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Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

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.

Androgen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

Background Hepatocellular carcinoma (HCC) remains a medical challenge due to its high proliferation and metastasis. Although deubiquitinating enzymes (DUBs) play a key role in regulating protein degradation, their pathological roles in HCC have not been fully elucidated. Methods By using biomass spectrometry, co-immunoprecipitation, western blotting and immunofluorescence assays, we identify ribosomal protein S16 (RPS16) as a key substrate of ubiquitin-specific peptidase 1 (USP1). The role of USP1-RPS16 axis in the progression of HCC was evaluated in cell cultures, in xenograft mouse models, and in clinical observations. Results We show that USP1 interacts with RPS16. The depletion of USP1 increases the level of K48-linked ubiquitinated-RPS16, leading to proteasome-dependent RPS16 degradation. In contrast, overexpression of USP1-WT instead of USP1-C90A (DUB inactivation mutant) reduces the level of K48-linked ubiquitinated RPS16, thereby stabilizing RPS16. Consequently, USP1 depletion mimics RPS16 deficiency with respect to the inhibition of growth and metastasis, whereas transfection-enforced re-expression of RPS16 restores oncogenic-like activity in USP1-deficient HCC cells. Importantly, the high expression of USP1 and RPS16 in liver tissue is a prognostic factor for poor survival of HCC patients. Conclusions These findings reveal a previously unrecognized role for the activation of USP1-RPS16 pathway in driving HCC, which may be further developed as a novel strategy for cancer treatment.

Background We aimed to analyse the oral health status of adolescents in Shandong province, including dental caries and gingivitis, and their associated factors. Methods Adolescents aged 12–15-years in Shandong province were recruited. Caries and gingival status were assessed following the World Health Organisation diagnostic criteria. Information including the sociodemographic, oral hygiene knowledge, attitudes and practices were collected through the questionnaire. Chi-square test and multivariate logistic regression analysis were used to investigate the oral diseases associated factors. Results In total, 3868 students (50.2% males) were enrolled. Of these, 39.9% of the participants experienced caries, and 81.7% and 31.3% had calculus and bleeding gingival, respectively. Multivariate logistic regression analysis revealed that there was an association between dental caries and toothaches, dental visits and sleeping troubles caused by oral problems (P P Conclusion Compared to caries, worse gingival condition was more prevalent among adolescents in Shandong province. Brushing behaviour is associated with gingivitis, while dental visits and toothaches are associated with caries. Hence, prevention-oriented dental visits and oral hygiene training are strongly recommended to improve oral health status.

Objective: We aimed to analyse the oral health status of adolescents in Shandong province, including dental caries and gingivitis, and the relevant risk indicators.Methods: Adolescents aged 12-15-years in Shandong province were recruited. Caries and gingival status were assessed following the World Health Organisation diagnostic criteria. Information including the sociodemographic, oral hygiene knowledge, attitudes and practices were collected through the questionnaire. Chi-square test and multivariate logistic regression analysis were used to investigate the independent risk indicators.Results: In total, 3,868 students (50.2% males) were enrolled. Of these, 39.9% of the participants experienced caries, and 81.7% and 31.3% had calculus and bleeding gums, respectively. Multivariate logistic regression analysis revealed that there was an association between an increased risk of caries with toothaches, dental visits and sleeping troubles caused by oral problems (P < 0.024). A low-frequency of brushing, high sugar consumption and no flossing increased the risk of calculus formation and gum bleeding (P < 0.008).Conclusion: Compared to caries, worse gingival condition was more prevalent among adolescents in Shandong province and was not taken seriously. Brushing behaviour is associated with gingivitis, while dental visits and toothaches are associated with caries. Hence, prevention-oriented dental visits and oral hygiene training are strongly recommended to improve oral health status.Trial registration: Not applicable.

Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.

Background: 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. Methods: Spearman correlation analysis was performed to determine the relationship between blood bilirubin and clinical outcomes in a retrospective study. In vitro and in vivo assays were used to determine the effect of bilirubin on the sensitivity of melanoma cells to vemurafenib. Findings: 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. Interpretation: 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. Funding: National Natural Science Foundation of China (81773213 and 81972399), Natural Science Foundation research team of Guangdong Province (2018B030312001), and the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital (202011-204, 202011-106). Declaration of Interest: None to declare Ethical Approval: This study was approved by Institutional Animal Care and Use Committee.

Appropriate gene carriers are vital components of gene therapy for treating numerous intractable diseases. Compared with viral carriers, non-viral carriers exhibit lower immunogenicity and higher biosafety, which have received increasing attention. In particular, among non-viral vectors, gene vectors based on chitosan derivatives are considered a promising gene therapy tool and have been extensively studied due to the biocompatibility, biodegradability, and modifiability of chitosan. In this review, we first discussed the influence of chitosan parameters on the efficiency of gene therapy. More importantly, we summarized the recent research progress in various diseases of chitosan derivatives to deliver different gene therapy substances including plasmid (pDNA), short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), and clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPER-Cas9) system. Finally, the current challenges and future directions of chitosan derivatives as gene carriers are also proposed.

Both introducing oxygen vacancies (OVs) and enhancing charge transfer efficiency (CTE) have been proved to be effective strategies to improve the capability of the catalyst to activate peroxymonosulfate (PMS). The OVs on catalysts can promote the CTE of the catalyst/PMS oxidation system. However, current OVs introduction methods can only lead to very limited CTE enhancement. Here, the synthesis of CoP/CoOx heterostructured nanoparticles with abundant OVs and dramatically enhanced CTE through a reliable partial phosphidation method using ZIF-67 as a precursor was reported. The excellent CTE of the CoP/CoOx/PMS oxidation system was the result of the synergy of increased OVs and introduced CoP with high conductivity. When served as Fenton-like catalyst for tetracycline (TC) degradation via activating PMS, due to the synergy between abundant OVs and high CTE, CoP/CoOx exhibited superior performance for TC removal, with the pseudo-second-order kinetic rate constant ∼ 10.3 and 77.4 times that of CoPx and Co3O4, respectively. Moreover, the cobalt leakage (0.06 mg/L) was only about 1/2 and 1/3 of that of CoPx and Co3O4, respectively. The mechanism study suggested that SO4•−, •OH and O2•− played an important role in TC degradation. The excellent catalytic performance of CoP/CoOx was attributed to its abundant OVs and high CTE to generate more active oxygen species. This work provides new insights for designing and developing efficient catalysts for wastewater treatment via Fenton-like process.

The composite comprised of graphene and carbon nanotubes (CNTs) exhibited significantly enhanced electrochemical performance due both to the improved dispersion and inhibition of restacking of graphene and CNTs. In this work, graphene nanoribbons (GNRs)/CNTs composite (GNRs/CNTs) was synthesized on gram-scale by chemical vapor deposition. Under optimal growth conditions, the yield of GNRs/CNTs as high as 26 g per gram catalyst could be achieved in 30 min growth time. The morphology and quality of the as-synthesized composite was verified by using SEM, TEM and Raman spectroscopy. The electrochemical properties of GNRs/CNTs was evaluated using cyclic voltammetry (CV) and galvanostatic charge-discharge techniques. GNRs/CNTs exhibited specific capacitance of 242.3 F/g at 0.5 A g-1, which was over 4 times of that of CNTs. The GNRs/CNTs based electrodes exhibited excellent cycling stability at 1 A g-1 for over 4000 cycles, which can be attributed to the excellent electrical conductivity and the unique structure. When employed as electrode for membrane capacitive desalination, the desalination capacity of 16.46 mg g-1 has been achieved under 1.2 V with 500 mg L-1 NaCl solution as feeding water.

Two dimensional (2D) metal oxide are expected to be better adsorbents for heavy metal ions than their other low dimensional counterparts. In this work, non-layered 2D Fe2O3 nanosheets were synthesized by a simple combustion method and tested for Pb(II) removal from aqueous solution. The 2D Fe2O3 nanosheets exhibited high crystallinity and purity as confirmed by powder x-ray diffraction. As revealed by scanning electron microscope (SEM) and transmission electron microscope (TEM), the nanosheets with lateral size up to hundreds of microns that made it easy to be recollected after water treatment. The results of XRD and TEM indicated that the nanosheets showed preferentially exposed surfaces of (1 0 0), which has strong affinity for Pb(II). The nanosheets exhibited a moderate specific surface area of 12.19 m2/g with a small pore volume of 0.034 mL/g. The nanosheets exhibited excellent adsorption performance for Pb(II) in pH range from 3.0 to 6.0. The adsorption of Pb(II) conformed to the Langmuir isotherm model with the theoretical maximum adsorption capacity of Pb(II) estimated to be 436.83 mg/g. Kinetics study indicated that the adsorption process followed pseudo-second-order kinetics model. Based on the X-ray photoelectron spectroscopy and FTIR results of the nanosheets before and after Pb(II) adsorption, the adsorption of Pb(II) was dominated by the surface complexation and ion exchange of Pb(II) ions with surface hydroxyl groups. Given the low preparation cost and the excellent adsorption capacity, the non-layered 2D Fe2O3 nanosheets holds great potential as adsorbent for Pb(II) removal.

Biosurfactant is known as an efficient accelerator for hydrocarbon biodegradation by enhancing their bioavailability and facilitating their degradation by microorganisms. The present work aimed to characterize the structure of the biosurfactant produced by Paracoccus sp. MJ9 and to evaluate its potential use in diesel degradation in marine environment. In the present study, an efficient biosurfactant-producing strain, namely, Paracoccus sp. MJ9, was selected using an oil spreading test, drop collapse method and surface tension test in four petroleum-degrading strains isolated from Jiaozhou Bay in Qingdao, Shandong Province. Results showed that the surface-active substance produced by the strain MJ9 reduced the surface tension of water from 65.56 mN/m to 38.33 mN/m. Results of thin-layer chromatography analysis (TLC), fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H NMR) spectroscopy analysis indicated that the surface-active substance was rhamnolipid. Furthermore, diesel oil with MJ9 or crude biosurfactant produced by MJ9 was qualitatively analyzed by gas chromatography and mass spectrometry before and after biodegradation. Results showed that the removal efficiency of 81 % was achieved within 5 days. This work has screened and identified a bacterium with superior biosurfactant production capabilities, characterized the biosurfactant as rhamnolipid and indicated the potential applications in bioremediation processes to enhance the solubility of hydrophobic compounds.

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.

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.