Background:Our previous study indicates that leptin enhances gastric cancer (GC) invasion. However, the exact effect of leptin on GC metastasis and its underlying mechanism remain unclear. Intercellular adhesion molecule-1 (ICAM-1), a major molecule in stabilising cell–cell and cell–extracellular matrix interactions, is overexpressed and has crucial roles in tumour metastasis.Methods:Here, we investigated leptin and ICAM-1 expression in GC tissues. Furthermore, we characterised the influence of leptin on ICAM-1 expression in GC cells and elucidated the underlying mechanism.Results:Leptin and ICAM-1 were overexpressed in GC tissues, and a strong positive correlation was observed. They were also related with clinical stage or lymph node metastasis. Furthermore, leptin induced GC cell (AGS and MKN-45) migration by upregulating ICAM-1, and knockdown of ICAM-1 by small interference RNA (siRNA) blocked this process. Cell surface ICAM-1, as well as soluble ICAM-1 (sICAM-1), was also enhanced by leptin. Moreover, leptin increased ICAM-1 expression through Rho/ROCK pathway, which was attenuated by pharmacological inhibition of Rho (C3 transferase) or its downstream effector kinase Rho-associated protein kinase (ROCK) (Y-27632).Conclusions:Our findings indicate that leptin enhances GC cell migration by increasing ICAM-1 through Rho/ROCK pathway, which might provide new insight into the significance of leptin in GC.

Background Circular RNAs (circRNAs) represent a novel type of regulatory RNA characterized by high evolutionary conservation and stability. CircRNAs are expected to be potential diagnostic biomarkers and therapeutic targets for a variety of malignancies. However, the regulatory functions and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. Methods By using RNA high-throughput sequencing technology, qRT-PCR and in situ hybridization assays, we screened dysregulated circRNAs in breast cancer and TNBC tissues. Then in vitro assays, animal models and patient-derived organoids (PDOs) were utilized to explore the roles of the candidate circRNA in TNBC. To investigate the underlying mechanisms, RNA pull-down, RNA immunoprecipitation (RIP), co immunoprecipitation (co-IP) and Western blotting assays were carried out. Results In this study, we demonstrated that circRNA-CREIT was aberrantly downregulated in doxorubicin resistant triple-negative breast cancer (TNBC) cells and associated with a poor prognosis. The RNA binding protein DHX9 was responsible for the reduction in circRNA-CREIT by interacting with the flanking inverted repeat Alu (IRAlu) sequences and inhibiting back-splicing. By utilizing in vitro assays, animal models and patient-derived organoids, we revealed that circRNA-CREIT overexpression significantly enhanced the doxorubicin sensitivity of TNBC cells. Mechanistically, circRNA-CREIT acted as a scaffold to facilitate the interaction between PKR and the E3 ligase HACE1 and promoted proteasomal degradation of PKR protein via K48-linked polyubiquitylation. A reduced PKR/eIF2α signaling axis was identified as a critical downstream effector of circRNA-CREIT, which attenuated the assembly of stress granules (SGs) to activate the RACK1/MTK1 apoptosis signaling pathway. Further investigations revealed that a combination of the SG inhibitor ISRIB and doxorubicin synergistically inhibited TNBC tumor growth. Besides, circRNA-CREIT could be packaged into exosomes and disseminate doxorubicin sensitivity among TNBC cells. Conclusions Our study demonstrated that targeting circRNA-CREIT and SGs could serve as promising therapeutic strategies against TNBC chemoresistance.

Screening toxic-element-free and biocompatible electrochemiluminophores was crucial for electrochemiluminescence (ECL) evolution. Herein, L-glutathione (GSH)-capped Ag−Ga−In−S (AGIS) nanocrystals (NCs) were prepared by doping Ag−In−S (AIS) NCs in a doping-in-growth way and utilized as a model for both ECL modulating and developing multinary NC-based electrochemiluminophores with enhanced ECL performance than trinary NCs. AGIS NCs not only primarily preserved the morphology, size, phase structure, and water monodisperse characteristics of AIS NCs with broadened band gap but also demonstrated obviously enhanced oxidative-reduction ECL than AIS NCs. Importantly, ECL of AGIS NCs was located at the nearinfrared region with a maximum emission wavelength of 744 nm and could be utilized for an ECL immunoassay with human prostate-specific antigen (PSA) as a model, which exhibited a linearity range from 0.05 pg/mL to 1.0 ng/mL and a low limit of detection of 0.01 pg/mL (S/N = 3). This work provided a promising alternative to the traditional binary NCs for developing toxicelement-free and biocompatible electrochemiluminophores with efficient near-infrared ECL.

No abstract

The penetration of organophosphate triesters (tri-OPEs) and diesters (di-OPEs) across the blood–brain barrier and their influencing factors remain unclear in humans. In this study, 21 tri-OPEs and 8 di-OPEs were measured in 288 paired serum and cerebrospinal fluid (CSF) samples collected in Jinan, China. Six tri-OPEs were frequently detected in both serum and CSF, with median concentrations ranging from 0.062 to 1.62 and 0.042–1.11 ng/mL, respectively. Their penetration efficiencies across the blood–CSF barrier (BCSFB) (R CSF/serum, C CSF/C serum) were calculated at 0.667–2.80, and these efficiencies first increased and then decreased with their log K ow values. The reduced penetration efficiencies of triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) may be attributed to their strong binding affinities for human serum albumin and p-glycoprotein due to their high hydrophobicity and aryl structure, as indicated by molecular docking. This suggests that active efflux transport may be involved in the penetration of TPHP and EHDPP in addition to passive diffusion similar to the other four tri-OPEs. Di-OPEs were found in few serum samples and even fewer CSF samples, indicating their limited BCSFB permeability. This may be due to their high polarity, low hydrophobicity, and ionic state in blood. This study has important implications for understanding the neurotoxicity of tri-OPEs and di-OPEs and the underlying mechanisms.