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YTH domain family 2 (YTHDF2) is the first identified N6‐methyladenosine (m6A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90β) and STIP1 homology and U‐box‐containing protein 1 (STUB1) physically interact with YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of HSP90β is required for its interaction with STUB1 and YTHDF2. HSP90β inhibits the STUB1‐induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90β and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90β is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90β. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC. [ABSTRACT FROM AUTHOR]

It's highly desired but challenging to synthesize self-supporting nanohybrid made of conductive nanoparticles with metal organic framework (MOF) materials for the application in the electrochemical field. In this work, we report the preparation of Ni2P embedded Ni-MOF nanosheets supported on nickel foam through partial phosphidation (Ni2P@Ni-MOF/NF). The self-supporting Ni2P@Ni-MOF/NF was directly tested as electrode for urea electrolysis. When served as anode for urea oxidation reaction (UOR), it only demands 1.41 V (vs RHE) to deliver a current of 100 mA cm−2. And the overpotential of Ni2P@Ni-MOF/NF to reach 10 mA cm−2 for hydrogen evolution reaction HER was only 66 mV, remarkably lower than Ni2P/NF (133 mV). The exceptional electrochemical performance was attributed to the unique structure of Ni2P@Ni-MOF and the well exposed surface of Ni2P. Furthermore, the Ni2P@Ni-MOF/NF demonstrated outstanding longevity for both HER and UOR. The electrolyzer constructed with Ni2P@Ni-MOF/NF as bifunctional electrode can attain a current density of 100 mA cm−2 at a cell voltage as low as 1.65 V. Our work provides new insights for prepare MOF based nanohydrid for electrochemical application. [ABSTRACT FROM AUTHOR]

Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Here, we show that blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells. [ABSTRACT FROM AUTHOR]

Proanthocyanidins (PCs) have shown inhibition of oxidative damage by improving Nrf-2 expression in many tissues. However, the cytoprotective effects of PCs on H2O2-induced tendon damage have not been verified. The current study was aimed at assessing the cytoprotection of PCs on the oxidative cellular toxicity of tendon-derived stem cells (TDSCs) induced by H2O2. The TDSCs were isolated from patellar tendons of Sprague Dawley (SD) rats, and the cells after third passage were used for subsequent experiments. The isolated cells were identified by flow cytometry assay and multidifferentiation potential assay. Cell Counting Kit-8 assay was performed to examine cell viability. Real-Time PCR and Western Blot were employed to, respectively, assess the mRNA and protein expressions of Nrf-2, GCLM, NQO-1, and HO-1. PCs significantly improved the cell viability of TDSCs. Furthermore, H2O2 upregulated Nrf-2, GCLM, NQO-1, and HO-1 without significant difference, while the proteins expressions were increased with significant difference in PCs group and PCs + H2O2 cotreated group. All the findings indicated that PCs could protect against the oxidative damage induced by H2O2 in TDSCs, and the cytoprotective effects might be due to the ability of PCs to activate the expressions of GCLM, HO-1, and NQO-1 via upregulating Nrf-2 signaling pathway. [ABSTRACT FROM AUTHOR]

Primary frozen shoulder (PFS) is a common condition of uncertain etiology that is characterized by shoulder pain and restriction of active and passive glenohumeral motions. The pathophysiology involves chronic inflammation and fibrosis of the joint capsule. Single nucleotide polymorphisms (SNPs) at IL-1β, MMP3, TGF-β1, and GDF5 have been associated with risk of a variety of inflammatory diseases; however, no studies have examined these SNPs with susceptibility to PFS. We investigated allele and genotype frequencies of rs1143627 at IL-1β, rs650108 at MMP-3, rs1800469 at TGF-β1, and rs143383 at GDF5 in 42 patients with PFS and 50 healthy controls in a Chinese Han population. Serum samples from both cohorts were evaluated to determine the expression levels of IL-1β. We found that the IL-1β rs1143627 CC genotype was associated with a decreased risk of PFS compared to the TT genotype (P=0.022) and that serum IL-1β was expressed at a significantly higher level in the PFS cohort compared to that found in the control group (P<0.001). Our findings indicated no evidence of an association between rs650108, rs1800469, or rs143383 and PFS. IL-1β is associated with susceptibility to PFS and may have a role in its pathogenesis in a Chinese Han population. [ABSTRACT FROM AUTHOR]

Rotator cuff tear (RCT) is the primary cause of shoulder pain and disability and frequently trigger muscle degeneration characterised by muscle atrophy, fatty infiltration and fibrosis. Single‐nucleus RNA sequencing (snRNA‐seq) was used to reveal the transcriptional changes in the supraspinatus muscle after RCT. Supraspinatus muscles were obtained from patients with habitual shoulder dislocation (n = 3) and RCT (n = 3). In response to the RCT, trajectory analysis showed progression from normal myonuclei to ANKRD1+ myonuclei, which captured atrophy‐and fatty infiltration‐related regulons (KLF5, KLF10, FOSL1 and BHLHE40). Transcriptomic alterations in fibro/adipogenic progenitors (FAPs) and muscle satellite cells (MuSCs) have also been studied. By predicting cell–cell interactions, we observed communication alterations between myofibers and muscle‐resident cells following RCT. Our findings reveal the plasticity of muscle cells in response to RCT and offer valuable insights into the molecular mechanisms and potential therapeutic targets of RCT. [ABSTRACT FROM AUTHOR]

Wear particulate debris-induced osteoclast over-activation is a major causative factor in periprosthetic osteolysis and aseptic loosening, resulting in the non-infectious failure of total joint arthroplasty. To mitigate such pathological bone loss, various therapeutic targets have been identified. Oxidative stress is one of the main contributing factors in the promotion of osteoclastogenesis. Herein, using a template-assisted approach, hollow ruthenium oxide (RuO 2 ) nanospheres are synthesized as an effective antioxidant for the treatment of CoCrMo alloy particles-induced osteolysis. Hollow RuO 2 significantly suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis, bone resorption, and the expression of specific markers (including NFATc1, c-Fos, MMP9, CTSK, and DC-STAMP) of bone marrow-derived macrophages via inhibition of the nuclear factor kappa-B (NF-κB) and tumor necrosis factor (TNF)-α pathways. In mouse calvaria, hollow RuO 2 nanozymes demonstrate an appreciable attenuation in osteoclast differentiation, bone loss, and soft tissue malformations induced by CoCrMo alloy particles. This study envisions that the antioxidant nanozymes may be further applied as a therapeutic entity in the prevention and treatment of other inflammatory and oxidative stress-related ailments., (© 2024 Wiley‐VCH GmbH.)

Prostate cancer (PC) remains a great medical challenge due to its high incidence and the development of castration resistance in patients treated with androgen deprivation therapy. Deubiquitinases, the enzymes that specifically hydrolyze ubiquitin chains on their substrates, were recently proposed as a serious of critical therapeutic targets for cancer treatment. Our previous study has been reported that the ubiquitin specific peptidase 1 (USP1) functionally acts as a deubiquitinase of sine oculis homeobox homolog 1 (SIX1) and contributes to the proliferation and castration resistance of PC. The stabilization of SIX1 by USP1 partially depends on the status of glucose-regulated protein 75 (GRP75). In this study, we aimed to identify a SIX1 degradation inducer via inhibiting the USP1-SIX1 axis. we screened a range of kinase inhibitors and showed that SNS-032 is the best candidate to trigger the ubiquitinated degradation of SIX1. SNS-032 not only restrains activity of the USP1-SIX1 axis and cell cycle progression, but also results in apoptosis of PC cells. Moreover, the combination of SNS-032 and enzalutamide synergistically induces apoptosis and downregulates expression of USP1, SIX1, and AR/AR-V7 in AR-V7 highly expressed 22Rv1 cells. Overall, our findings may develop a novel and effective strategy to overcome castration resistance in PC for the identification of a SIX1 degradation inducer via targeting the USP1-SIX1 axis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Proanthocyanidins (PCs) have shown inhibition of oxidative damage by improving Nrf-2 expression in many tissues. However, the cytoprotective effects of PCs on H 2 O 2 -induced tendon damage have not been verified. The current study was aimed at assessing the cytoprotection of PCs on the oxidative cellular toxicity of tendon-derived stem cells (TDSCs) induced by H 2 O 2 . The TDSCs were isolated from patellar tendons of Sprague Dawley (SD) rats, and the cells after third passage were used for subsequent experiments. The isolated cells were identified by flow cytometry assay and multidifferentiation potential assay. Cell Counting Kit-8 assay was performed to examine cell viability. Real-Time PCR and Western Blot were employed to, respectively, assess the mRNA and protein expressions of Nrf-2, GCLM, NQO-1, and HO-1. PCs significantly improved the cell viability of TDSCs. Furthermore, H 2 O 2 upregulated Nrf-2, GCLM, NQO-1, and HO-1 without significant difference, while the proteins expressions were increased with significant difference in PCs group and PCs + H 2 O 2 cotreated group. All the findings indicated that PCs could protect against the oxidative damage induced by H 2 O 2 in TDSCs, and the cytoprotective effects might be due to the ability of PCs to activate the expressions of GCLM, HO-1, and NQO-1 via upregulating Nrf-2 signaling pathway.