N6-Methyladenosine Modification and Prognostic Analysis of UBE2K in Hepatocellular Carcinoma: A Potential Target.

The treatment of hepatocellular carcinoma (HCC) is still relatively lacking, the prognosis is poor, and the potential mechanism of carcinogenesis has not been thoroughly studied. In this study, Ubiquitin-conjugating enzyme E2K (UBE2K) transcript levels in HCC patients were up-regulated in two databases, GEO and TCGA. External validation was performed using Western blot experiments. Compared to normal liver cells, UBE2K was upregulated in HCC cell lines. The survival curve and prognosis model revealed that the expression of UBE2K was of high prognostic value in patients with HCC. Transwell assay, wound healing assay and sphere formation assay were used to evaluate the effects of knockdown and overexpression of UBE2K on HCC cells. Overexpression of UBE2K promoted the invasion, migration and stemness of HCC cells, while knocking down UBE2K attenuated the invasion, migration and stemness of HCC cells. Then, through a series of functional analysis (GO and KEEG), it was found that UBE2K played an important role in mRNA processing. We speculate that UBE2K may be involved in HCC progression through its own N6-methyladenosine modification. We therefore used a global methylation inhibitor (3-deazaadenosine) to treat HCC cells and found a gradient increase in the mRNA level of UBE2K. Collectively, the results suggest that UBE2K may be a promising molecular target for the treatment of HCC.

MEX3C as a potential target for hepatocellular carcinoma drug and immunity: combined therapy with Lenvatinib.

BACKGROUND: The immune microenvironment within hepatocellular carcinoma (HCC) is remarkably intricate. Although the combination of an immune checkpoint inhibitor and Lenvatinib can extend the overall survival of HCC patients, the outcome remains suboptimal. METHODS: We assessed alterations in MEX3C expression during hepatocarcinogenesis by validating multiple databases and subsequently developed a predictive model. Subsequently, we enriched the associated genes of MEX3C to investigate its functional role. We examined the correlation between MEX3C expression levels and immune infiltrating cells. The effects of MEX3C knockdown and Lenvatinib on hepatoma cells were observed by cell function experiments. RESULTS: MEX3C expression is elevated in HCC compared to normal tissues, and its high expression correlates with poor prognosis. Immune checkpoint expression was elevated in the high MEX3C expression group, concomitant with heightened myeloid-derived suppressor cell (MDSC) expression. The combination of MEX3C knockdown and Lenvatinib demonstrated a stronger inhibitory effect on HCC cells compared to Lenvatinib alone. CONCLUSION: MEX3C shows promise as a potential therapeutic target for treating HCC. Furthermore, the combination of MEX3C knockdown and Lenvatinib could offer a novel therapeutic avenue for HCC treatment.

Carbon dot nanozymes as free radicals scavengers for the management of hepatic ischemia-reperfusion injury by regulating the liver inflammatory network and inhibiting apoptosis.

BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is a pathophysiological process during liver transplantation, characterized by insufficient oxygen supply and subsequent restoration of blood flow leading to an overproduction of reactive oxygen species (ROS), which in turn activates the inflammatory response and leads to cellular damage. Therefore, reducing excess ROS production in the hepatic microenvironment would provide an effective way to mitigate oxidative stress injury and apoptosis during HIRI. Nanozymes with outstanding free radical scavenging activities have aroused great interest and enthusiasm in oxidative stress treatment. RESULTS: We previously demonstrated that carbon-dots (C-dots) nanozymes with SOD-like activity could serve as free radicals scavengers. Herein, we proposed that C-dots could protect the liver from ROS-mediated inflammatory responses and apoptosis in HIRI, thereby improving the therapeutic effect. We demonstrated that C-dots with anti-oxidative stress and anti-inflammatory properties improved the survival of L-02 cells under H2O2 and LPS-treated conditions. In the animal model, Our results showed that the impregnation of C-dots could effectively scavenge ROS and reduce the expression of inflammatory cytokines, such as IL-1ß, IL-6, IL-12, and TNF-α, resulting in a profound therapeutic effect in the HIRI. To reveal the potential therapeutic mechanism, transcriptome sequencing was performed and the relevant genes were validated, showing that the C-dots exert hepatoprotective effects by modulating the hepatic inflammatory network and inhibiting apoptosis. CONCLUSIONS: With negligible systemic toxicity, our findings substantiate the potential of C-dots as a therapeutic approach for HIRI, thereby offering a promising intervention strategy for clinical implementation.

Analysis and Functional Verification of PlPM19L Gene Associated with Drought-Resistance in Paeonia lactiflora Pall.

The herbaceous peony (Paeonia lactiflora Pall.) is widely cultivated as an ornamental, medicinal and edible plant in China. Drought stress can seriously affect the growth of herbaceous peony and reduce its quality. In our previous research, a significantly differentially expressed gene, PM19L, was obtained in herbaceous peony under drought stress based on transcriptome analysis, but little is known about its function. In this study, the first PM19L that was isolated in herbaceous peony was comprised of 910 bp, and was designated as PlPM19L (OP480984). It had a complete open reading frame of 537 bp and encoded a 178-amino acid protein with a molecular weight of 18.95 kDa, which was located in the membrane. When PlPM19L was transferred into tobacco, the transgenic plants had enhanced tolerance to drought stress, potentially due to the increase in the abscisic acid (ABA) content and the reduction in the level of hydrogen peroxide (H2O2). In addition, the enhanced ability to scavenge H2O2 under drought stress led to improvements in the enzyme activity and the potential photosynthetic capacity. These results combined suggest that PlPM19L is a key factor to conferring drought stress tolerance in herbaceous peony and provide a scientific theoretical basis for the following improvement in the drought resistance of herbaceous peony and other plants through genetic engineering technology.

HIF-1α-activated TM4SF1-AS1 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by enhancing TM4SF1 expression.

Long non-coding RNAs (lncRNAs) are essential drivers or suppressors in human hepatocellular carcinoma (HCC) by participating in controlling transcription, translation, mRNA stability, and protein degradation protein-protein interaction. TM4SF1-AS1 is recently identified as a tumor-promoting factor in lung cancer. Nevertheless, its function in HCC and related molecular mechanisms remain unknown. Here, our data indicated that either hypoxia or hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (DMOG) induced the upregulation of TM4SF1-AS1 in HCC cells. HIF-1α knockdown rather than HIF-2α silencing remarkably abrogated hypoxia-upregulated TM4SF1-AS1 expression. Furthermore, we confirmed the elevated expression of TM4SF1-AS1 in HCC tissue samples and cell lines. The silencing of TM4SF1-AS1 prominently inhibited the proliferative, migratory, and invasive abilities of HCC cells. TM4SF1-AS1 depletion significantly blocked hypoxia-enhanced Hep3B cell proliferation and mobility. Interfering TM4SF1-AS1 remarkably reduced TM4SF1 mRNA and protein levels in HCC cells. But TM4SF1-AS1 knockdown did not impact the stability of TM4SF1 mRNA. Hypoxia enhanced the expression of TM4SF1 mRNA, which was subsequently decreased by TM4SF1-AS1 knockdown in HCC cells. We confirmed the positive correlation between TM4SF1 mRNA and TM4SF1-AS1 expression in HCC specimens. Finally, TM4SF1 prominently reversed the inhibitory role of TM4SF1-AS1 depletion in Hep3B cells. In summary, hypoxia-responsive TM4SF1-AS1 was overexpressed in human HCC and contributed to the malignant behaviors of tumor cells by enhancing TM4SF1-AS1 expression.

Knockout of CNR1 prevents metabolic stress-induced cardiac injury through improving insulin resistance (IR) injury and endoplasmic reticulum (ER) stress by promoting AMPK-alpha activation.

Obesity and diabetes are associated with diabetic cardiomyopathy (DCM). However, the pathogenesis of DCM is not fully understood. Cannabinoid receptor gene (CNR1) has been a drug target for the treatment of obesity. Here, we reported that CNR1 expression was increased in high fat diet (HFD)-induced heart of mice. Following, the wild type (CNR1+/+) and CNR1-knockout (CNR1-/-) mice were employed and subjected to HFD treatments for 16 weeks to further investigate the effects of CNR1 on DCM. The results indicated that CNR1 knockout mice after HFD feeding exhibited a significant decrease of body weight and lipid accumulation in serum. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) analysis indicated that HFD-induced insulin resistance was attenuated by CNR1 deficiency. HFD-triggered cardiac dysfunction was also improved by CNR1 knockout using echocardiographic analysis. Further, CNR1 suppression increased expressions of genes promoting fatty acid oxidation, and mitochondrial biogenesis. Also, TUNEL staining showed that CNR1 inhibition markedly reduced apoptotic levels in heart tissue sections of HFD-fed mice. Importantly, HFD-induced insulin resistance was prevented by CNR1-knockout through decreasing p-IRS1Ser expressions, and increasing phosphorylated insulin receptor substrate 1 (p-IRS1Tyr), phospho-AMP-activated protein kinase α (AMPKα) and phospho-acetyl-CoA carboxylase α (ACCα) expressions in heart tissue samples. In addition, CNR1 knockout impeded endoplasmic reticulum (ER) stress caused by HFD via down-regulating phospho-protein kinase-like ER kinase (PERK), phospho-eukaryotic initiation factor-2α (eIF2α), activating transcription factor 4 (ATF4) and ATF6 in heart tissue samples. Of note, we found that CNR1 knockout-improved insulin resistance, ER stress and lipid accumulation was diminished by AMPKα suppression using its inhibitor, Compound C. Therefore, the results demonstrated that therapeutic CNR1 inhibition could alleviate the progression of DCM.

Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) may be a biomarker for vascular function and cardiovascular risk in patients with coronary artery disease (CAD). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the function of EPCs. This study aimed to examine whether hypermethylation of DDAH2 promoter contributes to impaired function of EPCs in CAD patients. METHODS: Peripheral blood mono-nuclear cells from 25 CAD patients and 15 healthy volunteers were collected and differentiated into EPCs. EPCs were tested for their adhesive capability. DDAH2 mRNA expression was analyzed by real-time PCR, and the methylation of DDAH2 promoter was detected by bisulfite genomic sequencing. RESULTS: DDAH2 promoter in EPCs from CAD patients was hypermethylated and the methylation level was negatively correlated to DDAH2 mRNA level and adhesion function of EPCs. Homocysteine impaired the adhesion function of EPCs, accompanied by lower DDAH2 expression and higher methylation level of DDAH2 promoter, compared to controls. These effects of homocysteine were reversed by pretreatment with Aza, an inhibitor of DNA methyltransferase. CONCLUSION: Hypermethylation in DDAH2 promoter is positively correlated to the dysfunction of EPCs in CAD patients. Homocysteine disrupts EPCs function via inducing the hypermethylation of DDAH2 promoter, suggesting a key role of epigenetic mechanism in the progression of atherosclerosis.

UCHL3 promotes hepatocellular carcinoma progression by stabilizing EEF1A1 through deubiquitination.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the second leading cause of global cancer-related deaths and is characterized by a poor prognosis. Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) have been proved to play important roles in various human cancers, whereas the deubiquitination of EEF1A1 was poorly understood. METHODS: The binding and regulatory relationship between Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) and EEF1A1 was validated using clinical tissue samples, reverse transcription quantitative real-time fluorescence quantitative PCR (RT-qPCR), Western blotting, co-immunoprecipitation, and immunofluorescence, as well as ubiquitin detection and cyclohexamide tracking experiments. Finally, the impact of the UCHL3/EEF1A1 axis on HCC malignant behavior was analyzed through functional experiments and nude mouse models. RESULTS: UCHL3 was found to have a high expression level in HCC tissues. Tissue samples from 60 HCC patients were used to evaluate the correlation between UCHL3 and EEF1A1. UCHL3 binds to EEF1A1 through the lysine site, which reduces the ubiquitination level of EEF1A1. Functional experiments and nude mouse models have demonstrated that the UCHL3/EEF1A1 axis promotes the migration, stemness, and drug resistance of HCC cells. Reducing the expression of EEF1A1 can reverse the effect of UCHL3 on the malignant behavior of HCC cells. CONCLUSION: Our findings revealed that UCHL3 binds and stabilizes EEF1A1 through deubiquitination. UCHL3 and EEF1A1 formed a functional axis in facilitating the malignant progression of HCC, proving new insights for the anti-tumor targeted therapy for HCC.

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignant tumor that poses a major threat to people's lives and health. Previous studies have found that multiple deubiquitinating enzymes are involved in the pathogenesis of HCC. The purpose of this work was to elucidate the function and mechanism of the deubiquitinating enzyme USP40 in HCC progression. METHODS: The expression of USP40 in human HCC tissues and HCC cell lines was investigated using RT-qPCR, western blotting and immunohistochemistry (IHC). Both in vitro and in vivo experiments were conducted to determine the crucial role of USP40 in HCC progression. The interaction between USP40 and Claudin1 was identified by immunofluorescence, co-immunoprecipitation and ubiquitination assays. RESULTS: We discovered that USP40 is elevated in HCC tissues and predicts poor prognosis in HCC patients. USP40 knockdown inhibits HCC cell proliferation, migration and stemness, whereas USP40 overexpression shows the opposite impact. Furthermore, we confirmed that Claudin1 is a downstream gene of USP40. Mechanistically, USP40 interacts with Claudin1 and inhibits its polyubiquitination to stabilize Claudin1 protein. CONCLUSIONS: Our study reveals that USP40 enhances HCC malignant development by deubiquitinating and stabilizing Claudin1, suggesting that targeting USP40 may be a novel approach for HCC therapy.

UBE2K regulated by IGF2BP3 promotes cell proliferation and stemness in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a noteworthy malignant carcinoma with an unsatisfactory prognosis attributed to late diagnosis. Ubiquitin­conjugating enzyme E2K (UBE2K) has been found to serve important roles in a number of diseases. However, its function and the exact molecular mechanism of UBE2K in PDAC remain to be elucidated. The present study discovered that UBE2K was expressed at high levels and indicated the poor prognosis of patients with PDAC. Following this, the CCK­8, colony formation, and sphere formation assays showed that UBE2K promoted proliferation and the stemness phenotype of PDAC cells in vitro. Evidence from subcutaneous tumor­bearing nude mice experiments further confirmed that UBE2K enhanced PDAC cell tumorigenesis in vivo. Additionally, the present study demonstrated that insulin­like growth factor 2 RNA binding protein 3 (IGF2BP3) functioned as an RNA­binding protein to increase UBE2K expression by enhancing the RNA stability of UBE2K. The knockdown or overexpression of IGF2BP3 could attenuate the change in cells growth induced by the overexpression or knockdown of UBE2K. In summary, the findings indicated the oncogenic roles of UBE2K in PDAC. In addition, IGF2BP3 and UBE2K constitute a functional axis to regulate the malignant progression of PDAC.

Hypoxia-induced UBE2K promotes the malignant progression of HCC.

BACKGROUND: Hypoxia critically drives malignant tumor development and is characteristic of hepatocellular carcinoma (HCC), where HIF-1α plays a crucial role. The ubiquitin-conjugating enzyme E2K (UBE2K) is known to participate in the advancement of several human cancers. However, the role of UBE2K in HCC or whether it is a hypoxia-responsive gene remains to be further identified. METHOD: We performed a microarray to measure the gene expression differences between normoxia and hypoxia. CoCl2 mimicked the hypoxic condition. The protein and RNA expression of HIF-1α, UBE2K, and Actin in HCC cells were measured by western blotting(WB) and RT-qPCR, respectively. Immunohistochemical (IHC) staining analyzed the expression of UBE2K and HIF-1α in HCC tissues. CCK-8 and colony formation assay evaluated the HCC cell growth. Scratch healing and transwell assays were used to detect the migration capability of the cells. Lipofectamine 3000 was used to transfect the plasmids or siRNAs to HCC cells. RESULTS: We identified UBE2K as a potential hypoxia-responsive gene. Our study showed that hypoxia induced HIF-1α-mediated increase of UBE2K levels in HCC cells, which decreased under HIF-1α deficiency under hypoxia. Further bioinformatics analysis based on UALCAN and GEPIA databases confirmed that UBE2K was highly expressed in HCC tissues and positively associated with HIF-1α expression. Functionally, Hep3B and Huh7 cell proliferation and migration were stimulated upon UBE2K overexpression, while the UBE2K knockdown suppressed such effect. Furthermore, functional rescue experiment proved that depletion of UBE2K inhibited hypoxia-induced cell proliferation and migration in HCC cells. In contrast, enhancing UBE2K levels rescued cell proliferation and migration repression caused by HIF-1α deficiency in hypoxia. CONCLUSION: Our results established UBE2K as a potential hypoxia-inducible gene in HCC cells, positively regulated by HIF-1α in hypoxia. Moreover, UBE2K served as an oncogene and cooperated with HIF-1α to form a functional HIF-1α/UBE2K axis to trigger HCC progression, highlighting a potential application of UBE2K as a therapeutic target for HCC treatment.

Resistance of Lenvatinib in Hepatocellular Carcinoma.

Lenvatinib is a multikinase inhibitor which mainly hinders liver cancer proliferation by inhibiting angiogenesis. In 2018, Lenvatinib was approved for the first-line treatment of patients with advanced hepatocellular carcinoma [HCC] in the United States, the European Union, Japan, and China. Lenvatinib has been established as a sorafenib replacement drug with a higher objective response rate [ORR], longer progression-free survival [PFS], and time to progression [TTP]. Lenvatinib resistance during hepatocellular carcinoma treatment has become increasingly common in recent years. Accordingly, it is necessary to determine factors associated with Lenvatinib resistance and explore solutions. In this review, we sought to explore the drug resistance mechanisms of Lenvatinib in liver cancer and methods to reduce drug resistance and summarized the recent achievements of Lenvatinib in liver cancer treatment.

Role of ubiquitin specific proteases in the immune microenvironment of prostate cancer: A new direction.

Regulation of ubiquitination is associated with multiple processes of tumorigenesis and development, including regulation of the tumor immune microenvironment. Deubiquitinating enzymes (DUBs) can remove ubiquitin chains from substrates, thereby stabilizing target proteins and altering and remodeling biological processes. During tumorigenesis, deubiquitination-altered biological processes are closely related to tumor metabolism, stemness, and the immune microenvironment. Recently, tumor microenvironment (TME) modulation strategies have attracted considerable attention in cancer immunotherapy. Targeting immunosuppressive mechanisms in the TME has revolutionized cancer therapy. Prostate cancer (PC) is one of the most common cancers and the second most common cause of cancer-related death in men worldwide. While immune checkpoint inhibition has produced meaningful therapeutic effects in many cancer types, clinical trials of anti-CTLA4 or anti-PD1 have not shown a clear advantage in PC patients. TME affects PC progression and also enables tumor cell immune evasion by activating the PD-1/PD-L1 axis. Over the past few decades, an increasing number of studies have demonstrated that deubiquitination in PC immune microenvironment may modulate the host immune system's response to the tumor. As the largest and most diverse group of DUBs, ubiquitin-specific proteases (USPs) play an important role in regulating T cell development and function. According to current studies, USPs exhibit a high expression signature in PC and may promote tumorigenesis. Elevated expression of USPs often indicates poor tumor prognosis, suggesting that USPs are expected to develop as the markers of tumor prognosis and even potential drug targets for anti-tumor therapy. Herein, we first summarized recent advances of USPs in PC and focused on the relationship between USPs and immunity. Additionally, we clarified the resistance mechanisms of USPs to targeted drugs in PC. Finally, we reviewed the major achievement of targeting USPs in cancers.

Immune Evasion and Drug Resistance Mediated by USP22 in Cancer: Novel Targets and Mechanisms.

Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4+ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.

Case Report: Retroperitoneal Sarcoma in Six Operations: Our Experience in Operative Management of Blood Vessels.

Here we introduce a case of retroperitoneal liposarcoma, which is characterized by repeated recurrences after surgery, and has undergone a total of 6 operations. The diameter of the tumor was about 26 cm at the time of the patient's diagnosis. The imaging examination revealed that the surrounding organs and blood vessels were invaded, which brought great challenges to radical resection. The postoperative pathology of the patient's first operation was dedifferentiated liposarcoma, and some areas showed myxofibrosarcoma differentiation. With the recurrence of sarcoma, myxofibrosarcoma dedifferentiated into rhabdomyosarcoma, and malignant fibrous histiocytoma appeared in some areas. How to treat this type of patient after recurrence? How to deal with blood vessels wrapped by sarcoma during surgery? The medical community has not yet reached the same conclusion. We describe the process of treating the patient and the experience of dealing with blood vessels during surgery.

The Emerging Role of RNA N6-Methyladenosine Modification in Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most common malignant cancers, ranking the seventh highest causes of cancer-related deaths globally. Recently, RNA N6-methyladenosine (m6A) is emerging as one of the most abundant RNA modifications in eukaryote cells, involved in multiple RNA processes including RNA translocation, alternative splicing, maturation, stability, and degradation. As reported, m6A was dynamically and reversibly regulated by its "writers", "erasers", and "readers", Increasing evidence has revealed the vital role of m6A modification in the development of multiple types of cancers including PC. Currently, aberrant m6A modification level has been found in both PC tissues and cell lines. Moreover, abnormal expressions of m6A regulators and m6A-modified genes have been reported to contribute to the malignant development of PC. Here in this review, we will focus on the function and molecular mechanism of m6A-modulated RNAs including coding RNAs as well as non-coding RNAs. Then the m6A regulators will be summarized to reveal their potential applications in the clinical diagnosis, prognosis, and therapeutics of PC.

Research Progress of DUB Enzyme in Hepatocellular Carcinoma.

According to GLOBOCAN 2021 cancer incidence and mortality statistics compiled by the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the most common malignancy in the human liver and one of the leading causes of cancer death worldwide. Although there have been great advances in the treatment of HCC, such as regofenib, sorafenib, and lomvatinib, which have been developed and approved for the clinical treatment of advanced or metastatic HCC. However, they only prolong survival by a few months, and patients with advanced liver cancer are susceptible to tumor invasion metastasis and drug resistance. Ubiquitination modification is a type of post-translational modification of proteins. It can affect the physiological activity of cells by regulating the localization, stability and activity of proteins, such as: gene transcription, DNA damage signaling and other pathways. The reversible process of ubiquitination is called de-ubiquitination: it is the process of re-releasing ubiquitinated substrates with the participation of de-ubiquitinases (DUBs) and other active substances. There is growing evidence that many dysregulations of DUBs are associated with tumorigenesis. Although dysregulation of deuquitinase function is often found in HCC and other cancers, The mechanisms of action of many DUBs in HCC have not been elucidated. In this review, we focused on several deubiquitinases (DUBs) associated with hepatocellular carcinoma, including their structure, function, and relationship to hepatocellular carcinoma. hepatocellular carcinoma was highlighted, as well as the latest research reports. Among them, we focus on the USP family and OTU family which are more studied in the HCC. In addition, we discussed the prospects and significance of targeting DUBs as a new strategy for the treatment of hepatocellular carcinoma. It also briefly summarizes the research progress of some DUB-related small molecule inhibitors and their clinical application significance as a treatment for HCC in the future.

CircWEE1/miR-138 axis promotes the malignant progression of glioma by regulating SIRT1.

BACKGROUND: This study aims to reveal the potential impact of circWEE1 on the malignant progression of gliomas and its mechanism. METHODS: Real-time quantitative polymerase chain reaction (qRT-PCR) were used to detect circWEE1 levels in glioma tissues and cell lines. The relationship between circWEE1 expression and glioma metastasis was analyzed. RESULTS: After knocking out or over-expressing circWEE1, the effects on glioma cells were examined separately. Subsequently, the regulatory relationship of circWEE1 to miR-138 was detected by a dual luciferase reporter gene. In addition, we evaluated the role of silent information regulator 1 (SIRT1) in the progression of gliomas affected by circWEE1 through a rescue experiment. CircWEE1 was significantly up-regulated in glioma tissues and cell lines. At the same time, its expression level was significantly higher in glioma patients with lymphatic or distant metastasis than in glioma patients with non-metastasis. The down-regulation of circWEE1 reduced the viability, migration, and invasion ability of T98-G cells. The expression of miR-138 is negatively regulated by WEE1, while miR-138 directly targets and regulates the expression of SIRT1. CONCLUSIONS: The rescue experiment confirmed that SIRT1 is a regulator of circWEE1 in the malignant progression of glioma. In summary, the CircWEE1/miR-138 axis may regulate SIRT1 to promote malignant progression in glioma.

Association between glycemic control assessed by continuous glucose monitoring and stroke in patients with atrial fibrillation and diabetes mellitus.

BACKGROUND: Both atrial fibrillation (AF) and diabetes mellitus (DM) are documented risk factors for stroke; however, whether glycemic control is associated with the prevalence of stroke remains unclear in patients with AF and DM. The purpose of this study was to investigate the association between glycemic control assessed by continuous glucose monitoring (CGM) and the risk of stroke. METHODS: In total, 510 AF patients with DM from April 2013 to June 2017 were included. The subcutaneous sensor of CGM was inserted after hospital admission and lasted for 72 consecutive hours. Time in range (TIR), a novel metric derived from CGM, was defined as the time spent in the target range (3.9-10 mmol/L). A logistic regression model was constructed by regarding TIR as a categorical variable and a continuous variable, respectively. RESULTS: The mean age of the 510 enrolled patients was 69.8 years. Patients who had previously suffered from stroke had a markedly lower TIR than those without diagnosed stroke (55.1%±19.0% vs. 64.2%±15.1%, P<0.001). Compared to patients with TIR ≤46%, the risk of stroke decreased significantly with increasing TIR quartiles: adjusted odds ratios (ORs) of 0.80 for TIR of 46-65%, 0.64 for TIR of 65-81%, and 0.59 for TIR of >81% (all P<0.001). Taking TIR as a continuous variable, the adjusted OR was 0.89 [95% confidence interval (CI): 0.82-0.95] per 10% increment in TIR. CONCLUSIONS: This study found that better TIR is independently associated with a decreased risk of stroke in patients with AF and DM.

Effects of resveratrol in the signaling of neuropathic pain involving P2X3 in the dorsal root ganglion of rats.

Neuropathic pain is a major public health problem because it has a considerable impact on life quality of patients. Neuropathic pain caused by a lesion or disease of the somatosensory nervous system, which causes unpleasant and abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). P2X receptors from dorsal root ganglion (DRG) play a crucial role in facilitating pain transmission at peripheral and spinal sites. Resveratrol (Res) has neuroprotective effects and improves the pathological and behavioral outcomes of various types of nerve injury. The present study examined the effects of Res on neuropathic pain. Neuropathic pain animal model was created by partial sciatic nerve ligation (pSNL) surgery. We found that consecutive intraperitoneal administration of Res for 21 days reduced the mechanical and thermal nociceptive responses induced by pSNL in a dose-dependent manner. Moreover, Res administration reversed P2X3 expression and phosphorylation of ERK in DRG neurons after peripheral nerve injury. Our results suggested that Res may ameliorate neuropathic pain by suppressing P2X3 up-regulation and ERK phosphorylation in DRG of neuropathic pain rats. Therefore, we concluded that Res has a significant analgesic effect on alleviating neuropathic pain, and thus may serve as a therapeutic approach for neuropathic pain.