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Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells in vitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model in vivo. In vitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: To prepare polylactic acid microneedles (PLAMNs) with sustained antibacterial effect to avoid skin infection caused by traditional MNs-based biosensors., Methods: Silver nanoparticles (AgNPs) were synthesized using an in-situ reduction process with polydopamine (PDA). PLAMNs were fabricated using the hot-melt method. A series of pressure tests and puncture experiments were conducted to confirm the physicochemical properties of PLAMNs. Then AgNPs were modified on the surface of PLAMNs through in-situ reduction of PDA, resulting in the formation of PLAMNs@PDA-AgNPs. The in vitro antibacterial efficacy of PLAMNs@PDA-AgNPs was evaluated using agar diffusion assays and bacterial liquid co-culture approach. Wound healing and simulated long-term application were performed to assess the in vivo antibacterial effectiveness of PLAMNs@PDA-AgNPs., Results: The MNs array comprised 169 tiny needle tips in pyramidal rows. Strength and puncture tests confirmed a 100% puncture success rate for PLAMNs on isolated rat skin and tin foil. SEM analysis revealed the integrity of PLAMNs@PDA-AgNPs with the formation of new surface substances. EDS analysis indicated the presence of silver elements on the surface of PLAMNs@PDA-AgNPs, with a content of 14.44%. Transepidermal water loss (TEWL) testing demonstrated the rapid healing of micro-pores created by PLAMNs@PDA-AgNPs, indicating their safety. Both in vitro and in vivo tests confirmed antibacterial efficacy of PLAMNs@PDA-AgNPs., Conclusions: In conclusion, the sustained antibacterial activity exhibited by PLAMNs@PDA-AgNPs offers a promising solution for addressing skin infections associated with MN applications, especially when compared to traditional MN-based biosensors. This advancement offers significant potential for the field of MN technology., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Non-small cell lung cancer (NSCLC) has a poor prognosis and usually presents resistance against radiotherapy. MEK inhibitors have been proven to possess a radiosensitization effect. The compound KZ-001 as a particular MEK inhibitor is superior to the listed MEK inhibitor AZD6244., Objective: To investigate whether KZ-001 could enhance the radiosensitivity of NSCLC cell lines in vitro., Methods: MTT and colony formation assay were used to evaluate the radiosensitivity effect of KZ-001. Immunofluorescence, cell cycle, apoptosis staining, and western blot experiments were used to explore the radiosensitivity mechanism., Results: KZ-001 significantly decreased A549 cell viability at 6 Gy and 8 Gy radiation doses and caused the radiosensitivity at 1 Gy, 4 Gy, and 6 Gy in colony formation experiments. The A549 apoptosis ratio induced by irradiation (IR) combined with KZ-001 increased significantly in comparison with that by IR monotherapy (10.57% vs. 6.23%, P = 0.0055). The anti-apoptosis marker Bcl-XL was found downregulated in KZ-001 and IR-treated A549/H460 cells, but apoptosis marker Bax was downregulated in H460. Extracellular regulated protein kinases (ERK1/2) phosphorylation of H460 cells could be blocked both by IR alone and IR combined with KZ-001. IR combined with KZ-001 is able to inhibit ERK activation of A549 cells apparently. KZ-001 increased the proportion of G2 phase in irradiated cells from 21.24% to 32.22%. KZ-001 could also significantly increase the double-strand break damage cell ratio to more than 30% compared to the irradiation alone group., Conclusions: MEK1/2 inhibitor KZ-001 is a potential radiosensitizer for clinical applications., (© 2023 Gongchao Huang et al., published by Sciendo.)

Acyl-CoA synthetases (ACSs) are responsible for acyl-CoA synthesis from nonpolar hydrophilic fatty acids and play a vital role in many metabolic processes. As a category of ACS isozymes, members of ACS family (AACS, ACSF2-3, AASDH) participate in lipid metabolism; however, their expression patterns, regulatory mechanisms and effects in hepatocellular carcinoma (HCC) are poorly understood. Here, through evaluating the expression profiles of ACSF gene family, we found that upregulated AACS might be more significant and valuable in development and progression of HCC. Consequently, the mRNA expression levels of AACS and ACSF2 was accordantly increased in HCC. Kaplan-Meier plotter revealed that HCC patients with high level of AACS were highly related to a shorter overall survival time and relapse-free survival. Genetic alterations using cBioPortal revealed that the alteration rate of AACS were 5%. We also found that the functions of ACSF gene family were linked to several cancer-associated pathways, including long-term potentiation, phospholipase D signaling pathway and purine metabolism. TIMER database indicated that the AACS and ACSF2 had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Diseasemeth database revealed that the global methylation levels of ACSF2 was higher in HCC patients. In conclusion, this study firstly demonstrated that Acyl-CoA synthesis gene family, in particular, AACS, could be associated with immune microenvironment, thereby influencing the development and prognosis of patients with HCC.

Pyroptosis is a regulated cell death pathway involved in numerous human diseases, especially malignant tumors. Recent studies have identified multiple pyroptosis-associated signaling molecules, like caspases, gasdermin family and inflammasomes. In addition, increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers. Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells, such as CD4 + and CD8 + T cells, thus strengthening the sensitivity to therapeutic strategies. In this review, we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation. We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors. Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy., (© 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Theoretical studies of the dynamics of the abstraction reaction, H' + HBr (v=0,j=0) --> H'H + Br, have been performed with quasiclassical trajectory method (QCT) on a new ab initio potential energy surface (Y. Kurosaki and T. Takayanagi, private communication). The calculated QCT cross sections are in good agreement with earlier quantum wave packet results over most of the collision energy range from 0.1 to 2.6 eV, and the state-resolved rotational distributions of the product H'H molecule are quantitatively consistent with the experimental results. Comparisons of the QCT-calculated rotational-state-resolved cross sections on different potential energy surfaces show that the characteristics of the potential energy surface in the region far away from the minimum energy path have a large influence on the title abstraction reaction dynamics, and the indirect reactions that do not follow the minimum energy path have little influence on the differential cross sections (DCS). The DCSs are mainly governed by the direct reactions that do follow the minimum energy path, at both low and high collision energies. The degree of the rotational alignment of the product H'H molecule is strong at high collision energies, which means that the influence of the indirect reactions on the product rotational alignment is negligible, whereas the distribution of P(varphi(r)) is sensitive to the indirect reactions at high collision energies. With increasing collision energy, the polarization of the product rotational angular momentum decreases and the molecular rotation of the product prefers an in-plane reaction mechanism rather than the out-of-plane mechanism.