1 expression could be induced by BPS in the presence of TRß. Further, in CYP26A1 and TRß- deficient eyes, 100 µg/L BPS could no longer promote atRA metabolism, or decrease the all-trans-retinol and 11-cis retinal contents in visual cycle, demonstrating that BPS exposure disturbed CYP26A1-mediated visual retinoids metabolism via TRß. Overall, this study highlights the role of TRß in mediating the retinoids homeostasis disruption caused by BPS, and provides new clues for exploring molecular targets of visual toxicity under pollutants stress.

Mechanism of bisphenol S exposure on color sensitivity of zebrafish larvae.

Color vision, initiated from cone cells, is vitally essential for identifying environmental information in vertebrate. Although the retinotoxicity of bisphenol S (BPS) has been reported, data on the influence of BPS treatment on cone cells are scarce. In the present study, transgenic zebrafish (Danio rerio) labeling red and ultraviolet (UV) cones were exposed to BPS (0, 1, 10, and 100 µg/L) during the early stages of retinal development, to elucidate the mechanism underlying its retinal cone toxicity of BPS. The results showed that 10 and 100 µg/L BPS induced oxidative DNA damage, structural damage (decreased number of ribbon synapses), mosaic patterning disorder, and altered expression of genes involved in the phototransduction pathway in red and UV cones. Furthermore, BPS exposure also caused abnormal development of key neurons (retinal ganglion cells, optic nerve, and hypothalamus), responsible for transmitting the light-electrical signal to brain, and thereby resulted in inhibition of light-electrical signal transduction, finally diminishing the spectral sensitivity of zebrafish larvae to long- and short-type light signal at 5 day post fertilization. This study highlights the cone-toxicity of environmental relevant concentrations of BPS, and clarifies the mechanism of color vision impairment induced by BPS at the cellular level, updating the understanding of visual behavior driven by environmental factors.

Bisphenol S disrupts opsins gene expression and impairs the light-sensing function via antagonizing TH-TRß signaling pathway in zebrafish larvae.

Bisphenol S (BPS) is extensively used in "bisphenol A-free" products such as baby bottles. Although the visual toxicity of BPS has been reported, the underlying mechanism was largely unknown. In the present study, zebrafish were exposed to 0, 4 and 400 nM BPS from 2 h post-fertilization (hpf) to 120 hpf to further explore the thyroid disruption mechanism underlying the BPS induced impairment of visual function. The results showed that BPS decreased T3 levels in larval eyes, induced retinal expression of thyroid hormone receptor ß (TRß), and thereby down-regulated the expression of TH-mediated opsin genes (opn1lw1, opn1lw2, opn1mw1, opn1mw2, opn1mw3, and opn1sw2) and impaired subsequent phototransduction pathways, leading to decreased visually mediated phototactic response and body color adaptation but stimulated visual motor response (VMR). Combining exposure of exogenous T3 or 1-850 (antagonist for TRß) with BPS could partly compensate the inhibited expression of opsin genes (opn1mw2, opn1lw1, and opn1lw2) and alleviate the hyperactivity of larval VMR caused by BPS alone, suggesting that BPS disrupted the opsins expression and also light-sensing function via antagonizing TH-TRß signaling pathway. This study underlined the importance of TH signaling in regulating the proper vision and proposed a novel mechanism for the visual toxicity of BPS.

Vitamin D protects silica particles induced lung injury by promoting macrophage polarization in a KLF4-STAT6 manner.

Silicosis is one of the severest occupational diseases worldwide, manifesting as infiltration of inflammatory cells, excessive secretion of pro-inflammatory mediators and pulmonary diffuse fibrosis. Macrophages polarization to M2 is one of the major strategies that attenuates inflammatory response. Our previous study found that vitamin D could protect against silica-induced lung injury by damping the secretion of pro-inflammatory cytokines. Here we further identified that vitamin D attenuated silica particles-induced lung inflammation by regulating macrophage polarization in a KLF4-STAT6 manner. Myeloid-specific Stat6 knockout (cKO) mice were generated for in vivo studies. Primary macrophages purified from bronchoalveolar lavage fluid (BALF) of wildtype or Stat6 cKO mice and differentiated THP-1 cells were used for in vitro studies. Vitamin D was found to promote alveolar macrophage polarizing to M2 phenotype through the STAT6 signaling pathway, as demonstrated by worse lung inflammation and ablated protection of vitamin D in silica particles-instilled Stat6 cKO mice. Mechanismly, vitamin D upregulated KLF4 expression in the alveolar macrophage, which synergistically activated STAT6. Additionally, KLF4 was found to upregulate macrophages autophagy, which protected them from silica particles-induced oxidative stress and cell apoptosis. The protective effects of vitamin D were dismissed by silencing KLF4. Our study demonstrates the potential mechanism of vitamin D-mediated macrophage polarization and reveals the therapeutic application of vitamin D in inflammatory disease.

Conduction of a chemical structure-guided metabolic phenotype analysis method targeting phenylpropane pathway via LC-MS: Ginkgo biloba and soybean as examples.

The phenylpropane pathway (PPP) is one of the most extensively investigated metabolic routes. This pathway biosynthesizes many important active ingredients such as phenylpropanoids and flavonoids that affect the flavor, taste and nutrients of food. How to elucidate the metabolic phenotype of PPP is fundamental in food research and development. In this study, we designed a structural periodical table filled with 103 metabolites produced from PPP. All of them especially the 62 structural isomers were qualified and quantified with high resolution and sensitivity via multiple reaction mode in liquid chromatography tandem triple quadrupole mass spectrometry. Ginkgo biloba and soybean were used as samples for the practical application of this method: The delicate spatial-temporal metabolic balance of PPP from ginkgo biloba has been first elucidated; It is first confirmed that the salt and draught stresses could redirect the biosynthesis trend of PPP to produce more isoflavones in soybean leaves.

Transgenerational effects of parental bisphenol S exposure on zebrafish (Danio rerio) reproduction.

Bisphenol S (BPS) is extensively used for production of polycarbonates and other commodities, and is often detected in environment and biota. Parental BPS exposure has been reported to interfere with reproductive development of offspring, but limited information is available on its multigenerational reproductive toxicity. In our present study, zebrafish (Danio rerio) were exposed to BPS (1 and 100 µg/L) from 3 hpf to 120 dpf, and the effects on reproduction, sex steroid hormones, DNA methylation levels and gene transcription involved in steroidogenesis and DNA methylation were investigated in unexposed F1-2 offspring. The results showed that 100 µg/L BPS exposure increased DNA methylation in F1 testes, and 1 µg/L BPS led to DNA methylation in F2 ovaries. The increased DNA methylation levels led to decreased expression of steroidogenic enzymes, including cyp11a, cyp17 and 3ßhsd, which might be a main reason for the elevated plasma 17ß-estradiol and decreased testosterone levels. In addition, sex ratio indicated a female dominance trend, and reproductive capacity of male fish was severely impaired. Overall, these findings suggest that parental BPS exposure impairs reproductive development of unexposed offspring via DNA methylation and BPS-induced epigenetic modification inheritance has a long-term effect on the fitness and sustainability of fish populations.

STAT6 contributes to renal fibrosis by modulating PPARα-mediated tubular fatty acid oxidation.

Lipid metabolism, especially fatty acid oxidation (FAO) dysfunction, is a major driver of renal fibrosis; however, the detailed regulatory mechanisms involved remain unclear. In this study, we showed that there existed an association between the signal transducer and activator of transcription 6 (STAT6) and tubular lipid metabolism in fibrotic kidneys. Specifically, STAT6 was activated along with the accumulation of lipids via the downregulation of FAO-related genes when mice were subjected to unilateral ureteral obstruction (UUO) or high-fat diet challenge. Tubular-specific depletion, or pharmacologic inhibitor of Stat6 in mice, and Stat6 knockdown in cultured tubular cells attenuated lipid accumulation and renal fibrosis by enhancing FAO. Mechanistically, STAT6 transcriptionally inhibited the expression of PPARα and its FAO-related target genes through a sis-inducible element located in the promoter region of the protein. In conclusion, our study demonstrates the mechanistic details of STAT6-mediated FAO dysregulation in the progression of renal fibrosis and provides a preclinical rationale for efforts to improve the management of renal fibrosis brought about by FAO dysregulation.

STAT6/VDR Axis Mitigates Lung Inflammatory Injury by Promoting Nrf2 Signaling Pathway.

Lung inflammatory injury is a global public health concern. It is characterized by infiltration of diverse inflammatory cells and thickening of pulmonary septum along with oxidative stress to airway epithelial cells. STAT6 is a nuclear transcription factor that plays a crucial role in orchestrating the immune response, but its function in tissue inflammatory injury has not been comprehensively studied. Here, we demonstrated that STAT6 activation can protect against particle-induced lung inflammatory injury by resisting oxidative stress. Specifically, genetic ablation of STAT6 was observed to worsen particle-induced lung injury mainly by disrupting the lungs' antioxidant capacity, as reflected by the downregulation of the Nrf2 signaling pathway, an increase in malondialdehyde levels, and a decrease in glutathione levels. Vitamin D receptor (VDR) has been previously proved to positively regulate Nrf2 signals. In this study, silencing VDR expression in human bronchial epithelial BEAS-2B cells consistently suppressed autophagy-mediated activation of the Nrf2 signaling pathway, thereby aggravating particle-induced cell damage. Mechanically, STAT6 activation promoted the nuclear translocation of VDR, which increased the transcription of autophagy-related genes and induced Nrf2 signals, and silencing VDR abolished these effects. Our research provides important insights into the role of STAT6 in oxidative damage and reveals its potential underlying mechanism. This information not only deepens the appreciation of STAT6 but also opens new avenues for the discovery of therapies for inflammatory respiratory system disorders.

17ß-Trenbolone binds to androgen receptor, decreases number of primordial germ cells, modulates expression of genes related to sexual differentiation, and affects sexual differentiation in zebrafish (Danio rerio).

Exposure to 17ß-trenbolone caused a skewed sex ratio in fish. However, the molecular initiating event and key molecular event(s) remain unknown. In this study, zebrafish were exposed to 17ß-trenbolone at nominal concentrations of 2 ng/L, 20 ng/L, 200 ng/L, and 2000 ng/L from fertilization to 60 days post fertilization (dpf). First, the sex ratio at 60 dpf was calculated to evaluate adverse outcomes on sexual differentiation. 17ß-Trenbolone caused a skewed sex ratio toward males, with intersex individuals observed in the 20 ng/L group and all-male populations found in the 200 ng/L and 2000 ng/L groups. Then, the distribution and number of primordial germ cells, the expression of sex differentiation-related genes, and plasma vitellogenin concentrations were detected in wild-type zebrafish and the EGFP-nanos-3'UTR transgenic line using whole-mount in situ hybridization, real-time PCR, EGFP fluorescence quantification, and enzyme-linked immunosorbent assay. The results indicated that 17ß-trenbolone exposure decreased the number of primordial germ cells at 1 dpf and 3 dpf, decreased expression of ovarian differentiation-related genes foxl2 and cyp19a1a at 60 dpf, increased expression of testis differentiation-related genes dmrt1, sox9a, and amh at 60 dpf, and decreased plasma vitellogenin levels at 60 dpf, revealing the key molecular events at different time points involved in affected sexual differentiation by 17ß-trenbolone. Finally, molecular docking showed that 17ß-trenbolone docked into ligand-binding domain of zebrafish androgen receptor with high binding energy (-3.72 kcal/mol), suggesting that binding to androgen receptor is the molecular initiating event affecting sexual differentiation by 17ß-trenbolone. We found that 17ß-trenbolone can bind to the zebrafish androgen receptor, decrease the number of primordial germ cells during the early embryonic stage, modulate the expression of genes related to sexual differentiation during gonadal differentiation, and eventually cause a skewed sex ratio toward males in adults.

Upregulation of autophagy in M2 macrophage by vitamin D alleviates crystalline silica-induced pulmonary inflammatory damage.

Crystalline silica (CS) is a universal environmental pollutant, which causes a typical inflammatory lung injury. Vitamin D shows huge potential against particles-induced lung injury, while little known about the molecular mechanism involved in macrophage autophagy. In this study, we aim to identify the protective effects of vitamin D on CS caused lung inflammatory injury and clarify the detail mechanism. After exposure to CS (3 mg/mice in 50 µl PBS), wildtype and Atg7flox/flox Lyz2-cre mice were treated with or without vitamin D3 (40,000 IU/kg). The results indicated that exposure to CS caused an obvious lung injury, manifesting as pathological structural changes, macrophage-dominated inflammatory cell infiltration and increased pro-inflammatory cytokines. Remarkably, these damages were more serious in Atg7flox/flox Lyz2-cre mice. Vitamin D was found to inverse CS-induced inflammatory cell infiltration and restored anti-inflammatory M2 macrophages by inducing autophagy, which attenuated lung injury, as determined by decreased levels of apoptosis and inflammatory response. While, this effects of vitamin D were slashed in Atg7flox/flox Lyz2-cre mice. This study reveals the adverse effect of CS on lung tissue and the protective mechanism of vitamin D involved in M2 macrophages autophagy, which attenuates CS-caused lung injury.

Unraveling the mechanism of long-term bisphenol S exposure disrupted ovarian lipids metabolism, oocytes maturation, and offspring development of zebrafish.

Bisphenol S (BPS) acts as a xenoestrogen and disturbs the female reproductive system; however, the underlying mechanism has not been elucidated. In this study, the effect of chronic BPS exposure (1 µg/L and 100 µg/L) on ovarian lipid metabolism in zebrafish was investigated to determine its influence on adult reproductive capacity and offspring development. The results showed that long-term (240 days) exposure to BPS induced lipid accumulation in the ovaries by promoting the transport of more lipids from the circulation to the ovaries and by upregulating triacylglycerol synthesis-related genes. Significantly increased expression of cpt2, acadm, acadl, and pparα, which are involved in ß-oxidation in the ovarian mitochondria, indicated that more energy was provided for oocyte maturation in exposed zebrafish ovaries. Thus, the proportion of full-grown stage oocytes in ovaries and egg reproduction were elevated at an accelerated rate, which earlier than normal reproductive cycle (8-10 days posts pawning). Moreover, the maternally BPS-exposed F1 embryos (2 h post-spawning, hpf) showed higher neutral lipid levels, impaired hatching capacity, and increased occurrence of larval deformities. All these findings demonstrated that stimulated lipid synthesis and ß-oxidation in zebrafish ovaries significantly contribute to BPS-induced oocyte precociousness with subsequent effects on the development of unexposed offspring. This study provides new insight into the impact of xenoestrogens on oviparous reproduction in females and offspring development from the perspective of ovarian lipid metabolism.

Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation.

Bixin, a natural carotenoid extracted from the seeds of Bixa orellana, has antioxidant and anti-inflammation effects. However, the pharmacological effects and underlying mechanisms of bixin in kidney interstitial fibrosis remain unknown. Partial epithelial-to-mesenchymal transition (EMT) of tubular cells has been linked to renal interstitial fibrosis. Here, we found that in the unilateral ureteral obstruction model, bixin administration could ameliorate kidney interstitial fibrosis. The expression of signal transducer and activator of transcription 6 (STAT6) was dramatically increased in renal tubular cells. Bixin treatment inhibited STAT6 induction. The activation of STAT6 signaling was essential for transforming growth factor ß1, fibrotic markers, and EMT-related protein expression in HK2 cells, which was confirmed by using the Stat6-/- mice. Ubiquitination, but not the acetylation level of STAT6, was induced by bixin treatment and promoted the suppression of phosphorylation and stability of STAT6. P62-dependent autophagy might be involved in this process. The study demonstrated that bixin can be exploited therapeutically to alleviate renal interstitial fibrosis by targeting STAT6 signaling deactivation.

Erratum to: Pharmaceutic application of vitamin D3 on particle-induced fibrotic effects through induction of Nrf2 signals.

[This corrects the article DOI: 10.1093/toxres/tfaa003.].

Pharmaceutic application of vitamin D3 on particle-induced fibrotic effects through induction of Nrf2 signals.

Fine particulate matter, a major air pollutant across the world, causes a series of pulmonary diseases. Vitamin D is a typical vitamin with emerging roles in inflammation and fibrosis. Different situations and diseases need different doses and modes of vitamin D administration, which challenges the existing vitamin D supplementary rules. Thus, studies of vitamin D applications and their mechanisms in various diseases are important for its future therapeutic applications. In this study, the therapeutic application of vitamin D3 in chronic particle-exposure-associated lung fibrosis and tissue remodeling was investigated. In vivo studies showed that vitamin D3 significantly attenuated fibrosis effects by decreasing α-smooth muscle actin-regulated extracellular matrix deposition and restoring expressions of E-cadherin and N-cadherin. With the importance of activated macrophage in the regulation of local epithelium and fibroblast in the process of tissue fibrosis, two separate in vitro systems of co-culture of macrophages with lung epithelium or fibroblast were built. The results confirmed that vitamin D3 promoted the proliferation of lung epithelium and depressed the fibrosis effects of fibroblasts as well. In addition, our results indicated that the therapeutic effects of vitamin D3 were through Nrf2 signals. Our work provides convincing experimental evidence for vitamin D therapeutic application to promote tissue repair and improve particle-associated lung fibrosis.

Bixin Confers Prevention against Ureteral Obstruction-Caused Renal Interstitial Fibrosis through Activation of the Nuclear Factor Erythroid-2-Related Factor2 Pathway in Mice.

Bixin is a natural carotenoid isolated from the seeds of Bixa orellana, with numerous important pharmacological activities, including antioxidant and antifibrotic effects. The nuclear factor erythroid-2-related factor2 (Nrf2) signaling pathway induced by bixin is involved in the process. Excessive reactive oxygen species generation in tubular cells contributes to kidney interstitial fibrosis. The potential therapeutic strategy for bixin in alleviating kidney fibrosis remains largely unclear. In this study, we used unilateral ureteral obstruction (UUO) to establish a renal fibrotic model. Dramatic oxidative DNA damage occurs in kidneys, especially in tubular cells after UUO. In cultured tubular cells, bixin could induce Nrf2 signaling activation by suppressing Nrf2 ubiquitination and increasing its protein stability. Transforming growth factor beta 1-induced epithelial-to-mesenchymal transition (EMT) and extracellular matrix production were suppressed by bixin, and blockade of Nrf2 activation by small interfering RNA could largely reverse the protective effect of bixin. In vivo studies showed that administration of bixin induces Nrf2 signaling activation in tubular cells and markedly attenuates partial EMT of tubular cells and kidney interstitial fibrosis after subjecting to UUO. Together, this study implies that bixin may protect against kidney interstitial fibrosis through stimulating Nrf2 activation in renal tubular cells.

Bisphenol S exposure alters behavioral parameters in adult zebrafish and offspring.

The environmental emission of bisphenol S (BPS), which is globally utilized in the manufacturing of polycarbonates, epoxy resin and thermal paper, has affected the aquatic ecosystem. Thus, effects of BPS exposure on the fitness of aquatic animals have been noted. Here, adult male and female zebrafish were used as aquatic model organisms and separately exposed to environmentally relevant doses of BPS (0, 1, 10 and 100 µg/L) for 14 days. The results showed that BPS changed the body pigment of zebrafish and slowed the maturation of oocytes in the ovary, resulting in a significant decrease in the shoaling behavior of adult zebrafish and the attraction of BPS-treated females during the mating process. Furthermore, in the subgeneration of adult zebrafish exposed to BPS for 7 days, survival behaviors, such as locomotor, phototaxis and feeding behaviors, deviated from normal behaviors. After exposing the adult zebrafish to BPS for an additional 7 days, the above described survival behaviors and light adaptation were disrupted in offspring. Our data, based on intergenerational behavioral studies, demonstrate that BPS affects the behaviors of aquatic animals and the ability of offspring to feed and avoid predators, possibly jeopardizing the survival of aquatic animals.

Corrigendum: Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation.

[This corrects the article DOI: 10.3389/fcell.2020.576988.].

A review of arsenic exposure and lung cancer.

As a well-established human carcinogen, arsenic has increased the risk of lung cancer over the past decades. Wide exposure to arsenic in the environment has attracted the attention of scientists. Its carcinogenicity at early life stages has been observed in certain animal studies already, yet current evidence is insufficient to extrapolate this to humans. Although the mechanisms of lung cancer induced by arsenic remain unclear, most of them are related to the biotransformation of arsenic, which would further provide target sites for precaution and therapy. This review comprehensively summarizes current studies associated to arsenic exposure and lung cancer and the mechanism of its carcinogenesis in lung cancer in three sections, namely, epidemiological studies, experimental studies, and mechanistic studies. In addition, prevention and treatment strategies as well as directions for future studies are discussed.