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Abstract In nematode Caenorhabditis elegans , epidermal RNA interference (RNAi) knockdown of bli-1 encoding a cuticular collagen caused the toxicity induction of GO-PEG (PEG surface modified graphene oxide). In this study, we further found that epidermal RNAi knockdown of bli-1 increased expression of a microRNA let-7 , and let-7 mutation suppressed the susceptibility of bli-1(RNAi) nematodes to GO-PEG toxicity. let-7 regulated the toxicity induction of GO-PEG by suppressing expression and function of its direct targets (HBL-1 and LIN-41). Like the nematodes with epidermal RNAi knockdown of bli-1 , epidermal RNAi knockdown of hbl-1 or lin-41 also induced functional abnormality in epidermal barrier. Therefore, a signaling cascade of BLI-1- let-7 -HBL-1/LIN-41 was raised to be involved in GO-PEG toxicity induction. Our data imply the dysregulation of let-7- mediated molecular machinery for developmental timing control by GO-PEG in nematodes with deficit in epidermal barrier caused by bli-1(RNAi). Highlights • We determined molecular basis for epidermal BLI-1 against GO-PEG toxicity. • Signaling cascade of BLI-1- let-7 -HBL-1/LIN-41 was required for GO-PEG toxicity. • BLI-1 activates HBL-1 and LIN-41 by suppressing let-7 to exert protection function. [ABSTRACT FROM AUTHOR]

Graphene oxide (GO) exposure may cause damage to C. elegans. However, the role of autophagy and its interactive effect with oxidative response in GO toxicity still remain largely unclear. In the present study, we investigated the protective role of autophagy against GO and its association with oxidative response using C. elegans as an in vivo system. Results indicated that GO exposure induced autophagy in a dose dependent manner in C. elegans. Autophagy inhibitor 3-methyladenine (3-MA) and silencing autophagy genes lgg-1 , bec-1 and unc-51 exacerbated the toxicity of GO whereas autophagy activator rapamycin alleviated it. In addition, the antioxidant N-Acetyl- L -cysteine (NAC) effectively suppressed the toxicity of GO with increased resistance to oxidative stress. Worms with RNAi-induced antioxidative genes sod-1 , sod-2 , sod-3 and sod-4 knockdown were more sensitive to GO. 3-MA increased the expression of superoxide dismutase SOD-3 under GO exposure conditions and exacerbated the toxicity of GO under the anti-oxidation inaction condition by sod-3 RNAi. In contrast, NAC reduced autophagy levels in GO exposed nematodes and increased tolerance to GO in autophagy-defective worms. These results suggested that autophagy and antioxidative response provide complementary protection against GO in C. elegans. [Display omitted] • Autophagy exerts a protective response to cope with the toxicity of GO in C. elegans. • Oxidative response plays a protective role in response to GO in C. elegans. • Autophagy and oxidative act in a complementation way in the protective response. [ABSTRACT FROM AUTHOR]

Exposure to nanoplastics can induce toxicity on organisms at both parental generation (P0-G) and the offspring. However, the underlying mechanism remains unknown. Using Caenorhabditis elegans as a model organism, exposure to 20-nm polystyrene nanoparticle (PS-NP) (1–100 μg/L) upregulated the expressions of insulin ligands (INS-39, INS-3, and DAF-28), and this increase could be further detected in the offspring after PS-NP exposure. Germline ins-39 , ins-3 , and daf-28 RNAi induced resistance to transgenerational toxicity of PS-NP, indicating that increase in expression of these three insulin ligands mediated induction of transgenerational toxicity. These three insulin ligands transgenerationally activated function of insulin receptor DAF-2 to control transgenerational toxicity of PS-NP. Exposure to 1–100 μg/L PS-NP further upregulated DAF-2, AGE-1, and AKT-1 expressions and downregulated DAF-16 expression. During transgenerational toxicity control, DAF-16/AKT-1/AGE-1 was identified as downstream signaling cascade of DAF-2. Moreover, transcriptional factor DAF-16 activated two downstream targets of HSP-6 (a mitochondrial UPR marker) and SOD-3 (a mitochondrial SOD) to modulate transgenerational toxicity of PS-NP. Our findings indicate a crucial link between activation of insulin signaling and induction of transgenerational toxicity of nanoplastics at low concentrations in organisms. [Display omitted] • PS-NP exposure induced transgenerational increase in expression of insulin ligands. • Activation of insulin signaling mediates induction of transgenerational PS-NP toxicity. • Insulin ligands transgenerationally activated function of insulin receptor DAF-2. • DAF-16 activated targets of HSP-6 and SOD-3 to control transgenerational PS-NP toxicity. [ABSTRACT FROM AUTHOR]

• Bioassay-guided isolation was performed to investigate the constituents in stem of Vigna angularis. • A new compound and a compound isolated from nature source firstly, along with 14 known compounds were isolated. • Most of the compounds shown significant α -glucosidase inhibitory activity. • Enzyme kinetic analysis was conducted to determine type of inhibition and inhibition kinetic constant. Stem of Vigna angularis (Willd.) Ohwi & H. Ohashi (VAS) is a main byproduct with considerable bioactivities. In present study, a bioassay-guided phytochemical investigation was used and led to the isolation of 16 compounds including one new compound (1) and one compound (2) isolated from nature source firstly along with 14 known compounds (3 – 16). The structures of isolates were identified by NMR and HR-ESI-MS data. The ability of antioxidant and α -glucosidase inhibition of the compounds were measured in vitro. Most of the ingredients shown strong ABTS radical scavenging activity (IC 50 = 4.21–14.93 μM) and α -glucosidase inhibitory activity (IC 50 = 0.05–34.14 μM). Enzyme kinetic analysis and molecular docking of compounds 1 and 2 were conducted. Compounds 1 and 2 were competitive inhibitor for α -glucosidase, with the inhibition kinetic constant value of 1.03 and 1.06 μM, respectively. The potent α -glucosidase inhibitory ability of compounds 1 and 2 resulted from firm binding with the active site of α -glucosidase. [ABSTRACT FROM AUTHOR]

[Display omitted] • OTP-3 directly binds to EGFR extracellular domain decreases EGF and EGFR binding affinities by combination with nimotuzumab. • Nimotuzumab combined with OTP-3 exerts growth inhibitory activities in wild-type EGFR cell lines. • Treatment with OTP-3 and nimotuzumab inhibits EGF/EGFR signaling pathway, promotes EGFR degradation. • Combined treatment with OTP-3 and nimotuzumab achieves complete tumor regression in mouse tumor models. Aberrant activation of epidermal growth factor receptor (EGFR) plays a pivotal role in cancer initiation and progression and has gained attention as an anticancer drug target. EGFR monoclonal antibodies have been canonically used in non-small cell lung cancer (NSCLC) treatment. However, a basal level of ligand-independent EGFR signaling pro-survival properties limit the clinical efficacy of EGFR monoclonal antibodies. Therefore, targeting EGFR by inducing degraders is a promising approach towards improving therapeutic efficacy and augmenting the effect of nimotuzumab. Here we describe rational discovery of OTP-3, an oxidized (−)-Epigallocatechin gallate (EGCG) derivative that elicits potent anticancer activity in EGFR wild type NSCLC. Mechanistic studies disclosed that OTP-3 directly binds to EGFR extracellular domain decreases EGF and EGFR binding affinities by combination with nimotuzumab. Molecular docking studies revealed that OTP-3-EGFR is a very stable complex. Further analyses showed that nimotuzumab combined with OTP-3 resulted in significantly promoted EGFR degradation and repressed downstream survival pathways. Accordingly, OTP-3 combined with nimotuzumab significantly inhibits tumor growth through degrading EGFR in vivo. Thus, OTP-3 can also serve as an effective therapeutic agent in NSCLC where it can augment the effects of nimotuzumab, a valuable property for combination agents. [ABSTRACT FROM AUTHOR]