Glucagon-like peptide-1 analog liraglutide reduces fat deposition in chicken adipocytes.

Previously, we reported that glucagon-like peptide-1 (GLP-1) and its analog liraglutide could inhibit fat de novo synthesis in the liver and reduce abdominal fat accumulation in broiler chickens. Nevertheless, the impact of GLP-1 on adipocyte fat deposition remains enigmatic. This study aimed to investigate the effects of GLP-1, via its analog liraglutide, on chicken chicken adipocytes in vitro. Chemical assays, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were employed to assess the proliferation, differentiation, and fat deposition of chicken adipocytes. Our findings indicated that liraglutide significantly suppressed cell proliferation and promoted preadipocyte differentiation in comparison to the control group. This was evidenced by elevated triglyceride (TG) content and upregulated mRNA expression of lipogenesis-related enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), as well as regulators including peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element binding protein-1 (SREBP1) and CCAAT/enhancer binding protein α (CEBPα). In mature adipocytes, liraglutide attenuated fat deposition by inhibiting fat de novo synthesis, evidenced by decreased mRNA expression of ACC, FAS, PPARγ, C/EBPα, and SREBP1, and concurrent upregulation of phosphorylated AMP-activated protein kinase (p-AMPK) and phosphorylated ACC (p-ACC). This resulted in reduced accumulation of lipid droplets and TG content in mature adipocytes. Collectively, our findings indicate that liraglutide suppresses the proliferation of preadipocytes, enhances their differentiation, and concurrently inhibits de novo lipogenesis in mature adipocytes. This observation offers profound insights into the mechanisms that underlie liraglutide's anti-adipogenic effects, which could have significant implications for the treatment of obesity in broiler chickens.

Association of urine glyphosate levels with renal injury biomarkers in children living close to major vegetable-producing regions in China.

Glyphosate (GLY)-based herbicides exposure contributes to renal dysfunction in experimental conditions, but the effects on humans are rarely reported. Biomonitoring is practically relevant for evaluating the association of urine GLY levels and renal damage in children living close to vegetable-cultivating regions. In this study, we collected the first-morning void urine samples of 239 healthy children (aged 3-12, 48.12 % boys) living near major vegetable-producing regions in March-May and August 2023 in Shandong Province, China. Urine levels of GLY and kidney injury-associated biomarkers were determined using ELISA kits to assess their correlation. GLY was detected in 92.05 % of urine samples (220 out of 239 participants) and the geometric concentration (GM) was 7.429 µg/L (range: 0.625 to 38.267 µg/L). Binary logistic regression and multivariate regression analysis revealed GLY detectability and levels positively correlated with home ventilation and self-producing vegetable intake of the subjects, as well as sampling periods. Moreover, a statistically significant concentration association with urine GLY was found for kidney injury-associated biomarkers (NGAL and KIM-1) (R2 = 0.923 and 0.855, respectively). Additionally, risk assessment revealed that the maximum value of probable daily intake was 0.150 mg/kg bw/day, accounting for 30.1 % of the established Acceptable Daily Intake of GLY. This study unveils a positive correlation between continuous GLY-based herbicide exposure and renal injury biomarkers of children. A large-scale epidemiological study is warranted for comprehensively assessing the effects of GLY-based herbicides on kidney function of the entire public.

Grape seed-derived procyanidin inhibits glyphosate-induced hepatocyte ferroptosis via enhancing crosstalk between Nrf2 and FGF12.

BACKGROUND: Glyphosate (GLY) exposure induces hepatocyte ferroptosis through overproduction of reactive oxygen species, regarded as an important contributor to liver damage. Grape seed-derived procyanidin (GSDP) has been reported to be an effective antioxidant, but whether and, if any, how GSDP can attenuate GLY-induced liver injury via inhibiting ferroptosis is unclear. PURPOSE: The current study aimed to investigate the hepato-protective effects and possible mechanisms of GSDP. METHODS: GLY-induced liver damage mice model was established to explore the hepatoprotective roles of GSPE in vivo. Subsequently, bioinformatics methodology was used to predict the key pathways and factors related to the action targets of GSPE against hepatocyte ferroptosis. Finally, we explored the roles of nuclear factor E2 related factor 2 (Nrf2) and fibroblast growth factor 21 (FGF21) in blunting GLY-induced liver damage via suppressing ferroptosis in vitro. RESULTS: GSDP exerts hepato-protective effects in vivo and in vitro through reduced oxidative stress and inhibited ferroptosis, which was related to the activation of Nrf2. Bioinformatics analysis showed an interaction between Nrf2 and FGF21. Furthermore, Nrf2 inhibition reduced FGF21 expression in the mRNA and protein levels. Fgf21 knockdown suppressed Nrf2 expression level, but recombinant FGF21 protein increased Nrf2 expression and promoted Nrf2 translocation into nucleus, suggesting a crosstalk between Nrf2 and FGF21. Intriguingly, the decreased levels of Nrf2 and FGF21 compromised the protective roles of GSDP against GLY-induced hepatocyte ferroptosis. CONCLUSION: These findings suggest that GSDP attenuates GLY-caused hepatocyte ferroptosis via enhancing the interplay between Nrf2 and FGF21. Thus, GSDP may be a promising natural compound to antagonize ferroptosis-related damage.

Mechanistic revealing of reproductive behavior impairment in male guppy (Poecilia reticulata) induced by environmentally realistic 2,2'-dithiobis-pyridine exposure.

Although (PS)2, the primary degradation product of emerging antifouling biocides metal pyrithiones (MePTs), can disrupt the reproductive behavior of fish at an environmentally relevant ng/L level, the underlying mechanism is still largely unknown. This study exposed sexually mature male guppy (Poecilia reticulata) to 20, 200, and 2000 ng/L (PS)2 to explore the compromised effect of (PS)2 on reproductive behavior through a realistic competing scenario. The results showed that (PS)2 suppressed male guppies' sexual interest to stimulus females, reduced their competitive behavior frequencies toward rival males, and decreased their mating time and frequency. (PS)2 exposure did not affect male guppies' secondary sexual characteristics or induce estrogenic activity. Whole-brain transcriptome sequencing identified 1070 differentially expressed genes (DEGs) with 872 up-regulated genes, which were functionally enriched into Gene Ontology terms pertaining to extracellular matrix (ECM) and extracellular region. KEGG enrichment for the DEGs uncovered that the activations of ECM-receptor interaction and focal adhesion pathways could be the underlying molecular mechanism implicated in the (PS)2 induced reproductive behavior impairment. This work would deliver a substantial contribution to the understanding of the ecological safety of MePTs biocides.

Combined exposure to environmentally relevant copper and 2,2'-dithiobis-pyridine induces significant reproductive toxicity in male guppy (Poecilia reticulata).

Metal pyrithiones (MePTs), the most widely used biocides in antifouling paints (AFs) coated on the hulls, are usually used in combination with Cu-containing substances. In the aquatic environment, 2,2'-dithiobis-pyridine ((PS)2), the main degradation product of MePTs, and Cu usually coexist. However, their combined impacts on aquatic organisms are unclear. This study exposed male guppy (Poecilia reticulata) to an environmentally realistic concentration of Cu (10 µg/L) alone or Cu (10 µg/L) combined with 20, 200, and 2000 ng/L (PS)2 to explore their combined reproductive toxicity. The results showed that co-exposure to Cu and (PS)2 increased Cu accumulation in the fish body in a dose-dependent manner and induced obvious spermatozoon apoptosis and necrosis, which was mediated by the peroxidation and caspase activation. Compared to Cu alone, co-exposure to Cu and 200, 2000 ng/L (PS)2 significantly decreased the testosterone level and collapsed spermatogenesis, and depressed male's sexual interest and mating behavior were observed in three co-exposure groups. Moreover, co-exposure to Cu and (PS)2 increased the disturbance on cyp19a and cyp19b transcription and suppressed the "display" reproductive behavior. Eventually, co-exposure to Cu and (PS)2 caused male reproductive failure. Therefore, the concurrence of Cu and (PS)2 induced significant reproductive toxicity in male guppies and would threaten the sustainability of fish populations. Considering the extensive usage of MePTs products in the AFs, their ecological risk warrants more evaluation.

Bisphenol S promotes the cell cycle progression and cell proliferation through ERα-cyclin D-CDK4/6-pRb pathway in MCF-7 breast cancer cells.

Bisphenol S (BPS), exhibiting estrogenic activity, has been reported to promote cell proliferation in MCF-7 breast cancer cells; however, the underlying mechanism remains unclear. In this study, BPS (1-100 µM) significantly promoted cell proliferation in ERα positive MCF-7 cells, but not in ERα negative MDA-MB-231 or SK-BR-3 cells, confirming the important role of ERα in BPS-induced cell proliferation. Results of the flow cytometry analysis indicated that 10 µM BPS promoted MCF-7 proliferation by accelerating G1 to S phase transition of the cell cycle. BPS increased cyclin D1 expression and phospho-retinoblastoma (p-Rb) levels, resulting in the release of E2F transcription factors and the increased expression of downstream cyclin E2 and cyclin A2 genes to promote the cell cycle progression. Moreover, BPS-induced Rb phosphorylation and cell cycle progression were prevented by the ERα inhibitor ICI 182,780 and methylpiperidino pyrazole, as well as cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitor PD 0332991, indicating that the underlying mechanisms involve ERα-dependent pathways but also mediated by cyclin D-CDK4/6. Overall, our result showed, for the first time, that BPS promoted cell cycle progression and cell proliferation through the ERα-cyclin D-CDK4/6-pRb pathway in MCF-7 breast cancer cells. This study provides a novel insight regarding the potential role of cyclin D-CDK4/6-pRb pathway in mediating the proliferative effects of BPS in breast cancer cells.