Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120ub1 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation, and this process is not affected by H2AK119 ubiquitination catalyzed by PRC1. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during tumor progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of tumor patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for cancer intervention.

Histone methyltransferase SUV39H2 regulates apoptosis and chemosensitivity in prostate cancer through AKT/FOXO signaling pathway.

Prostate cancer (PCa) is one of the most common malignant tumors that exhibit both chemoresistance and recurrence. SUV39H2 is highly expressed in many types of human tumors, but its role in the development and progression of PCa has never been clarified. The aim of this study is to elucidate the role of SUV39H2 in the development and progression of PCa, its association with the AKT/FOXO signaling pathway, and its potential implications for PCa diagnosis and treatment. SUV39H2 expression was analyzed in The Cancer Genome Atlas (TCGA) and genotype tissue expression pan-cancer data. The TCGA database was evaluated for SUV39H2 enrichment and its correlation to immune cell infiltration. SUV39H2 levels in PCa tissues and control tissues were determined in 30 patients using qPCR and IHC. Clinical relevance was assessed via The Cancer Genome Atlas (TCGA). In vitro assessments including colony formation assays, Western Blot analysis, CCK-8 assays, and flow cytometry were utilized to establish SUV39H2's contribution to PCa cell growth. The influence of SUV39H2 on PC3 and DU145 cell proliferation was assessed through a cell line-derived xenograft model. Sphere formation assays and qPCR were employed to delineate SUV39H2's role in PCa stemness and chemosensitivity. In vitro macrophage polarization assays provided insights into SUV39H2's association with M2 macrophages, while enrichment analysis shed light on its role in FOXO signaling. PCa tissues expressed higher levels of SUV39H2 than normal tissues. By knocking down SUV39H2, PCa cells were made more chemosensitive to docetaxel and cell proliferation and stemness were inhibited. Additionally, SUV39H2 knockdown significantly inhibited in vivo PCa cell growth and inhibited the polarization of macrophages. Furthermore, SUV39H2 was found to regulate AKT/FOXO signaling by increasing Akt and FOXO3a phosphorylation. Our findings highlight SUV39H2's role in PCa cell apoptosis and chemosensitivity mainly by regulating the AKT/FOXO signaling pathway and suggest that SUV39H2 could be a potential target for PCa diagnosis and treatment.

Deciphering the molecular nexus between Omicron infection and acute kidney injury: a bioinformatics approach.

Background: The ongoing global health crisis of COVID-19, and particularly the challenges posed by recurrent infections of the Omicron variant, have significantly strained healthcare systems worldwide. There is a growing body of evidence indicating an increased susceptibility to Omicron infection in patients suffering from Acute Kidney Injury (AKI). However, the intricate molecular interplay between AKI and Omicron variant of COVID-19 remains largely enigmatic. Methods: This study employed a comprehensive analysis of human RNA sequencing (RNA-seq) and microarray datasets to identify differentially expressed genes (DEGs) associated with Omicron infection in the context of AKI. We engaged in functional enrichment assessments, an examination of Protein-Protein Interaction (PPI) networks, and advanced network analysis to elucidate the cellular signaling pathways involved, identify critical hub genes, and determine the relevant controlling transcription factors and microRNAs. Additionally, we explored protein-drug interactions to highlight potential pharmacological interventions. Results: Our investigation revealed significant DEGs and cellular signaling pathways implicated in both Omicron infection and AKI. We identified pivotal hub genes, including EIF2AK2, PLSCR1, GBP1, TNFSF10, C1QB, and BST2, and their associated regulatory transcription factors and microRNAs. Notably, in the murine AKI model, there was a marked reduction in EIF2AK2 expression, in contrast to significant elevations in PLSCR1, C1QB, and BST2. EIF2AK2 exhibited an inverse relationship with the primary AKI mediator, Kim-1, whereas PLSCR1 and C1QB demonstrated strong positive correlations with it. Moreover, we identified potential therapeutic agents such as Suloctidil, Apocarotenal, 3'-Azido-3'-deoxythymidine, among others. Our findings also highlighted a correlation between the identified hub genes and diseases like myocardial ischemia, schizophrenia, and liver cirrhosis. To further validate the credibility of our data, we employed an independent validation dataset to verify the hub genes. Notably, the expression patterns of PLSCR1, GBP1, BST2, and C1QB were consistent with our research findings, reaffirming the reliability of our results. Conclusion: Our bioinformatics analysis has provided initial insights into the shared genetic landscape between Omicron COVID-19 infections and AKI, identifying potential therapeutic targets and drugs. This preliminary investigation lays the foundation for further research, with the hope of contributing to the development of innovative treatment strategies for these complex medical conditions.

Integrative analysis of potential diagnostic markers and therapeutic targets for glomerulus-associated diabetic nephropathy based on cellular senescence.

Introduction: Diabetic nephropathy (DN), distinguished by detrimental changes in the renal glomeruli, is regarded as the leading cause of death from end-stage renal disease among diabetics. Cellular senescence plays a paramount role, profoundly affecting the onset and progression of chronic kidney disease (CKD) and acute kidney injuries. This study was designed to delve deeply into the pathological mechanisms between glomerulus-associated DN and cellular senescence. Methods: Glomerulus-associated DN datasets and cellular senescence-related genes were acquired from the Gene Expression Omnibus (GEO) and CellAge database respectively. By integrating bioinformatics and machine learning methodologies including the LASSO regression analysis and Random Forest, we screened out four signature genes. The receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic performance of the selected genes. Rigorous experimental validations were subsequently conducted in the mouse model to corroborate the identification of three signature genes, namely LOX, FOXD1 and GJA1. Molecular docking with chlorogenic acids (CGA) was further established not only to validate LOX, FOXD1 and GJA1 as diagnostic markers but also reveal their potential therapeutic effects. Results and discussion: In conclusion, our findings pinpointed three diagnostic markers of glomerulus-associated DN on the basis of cellular senescence. These markers could not only predict an increased risk of DN progression but also present promising therapeutic targets, potentially ushering in innovative treatments for DN in the elderly population.

Association of Cerebral Small Vessel Disease With Gait and Balance Disorders.

Cerebral small vessel disease (CSVD) is a common cerebrovascular disease and an important cause of gait and balance disorders. Gait and balance disorders can further lead to an increased risk of falls and a decreased quality of life. CSVD can damage gait and balance function by affecting cognitive function or directly disrupting motor pathways, and different CSVD imaging features have different characteristics of gait and balance impairment. In this article, the correlation between different imaging features of sporadic CSVD and gait and balance disorders has been reviewed as follows, which can provide beneficial help for standardized management of CSVD.

Periventricular white matter hyperintensities are associated with gait and balance in patients with minor stroke.

Objective: Cerebral small vessel disease (CSVD) is associated with gait and balance deficits in older adults. However, the effect of CSVD-related brain injury on post-stroke mobility is unknown. This study aimed to investigate the association of CSVD with gait and balance impairment after a minor stroke. Methods: A total of 273 patients with a minor stroke (NIHSS ≤ 5 points) who were hospitalized at the Affiliated Hospital of Qingdao University were enrolled. The manifestations of white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), and cerebral microbleeds (CMB) were statistically analyzed according to magnetic resonance imaging results, and the total burden score of CSVD was calculated. Gait function was assessed by a 6-m walking speed test, and balance function was assessed by the timed-up-and-go (TUG) test. Linear regression analysis was applied to determine the association after adjusting for key variables. Results: The correlation results showed that in patients with minor stroke, age, sex, smoking history, and the infarct site were associated with gait speed, and age and the infarct site were associated with the TUG test. In the univariate linear regression model, periventricular white matter hyperintensities (PVWMH), deep white matter hyperintensities (DWMH), and the total burden of CSVD were correlated with gait speed, while only PVWMH correlated with the TUG test. After adjusting for confounders, only PVWMH were independent predictors of gait speed (ß = -0.089, p < 0.05) and the TUG test (ß = 0.517, p < 0.05). Conclusions: Our study confirmed that CSVD is associated with gait and balance disorders after a minor stroke. PVWMH are independent predictors of gait and balance disorders in patients with minor stroke. These findings should be confirmed in larger prospective studies.

Ball milling potassium ferrate activated biochar for efficient chromium and tetracycline decontamination: Insights into activation and adsorption mechanisms.

Herein, novel Fe-biochar composites (MBCBM500 and MBCBM700) were synthesized through K2FeO4 co-pyrolysis and ball milling, and were used to eliminate Cr(VI)/TC from water. Characterization results revealed that higher temperature promoted formation of zero-valent iron and Fe3C on MBCBM700 through carbothermal reduction between K2FeO4 and biochar. The higher specific surface area and smaller particle size of MBCBM500/700 stemmed from the corrosive functions of K and the ball milling process. And the maximal uptake amount of MBCBM700 for Cr(VI)/TC was 117.49/90.31 mg/g, relatively higher than that of MBCBM500 (93.86/84.15 mg/g). Furthermore, ion exchange, pore filling, precipitation, complexation, reduction and electrostatic attraction were proved to facilitate the adsorption of Cr(VI), while hydrogen bonding force, pore filling, complexation and π-π stacking were the primary pathways to eliminate TC. This study provide a reasonable design of Fe-carbon materials for Cr(VI)/TC contained water remediation, which required neither extra modifiers nor complex preparation process.

One-pot synthesis of porous N-doped hydrochar for atrazine removal from aqueous phase: Co-activation and adsorption mechanisms.

KOH-activated N-doped hydrochar (KHCN) was synthesized via co-activation method to eliminate atrazine (AT) in water efficiently. Compared to primitive HC, KHCN had advantages of splendid specific surface area (1205.82 m2/g) and developed microsphere structures on the surface. Specially for KHCN, the extra melamine added strengthened and preserved partial structure of polar oxygen-containing groups that were decomposed in the process of pore making. Besides, the estimated uptake amount of AT onto KHCN (216.50 mg/g) was remarkably superior to KHC (114.25 mg/g). KHCN exhibited the pH-dependence for AT removal, and presented excellent uptake capacity at a relatively neutral environment. Notably, the proposed mechanisms for AT removal by KHCN included electrostatic attraction, pore filling, π-π EDA, H-bond as well as hydrophilic effect. Hence, the porous N-doped hydrochar was a kind of adsorbent which was easy to prepare and had the application prospect for AT removal in natural water.

Effective lead passivation in soil by bone char/CMC-stabilized FeS composite loading with phosphate-solubilizing bacteria.

Bioremediation by phosphate-solubilizing bacteria (PSB) has attracted extensive attentions due to its economical and eco-friendly properties for lead (Pb) passivation in soil. Herein, bone char (BC) supported biochemical composite (CFB1-P) carrying advantages of BC, PSB, iron sulfide (FeS) and carboxymethyl cellulose (CMC) was designed and applied to Pb passivation. The composite at a mass ratio of BC:CMC:FeS = 1:1:1 possessed high passivation efficiency (65.47%), and has been demonstrated to offer appropriate habitat environment for PSB to defend against Pb(II) toxicity, thus enhancing the phosphate-solubilizing amount of PSB to 140.72 mg/L for passivating Pb(II). Batch experiments showed that the CFB1-P possessed excellent adsorption properties with maximal monolayer Pb(II) uptake of 452.99 mg/g during an extensive pH range of 2.0-6.0. Furthermore, by applying CFB1-P dosage of 3% into Pb-contaminated soil, the labile Pb fractions were reduced from 29.05% to 6.47% after simulated remediation of 10 days, and converted into steady fractions. The CFB1-P was demonstrated to achieve high Pb(II) passivation through combined functions of chemical precipitation, complexation, electrostatic attraction and biomineralization, accompanied by the formation of more stable crystal structures, for instance, Pb5(PO4)3OH, Pb3(PO4)2 and PbS. These results suggested CFB1-P as a potential alternative for efficient remediation of Pb-contaminated soil.

HBeAg-negative Patients with Chronic Hepatitis B Virus Infection and Normal Alanine Aminotransferase: Wait or Treat?

Alanine aminotransferase (ALT) is a common clinical indicator of liver inflammation. The current Chinese guidelines for the management of chronic hepatitis B (CHB) recommend antiviral treatment for patients with detectable hepatitis B virus (HBV) DNA and persistent ALT levels (ALTs) exceeding the upper limit of normal. However, it has been recently reported that patients with chronic HBV infection, especially HBeAg-negative patients with persistently normal ALTs, may have liver biopsy findings of significant inflammation and fibrosis. For HBeAg-negative patients with chronic HBV infection and normal ALTs, many controversial questions have been asked. To treat or not? When to initiate the treatment? Which drug is appropriate? In this review, we summarize the available data on the management of HBeAg-negative patients with chronic HBV infection and normal ALTs with the aim of improving the current clinical management.

Microwave-assisted one pot synthesis of ß-cyclodextrin modified biochar for concurrent removal of Pb(II) and bisphenol a in water.

Herein, ß-cyclodextrin (ß-CD) functionalized rice husk-derived biochar (BC) was conveniently and fast synthesized via microwave (MW)-assisted one pot process, and employed for simultaneous elimination of bisphenol A (BPA) and plumbum (Pb). Profiting by microwave irradiation, the surface modification was implemented in 15 min and the prepared BCMW-ß-CD presented an excellent adsorption performance with a heterogeneous adsorption capacity of 209.20 mg/g for BPA and a theoretical monolayer uptake of 240.13 mg/g for Pb(II) in the mono-component system. Furthermore, the BCMW-ß-CD could simultaneously achieve efficient cleanup of BPA and Pb(II) through avoiding the competitive behaviors between them, which were due to the different adsorption mechanisms for Pb(II) (i.e. electrostatic attraction and complexation) and BPA (i.e. host-guest supramolecular and π-π interactions). Moreover, the adsorbed BPA and Pb(II) could be sequentially desorbed with mild decrease in the adsorption performance of BCMW-ß-CD even after five cycles in the Pb(II)-BPA multi-component system.