Profiling dendritic cells subsets in renal tissue of patients with crescentic glomerulonephritis.

BACKGROUND: Dendritic cells (DCs) have been speculated to be involved in the pathogenesis of glomerular diseases. However, the numbers and distribution of DC subsets in the kidneys of patients with crescentic glomerulonephritis (CrGN) have not been clearly elucidated. METHODS: A total of 26 patients with biopsy-proven CrGN were enrolled. Indirect immunofluorescence staining was used to quantify DC subsets in renal specimens. Double staining of HLA with CD11C, BDCA2 and CD209 respectively was performed to detect DC subsets. The correlation between DC subsets infiltrated in the kidney and clinical and pathological parameters was investigated. RESULTS: DC subsets were predominantly present in the kidney interstitium, particularly in the peri-glomerular area. The numbers of CD11C+DCs, BDCA2+DCs and CD209+DCs increased in the patients with CrGN and varied among different types of CrGN. Though significant correlation between DC subsets and the percentage of crescents had not been identified, a notable increase in the number of CD11C+DCs were observed with the chronic development of crescents. Furthermore, patients with severe tubulointerstitial injury exhibited significantly more infiltrations of CD11C+DCs, BDCA2+DCs and CD209+DCs. Moreover, the numbers of CD11C+DCs and BDCA2+DCs were found to correlate with the level of serum C3. CONCLUSIONS: Patients with CrGN showed increased kidney infiltration of DC subsets, primarily localized in the renal interstitium and peri-glomerular region. The correlation between DC subsets and fibrosis of crescent and severe tubulointerstitial injury implied a potential involvement of DCs in the development of CrGN.

Spatial analysis for interval-valued data.

Symbolic data analysis deals with complex data with symbolic objects, such as lists, histograms, and intervals. Spatial analysis for symbolic data is relatively underexplored. To fill the gap, this paper proposes a statistical framework for spatial interval-valued data (SIVD) analysis. We provide geostatistical methods for spatial prediction, predictive performance measure for prediction assessment, and visualization for mapping SIVD. The proposed methods are illustrated with both simulated and real examples.

Impact of Driver Mutations on Metastasis-Free Survival in Uveal Melanoma: A Meta-Analysis.

The prognosis of uveal melanoma is significantly influenced by the risk of metastasis, which varies according to clinical and genetic features. Driver mutations can predict the likelihood of disease progression and survival, although the data in the literature are inconsistent. This meta-analysis aimed to evaluate the prognostic significance of driver mutations, including GNAQ, GNA11, BAP1, and SF3B1, in the advancement of uveal melanoma. A comprehensive search of databases yielded relevant studies, and data from 13 studies (848 eyes) were synthesized to assess the impact of these mutations on metastasis-free survival. The BAP1 mutation and negative immunohistochemistry were associated with a higher risk of metastasis (logHR = 1.44, 95% CI 1.05-1.83). GNAQ, GNA11, and SF3B1 mutations did not show a significant increase in risk. In summary, BAP1 has proven to reliably predict the likelihood of disease progression in uveal melanoma, while further studies are needed to establish the significance of other driver mutations.

In Vitro Bioassay for Damage-Associated Molecular Patterns Arising from Injured Oral Cells.

Gingival fibroblasts are a significant source of paracrine signals required to maintain periodontal homeostasis and to mediate pathological events linked to periodontitis and oral squamous cell carcinomas. Among the potential paracrine signals are stanniocalcin-1 (STC1), involved in oxidative stress and cellular survival; amphiregulin (AREG), a growth factor that mediates the cross-talk between immune cells and epithelial cells; chromosome 11 open reading frame 96 (C11orf96) with an unclear biologic function; and the inflammation-associated prostaglandin E synthase (PTGES). Gingival fibroblasts increasingly express these genes in response to bone allografts containing remnants of injured cells. Thus, the gene expression might be caused by the local release of damage-associated molecular patterns arising from injured cells. The aim of this study is consequently to use the established gene panel as a bioassay to measure the damage-associated activity of oral cell lysates. To this aim, we have exposed gingival fibroblasts to lysates prepared from the squamous carcinoma cell lines TR146 and HSC2, oral epithelial cells, and gingival fibroblasts. We report here that all lysates significantly increased the transcription of the entire gene panel, supported for STC1 at the protein level. Blocking TGF-ß receptor 1 kinase with SB431542 only partially reduced the forced expression of STC1, AREG, and C11orf96. SB431542 even increased the PTGES expression. Together, these findings suggest that the damage signals originating from oral cells can change the paracrine activity of gingival fibroblasts. Moreover, the expression panel of genes can serve as a bioassay for testing the biocompatibility of materials for oral application.

uL3 Regulates Redox Metabolism and Ferroptosis Sensitivity of p53-Deleted Colorectal Cancer Cells.

Despite advancements in therapeutic strategies, the development of drug resistance and metastasis remains a serious concern for the efficacy of chemotherapy against colorectal cancer (CRC). We have previously demonstrated that low expression of ribosomal protein uL3 positively correlates with chemoresistance in CRC patients. Here, we demonstrated that the loss of uL3 increased the metastatic capacity of CRC cells in chick embryos. Metabolomic analysis revealed large perturbations in amino acid and glutathione metabolism in resistant uL3-silenced CRC cells, indicating that uL3 silencing dramatically triggered redox metabolic reprogramming. RNA-Seq data revealed a notable dysregulation of 108 genes related to ferroptosis in CRC patients. Solute Carrier Family 7 Member 11 (SLC7A11) is one of the most dysregulated genes; its mRNA stability is negatively regulated by uL3, and its expression is inversely correlated with uL3 levels. Inhibition of SLC7A11 with erastin impaired resistant uL3-silenced CRC cell survival by inducing ferroptosis. Of interest, the combined treatment erastin plus uL3 enhanced the chemotherapeutic sensitivity of uL3-silenced CRC cells to erastin. The antimetastatic potential of the combined strategy was evaluated in chick embryos. Overall, our study sheds light on uL3-mediated chemoresistance and provides evidence of a novel therapeutic approach, erastin plus uL3, to induce ferroptosis, establishing individualized therapy by examining p53, uL3 and SLC7A11 profiles in tumors.

Exploratory Tau PET/CT with [11C]PBB3 in Patients with Suspected Alzheimer's Disease and Frontotemporal Lobar Degeneration: A Pilot Study on Correlation with PET Imaging and Cerebrospinal Fluid Biomarkers.

Accurately diagnosing Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is challenging due to overlapping symptoms and limitations of current imaging methods. This study investigates the use of [11C]PBB3 PET/CT imaging to visualize tau pathology and improve diagnostic accuracy. Given diagnostic challenges with symptoms and conventional imaging, [11C]PBB3 PET/CT's potential to enhance accuracy was investigated by correlating tau pathology with cerebrospinal fluid (CSF) biomarkers, positron emission tomography (PET), computed tomography (CT), amyloid-beta, and Mini-Mental State Examination (MMSE). We conducted [11C]PBB3 PET/CT imaging on 24 patients with suspected AD or FTLD, alongside [11C]PiB PET/CT (13 patients) and [18F]FDG PET/CT (15 patients). Visual and quantitative assessments of [11C]PBB3 uptake using standardized uptake value ratios (SUV-Rs) and correlation analyses with clinical assessments were performed. The scans revealed distinct tau accumulation patterns; 13 patients had no or faint uptake (PBB3-negative) and 11 had moderate to pronounced uptake (PBB3-positive). Significant inverse correlations were found between [11C]PBB3 SUV-Rs and MMSE scores, but not with CSF-tau or CSF-amyloid-beta levels. Here, we show that [11C]PBB3 PET/CT imaging can reveal distinct tau accumulation patterns and correlate these with cognitive impairment in neurodegenerative diseases. Our study demonstrates the potential of [11C]PBB3-PET imaging for visualizing tau pathology and assessing disease severity, offering a promising tool for enhancing diagnostic accuracy in AD and FTLD. Further research is essential to validate these findings and refine the use of tau-specific PET imaging in clinical practice, ultimately improving patient care and treatment outcomes.

The 22q11.2 Deletion Syndrome from A Biopsychosocial Perspective: A Series of Cases with an ICF-Based Approach.

The 22q11.2 deletion syndrome (DS) can have a significant impact on functionality. The purpose was to describe 22q11.2DS children with functioning from a biopsychosocial perspective, focusing on the impact of children's health condition from domains of the International Classification of Functioning, Disability, and Health (ICF). METHODS: A descriptive, cross-sectional case series study with seven 22q11.2DS children. A questionnaire with an ICF checklist for 22q11.2DS was completed using a structured interview. The Wechsler Abbreviated Scale of Intelligence (WASI) was used to determine the Intelligence Quotient (IQ). RESULTS: Seven participants from 7 to 12 years old, presented some level of IQ impairment. It was observed that 22q11.2DS children experience significant intellectual, cognitive, and speech impairments across ICF Body Function domains. Impairments related to nose and pharynx were found in only one patient. The most relevant categories considered limitations in the Activity and Participation components pertained to producing nonverbal messages, communication, handling stress, and social interaction. Family, health professionals, and acquaintances were perceived as facilitators in the component Environmental Factors. CONCLUSION: The sample has its functioning affected by aspects that go beyond impairments in body structure and function. The organization of information from the perspective of the ICF is a different approach that helps clinical reasoning.

Potential Involvement of MnCYP710A11 in Botrytis cinerea Resistance in Arabidopsis thaliana and Morus notabilis.

Cytochrome P450 (CYP) is a crucial oxidoreductase enzyme that plays a significant role in plant defense mechanisms. In this study, a specific cytochrome P450 gene (MnCYP710A11) was discovered in mulberry (Morus notabilis). Bioinformatic analysis and expression pattern analysis were conducted to elucidate the involvement of MnCYP710A11 in combating Botrytis cinerea infection. After the infection of B. cinerea, there was a notable increase in the expression of MnCYP710A11. MnCYP710A11 is overexpressed in Arabidopsis and mulberry and strongly reacts to B. cinerea. The overexpression of the MnCYP710A11 gene in Arabidopsis and mulberry led to a substantial enhancement in resistance against B. cinerea, elevated catalase (CAT) activity, increased proline content, and reduced malondialdehyde (MDA) levels. At the same time, H2O2 and O2- levels in MnCYP710A11 transgenic Arabidopsis were decreased, which reduced the damage of ROS accumulation to plants. Furthermore, our research indicates the potential involvement of MnCYP710A11 in B. cinerea resistance through the modulation of other resistance-related genes. These findings establish a crucial foundation for gaining deeper insights into the role of cytochrome P450 in mulberry plants.

Information and resources VA health system leaders need to manage enrollment and retention for Post-9/11 veterans.

OBJECTIVE: To understand Veterans Health Administration (VA) leaders' information and resource needs for managing post-9/11 Veterans' VA enrollment and retention. DATA SOURCES AND STUDY SETTING: Interviews conducted from March-May 2022 of VA Medical Center (VAMC) leaders (N = 27) across 15 sites, using stratified sampling based on VAMC characteristics: enrollment rates, number of recently separated Veterans in catchment area, and state Medicaid expansion status. STUDY DESIGN: Interview questions were developed using Petersen et al.'s Factors Influencing Choice of Healthcare System framework as a guide. Interviews were transcribed verbatim, and two coders analyzed the interviews using Atlas.ti, a qualitative software program. Coders followed the qualitative coding philosophy developed by Crabtree and Miller, a process of developing codes for salient concepts as they are identified during the analysis process. DATA COLLECTION/EXTRACTION METHODS: Two coders analyzed 22% (N = 6) of the interviews and discussed and adjudicated any discrepancies. One coder independently coded the remainder of the interviews. PRINCIPAL FINDINGS: Several key themes were identified regarding facilitators and barriers for VA enrollment including reputation for high-quality VA care, convenience of VA services, awareness of VA services and benefits, and VA mental health services. Nearly every VA leader actively used tools and data to understand enrollment and retention rates and sought to enroll and retain more Veterans. To improve the management of enrollment and retention, VA leaders would like data shared in an easily understandable format and the capability to share data between the VA and community healthcare systems. CONCLUSIONS: Enrollment and retention information is important for healthcare leaders to guide their health system decisions. Various tools are currently being used to try to understand the data. However, a multifunctional tool is needed to better aggregate the data to provide VA leadership with key information on Veterans' enrollment and retention.

Failure of ceftazidime/avibactam experimental therapy in the treatment of Klebsiella pneumoniae ST11 co-producing NDM-1 and OXA-48 carbapenemases infection.

Carbapenem-resistant organisms (CRO) represent a significant threat because of their widespread in hospital settings, difficult-to-treat, and association with high morbidity and mortality rates. Data on the efficacy of ceftazidime/avibactam (CAZ-AVI) among patients infected with CRO in Iran are lacking. Herein, we report a case of a 91-year-old man with infection caused by extensively drug-resistant ST11 co-harbouring blaNDM and blaOXA-48-like strain from seven isolates. During ICU hospitalization, 10 different antibiotics were prescribed to the patient, and CAZ-AVI was experimentally prescribed in combination with tobramycin and tigecycline to the patient for the first time in the teaching hospitals of Isfahan City. The patient died on the 56th day of hospitalization. The present study revealed that the use of CAZ-AVI should be limited to targeted therapy after susceptibility results and minimum inhibitory concentration values are available to the treating clinicians and not be used for empirical therapy of patients with an infection caused by CRO, underscoring the urgent need for stringent policies for antibiotic stewardship to preserve the activity of novel ß-lactam/ß-lactamase inhibitors.

Differences in Eotaxin Serum Levels between Polytraumatized Patients with and without Concomitant Traumatic Brain Injury-A Matched Pair Analysis.

Background/Objectives: Early detection of traumatic brain injury (TBI) is crucial for minimizing secondary neurological damage. Our study aimed to assess the potential of IL-4, IL-6, IL-7, IL-8, IL-10, TNF, and eotaxin serum levels-as a single clinical tool or combined into a panel-for diagnosing TBI in multiple injured patients. Methods: Out of 110 prospectively enrolled polytrauma victims (median age, 39 years; median ISS, 33; 70.9% male) admitted to our level I trauma center over four years, we matched 41 individuals with concomitant TBI (TBI cohort) to 41 individuals without TBI (non-TBI cohort) based on age, gender, Injury Severity Score (ISS), and mortality. Patients' protein levels were measured upon admission (day 0) and on days 1, 3, 5, 7, and 10 during routine blood withdrawal using one separation gel tube each time. Results: The median serum levels of IL-4, IL-6, IL-7, IL-8, IL-10, and TNF exhibited non-similar time courses in the two cohorts and showed no significant differences on days 0, 1, 3, 5, and 7. However, the median eotaxin levels had similar trend lines in both cohorts, with consistently higher levels in the TBI cohort, reaching significance on days 0, 3, and 5. In both cohorts, the median eotaxin level significantly decreased from day 0 to day 1, then significantly increased until day 10. We also found a significant positive association between day 0 eotaxin serum levels and the presence of TBI, indicating that for every 20 pg/mL increase in eotaxin level, the odds of a prevalent TBI rose by 10.5%. ROC analysis provided a cutoff value of 154 pg/mL for the diagnostic test (sensitivity, 0.707; specificity, 0.683; AUC = 0.718). Conclusions: Our findings identified the brain as a significant source, solely of eotaxin release in humans who have suffered a TBI. Nevertheless, the eotaxin serum level assessed upon admission has limited diagnostic value. IL-4, IL-6, IL-7, IL-8, IL-10, and TNF do not indicate TBI in polytraumatized patients.

Exosomal Small RNA Sequencing Profiles in Plasma from Subjects with Latent Mycobacterium tuberculosis Infection.

Despite huge efforts, tuberculosis (TB) is still a major public health threat worldwide, with approximately 23% of the human population harboring a latent TB infection (LTBI). LTBI can reactivate and progress to active and transmissible TB disease, contributing to its spread within the population. The challenges in diagnosing and treating LTBI patients have been major factors contributing to this phenomenon. Exosomes offer a novel avenue for investigating the process of TB infection. In this study, we conducted small RNA sequencing to investigate the small RNA profiles of plasma exosomes derived from individuals with LTBI and healthy controls. Our findings revealed distinct miRNA profiles in the exosomes between the two groups. We identified 12 differentially expressed miRNAs through this analysis, which were further validated via qRT-PCR using the same exosomes. Notably, six miRNAs (hsa-miR-7850-5p, hsa-miR-1306-5p, hsa-miR-363-5p, hsa-miR-374a-5p, hsa-miR-4654, has-miR-6529-5p, and hsa-miR-140-5p) exhibited specifically elevated expression in individuals with LTBI. Gene ontology and KEGG pathway analyses revealed that the targets of these miRNAs were enriched in functions associated with ferroptosis and fatty acid metabolism, underscoring the critical role of these miRNAs in regulating the intracellular survival of Mycobacterium tuberculosis (Mtb). Furthermore, our results indicated that the overexpression of miR-7850-5p downregulated the expression of the SLC11A1 protein in both Mtb-infected and Mtb-uninfected THP1 cells. Additionally, we observed that miR-7850-5p promoted the intracellular survival of Mtb by suppressing the expression of the SLC11A1 protein. Overall, our findings provide valuable insights into the role of miRNAs and repetitive region-derived small RNAs in exosomes during the infectious process of Mtb and contribute to the identification of potential molecular targets for the detection and diagnosis of latent tuberculosis.

Intensified Circulation of Echovirus 11 after the COVID-19 Pandemic in Poland: Detection of a Highly Pathogenic Virus Variant.

After the first phase of the COVID-19 pandemic in Europe, a new highly pathogenic variant of echovirus 11 (E11) was detected. The aim of this study was to analyze the genetic diversity of Polish E11 environmental and clinical strains circulating between 2017 and 2023 as well as compare them with E11 strains isolated from severe neonatal sepsis cases reported in Europe between 2022 and 2023. Additionally, the study explores the effectiveness of environmental monitoring in tracking the spread of new variants. For this purpose, the complete sequences of the VP1 capsid protein gene were determined for 266 E11 strains isolated in Poland from 2017 to 2023, and phylogenetic analysis was performed. In the years 2017-2023, a significant increase in the detection of E11 strains was observed in both environmental and clinical samples in Poland. The Polish E11 strains represented three different genotypes, C3, D5 and E, and were characterized by a high diversity. In Poland, the intensive circulation of the new variant E11, responsible for severe neonatal infections with a high mortality in Europe, was detected in the years 2022-2023. This investigation demonstrates the important role of environmental surveillance in the tracking of enteroviruses circulation, especially in settings with limited clinical surveillance.

Avian Coronavirus Infectious Bronchitis Virus Activates Mitochondria-Mediated Apoptosis Pathway and Affects Viral Replication by Inducing Reactive Oxygen Species Production in Chicken HD11 Cells.

Infectious bronchitis virus (IBV), a coronavirus that causes severe respiratory and gastrointestinal illness in poultry, leads to substantial economic losses. According to earlier research, IBV infection causes chicken macrophage HD11 cells to undergo cell apoptosis. Reactive oxygen species (ROS) and the IBV-activated intrinsic apoptotic signaling pathway were examined in this work. The findings demonstrate that IBV infection causes ROS to accumulate. Moreover, IBV infection decreased the mitochondrial transmembrane potential in HD11 cells, which could be blocked by ROS antioxidants (PDTC and NAC). The two antioxidants significantly affected the expression of Bcl-2 and Bax and further inhibited the activation of caspase-3 and apoptosis in HD11 cells. Additionally, IBV replication was decreased by blocking ROS accumulation. Pretreating HD11 cells with ammonium chloride (NH4Cl) prevented IBV from entering the cells and reduced the oxidative stress which IBV causes. The ability to accumulate ROS was also lost in UV-inactivated IBV. The IBV N protein induces cell apoptosis through the activation of ROS. These findings provide an explanation for the processes of IBV infection in immune cells by indicating that IBV-induced ROS generation triggers cell apoptosis in HD11 cells.

TrxR1 is involved in the activation of Caspase-11 by regulating the oxidative-reductive status of Trx-1.

Sepsis is a common complication of infections that significantly impacts the survival of critically patients. Currently, effective pharmacological treatment strategies are lacking. Auranofin, known as an inhibitor of Thioredoxin reductase (TrxR), exhibits anti-inflammatory activity, but its role in sepsis is not well understood. Here, we demonstrate the significant inhibitory effect of Auranofin on sepsis in a cecal ligation and puncture (CLP) mouse model. In vitro, Auranofin inhibits pyroptosis triggered by Caspase-11 activation. Further investigations reveal that inhibiting TrxR1 suppresses macrophage pyroptosis induced by E. coli, while TrxR2 does not exhibit this effect. TrxR1, functioning as a reductase, regulates the oxidative-reductive status of Thioredoxin-1 (Trx-1). Mechanistically, the modulation of Trx-1's reductive activity by TrxR1 may be involved in Caspase-11 activation-induced pyroptosis. Additionally, inhibiting TrxR1 maintains Trx-1 in its oxidized state. The oxidized form of Trx-1 interacts with Caveolin-1 (CAV1), regulating outer membrane vesicle (OMV) internalization. In summary, our study suggests that inhibiting TrxR1 suppresses OMV internalization by maintaining the oxidized form of Trx-1, thereby restricting Caspase-11 activation and alleviating sepsis.

Pseudoginsenoside-F11 reduces cognitive impairment and white matter injury in vascular dementia by alleviating autophagy-lysosomal pathway deficiency.

BACKGROUND: Vascular dementia (VaD) resulting from chronic cerebral hypoperfusion (CCH) induces cognitive impairment and white matter injury (WMI). We previously found that CCH induces dysfunction of the autophagy-lysosomal pathway (ALP) in white matter (WM) of rats. Enhancing oligodendrocyte autophagy to counteract ALP deficiency is beneficial for cognitive recovery. Pseudogenoside-F11 (PF11), a saponin extracted from Panax quinquefolium l., provides neuroprotective benefits in many animal models of cerebral ischemia and dementia. PURPOSE: To investigate how PF11 affects cognitive deterioration in rats with VaD induced by two vessel occlusion (2VO), and to determine if PF11 regulates ALP dysfunction in WM. METHODS: CCH-related VaD was induced in rats using the 2VO method. PF11 (6, 12, 24 mg/kg, intragastric administration) was given continuously for 4 weeks postoperatively. Behavioral tests related to cognitive function were performed on the 28th day following 2VO. Transmission electron microscopy, immunofluorescence, western blotting and Luxol fast blue staining were used to assess the WMI and the mechanism of action of PF11 in 2VO-induced VaD. RESULTS: PF11 (12 mg/kg) ameliorated 2VO-induced cognitive impairment. PF11 also alleviated WMI on the 28th day following 2VO, as characterized by reduction of neuronal axonal demyelination and axonal loss. Furthermore, PF11 prevented mature oligodendrocytes death by attenuating ALP deficiency in WM on the 14th day following 2VO, as manifested by enhancement of mechanistic target of rapamycin-mediated autophagy and lysosomal function, thereby reducing the aberrant accumulation of autophagy substrates and increasing the level of autophagosomes in WM. In addition, PF11 also prevented microglia and astrocytes from activating in WM on the 28th day following 2VO. CONCLUSION: PF11 significantly ameliorates cognitive impairment and WMI, and the mechanism is at least partly related to lessening ALP dysfunction in WM by enhancing autophagy and reducing lysosomal defects in oligodendrocytes.

Human microglial cells as a therapeutic target in a neurodevelopmental disease model.

Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions.

The CRL3KCTD10 ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11.

SLC7A11 is a cystine transporter and ferroptosis inhibitor. How the stability of SLC7A11 is coordinately regulated in response to environmental cystine by which E3 ligase and deubiquitylase (DUB) remains elusive. Here, we report that neddylation inhibitor MLN4924 increases cystine uptake by causing SLC7A11 accumulation, via inactivating Cullin-RING ligase-3 (CRL-3). We identified KCTD10 as the substrate-recognizing subunit of CRL-3 for SLC7A11 ubiquitylation, and USP18 as SLC7A11 deubiquitylase. Upon cystine deprivation, the protein levels of KCTD10 or USP18 are decreased or increased, respectively, contributing to SLC7A11 accumulation. By destabilizing or stabilizing SLC7A11, KCTD10, or USP18 inversely regulates the cystine uptake and ferroptosis. Biologically, MLN4924 combination with SLC7A11 inhibitor Imidazole Ketone Erastin (IKE) enhanced suppression of tumor growth. In human breast tumor tissues, SLC7A11 levels were negatively or positively correlated with KCTD10 or USP18, respectively. Collectively, our study defines how SLC7A11 and ferroptosis is coordinately regulated by the CRL3KCTD10/E3-USP18/DUB axis, and provides a sound rationale of drug combination to enhance anticancer efficacy.

DSCR1-1 attenuates osteoarthritis-associated chondrocyte injury by regulating the CREB1/ALDH2/Wnt/ß-catenin axis: An in vitro and in vivo study.

The progression of osteoarthritis (OA) includes the initial inflammation, subsequent degradation of the extracellular matrix (ECM), and chondrocyte apoptosis. Down syndrome candidate region 1 (DSCR1) is a stress-responsive gene and expresses in varied types of cells, including chondrocytes. Bioinformatics analysis of GSE103416 and GSE104739 datasets showed higher DSCR1 expression in the inflamed cartilage tissues and chondrocytes of OA. DSCR1 had two major isoforms, isoform 1 (DSCR1-1) and isoform 4 (DSCR1-4). We found that DSCR1-1 had a faster (in vitro) and higher expression (in vivo) response to OA compared to DSCR1-4. IL-1ß-induced apoptosis, inflammation, and ECM degradation in chondrocytes were attenuated by DSCR1-1 overexpression. DSCR1-1 triggered the phosphorylation of cAMP response element-binding 1 (CREB1) at 133 serine sites by decreasing calcineurin activity. Moreover, activated CREB1 moved into the cell nucleus and combined in the promoter regions of aldehyde dehydrogenase 2 (ALDH2), thus enhancing its gene transcription. ALDH2 could recover Wnt/ß-catenin signaling transduction by enhancing phosphorylation of ß-catenin at 33/37 serine sites and inhibiting the migration of ß-catenin protein from the cellular matrix to the nucleus. In vivo, adenoviruses (1 × 108 PFU) overexpressing DSCR1-1 were injected into the articular cavity of C57BL/6 mice with medial meniscus surgery-induced OA, and it showed that DSCR1-1 overexpression ameliorated cartilage injury. Collectively, our study demonstrates that DSCR1-1 may be a potential therapeutic target of OA.

Construction of a 5-Gene super-enhancer-related signature for osteosarcoma prognosis and the regulatory role of TNFRSF11B in osteosarcoma.

Osteosarcoma, one of the most common primary malignancies in children and adolescents, has the primary characteristics of a poor prognosis and high rate of metastasis. This study used super-enhancer-related genes derived from two different cell lines to construct five novel super-enhancer-related gene prognostic models for patients with osteosarcoma. The training and testing datasets were used to confirm the prognostic models of the five super-enhancer-related genes, which resulted in an impartial predictive element for osteosarcoma. The immunotherapy and prediction of the response to anticancer drugs have shown that the risk signature of the five super-enhancer-related genes positively correlate with chemosensitivity. Furthermore, functional analysis of the risk signature genes revealed a significant relationship between gene groups and the malignant characteristics of tumours. TNF Receptor Superfamily Member 11b (TNFRSF11B) was selected for functional verification. Silencing of TNFRSF11B suppressed the proliferation, migration, and invasion of osteosarcoma cells in vitro and suppressed osteosarcoma growth in vivo. Moreover, transcriptome sequencing was performed on MG-63 cells to study the regulatory mechanism of TNFRSF11B in osteosarcoma cells, and it was discovered that TNFRSF11B is involved in the development of osteosarcoma via the phosphoinositide 3-kinase signalling pathway. Following the identification of TNFRSF11B as a key gene, we selected an inhibitor that specifically targeted this gene and performed molecular docking simulations. In addition, risedronic acid inhibited osteosarcoma growth at both cellular and molecular levels. In conclusion, the super-enhancer-related gene signature is a viable therapeutic tool for osteosarcoma prognosis and treatment.