Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer's disease (AD) patients. However, the side effects observed in cli Show more
Β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) is a crucial protease in the production of amyloid-β (Aβ) in Alzheimer's disease (AD) patients. However, the side effects observed in clinical trials of BACE1 inhibitors, including reduction in brain volume and cognitive worsening, suggest that the exact role of BACE1 in AD pathology is not fully understood. To further investigate this, we examined cerebrospinal fluid (CSF) levels of BACE1 and its cleaved product sAPPβ that reflects BACE1 activity in the China Aging and Neurodegenerative Disorder Initiative cohort. We found significant correlations between CSF BACE1 or sAPPβ levels and CSF Aβ40, Aβ42, and Aβ42/Aβ40 ratio, but not with amyloid deposition detected by 18F-Florbetapir PET. Additionally, CSF BACE1 and sAPPβ levels were positively associated with cortical thickness in multiple brain regions, and higher levels of sAPPβ were linked to increased cortical glucose metabolism in frontal and supramarginal areas. Interestingly, individuals with higher baseline levels of CSF BACE1 exhibited slower rates of brain volume reduction and cognitive worsening over time. This suggests that increased levels and activity of BACE1 may not be the determining factor for amyloid deposition, but instead, may be associated with increased neuronal activity and potentially providing protection against neurodegeneration in AD. Show less
Inflammation significantly impacts Parkinson's disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive. To identify the peripheral biomarkers of PD and its cor Show more
Inflammation significantly impacts Parkinson's disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive. To identify the peripheral biomarkers of PD and its correlation with the motor and non-motor symptoms of PD. 79 PD patients and 65 controls were included in this study. Clinical information and the serum levels of IL-8, IL-27, IL-33, β-NGF, AgRP, and TRAILR2 in the participants were collected. Appropriate scales were used to assess the symptoms of PD. For the factors with significant differences in the two groups, multivariable logistic regression was used to determine its relationship with PD. Moreover, spearman correlation was conducted to explore the correlation between the factors and PD related symptoms. The IL-27 level was compared between the cognitively healthy PD group and the mild cognitive impairment in PD (PD-MCI). The serum level of TRAILR2 was positively correlated with age and was not associated with other clinical characteristics related to PD. Compared to controls, the serum levels of IL-27(P = 0.013) were increased whereas the levels of TRAILR2(P = 0.008) were decreased in PD patients. IL-8, IL-33, β-NGF, and AgRP showed no significant differences between the two groups. After controlling for the other variables, IL-27 was considered as an independent risk factor for PD in the multivariable logistic regression model. The receiver operating characteristic (ROC) curve for diagnosing PD with IL-27 yielded an area under the curve (AUC) of 0.621. Additionally, IL-27 level in PD patients was positively correlated with age, the disease duration, LEDD and negatively correlated with the MoCA scores. However, no significant difference was found in IL-27 levels between cognitively healthy PD and PD-MCI groups. Elevated serum IL-27 was a risk factor for PD and positively correlated with the cognitive decline in PD. Show less
Hepatocellular carcinoma (HCC) accounts for over 80% of primary liver cancers and is the third leading cause of cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is the primary etiolo Show more
Hepatocellular carcinoma (HCC) accounts for over 80% of primary liver cancers and is the third leading cause of cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is the primary etiological factor. Disulfidptosis is a newly discovered form of regulated cell death. This study aims to develop a novel HBV-HCC prognostic signature related to disulfidptosis and explore potential therapeutic approaches through risk stratification based on disulfidptosis. Transcriptomic data from HBV-HCC patients were analyzed to identify BHDRGs. A prognostic model was established and validated using machine learning, with internal datasets and external datasets for verification. We then performed immune cell infiltration analysis, tumor microenvironment (TME) analysis, and immunotherapy-related analysis based on the prognostic signature. Besides, RT-qPCR and immunohistochemistry were conducted. A prognostic model was constructed using five genes ( This study stratifies HBV-HCC patients into distinct subgroups based on BHDRGs, establishing a prognostic model with significant implications for prognosis assessment, TME remodeling, and personalized therapy in HBV-HCC patients. Show less
Platelets are small anucleate cells that play a key role in thrombosis and hemostasis. Our group previously identified apolipoprotein A-IV (apoA-IV) as an endogenous inhibitor of thrombosis by competi Show more
Platelets are small anucleate cells that play a key role in thrombosis and hemostasis. Our group previously identified apolipoprotein A-IV (apoA-IV) as an endogenous inhibitor of thrombosis by competitive blockade of the αIIbβ3 integrin on platelets. ApoA-IV inhibition of platelets was dependent on the N-terminal D5/D13 residues, and enhanced with absence of the C-terminus, suggesting it sterically hinders its N-terminal platelet binding site. The C-terminus is also the site of common apoA-IV polymorphisms apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). Interestingly, both are linked with an increased risk of cardiovascular disease, however, the underlying mechanism remains unclear. Here, we generated recombinant apoA-IV and found that the Q360H or T347S polymorphisms dampened its inhibition of platelet aggregation in human platelet-rich plasma and gel-filtered platelets, reduced its inhibition of platelet spreading, and its inhibition of P-selectin on activated platelets. Using an ex vivo thrombosis assay, we found that Q360H and T347S attenuated its inhibition of thrombosis at both high (1800s Show less
Indocyanine green (ICG) is widely used to stain the epiretinal membranes and internal limiting membranes during the pars plana vitrectomy (PPV). This study aims to evaluate the effect of ICG on rat re Show more
Indocyanine green (ICG) is widely used to stain the epiretinal membranes and internal limiting membranes during the pars plana vitrectomy (PPV). This study aims to evaluate the effect of ICG on rat retinas and various retinal cell lines, including ARPE-19 cells, rMC-1 cells, BV2 cells, HRMECs and R28 cells. ICG solutions were prepared and diluted with glucose solution (GS) according to the standard clinical protocols. The retinal cell lines, including ARPE-19 cells, rMC-1 cells, BV2 cells, HRMECs and R28 cells, were treated with the following solutions: normal glucose (NG, 5 mM), GS-1 (92.5 mM glucose), GS-2 (185.02 mM glucose), ICG-1 (92.5 mM glucose + 0.43 mM ICG), or ICG-2 (185.02 mM glucose + 0.86 mM ICG) for durations of 15 or 30 min. In vivo, the right eyes of the rats were intravitreally injected with ICG-1 or ICG-2 (2 μL), while the left eyes were intravitreally injected with GS-1 or GS-2, served as the osmotic controls, for 30 min or 60 min. The rats intravitreally injected with an equivalent volume of NG or 1x phosphate-buffered saline (1x PBS) were served as the normal control or vehicle control. The cell viability was measured with the Cell Counting Kit-8 (CCK-8), while the cell death in retinal cryosections was detected with the TUNEL assay. The viabilities of the different retinal cell lines involved in this study were significantly reduced by both ICG-1 and ICG-2 treatments at both time points, with ICG-2 resulting in lower cell viability compared to the NG group and the osmotic control group. Additionally, GS-2 treatment also exhibited a decrease in retinal cell viabilities in vitro. To further confirm these results, intravitreal injection of ICG or GS induced more apoptotic cell death in rat retinas as evidenced by the TUNEL assay. The exposure of ICG or its solvent leads to an augmented retinal cell death, which is directly proportional to the concentration and duration of exposure, both in vivo and in vitro. Caution should be exercised during vitrectomy procedures involving ICG administration during clinical practice. It is recommended to advocate for lower concentrations of ICG with reduced exposure time during ocular surgeries. Show less
Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global bu Show more
Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global burden of GBM is increasing notably due to limited treatment options, drug delivery problems, and the lack of characteristic molecular targets. OTU deubiquitinase 4 (OTUD4) is a potential predictive factor for several cancers such as breast cancer, liver cancer, and lung cancer. However, its function in GBM remains unknown. In this study, we found that high expression of OTUD4 is positively associated with poor prognosis in GBM patients. Moreover, we provided in vitro and in vivo evidence that OTUD4 promotes the proliferation and invasion of GBM cells. Mechanism studies showed that, on the one hand, OTUD4 directly interacts with cyclin-dependent kinase 1 (CDK1) and stabilizes CDK1 by removing its K11, K29, and K33-linked polyubiquitination. On the other hand, OTUD4 binds to fibroblast growth factor receptor 1 (FGFR1) and reduces FGFR1's K6 and K27-linked polyubiquitination, thereby indirectly stabilizing CDK1, ultimately influencing the activation of the downstream MAPK signaling pathway. Collectively, our results revealed that OTUD4 promotes GBM progression via OTUD4-CDK1-MAPK axis, and may be a prospective therapeutic target for GBM treatment. Show less
Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving c Show more
Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving cardiac hypertrophy have not been fully elucidated. This study aimed to investigate the therapeutic effects and underlying mechanism of Re on isoproterenol (ISO)-induced cardiac hypertrophy Show less
Boping Zhang, Fenfang Wu · 2024 · Archives of dermatological research · Springer · added 2026-04-24
Psoriasis is renowned for its chronic nature and complex pathophysiology, with exosomes playing a crucial regulatory role within it. However, the proteomic composition of exosomes extracted from psori Show more
Psoriasis is renowned for its chronic nature and complex pathophysiology, with exosomes playing a crucial regulatory role within it. However, the proteomic composition of exosomes extracted from psoriasis cells remains largely unexplored. This study aimed to analyze the proteomic makeup of exosomes derived from psoriasis-model keratinocytes and compare it with that of normal controls, with the goal of identifying specific proteins that could aid in understanding the disease's pathology and potentially serve as biomarkers or therapeutic targets. The normal cultured keratinocyte line HaCaT served as the control group, while a concentration of 10 ng/mL of TNF-α was utilized to stimulate HaCaT cells and induce the formation of psoriasis model cells for the test group. Exosomes were extracted and prepared from the culture supernatant using the magnetic bead method, and their identity was confirmed through transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Data-independent acquisition (DIA) mass spectrometry was employed to detect the protein composition of exosomes, followed by GO, KEGG, Reactome, and PPI analyses. The analysis revealed a total of 2796 proteins within the exosomes, with 131 showing significant differential expression between the test and control groups. Notably, this study identified the proteins ADO, CBX1, and MIF within the exosomes derived from psoriasis model cells for the first time, highlighting their potential roles in angiogenesis, epigenetic regulation, and inflammatory responses in psoriasis. Several differentially expressed proteins identified in the KEGG enrichment analysis were implicated in immune infiltration pathways, keratinocyte-regulating pathways, angiogenesis pathways, and inflammation pathways. The identification of unique proteins within exosomes derived from psoriasis-model cells offers novel insights into the molecular mechanisms underlying psoriasis. These findings pave the way for further research into the biological functions of these exosomal proteins and their potential utility in diagnosing and treating psoriasis. Show less
Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Show more
Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA. Show less
Multiple myeloma (MM) is a malignancy in which plasma cells proliferate abnormally, and it remains incurable. The cells are characterized by high levels of endoplasmic reticulum stress (ERS) and depen Show more
Multiple myeloma (MM) is a malignancy in which plasma cells proliferate abnormally, and it remains incurable. The cells are characterized by high levels of endoplasmic reticulum stress (ERS) and depend on the ERS response for survival. Thus, we aim to find an ERS-related signature of MM and assess its diagnostic value. We downloaded three datasets of MM from the Gene Expression Omnibus database. After identifying ERS-related differentially expressed genes (ERDEGs), we analyzed them using Gene Ontology enrichment analysis. A protein-protein interaction network, a transcription factor-mRNA network, a miRNA-mRNA network and a drug-mRNA network were constructed to explore the ERDEGs. The clinical application of these genes was identified by calculating the infiltration of immune cells and using receiver operating characteistic analyses. Finally, qPCR was performed to further confirm the roles of ERDEGs. We obtained nine ERDEGs of MM. Gene Ontology enrichment indicated that the ERDEGs played a role in the endoplasmic reticulum membrane. Additionally, the protein-protein interaction network showed interaction among the ERDEGs, and there were 20 proteins, 107 transcription factors, 42 drugs or molecular compounds and 51 miRNAs which were likely to interact with the nine genes. In addition, immune cell infiltration analyses showed that there was a strong correlation between the nine genes and immune cells, and these potential biomarkers exhibited good diagnostic values. Finally, the expression of ERDEGs in MM cells was different from that in healthy donor samples. The nine ERS-related genes, CR2, DHCR7, DNAJC3, KDELR2, LPL, OSBPL3, PINK1, VCAM1 and XBP1 are potential biomarkers of MM, and this supports further clinical development of the diagnosis and treatment of MM. Show less
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cance Show more
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor response to all therapeutic modalities and dismal prognosis. The presence of tertiary lymphoid structures (TLSs) in various solid cancers is of crucial prognostic significance, highlighting the intricate interplay between the tumor microenvironment and immune cells aggregation. However, the extent to which TLSs and immune status affect PDAC prognosis remains incompletely understood. Here, we sought to unveil the unique properties of TLSs in PDAC by leveraging both single-cell and bulk transcriptomics, culminating in a risk model that predicts clinical outcomes. We used TLS scores based on a 12-gene (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) and 9-gene (PTGDS, RBP5, EIF1AY, CETP, SKAP1, LAT, CCR6, CD1D, and CD79B) signature, respectively, and examined their distribution in cell clusters of single-cell data from PDAC samples. The markers involved in these clusters were selected to develop a prognostic model using The Cancer Genome Atlas Program database as the training cohort and Gene Expression Omnibus database as the validation cohort. Further, we compared the immune infiltration, drug sensitivity, and enriched and differentially expressed genes between the high- and low-risk groups in our model. Therefore, we established a risk model that has significant implications for the prognostic assessment of PADC patients with remarkable differences in immune infiltration and chemosensitivity between the low- and high-risk groups. This paradigm established by TLS-related cell marker genes provides a prognostic prediction and a panel of novel therapeutic targets for exploring potential immunotherapy. Show less
Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable Show more
Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8 Show less
Xiang Zhang, Jin Xu · 2024 · Journal of cellular and molecular medicine · Blackwell Publishing · added 2026-04-24
Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization Show more
Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization (MR) analysis was conducted on genome-wide association studies (GWASs)-based datasets to evaluate the causal relationship between FGF23, α-Klotho, FGFR1 and OP. The primary endpoint was the odds ratio (OR) of the inverse-variance weighted (IVW) approach. Furthermore, we stably transfected FGF23-mimic or siRNA-FGF23 into human bone marrow mesenchymal stem cells (hBMSCs) in culture and determined its cell proliferation and the effects on osteogenic differentiation. Using MR analysis, we demonstrated a strong correlation between serum FGF23 levels and Heel- and femoral neck-BMDs, with subsequent ORs of 0.919 (95% CI: 0.860-0.983, p = 0.014) and 0.751 (95% CI: 0.587-0.962; p = 0.023), respectively. The expression levels of FGF23 were significantly increased in femoral neck of patients with OP than in the control cohort (p < 0.0001). Based on our in vitro investigation, after overexpression of FGF23, compared to the control group, the BMSC's proliferation ability decreased, the expression level of key osteogenic differentiation genes (RUNX2, OCN and OSX) significantly reduced, mineralized nodules and ALP activity significantly decreased. After silencing FGF23, it showed a completely opposite trend. Augmented FGF23 levels are causally associated with increased risk of OP. Similarly, FGF23 overexpression strongly inhibits the osteogenic differentiation of hBMSCs, thereby potentially aggravating the pathological process of OP. Show less
Methylglyoxal-induced ROS elevation is the primary cause of neuronal damage. Metformin is a traditional hypoglycemic drug that has been reported to be beneficial to the nervous system. In this study, Show more
Methylglyoxal-induced ROS elevation is the primary cause of neuronal damage. Metformin is a traditional hypoglycemic drug that has been reported to be beneficial to the nervous system. In this study, flavonoids were found to enhance the protective effect of metformin when added at a molar concentration of 0.5%. The structure-activity relationship (SAR) analysis indicated that ortho- substitution in the B ring, and the absence of double bonds between the 2 and 3 position combined with the gallate substitution with R configuration at the 3 position in the C ring played crucial roles in the synergistic effects, which could be beneficial for designing a combination of the compounds. Additionally, the mechanism study revealed that a typical flavonoid, EGCG, enhanced ROS scavenging and anti-apoptotic ability via the BCL2/Bax/Cyto C/Caspase-3 pathway, and synergistically inhibited the expression of GSK-3β, BACE-1, and APP in PC-12 cells when used in combination with metformin. The dose of metformin used in the combination was only 1/4 of the conventional dose when used alone. These results suggested that ROS-mediated apoptosis and the pathways related to amyloid plaques (Aβ) formation can be the targets for the synergistic neuroprotective effects of flavonoids and metformin. Show less
Heat stress is the most common environmental stressor in poultry production, negatively affecting growth performance, meat quality, and welfare. Therefore, the aim of this study was to compare the nut Show more
Heat stress is the most common environmental stressor in poultry production, negatively affecting growth performance, meat quality, and welfare. Therefore, the aim of this study was to compare the nutritional effects of dietary supplementation with selenomethionine, Bacillus subtilis (BS), and a combination of selenomethionine and BS on broilers challenged with heat stress. A total of 300 21-day-old male broilers (Ross 308) were randomly assigned to 5 groups with 6 replicates of 10 broilers per each: control group (CON, broilers raised at 22 ± 2 °C), heat stress exposure group (HS, broilers raised at 32 ± 2 °C for 8 h/d), HSS group (HS group supplemented with 0.3 mg/kg selenomethionine), HSB group (HS group supplemented with 1 × 109 cfu/kg BS), and HSBS group (HS group supplemented with 0.3 mg/kg selenomethionine and × 109 cfu/kg BS). The experiment lasted for 21 d. The results indicated that, compared to the CON group, heat stress reduces (P < 0.05) broiler growth performance and damages the meat quality in breast and thigh muscles. Dietary supplementation with selenomethionine and BS did not improve the growth performance of broilers under heat stress. However, compared to the HS group, the HSS, HSB, and HSBS groups showed significantly increased (P < 0.05) pH45 min, redness (a*) and yellowness (b*), muscle fiber density, intramuscular fat, triglyceride content, and expression levels of Myf5, CAPN 2, FM, SLC27A1, A-FABP, H-FABP, APOB-100, and ACC in breast and thigh muscles. Meanwhile, these groups showed reduced (P < 0.05) lightness (L*), drip loss, shear force, muscle fiber cross-sectional area, and FM gene expression level. The HSBS group showed greater improvement in the physicochemical quality of muscle and volatile substances compared to the HSS and HSB groups. In conclusion, selenomethionine and BS improved meat quality and flavor in broilers under heat stress by modulating muscle fiber composition and characteristics, as well as increasing intramuscular fat deposition. Show less
Xiaojie Wei, Jing Wang, Enlu Yang+5 more · 2024 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
CA2 pyramidal neurons (PNs) are associated with social behaviors. The mechanisms, however, remain to be fully investigated. Here, we report that Efr3b, a protein essential for phospholipid metabolism Show more
CA2 pyramidal neurons (PNs) are associated with social behaviors. The mechanisms, however, remain to be fully investigated. Here, we report that Efr3b, a protein essential for phospholipid metabolism at the plasma membrane, is widely expressed in the brain, especially in the hippocampal CA2/CA3 areas. To assess the functional significance of Efr3b in the brain, we generated Efr3b Show less
Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in Show more
Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in NPC. In this study, we investigated the effect of miR-2110 on NPC metastasis and its related molecular basis. In addition, we also explored whether miR-2110 can be regulated by cinobufotalin (CB) and participate in the inhibition of CB on NPC metastasis. Bioinformatics, RT-PCR, and in situ hybridization were used to observe the expression of miR-2110 in NPC tissues and cells. Scratch, Boyden, and tail vein metastasis model of nude mouse were used to detect the effect of miR-2110 on NPC metastasis. Western blot, Co-IP, luciferase activity, colocalization of micro confocal and ubiquitination assays were used to identify the molecular mechanism of miR-2110 affecting NPC metastasis. Finally, miR-2110 induced by CB participates in CB-stimulated inhibition of NPC metastasis was explored. The data showed that increased miR-2110 significantly suppresses NPC cell migration, invasion, and metastasis. Suppressing miR-2110 markedly restored NPC cell migration and invasion. Mechanistically, miR-2110 directly targeted FGFR1 and reduced its protein expression. Decreased FGFR1 attenuated its recruitment of NEDD4, which downregulated NEDD4-induced phosphatase and tensin homolog (PTEN) ubiquitination and degradation and further increased PTEN protein stability, thereby inactivating PI3K/AKT-stimulated epithelial-mesenchymal transition signaling and ultimately suppressing NPC metastasis. Interestingly, CB, a potential new inhibitory drug for NPC metastasis, significantly induced miR-2110 expression by suppressing PI3K/AKT/c-Jun-mediated transcription inhibition. Suppression of miR-2110 significantly restored cell migration and invasion in CB-treated NPC cells. Finally, a clinical sample assay indicated that reduced miR-2110 was negatively correlated with NPC lymph node metastasis and positively related to NPC patient survival prognosis. In summary, miR-2110 is a metastatic suppressor involving in CB-induced suppression of NPC metastasis. Show less
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune respo Show more
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent. Show less
Cyanidin has a protective effect on the nervous system and has been reported to treat tumor effectively. However, its impact on glioma stem cells (GSC) is unknown. Using seven GSC lines, the anti-tumo Show more
Cyanidin has a protective effect on the nervous system and has been reported to treat tumor effectively. However, its impact on glioma stem cells (GSC) is unknown. Using seven GSC lines, the anti-tumor effect of cyanidin is tested. The effect of cyanidin on the cell viability in each cell line is evaluated. Wnt signaling pathway-related genes are checked after treatment of cyanidin. Cytoplasmic/nuclear β-catenin protein levels post cyanidin treatment is detected. Protein levels of c-Myc after cyanidin treatment are determined. Twist1 and Snail1 protein levels after cyanidin treatment are checked as well. Cyanidin significantly reduces the cell viability of all GSCs, and exhibited the most substantial effect in GBM2 but no apparent effect in 293T cells. It can regulate the Wnt signaling pathway of all GSC lines. In the GBM2, GBM7, G166, and G179 cell lines, there is upregulation of Cyanidin exerts an anti-tumor effect in glioma stem cell lines, probably through the Wnt signaling pathway. Show less
Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Show more
Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75-/-) mice. Gpr75-/- mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob-mutant (Lepob-mutant) mice and adenylate cyclase 3-mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake. Show less
Cardiovascular disease (CVD) is the leading cause of death worldwide, and statin therapy is the cornerstone of atherosclerotic cardiovascular disease. However, clinical practice is unsatisfactory, and Show more
Cardiovascular disease (CVD) is the leading cause of death worldwide, and statin therapy is the cornerstone of atherosclerotic cardiovascular disease. However, clinical practice is unsatisfactory, and there is significant interest in the risk of residual cardiovascular events. Traditional study methods make it difficult to exclude the crosstalk of confounding factors, and we investigated the impact of the ApoB/ApoA1 ratio on CVD using two-sample Mendelian randomization (MR) and multivariate Mendelian randomization (MVMR) methods. Two-sample MR and MVMR analyses were performed using pooled statistics from genome-wide association studies (GWAS) of ApoB/ApoA1 ratio (BAR), lipoprotein (a) (Lp(a)), and triglyceride (TG) in Europeans to assess the causal relationship between BAR, Lp(a), and TG with coronary artery disease (CAD). The genetic prediction of BAR was significantly correlated with CAD (Inverse variance weighted (IVW) beta = 0.255; OR = 1.291; 95 % CI = 1.061-1.571; P = 0.011) in a two-sample MR analysis. MVMR studies showed that BAR (beta = 0.373; OR = 1.452; 95 % CI = 1.305-1.615; P = 7.217e-12), Lp (a) (beta = 0.238; OR = 1.269; 95 % CI = 1.216-1.323; P = 2.990e-28), and TG (beta = 0.155; OR = 1.168; 95 % CI = 1.074-1.270; P = 2.829e-04) were significantly associated with CAD. After further colinearity analyses of LASSO regressions, the results of multivariate analyses were similar for IVW, MR-Egger, MR-Lasso, and median methods. BAR is causally related to coronary artery disease. BAR is an independent predictor of CAD risk, independent of routine lipid measurements and other risk factors. TG and Lp(a) may be causally related to CAD, subject to verification in clinical practice. Show less
AXIN1 is a major component of the β-catenin destruction complex and is frequently mutated in various cancer types, particularly liver cancers. Truncating AXIN1 mutations are recognized to encode a def Show more
AXIN1 is a major component of the β-catenin destruction complex and is frequently mutated in various cancer types, particularly liver cancers. Truncating AXIN1 mutations are recognized to encode a defective protein that leads to β-catenin stabilization, but the functional consequences of missense mutations are not well characterized. Here, we first identified the GSK3β, β-catenin, and RGS/APC interaction domains of AXIN1 that are the most critical for proper β-catenin regulation. Analysis of 80 tumor-associated variants in these domains identified 18 that significantly affected β-catenin signaling. Coimmunoprecipitation experiments revealed that most of them lost binding to the binding partner corresponding to the mutated domain. A comprehensive protein structure analysis predicted the consequences of these mutations, which largely overlapped with the observed effects on β-catenin signaling in functional experiments. The structure analysis also predicted that loss-of-function mutations within the RGS/APC interaction domain either directly affected the interface for APC binding or were located within the hydrophobic core and destabilized the entire structure. In addition, truncated AXIN1 length inversely correlated with the β-catenin regulatory function, with longer proteins retaining more functionality. These analyses suggest that all AXIN1-truncating mutations at least partially affect β-catenin regulation, whereas this is only the case for a subset of missense mutations. Consistently, most colorectal and liver cancers carrying missense variants acquire mutations in other β-catenin regulatory genes such as APC and CTNNB1. These results will aid the functional annotation of AXIN1 mutations identified in large-scale sequencing efforts or in individual patients. Characterization of 80 tumor-associated missense variants of AXIN1 reveals a subset of 18 mutations that disrupt its β-catenin regulatory function, whereas the majority are passenger mutations. Show less
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients fr Show more
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients from 13 unrelated families who carried biallelic variants in the We detected 21 variants in three Patients with variants in the three Show less
Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and nega Show more
Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Show less
Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim Show more
Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL. Show less
Rosette-Forming Glioneuronal Tumors (RGNTs) are rare, typically benign central nervous system tumors primarily located in the fourth ventricle and pineal region. Despite being classified as WHO grade Show more
Rosette-Forming Glioneuronal Tumors (RGNTs) are rare, typically benign central nervous system tumors primarily located in the fourth ventricle and pineal region. Despite being classified as WHO grade I with generally favorable prognoses, RGNTs present complexities in their molecular mechanisms, occasional malignant transformation, and epidemiological characteristics that require further investigation. This study systematically reviews the existing literature to analyze the epidemiological patterns, MRI characteristics, pathological features, diagnostic challenges, and molecular mechanisms associated with RGNTs, aiming to provide a comprehensive theoretical foundation for clinical practice and future research. Through an in-depth review of recent studies, key molecular mechanisms, including mutations in This study concludes that while current treatment strategies focus on surgical resection, integrating molecular diagnostics and targeted therapies may be essential for managing recurrent or refractory RGNTs. Future research should explore the impact of various gene mutations on tumor behavior and their correlation with clinical outcomes, to optimize individualized therapeutic strategies and improve patient survival and quality of life. Show less
Cancer stem cells (CSCs) contribute to metastasis and drug resistance to immunotherapy in lung adenocarcinoma (LUAD), so the stemness evaluation of cancer cells is of great significance. The single-ce Show more
Cancer stem cells (CSCs) contribute to metastasis and drug resistance to immunotherapy in lung adenocarcinoma (LUAD), so the stemness evaluation of cancer cells is of great significance. The single-cell RNA sequencing (scRNA-seq) data of the GSE149655 dataset were collected and analyzed. Malignant cells were distinguished by CopyKAT. CytoTRACE score of marker genes in malignant cells was counted by CytoTRACE to construct the stemness score formula. Sample stemness score in TCGA was determined by the formula and divided into high-, medium- and low-stemness score groups. LASSO and COX regression analyses were carried out to screen the key genes related to the prognosis of LUAD from the differentially expressed genes (DEGs) in high- and low-stemness score groups and a risk score model was constructed. Seven types of cells were identified from a total of 4 samples, and 193 marker genes of 3455 malignant cells were identified. There were 1098 DEGs between low- and high-stemness score groups of TCGA, of which CPS1, CENPK, GJB3, and TPSB2 constituted gene signatures. The 4-gene signature could independently evaluate LUAD survival in the training and validation sets and showed an acceptable area under the receiver operator characteristic (ROC) curves (AUCs). This study provides insights into the cellular heterogeneity of LUAD and develops a new cancer stemness evaluation indicator and a 4-gene signature as a potential tool for evaluating the response of LUAD to immune checkpoint blockade (ICB) therapy or antineoplastic therapy. Show less
Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible ca Show more
Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation. Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence. We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived. Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated "Endothelial-Monocyte-Neutrophil" axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD. Show less
FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molec Show more
FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aβ We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD. Show less