The clinical effect of gratitude extension-construction theory nursing program on bladder cancer patients with fear of cancer recurrence.

Objective: To explore the clinical effect of bladder cancer patients with Fear of Cancer Recurrence (FCR) after applying the gratitude extension construction theory nursing program. Methods: 168 patients with bladder cancer hospitalized in the Department of Urology from December 2021 to June 2023 in a hospital are study subjects. The experimental subjects are uniformly designed as an experimental group and a control group, with 52 participants in each group. The former receives routine nursing care, while the later receives nursing interventions based on gratitude extension construction theory. The baseline data, Quality of life Questionnaire-core 30, Quality of Life Questionnaire-non Invasive Bladder Cancer 24, Fear of Progression Questionnaire-Short Form, gratitude level questionnaire, Self-Rating Depression Scale, Self-rating Anxiety Scale, patient compliance behavior score, Overall Survival, and Progression-free Survival are evaluated. Results: The basic data revealed no statistical significance. The quality of life questionnaire-core 30 and quality of life questionnaire-noninvasive bladder cancer 24 was no significant difference before treatment and after treatment for 1 month. After 9 months, There was a significant difference in pre-treatment scores. The experimental group had no significant difference before and after treatment. For the overall survival rates, the two groups were 67.25% and 79.56%. The progression-free survival rates were 56.35% and 72.35%, respectively, with statistical difference. The compliance rates were 86.54% and 98.08%. The compliance rate of the experimental group exceeded the control group. After 3, 6, and 12 months, the gratitude level questionnaire score and the fear of progression questionnaire-short form in the experimental group were improved. After 3, 6, and 12 months, the control group had no statistically significant difference in the gratitude level questionnaire and the fear of progression questionnaire-short form scores. Compared with the control group, the scores on the gratitude level questionnaire and the fear of progression questionnaire-short form were significantly higher after 3, 6, and 12 months of intervention. Conclusion: After applying the gratitude extension construction theory nursing program, the FCR of bladder cancer patients is significantly reduced. The quality of life and compliance rate are significantly improved, and anxiety and depression are relieved.

Impact of ERAS on Hysteromyomectomy: A Study on Anxiety, Depression, and Ovarian Function.

Objective: To analyze the application of the Enhanced Recovery After Surgery (ERAS) nursing mode in patients undergoing radical cystectomy with urinary diversion. Methods: A retrospective analysis was conducted on clinical data of 72 patients with bladder cancer who underwent "robot-assisted laparoscopic radical cystectomy + urinary diversion" in Nanjing University Medical College Affiliated Gulou Hospital between January 2021 and January 2023. All patients met the complete inclusion criteria. They were divided into a control group (n=35) and a observation group (n=37). Patients in the control group received routine rehabilitation nursing intervention, while patients in the study group received ERAS nursing mode intervention. The outcomes include time to first intake, time to first defecation, duration of enteral nutrition, duration of antibiotic use, duration of drainage tube placement, length of hospital stay, psychological status Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), quality of life (SF-36) scores, sexual function assessment Arizona Sexual Experience Scale (ASEX), International Index of Erectile Function-5 (IIEF-5), and occurrence of complications were compared between the two groups. Results: In the observation group, perioperative indicators, psychological status, quality of life, sexual function, and complication rates were notably improved compared to the control group (all P < .05). Conclusion: ERAS nursing mode intervention in bladder cancer patients exhibited significant effectiveness, enhancing postoperative recovery, reducing anxiety and depression, improving quality of life and sexual function, and lowering complication risks. These findings support the clinical merit and applicability of ERAS nursing in urinary diversion for bladder cancer patients.

Effects of sinomenine on a rat orthotopic liver carcinoma model.

OBJECTIVE: Liver carcinoma is a common malignant tumor. In this study, an orthotopic liver carcinoma model was established by B-ultrasound, and the therapeutic effect of sinomenine (Sin) on the disease was investigated. METHODS: SD rats were randomly divided into control, Sin, Sorafenib (Sor), and combination (Sin+Sor) groups (n=8). An orthotopic liver carcinoma model was established by inoculating N1-S1 cells into the rat liver by B-ultrasound-guided, and tumor volume was monitored three times by B-ultrasound after inoculation. After drug treatment, the tumor tissues were stained with HE and TUNEL, and the levels of inflammatory cytokines, ALT and AST were detected by ELISA. The numbers of erythrocytes, leukocytes and platelets were detected. Immunohistochemistry and immunofluorescence were used to detect the expression of Ki-67, CD44, VEGF and CD31. The levels of cell cycle, apoptosis-related proteins were detected by western blot. RESULTS: B-ultrasound monitoring found that Sin reduced tumor volume. Moreover, Sin improved tissue lesions, and promoted cancer cell apoptosis. Sin decreased the levels of inflammatory cytokines, AST and ALT, and decreased the numbers of erythrocytes, leukocytes and platelets. Simultaneously, the expressions of Ki-67, CD44, VEGF and CD31 were decreased in the Sin group. Furthermore, Sin decreased the Bcl-2, Cyclin D1, CDK4, CDK6 and Survivin levels, but increased Bax, Cleaved-caspase3/pro-caspase3, P21 and P27 levels. More importantly, the combination of Sin and Sor treatment was more effective than treatment alone. CONCLUSION: A rat orthotopic liver carcinoma model was established under the guidance of B-ultrasound, and Sin had a therapeutic effect on orthotopic liver carcinoma.

Crocin exerts anti-tumor effect in colon cancer cells via repressing the JAK pathway.

Crocin has been reported to have therapeutic effects on multiple cancers including colon cancer, but its specific mechanism is still ambiguous and needs to be further explored. Human colorectal adenocarcinoma cells (HCT-116) and human normal colonic epithelial cells (CCD841) were first treated with increasing concentrations of crocin. Subsequently, with 150 and 200 µM of crocin, the cell vitality was examined by cell counting kit 8. Cell apoptosis and proliferation were tested by TUNEL staining and colony formation assay, respectively. The expression of Ki-67 was assessed by immunofluorescence. Enzyme-linked immunosorbent assay was used to evaluate the level of inflammation- and oxidative-related factors. The reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) were examined by flow cytometer. Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3), and extracellular regulated protein kinases (ERK) in HCT-116 cells were tested by Western blot. Different concentrations of crocin barely affected the CCD841 cell vitality, while crocin restrained the HCT-116 cells vitality, proliferation and the expression of Ki-67, while inducing apoptosis in a concentration-dependent manner. Moreover, the contents of inflammation- and oxidative-related factors in HCT-116 cells were largely blunted by crocin that enhanced ROS and restrained the MMP and suppressed p-JAK2/JAK2, p-STAT3/STAT3, and p-ERK/ERK expression in HCT-116 cells. Crocin induced apoptosis and restored mitochondrial function in HCT-116 cells via repressing the JAK pathway. If the threptic effect works in patients, it could herald a new, effective treatment for colon cancer, improving the patients' prognosis and quality of life.

Resveratrol Enhances the Radiosensitivity by Inducing DNA Damage and Antitumor Immunity in a Glioblastoma Rat Model under 3 T MRI Monitoring.

Glioblastoma (GBM) is the most common intracranial tumor with characteristic of malignancy. Resveratrol, a natural originated polyphenolic compound, has been reported to act as a potential radiosensitizer in cancer therapy. Magnetic resonance imaging (MRI) is the first choice for the diagnosis, pathological grading, and efficacy evaluation of GBM. In this study, MRI was applied to observe whether resveratrol could intensify the anti-GBM tumor effect by enhancing antitumor immunity during radiotherapy. We established an intracranial C6 GBM model in SD rats, treated with radiation and resveratrol. The increased body weight, the inhibition on mortality, and tumor volume in radiated- GBM rats were further enhanced by resveratrol addition, while the pathological damage of brain was alleviated. The modulation of radiation on inflammation, cell cycle, and apoptosis was strengthened by resveratrol; and Ki-67, PD-L1, and cell cycle- and apoptosis-related protein expressions were also improved by cotreatment. Besides, cotreatment attenuated DNA damage and induced G0/G1-phase cell arrest of GBM rats, accompanied with the changed expression of ATM-AKT-STAT3 pathway-related proteins. Moreover, the percentages of CD3+CD8+T cells and IFN-γ +CD8+T cells were enhanced, while (CD4+CD25+Foxp3)/CD4+T cells were decreased by radiation or resveratrol, which was strengthened by cotreatment. The modulation effect of cotreatment on CD3, Foxp3, and IFN-γ levels was also stronger than radiation or resveratrol alone. To conclude, resveratrol enhanced the effect of radiotherapy by inducing DNA damage and antitumor immunity in the intracranial C6 GBM.

Construction of a New Tumor Immunity-Related Signature to Assess and Classify the Prognostic Risk of Colorectal Cancer.

PURPOSE: Although immunotherapy and checkpoint inhibitors contribute to the treatment of colorectal cancer (CRC), few patients can benefit from these treatments. Therefore, our goal was to develop a marker based on immune-related genes to predict the prognosis of patients with CRC to guide treatment strategies. METHODS: Gene expression data from colorectal cancer patients in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas were analyzed systematically. We used Cox regression to identify immune-related genes with potential prognostic value. The expression of immune genes, infiltration level of immune cells, and several immune-related molecules were further compared between the high-risk and low-risk groups. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used for functional analysis. RESULTS: Five GEO datasets were integrated into a merged GEO dataset, which showed obvious survival in StromalScore and ESTIMATEScore. WGCNA showed that 749 genes of the pink module are related to immunity, 95 of which are related to prognosis, correlating with cytokine-cytokine receptor interaction and natural killer cell-mediated cytotoxicity. Among these genes, an 11-gene signature was developed through stability selection and LASSO Cox regression. Univariate and multifactorial Cox regression analyses demonstrated that gene signature was an independent prognostic factor for predicting survival in patients with colorectal cancer. Samples from the low-risk group may be more sensitive to immunotherapy. In addition, the nomogram risk prediction model effectively predicted the prognosis of CRC patients by appropriately stratifying the risk scores. CONCLUSION: In conclusion, we developed a novel immune-related gene signature that may be useful in predicting cancer progression and prognosis, thus contributing to the individualized management of colorectal cancer patients.

Inhibition of ribosomal RNA processing 15 Homolog (RRP15), which is overexpressed in hepatocellular carcinoma, suppresses tumour growth via induction of senescence and apoptosis.

Recent studies suggest that RRP15 (Ribosomal RNA Processing 15 Homolog) might be a potential target for cancer therapy. However, the role of RRP15 in hepatocarcinogenesis remains poorly delineated. In this study, we aimed to evaluate the expression and biological function of RRP15 in human hepatocellular carcinoma (HCC). We show that RRP15 was up regulated in HCC cell lines and tumours. Up-regulation of RRP15 in HCC tumours was also correlated with unfavorable prognosis. We further show that the frequent up-regulation of RRP15 in HCCs is at least partly driven by recurrent gene copy gain at chromosome 1q41. Functional studies indicated that RRP15 knockdown suppresses HCC proliferation and growth both in vitro and in vivo. Mechanistically, RRP15 depletion in p53-wild-type HepG2 cells induced senescence via activation of the p53-p21 signalling pathway through enhanced interaction of RPL11 with MDM2, as well as inhibition of SIRT1-mediated p53 deacetylation. Moreover, RRP15 depletion in p53-mutant PLC5 and p53-deleted Hep3B cells induced metabolic shift from the glycolytic pentose-phosphate to mitochondrial oxidative phosphorylation via regulating a series of key genes such as HK2 and TIGAR, and thus, promoted the generation of ROS and apoptosis. Taken together, our findings provide evidence for an important role of the RRP15 gene in hepatocarcinogenesis through regulation of HCC proliferation and growth, raising the possibility that targeting RRP15 may represent a potential therapeutic strategy for HCC treatment.

Elevated post-ischemic ubiquitination results from suppression of deubiquitinase activity and not proteasome inhibition.

Cerebral ischemia-reperfusion increases intraneuronal levels of ubiquitinated proteins, but the factors driving ubiquitination and whether it results from altered proteostasis remain unclear. To address these questions, we used in vivo and in vitro models of cerebral ischemia-reperfusion, in which hippocampal slices were transiently deprived of oxygen and glucose to simulate ischemia followed by reperfusion, or the middle cerebral artery was temporarily occluded in mice. We found that post-ischemic ubiquitination results from two key steps: restoration of ATP at reperfusion, which allows initiation of protein ubiquitination, and free radical production, which, in the presence of sufficient ATP, increases ubiquitination above pre-ischemic levels. Surprisingly, free radicals did not augment ubiquitination through inhibition of the proteasome as previously believed. Although reduced proteasomal activity was detected after ischemia, this was neither caused by free radicals nor sufficient in magnitude to induce appreciable accumulation of proteasomal target proteins or ubiquitin-proteasome reporters. Instead, we found that ischemia-derived free radicals inhibit deubiquitinases, a class of proteases that cleaves ubiquitin chains from proteins, which was sufficient to elevate ubiquitination after ischemia. Our data provide evidence that free radical-dependent deubiquitinase inactivation rather than proteasomal inhibition drives ubiquitination following ischemia-reperfusion, and as such call for a reevaluation of the mechanisms of post-ischemic ubiquitination, previously attributed to altered proteostasis. Since deubiquitinase inhibition is considered an endogenous neuroprotective mechanism to shield proteins from oxidative damage, modulation of deubiquitinase activity may be of therapeutic value to maintain protein integrity after an ischemic insult.

Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense.

Mutation and prevalence of pathogenic viruses prompt the development of broad-spectrum antiviral strategies. Viperin is a potent antiviral protein that inhibits a broad range of viruses. Unexpectedly, we found that Viperin protein production in epithelium is defective in response to both viruses and interferons (IFNs). We further revealed that viruses and IFNs stimulate expression of the acetyltransferase HAT1, which induces Lys197-acetylation on Viperin. Viperin acetylation in turn recruits UBE4A that stimulates K6-linked polyubiquitination at Lys206 of Viperin, leading to Viperin protein degradation. Importantly, UBE4A deficiency restores Viperin protein production in epithelium. We then designed interfering peptides (IPs) to inhibit UBE4A binding with Viperin. We found that VIP-IP3 rescues Viperin protein production in epithelium and therefore enhances cellular antiviral activity. VIP-IP3 renders mice more resistant to viral infection. These findings could provide strategies for both enhancing host broad-spectrum antiviral response and improving the efficacy of IFN-based antiviral therapy.

Prohibitin levels regulate OMA1 activity and turnover in neurons.

The GTPase OPA1 and the AAA-protease OMA1 serve well-established roles in mitochondrial stress responses and mitochondria-initiated cell death. In addition to its role in mitochondrial membrane fusion, cristae structure, and bioenergetic function, OPA1 controls apoptosis by sequestering cytochrome c (cyt c) in mitochondrial cristae. Cleavage of functional long OPA1 (L-OPA1) isoforms by OMA1 inactivates mitochondrial fusion and primes apoptosis. OPA1 cleavage is regulated by the prohibitin (PHB) complex, a heteromeric, ring-shaped mitochondrial inner membrane scaffolding complex composed of PHB1 and PHB2. In neurons, PHB plays a protective role against various stresses, and PHB deletion destabilizes OPA1 causing neurodegeneration. While deletion of OMA1 prevents OPA1 destabilization and attenuates neurodegeneration in PHB2 KO mice, how PHB levels regulate OMA1 is still unknown. Here, we investigate the effects of modulating neuronal PHB levels on OMA1 stability and OPA1 cleavage. We demonstrate that PHB promotes OMA1 turnover, effectively decreasing the pool of OMA1. Further, we show that OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid. CL binding promotes OMA1 turnover, as we show that deleting the CL-binding domain of OMA1 decreases its turnover rate. Since PHB is known to stabilize CL, these data suggest that PHB modulates OMA1 through CL. Furthermore, we show that PHB decreases cyt c release induced by tBID and attenuates caspase 9 activation in response to hypoxic stress in neurons. Taken together, our results suggest that PHB-mediated CL stabilization regulates stress responses and cell death through OMA1 turnover and cyt c release.

ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase ß-TrCP.

Outbreaks of viral infections are a global health burden. Although type I interferon (IFN-I) exerts broad-spectrum antiviral effects, its antiviral efficacy in host cells is largely restricted by viruses. How the antiviral efficacy of IFN-I can be improved remains to be explored. Here, we identified the ADP-ribosyltransferase poly(ADP-ribose) polymerase family member 11 (PARP11) as a potent regulator of IFN-I antiviral efficacy. PARP11 does not restrict IFN-I production induced by vesicular stomatitis virus or Sendai virus but inhibits the strength of IFN-I-activated signalling. Mechanistically, PARP11 mono-ADP-ribosylates the ubiquitin E3 ligase ß-transducin repeat-containing protein (ß-TrCP). Mono-ADP-ribosylation of ß-TrCP promotes IFNα/ß receptor subunit 1 (IFNAR1) ubiquitination and degradation. Moreover, PARP11 expression is upregulated by virus infections, including vesicular stomatitis virus, herpes simplex virus-1 and influenza A virus, thus promoting ADP-ribosylation-mediated viral evasion. We further highlight the potential for repurposing clinical ADP-ribosylation inhibitors. We found that rucaparib can target PARP11 to stabilize IFNAR1 and therefore exhibits efficient enhancement of IFN-I signalling and the host antiviral response. Consequently, rucaparib renders mice more resistant to viral infection. Our study updates the understanding of how ß-TrCP regulates its substrates and may provide a druggable target for improving IFN antiviral efficacy.

A multidisciplinary clinic approach to improve physician-related diagnostic delay for patients with axial spondyloarthritis: a retrospective study.

OBJECTIVE: To assess the diagnostic delay (DD) and physician-related DD (pDD) in patients with axial spondyloarthritis (SpA) and the potential benefits of a multidisciplinary clinic (MDC) approach. METHODS: A retrospective study was undertaken among patients with axial SpA, which aimed to analyse DD, pDD and their risk factors. The influence of pDD on disease outcomes was examined. The pDDs among consecutive SpA patients in an MDC cohort were compared with propensity score matched historical controls (1:1). RESULTS: A total of 208 patients with axial SpA formed the historical control group and 49 patients with axial SpA formed the MDC cohort after introduction of the MDC. The median DD and pDD in the historical controls were 25.5 and 10.0 months, respectively. A cut-off of pDD > 4 months was associated with more active disease and functional impairment. An initial visit to a non-rheumatologist was the most significant risk factor for pDD. Following MDC introduction, the median pDD decreased from 13 months to 1 month after adjustments were made for confounders such as sex, education level, history of smoking, human leukocyte antigen-B27 status and SpA/ankylosing spondylitis classification criteria. CONCLUSION: The MDC was a promising approach that resulted in a reduced pDD among patients with axial SpA.

Proton pump inhibitor pantoprazole inhibits gastric cancer metastasis via suppression of telomerase reverse transcriptase gene expression.

The effect of proton pump inhibitors (PPIs) on cancer risk has received much attention recently. Over the last two decades, we and others have disclosed that PPIs exerted anticancer effects. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance. The activation of TERT is considered a crucial step in tumorigenesis; therefore, it is a potential therapeutic target against cancer. However, whether PPIs suppress gastric cancer by targeting TERT remains elusive. Our study demonstrated that PPZ treatment repressed TERT expression in gastric cancer cells via regulating TERT promoter activity by disturbing the interaction of STAT3 with the TERT gene. Additionally, PPZ led to chromatin remodeling within the TERT gene and resulted in a more compacted spatial conformation that is known to be associated with gene silencing. PPZ downregulated the TERT gene to inactivate the Wnt/ß-catenin signaling pathway and reverse the EMT process, finally inhibiting gastric cancer metastasis both in vitro and in vivo. Our results suggest that PPIs may be potentially developed as effective as well as relatively safe and specific anticancer agents.

Prohibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress.

Prohibitin (PHB) is a ubiquitously expressed and evolutionarily conserved mitochondrial protein with multiple functions. We have recently shown that PHB up-regulation offers robust protection against neuronal injury in models of cerebral ischemia in vitro and in vivo, but the mechanism by which PHB affords neuroprotection remains to be elucidated. Here, we manipulated PHB expression in PC12 neural cells to investigate its impact on mitochondrial function and the mechanisms whereby it protects cells exposed to oxidative stress. PHB over-expression promoted cell survival, whereas PHB down-regulation diminished cell viability. Functionally, manipulation of PHB levels did not affect basal mitochondrial respiration, but it increased spare respiratory capacity. Moreover, PHB over-expression preserved mitochondrial respiratory function of cells exposed to oxidative stress. Preserved respiratory capacity in differentiated PHB over-expressing cells exposed to oxidative stress was associated with an elongated mitochondrial morphology, whereas PHB down-regulation enhanced fragmentation. Mitochondrial complex I oxidative degradation was attenuated by PHB over-expression and increased in PHB knockdown cells. Changes in complex I degradation were associated with alterations of respiratory chain supercomplexes. Furthermore, we showed that PHB directly interacts with cardiolipin and that down-regulation of PHB results in loss of cardiolipin in mitochondria, which may contribute to destabilizing respiratory chain supercomplexes. Taken together, these data demonstrate that PHB modulates mitochondrial integrity and bioenergetics under oxidative stress, and suggest that the protective effect of PHB is mediated by stabilization of the mitochondrial respiratory machinery and its functional capacity, by the regulation of cardiolipin content. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

Estrogen receptor beta modulates permeability transition in brain mitochondria.

Recent evidence highlights a role for sex and hormonal status in regulating cellular responses to ischemic brain injury and neurodegeneration. A key pathological event in ischemic brain injury is the opening of a mitochondrial permeability transition pore (MPT) induced by excitotoxic calcium levels, which can trigger irreversible damage to mitochondria accompanied by the release of pro-apoptotic factors. However, sex differences in brain MPT modulation have not yet been explored. Here, we show that mitochondria isolated from female mouse forebrain have a lower calcium threshold for MPT than male mitochondria, and that this sex difference depends on the MPT regulator cyclophilin D (CypD). We also demonstrate that an estrogen receptor beta (ERß) antagonist inhibits MPT and knockout of ERß decreases the sensitivity of mitochondria to the CypD inhibitor, cyclosporine A. These results suggest a functional relationship between ERß and CypD in modulating brain MPT. Moreover, co-immunoprecipitation studies identify several ERß binding partners in mitochondria. Among these, we investigate the mitochondrial ATPase as a putative site of MPT regulation by ERß. We find that previously described interaction between the oligomycin sensitivity-conferring subunit of ATPase (OSCP) and CypD is decreased by ERß knockout, suggesting that ERß modulates MPT by regulating CypD interaction with OSCP. Functionally, in primary neurons and hippocampal slice cultures, modulation of ERß has protective effects against glutamate toxicity and oxygen glucose deprivation, respectively. Taken together, these results reveal a novel pathway of brain MPT regulation by ERß that could contribute to sex differences in ischemic brain injury and neurodegeneration.

PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/ß-catenin signaling pathway.

BACKGROUND: Protein regulator of cytokinesis-1 (PRC1) belongs to the microtubule-associated proteins (MAPs) family, and is involved in cytokinesis. Recent investigations suggest PRC1 involvement in human carcinogenesis, including breast carcinoma, hepatocellular carcinoma and etc. However, whether PRC1 contributes to lung adenocarcinoma tumorigenesis remains unknown. METHODS: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blotting and Immunohistochemical staining (IHC) were used to evaluate and contrast the PRC1 expression profile in lung adenocarcinoma and adjacent normal lung tissues. We examined the clinical use of PRC1 in lung adenocarcinoma prognosis. Additionally, the tumorigenesis impact of PRC1 in lung adenocarcinoma cells was verified via in vitro and in vivo metastasis and tumorigenesis assays. Notably, Next Generation Sequencing (NGS) was performed to investigate the molecular mechanism underlying the oncogenic role of PRC1 in lung adenocarcinoma. RESULTS: PRC1 mRNA and protein expressions were upregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues. PRC1 protein overexpression correlated with lymph node metastasis and was an independent poor prognostic factor for lung adenocarcinoma patients. Our data implied that PRC1 depletion limited the proliferation and invasion of lung adenocarcinoma cells in vitro and lowered tumor development and lung metastasis in vivo. Remarkably, limiting PRC1 substantially prompted G2/M phase cell cycle arrest and apoptosis. Mechanistically, by conducting NGS on PRC1-depleted A549 cells and control cells, we discovered that PRC1 expression was significantly correlated with the Wnt signaling pathway. CONCLUSIONS: This investigation offers confirmation that PRC1 is a prognostic and promising therapeutic biomarker for people with lung adenocarcinoma and takes on a key part in the activation of the Wnt/ß-catenin pathway in lung adenocarcinoma development.

Ubiquitin C-terminal hydrolase-L3 promotes interferon antiviral activity by stabilizing type I-interferon receptor.

Type-I interferons (IFN-I) are important antiviral drugs which are widely used in clinical therapy of diverse viral infections. However, understanding the detailed mechanisms for IFN-I antiviral signaling remains a major challenge, and may provide novel targets for IFN-based antiviral therapy. So far, the roles of deubiquitinases (DUBs) in regulating IFN-I antiviral activity are still largely unexplored. Here, we find that Ubiquitin C-terminal hydrolase-L3 (UCHL3) plays an important role in regulating type I-interferon (IFN-I) mediated antiviral response. Interestingly, we find that UCHL3 regulates COPS5-dependent deneddylation of Cullin1, which is an essential component of SCFß-TrCP complex and associated with SCFß-TrCP activities. Furthermore, we reveal that UCHL3 physically interacts with COPS5, and determines the level and protein stability of cellular COPS5 by deubiquitinating COPS5. We further demonstrate that UCHL3 upregulates the levels of SCFß-TrCP substrates including IFN-I receptor IFNAR1, which enhances IFN-I mediated signaling pathway and antiviral activity. These findings identify COPS5 as a novel in vivo substrate of UCHL3, and uncover the deubiquitination-deneddylation mediated regulation for IFN-I signaling and antiviral function, which may provide a novel strategy for improving IFN-based antiviral therapy.

Deubiquitinase USP33 is negatively regulated by ß-TrCP through ubiquitin-dependent proteolysis.

Ubiquitin-mediated proteolysis regulates cellular levels of various proteins, and therefore plays important roles in controlling cell signaling and disease progression. The Skp1-Cul1-F-box ubiquitin ligase ß-TrCP is recognized as an important negative regulator for numerous key signaling proteins. Recently, the deubiquitinases (DUBs) have turned out to be essential to regulate signaling pathways related to human diseases. However, whether ß-TrCP is able to regulate the deubiquitinase family members remains largely unexplored. Here, we found that ß-TrCP downregulated cellular levels of endogenous USP33. We also revealed that ß-TrCP interacted with USP33 independently of the classic binding motif for ß-TrCP, and mediated USP33 degradation via the ubiquitin proteasome pathway. Furthermore, we found that the WD40 motif of ß-TrCP and 201-400 amino acid motif of USP33 are required for the interaction between ß-TrCP and USP33. Consequently, ß-TrCP attenuated USP33-mediated inhibition of cell proliferation and cell invasion. Taken together, our study clarified that the E3 ligase ß-TrCP regulates cellular USP33 levels by the ubiquitin-proteasomal proteolysis.

Elevated PRC1 in gastric carcinoma exerts oncogenic function and is targeted by piperlongumine in a p53-dependent manner.

Gastric carcinoma is one of the most common malignancies worldwide and the second most frequent cause of cancer-related death in China. Protein regulator of cytokinesis 1 (PRC1) is involved in cytokinesis and plays key roles in microtubule organization in eukaryotes. This study was aimed to analyse the expression and to investigate the functional role of PRC1 in gastric tumorigenesis. The expression of PRC1 was evaluated by qRT-PCR, Western blot and immunohistochemistry. The biological function of PRC1 was determined by CCK-8 proliferation assays, monolayer colony formation, xenografted nude mice and cell invasion assays by shRNA-mediated knockdown in AGS and HGC27 cells. The regulation of PRC1 expression by piperlongumine was also investigated using dual-luciferase reporter assay and ChIP-qPCR analysis. PRC1 was up-regulated in primary gastric cancers. Overexpression of PRC1 in gastric cancers was associated with poor disease-specific survival and overall survival. PRC1 knockdown in AGS and HGC27 cell lines suppressed proliferation, reduced monolayer colony formation, inhibited cell invasion and migration ability and induced cell-cycle arrest and apoptosis. Inhibition of PRC1 also suppressed tumour growth in vivo. We finally confirmed that PRC1 is a novel downstream target of piperlongumine in gastric cancer. Our findings supported the oncogenic role of PRC1 in gastric carcinogenesis. PRC1 might serve as a prognostic biomarker and potential therapeutic target for gastric carcinoma.

Peripheral KATP activation inhibits pain sensitization induced by skin/muscle incision and retraction via the nuclear factor-κB/c-Jun N-terminal kinase signaling pathway.

The aim of the current study was to assess the effect of pinacidil activation of ATP­sensitive potassium (KATP) channels prior to skin/muscle incision and retraction (SMIR) surgery on peripheral and central sensitization, and investigate molecular interferential targets for preventive analgesia. Male Sprague-Dawley rats were randomly assigned to one of the following five groups: Control, incision (sham surgery), incision plus retraction (SMIR) group, SMIR plus pinacidil (pinacidil) group and the SMIR plus pyrrolidine dithiocarbamate (PDTC) group. The rats in the pinacidil and PDTC groups were intraperitoneally injected with pinacidil or PDTC, respectively, prior to the SMIR procedure. The mechanical withdrawal threshold (MWT) was determined. Western blotting was performed to detect the alterations in the subunits of the KATP channels, Kir6.1 and SUR2, levels of nuclear factor­κB (NF­κB) in the tissue around the incision and c­Jun N­terminal kinase (JNK) in the spinal cord. There was a significant increase observed in the levels of NF­κB and JNK following SMIR surgery compared with the control group, and a significant reduction in MWT and the levels of Kir6.1 and SUR2. Additionally, intraperitoneal administration of pinacidil inhibited the reduction in MWT, and Kir6.1 and SUR2 levels. SMIR was observed to result in increases in the levels of NF­κB and JNK. In addition, in the PDTC group, the alterations in MWT, NF­κB, JNK, Kir6.1 and SUR2 resulting from SMIR were blocked. The results of the current study suggest that the deteriorations in the microenvironment resulting from the SMIR procedure can induce peripheral and central sensitization, and that the activation of peripheral KATP by pinacidil prior to SMIR is able to inhibit peripheral and central sensitization via the NF­κB/JNK signaling pathway, thus resulting in preventive analgesia.