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Objective To explore the effects of the hypoxic hepatoma-derived exosome miR-1260b on the M2 subtype of tumor-associated macrophages and the underlying mechanism. Methods MHCC97H (97H) cells were treated with 100 μmol/L CoCl2 for 24 h to obtain hypoxic 97H cells. THP-1 cells were treated with propylene glycol methyl ether acetate (PMA) for 24 h to derive M0 macrophages. The relative expression of CD11b in THP-1 cells was measured by real-time quantitative PCR (RT-qPCR). After co-culture with normoxic/hypoxic 97H cells for 48 h, the relative gene expression of CD163, CD206, and TNF-α in M0 macrophages was measured by RT-qPCR. The exosomes of normoxic/hypoxic 97H cells were extracted by low temperature differential centrifugation. A transmission electron microscope was used to observe the shape of the exosomes. The particle diameter was measured using a nanoparticle tracking analyzer. Western blot was used to determine the relative expression of apoptosis-inducing factor 6-interacting protein (Alix) and calnexin in the exosomes. After co-culture with the exosomes for 48 h, the relative expression of CD206 in M0 macrophages was measured by RT-qPCR. The exosomes labeled with Dil stain were co-cultured with M0 macrophages for 24 h, and then M0 macrophages were examined for the fluorescence reaction using a fluorescence microscope. The expression of miR-1260b in the exosomes was measured by RT-qPCR. After M0 and M2 macrophages were transfected with miR-1260b Mimic/Inhibitor, the expression of CD206 and TNF-α in the cells was determined by RT-qPCR. After co-culture with normoxic/hypoxic 97H cells transfected with miR-1260b Inhibitor, M0 macrophages were measured for the relative expression of CD206 and TNF-α by RT-qPCR. Results There was significantly high expression of CD11b in M0 macrophages derived from THP-1 cells after 24 h PMA treatment (t=78.14,P

5-Fluorouracil (5-FU) chemoresistance contributes to poor therapeutic response and prognosis of gastric cancer (GC), for which effective strategies to overcome chemoresistance are limited. Here, using a CRISPR-Cas9 system, we identified that nitrilase family member 2 (NIT2) reverses chemoresistance independent of its metabolic function. Depletion or low expression of NIT2 led to 5-FU resistance in GC cell lines, patient-derived organoids, and xenografted tumors. Mechanistically, NIT2 interacted with bromodomain-containing protein 1 (BRD1) to inhibit HBO1-mediated acetylation of histone H3 at lysine-14 (H3K14ac) and RELA-targeted oxidative phosphorylation (OXPHOS) gene expression. Upon 5-FU stimulation, NIT2 phosphorylation by Src at Y49 promoted the dissociation of NIT2 from BRD1, followed by binding to E3 ligase CCNB1IP1, causing autophagic degradation of NIT2. Consequently, reduced NIT2 protein resulted in BRD1 forming phase separation and binding to histone H3, as well as increased RELA stability due to suppression of inhibitor of growth family member 4–mediated RELA ubiquitination. In addition, NIT2 expression negatively correlated with H3K14ac and OXPHOS and positively correlated with the chemotherapeutic responses and prognosis of patients with GC. Our findings reveal the moonlighting function of NIT2 in chemoresistance and underscore that OXPHOS blockade by metformin enhances 5-FU chemosensitivity upon NIT2 loss. Editor's summary: 5-Fluorouracil (5-FU) chemotherapy is commonly used to shrink advanced gastric cancers before any attempt at their resection. The development of resistance to 5-FU treatment can therefore greatly impede patient prognosis. Examining cell lines and patient-derived organoids, Wang et al. found that low expression of NIT2 promoted the onset of 5-FU chemoresistance in gastric cancer by increasing oxidative phosphorylation through a mechanism independent of its nitrilase enzymatic function. Using metformin as an oxidative phosphorylation inhibitor increased the therapeutic efficacy of 5-FU in patient-derived xenografts with low NIT2, indicating a potential avenue for tackling chemoresistance in this setting. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy‐activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin‐α1 and KPNB1/importin‐β1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor‐deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient‐derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients. [ABSTRACT FROM AUTHOR]

Hypoxia plays an important role in the metastasis of hepatocellular carcinoma (HCC). Exosomes have been widely studied as mediators of communication between tumours and immune cells. However, the specific mechanism by which hypoxic HCC cell‐derived exosomes suppress antitumor immunity is unclear. Hypoxia scores were determined for The Cancer Genome‐Liver Hepatocellular Carcinoma (TCGA‐LIHC) dataset patients, and HCC patients in the hyperhypoxic group had a higher degree of M2 macrophage infiltration. Patients in the M2 high‐invasion group had a lower probability of survival than those in the low‐invasion group. In vivo and in vitro experiments demonstrated that exosomes secreted by hypoxic HCC cells promote M2 macrophage polarization. This polarization induces apoptosis in CD8+ T cells. Additionally, it encourages epithelial–mesenchymal transition (EMT), which increases HCC migration. Exosomal miRNA sequencing revealed that miR‐1290 was highly expressed in exosomes secreted by hypoxic HCC cells. Mechanistically, miR‐1290 in macrophages inhibited Akt2 while upregulating PD‐L1 to promote M2 polarization, induce apoptosis in CD8+ T cells, and enhance EMT in HCC. Animal studies found that the miR‐1290 antagomir in combination with the immune checkpoint inhibitor produced better antitumor effects than the monotherapies. In conclusion, the secretion of exosome‐derived miR‐1290 from HCC cells in a hypoxic environment supported immune escape by HCC cells by promoting M2 macrophage polarization to induce apoptosis in CD8+ T cells and enhance EMT that promoted HCC metastasis. Therefore, miR‐1290 is an important molecule in antitumor immunity in HCC, and inhibition of miR‐1290 could provide a novel immunotherapeutic approach for HCC treatment. [ABSTRACT FROM AUTHOR]

The present study employed the social-ecological diathesis-stress model as a theoretical framework to extend previous research by examining the underlying mechanism and conditional process that contribute to the positive association between bullying victimization and internalizing problems among adolescents. A moderated mediation model involving peer autonomy support and self-esteem was tested using a sample of 1723 adolescents (50.7% girls; Mage = 12.79, SD = 1.58), who completed questionnaires assessing internalizing problems, bullying victimization, peer autonomy support, and self-esteem. The findings revealed that self-esteem partially mediated the positive association between bullying victimization and adolescents' internalizing problems. Specifically, bullying victimization was inversely related to self-esteem, which, in turn, was negatively associated with internalizing problems. Further moderation analyses demonstrated that these direct and indirect associations varied based on levels of peer autonomy support. Simple slope analyses specifically indicated that (a) peer autonomy support buffered against the negative association of bullying victimization with self-esteem and internalizing problems, and (b) peer autonomy support mitigated the negative association of self-esteem with internalizing problems. The elucidation of this mechanism and conditional process holds important implications for early interventions and prevention efforts aimed at mitigating the detrimental association of bullying victimization with adolescents' healthy emotional functions. [ABSTRACT FROM AUTHOR]

Aims: The current study aimed to examine the relationship between parental autonomy support and social competence among Chinese emerging adults, and explore whether social desirablity plays a mediating role between parental support and social competence. Methods: This study used cross-sectional and correlational design. Participants were 386 Chinese college students (72.8% girls) aged between 18 and 25 years. Data was collected via self-report questionnaires, including parental autonomy support (Genevie`ve A. Mageau, 2015), social desirablity (Karl Schuessler et al., 1978) and social competence(Valkenburg & Peter, 2008). Results: Structural equation modeling analysis controlling for age, gender and SES showed that (a) There was a significant positive correlation between parental autonomy support, social desirablity, and social competence; (b) Parental autonomy support was positively predicted to social desirablity and social competence; Social desirablity was positively predicted to social competence; (c) Social desirablity mediated the relationship between parental autonomy support and social competence.

Highlights: The electrochemical techniques utilizing metal-organic frameworks (MOFs)-based catalysts for converting CO2 into chemical species are discussed. The structure–activity relationship of MOF-based catalysts in electrocatalytic CO2 reduction reactions is thoroughly reviewed The challenges and opportunities of large-scale applications of MOF-based materials in electrochemical CO2 reduction reactions are discussed, and possible directions for the future development of MOFs and their derivatives are outlined. Electrochemically reducing CO2 to more reduced chemical species is a promising way that not only enables the conversion of intermittent energy resources to stable fuels, but also helps to build a closed-loop anthropogenic carbon cycle. Among various electrocatalysts for electrochemical CO2 reduction, multifunctional metal–organic frameworks (MOFs) have been employed as highly efficient and selective heterogeneous electrocatalysts due to their ultrahigh porosity and topologically diverse structures. Up to now, great progress has been achieved in the design and synthesis of highly active and selective MOF-related catalysts for electrochemical CO2 reduction reaction (CO2RR), and their corresponding reaction mechanisms have been thoroughly studied. In this review, we summarize the recent progress of applying MOFs and their derivatives in CO2RR, with a focus on the design strategies for electrocatalysts and electrolyzers. We first discussed the reaction mechanisms for different CO2RR products and introduced the commonly applied electrolyzer configurations in the current CO2RR system. Then, an overview of several categories of products (CO, HCOOH, CH4, CH3OH, and multi-carbon chemicals) generated from MOFs or their derivatives via CO2RR was discussed. Finally, we offer some insights and perspectives for the future development of MOFs and their derivatives in electrochemical CO2 reduction. We aim to provide new insights into this field and further guide future research for large-scale applications. [ABSTRACT FROM AUTHOR]