Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly disco Show more
Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146. Show less
BACE1 is the rate-limiting enzyme for β-amyloid (Aβ) production and therefore is considered a prime drug target for treating Alzheimer's disease (AD). Nevertheless, the BACE1 inhibitors failed in clin Show more
BACE1 is the rate-limiting enzyme for β-amyloid (Aβ) production and therefore is considered a prime drug target for treating Alzheimer's disease (AD). Nevertheless, the BACE1 inhibitors failed in clinical trials, even exhibiting cognitive worsening, implying that BACE1 may function in regulating cognition-relevant neural circuits. Here, we found that parvalbumin-positive inhibitory interneurons (PV INs) in hippocampal CA1 express BACE1 at a high level. We designed and developed a mouse strain with conditional knockout of BACE1 in PV neurons. The CA1 fast-spiking PV INs with BACE1 deletion exhibited an enhanced response of postsynaptic N-methyl-D-aspartate (NMDA) receptors to local stimulation on CA1 oriens, with average intrinsic electrical properties and fidelity in synaptic integration. Intriguingly, the BACE1 deletion reorganized the CA1 recurrent inhibitory motif assembled by the heterogeneous pyramidal neurons (PNs) and the adjacent fast-spiking PV INs from the superficial to the deep layer. Moreover, the conditional BACE1 deletion impaired the AMPARs-mediated excitatory transmission of deep CA1 PNs. Further rescue experiments confirmed that these phenotypes require the enzymatic activity of BACE1. Above all, the BACE1 deletion resets the priming of the fear memory extinction. Our findings suggest a neuron-specific working model of BACE1 in regulating learning and memory circuits. The study may provide a potential path of targeting BACE1 and NMDAR together to circumvent cognitive worsening due to a single application of BACE1 inhibitor in AD patients. Show less
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor Show more
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor DNA in stage IV GC have not yet been reported. We used next-generation sequencing (NGS) to analyze cfDNA and tumor DNA in 56 stage IV GC patients. Tumor DNA and cfDNA were analyzed using a 29-gene NGS panel. In tumor samples, the most commonly mutated gene was Show less
Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing w Show more
Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples, whose genomic characteristics and clinicopathologic features were also analyzed. Structural variations were identified in all patients with a mean of 349, which did not significantly influence prognosis. Copy loss occurred in all samples, while gains were detected in 77.9% of the samples. The high level of copy number variations was significantly associated with poor progression-free survival (PFS) and overall survival (OS). A total of 263 genes mutated in coding regions were identified, including 6 newly discovered genes (ROBO2, KMT2C, CXCR4, MYOM2, BCLAF1, and NRXN3) detected in ⩾ 10% of the cases. CD79B mutation was significantly associated with lower PFS, TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS. A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL. Show less
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestina Show more
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier. Show less
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole- Show more
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease. Show less
The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose Show more
The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose metabolism and decrease the expression of AD-related proteins. However, the effects of the combined intervention are unclear. The present study explored the effects of the supplementation of MCTs combined with DHA in improving brain glucose metabolism and decreasing AD-related protein expression levels in APP/PS1 mice. The mice were assigned into four dietary treatment groups: the control group, MCTs group, DHA group, and MCTs + DHA group. The corresponding diet of the respective groups was fed to mice from the age of 3 to 11 months. The results showed that the supplementation of MCTs combined with DHA could increase serum octanoic acid (C8:0), decanoic acid (C10:0), DHA, and β-hydroxybutyrate (β-HB) levels; improve glucose metabolism; and reduce nerve cell apoptosis in the brain. Moreover, it also aided with decreasing the expression levels of amyloid beta protein (Aβ), amyloid precursor protein (APP), β-site APP cleaving enzyme-1 (BACE1), and presenilin-1 (PS1) in the brain. Furthermore, the supplementation of MCTs + DHA was significantly more beneficial than that of MCTs or DHA alone. In conclusion, the supplementation of MCTs combined with DHA could improve energy metabolism in the brain of APP/PS1 mice, thus decreasing nerve cell apoptosis and inhibiting the expression of Aβ. Show less
In this work, a simple and sensitive electrochemical sensor was proposed for the detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity. Firstly, the BACE1 specific peptide w Show more
In this work, a simple and sensitive electrochemical sensor was proposed for the detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity. Firstly, the BACE1 specific peptide was modified onto the Au electrode to graft a single-strand DNA with polycytosine DNA sequence (dC Show less
Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in GBS. We measured the serum lipi Show more
Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in GBS. We measured the serum lipids profile in 85 GBS patients and compared it with that of 85 healthy controls matched for age and sex. Additionally, we analyzed the correlation between lipids and the severity, subtypes, precursor infections, clinical outcomes, clinical symptoms, immunotherapy, and other laboratory markers of GBS. Compared to the healthy controls, GBS exhibited significantly elevated levels of Apolipoprotein B (APOB), Apolipoprotein C2 (APOC2), Apolipoprotein C3 (APOC3), Apolipoprotein E (APOE), triglycerides (TG), and residual cholesterol (RC). Conversely, Apolipoprotein A1 (APOA1), Apolipoprotein A2 (APOA2), and high-density lipoprotein (HDL) were substantially lower in GBS. Severe GBS displayed noticeably higher levels of APOC3 and total cholesterol (TC) compared to those with mild disease. Regarding different clinical outcomes, readmitted GBS demonstrated higher RC expression than those who were not readmitted. Moreover, GBS who tested positive for neuro-virus antibody IGG in cerebrospinal fluid (CSF) exhibited heightened expression of APOC3 in comparison to those who tested negative. GBS with cranial nerve damage showed significantly reduced expression of HDL and APOA1 than those without such damage. Additionally, GBS experiencing limb pain demonstrated markedly decreased HDL expression. Patients showed a significant reduction in TC after intravenous immunoglobulin therapy. We observed a significant positive correlation between lipids and inflammatory markers, including TNF-α, IL-1β, erythrocyte sedimentation rate (ESR), white blood cells, monocytes, and neutrophils in GBS. Notably, APOA1 exhibited a negative correlation with ESR. Furthermore, our findings suggest a potential association between lipids and the immune status of GBS. The research demonstrated a strong connection between lipids and the severity, subtypes, clinical outcomes, precursor infections, clinical symptoms, immunotherapy, inflammation, and immune status of GBS. This implies that a low-fat diet or the use of lipid-lowering medications may potentially serve as an approach for managing GBS, offering a fresh viewpoint for clinical treatment of this condition. Show less
RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few re Show more
RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few reports on the regulatory effects of DUSP6 expression on hair follicle stem cells (HFSCs) and cellular processes, as well as the underlying mechanism. Here, we investigated the effect of DUSP6 level in HFSCs and the molecular mechanism underlying the functional regulation of HFSCs by DUSP6. Overexpression of DUSP6 significantly suppressed the proliferation of HFSCs by inducing cell cycle arrest in the G1 phase and by promoting apoptosis. Transcriptome analysis revealed a total of 217 differentially expressed genes between DUSP6-overexpressing and control HFSCs, of which 33 (15.2%) were upregulated in DUSP6-overexpressing cells. The two pathways with the most significant enrichment of differentially expressed genes were the TNF signaling pathway and cytokine-cytokine receptor interaction pathway, and the significantly enriched terms in the GO enrichment analysis involved cell attachment and cytokines. These results indicate that DUSP6 can function as an inhibitory factor in HFSCs through the induction of cell cycle arrest in the G1 phase and can promote apoptosis by mediating crosstalk among several pathways and cytokines.HighlightsWe constructed DUSP6 overexpression vectors to detect mRNA and protein expression levels related to high-quality brush hair in MAPK signaling pathway.We found that high expression level of DUSP6 can inhibit the proliferation of hair follicle stem cells (HFSCs) and promote cell apoptosis of HFSCs.DUSP6 may be involved in the growth regulation of HFSCs like Other studies in cancer, tumors by regulating the expression of cytokines, changing the transmission of signals between cells, activating or suppressing immune-related pathways. Show less
Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show tha Show more
Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493-encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA-binding protein PABPC4 and transferred to ribosomes for translation of a 95-amino-acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N-terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK-mediated AKT phosphorylation. Moreover, the formation of the SMIM26-AGK-SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493-encoded microprotein SMIM26 and establishes its anti-metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers. Show less
Atg11 is an adaptor protein required for the induction of selective autophagy via receptor binding. However, our understanding of the molecular mechanisms by which it regulates selective autophagy rem Show more
Atg11 is an adaptor protein required for the induction of selective autophagy via receptor binding. However, our understanding of the molecular mechanisms by which it regulates selective autophagy remains incomplete. Here, we show that Atg11 is phosphorylated by Atg1. Rapamycin treatment or starvation conditions induced slower electrophoretic mobility of Atg11 in an Atg1 kinase activity-dependent manner. Through Show less
Ulcerative colitis (UC) is a chronic and debilitating inflammatory bowel disease that impairs quality of life. Cuproptosis, a recently discovered form of cell death, has been linked to many inflammato Show more
Ulcerative colitis (UC) is a chronic and debilitating inflammatory bowel disease that impairs quality of life. Cuproptosis, a recently discovered form of cell death, has been linked to many inflammatory diseases, including UC. This study aimed to examine the biological and clinical significance of cuproptosis-related genes in UC. Three gene expression profiles of UC were obtained from the Gene Expression Omnibus (GEO) database to form the combined dataset. Differential analysis was performed based on the combined dataset to identify differentially expressed genes, which were intersected with cuproptosis-related genes to obtain differentially expressed cuproptosis-related genes (DECRGs). Machine learning was conducted based on DECRGs to identify signature genes. The prediction model of UC was established using signature genes, and the molecular subtypes related to cuproptosis of UC were identified. Functional enrichment analysis and immune infiltration analysis were used to evaluate the biological characteristics and immune infiltration landscape of signature genes and molecular subtypes. Seven signature genes (ABCB1, AQP1, BACE1, CA3, COX5A, DAPK2, and LDHD) were identified through the machine learning algorithms, and the nomogram built from these genes had excellent predictive performance. The 298 UC samples were divided into two subtypes through consensus cluster analysis. The results of the functional enrichment analysis and immune infiltration analysis revealed significant differences in gene expression patterns, biological functions, and enrichment pathways between the cuproptosis-related molecular subtypes of UC. The immune infiltration analysis also showed that the immune cell infiltration in cluster A was significantly higher than that of cluster B, and six of the characteristic genes (excluding BACE1) had higher expression levels in subtype B than in subtype A. This study identified several promising signature genes and developed a nomogram with strong predictive capabilities. The identification of distinct subtypes of UC enhances our current understanding of UC's underlying pathogenesis and provides a foundation for personalized diagnosis and treatment in the future. Show less
Phthalates are widely used synthetic chemicals that determine endocrine disruption effects on female reproductivity and oviposition. Our study demonstrated that the mitochondrial quality in ovarian gr Show more
Phthalates are widely used synthetic chemicals that determine endocrine disruption effects on female reproductivity and oviposition. Our study demonstrated that the mitochondrial quality in ovarian granulosa cells (GCs) is associated with a poor prognosis in female reproduction. However, the molecular mechanism of di-(2-ethylhexyl) phthalate (DEHP) exposure on the quail ovarian GC layer is still unknown. To validate the effects of DEHP on the GC layer, 8 days' old 150 female Japanese quail were treated orally with DEHP (250, 500, and 750 mg/kg BW/day) for 45 days to explore the toxic effects of DEHP on the ovarian GC layer. Histopathological assessment and ultrastructure observation found that DEHP decreased the thickness of the GC layer, resulted in mitochondrial damage, and activated mitocytosis. Additionally, the results further suggested that DEHP impacted the secretion of steroid hormones (reduced FSH, E2, and T levels and boosted Prog, PRL, and LH levels) by triggering mitocytosis (enhanced transcription of Show less
Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, Show more
Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, asthma and lung cancer on human. Long non-coding RNAs (lncRNAs) are considered as important regulator in promotion and progression of diverse cancers. However, the molecular mechanism of lncRNAs mediating PM-induced lung carcinogenesis remains unclear. In this study, we established a 16HBE malignant transformed cell induced by PM (Cells were treated with 20 μg/ml PM, which named PM-T cells) and explored the roles and mechanisms of lncRNAs in the malignant transformation induced by PM. Compared with 16HBE cells, various biological functions were changed in PM-T cells, such as cell proliferation, migration, cell cycle and apoptosis. LncRNA SPRY4-IT1 was significant down-regulated expression and associated with these biological effects. Our results showed that lncRNA SPRY4-IT1 overexpression reversed these functional changes mentioned above. The further studies indicated that lncRNA SPRY4-IT1 involved in PM-induced cell transformation by modulating Chk1 expression via negative regulation of DUSP6-ERK1/2. In conclusion, our studies suggested that lncRNA SPRY4-IT1 played the role as a tumor suppressor gene and might mediate 16HBE cells malignant transformation induced by PM through regulating DUSP6-ERK1/2-Chk1 signaling pathway. Show less
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present Show more
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non-muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co-immunoprecipitation, GST pull-down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non-muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin-specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co-expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10-MYH9-snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. Show less
Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and de Show more
Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and depression comorbidity. The gene expression profiles of psoriasis (GSE34248, GSE78097 and GSE161683) and depression (GSE39653) were downloaded from the Gene Expression Omnibus (GEO) DataSets. Functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis were performed, following identification of the common differentially expressed genes (DEGs) of psoriasis and depression. A total of 115 common DEGs (55 up-regulated and 60 down-regulated) were identified between psoriasis and depression. Functional analysis indicated that T cell activation and differentiation were predominantly implicated in the potential pathogenesis of these two diseases. In addition, Th17 cell differentiation and cytokines is closely related to both. Finally, 17 hub genes were screened, including CTLA4, LCK, ITK, IL7R, CD3D, SOCS1, IL4R, PRKCQ, SOCS3, IL23A, PDGFB, PAG1, TGFA, FGFR1, RELN, ITGB5 and TNXB, which re-emphasized the importance of the immune system in psoriasis and depression. Our study reveals the common pathogenesis of psoriasis and depression. These common pathways and hub genes may apply to a molecular screening tool for depression in psoriasis patients, which could help dermatologists optimize patient management in routine care. Show less
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 o Show more
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 on B cell metabolism and clarify the mechanisms via which IL-27 enhancing glycolysis to induce B cells hyperactivation. Peripheral CD19 Show less
This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. We examin Show more
This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes. Show less
Obesity has emerged as a critical and urgent health burden during the current global pandemic. Among multiple genetic causes, melanocortin receptor-4 (MC4R), involved in food intake and energy metabol Show more
Obesity has emerged as a critical and urgent health burden during the current global pandemic. Among multiple genetic causes, melanocortin receptor-4 (MC4R), involved in food intake and energy metabolism regulation through various signaling pathways, has been reported to be the lead genetic factor in severe and early onset obesity and hyperphagia disorders. Most previous studies have illustrated the roles of MC4R signaling in energy intake versus expenditure in the central system, while some evidence indicates that MC4R is also expressed in peripheral systems, such as the gut and endocrine organs. However, its physiopathological function remains poorly defined. This review aims to depict the central and peripheral roles of MC4R in energy metabolism and endocrine hormone homeostasis, the diversity of phenotypes, biased downstream signaling caused by distinct MC4R mutations, and current drug development targeting the receptor. Show less
The renal interstitial fibrosis contributes to the progression and deterioration of diabetic nephropathy (DN). Long noncoding RNA taurine-up-regulated gene 1 (TUG1) in kidneys may be down-regulated by Show more
The renal interstitial fibrosis contributes to the progression and deterioration of diabetic nephropathy (DN). Long noncoding RNA taurine-up-regulated gene 1 (TUG1) in kidneys may be down-regulated by hyperglycemia. We aim to explore its role in tubular fibrosis caused by high glucose and the possible target genes of TUG1. In this study, a streptozocin-induced accelerated DN mouse model and a high glucose-stimulated HK-2 cells model was established to evaluate TUG1 expression. Potential targets of TUG1 were analyzed by online tools and confirmed by luciferase assay. A rescue experiment and gene silencing assay were used to investigate whether TUG1 plays its regulation role Show less
Laura Schnöder, Wenqiang Quan, Ye Yu+7 more · 2023 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-β-peptide (Aβ) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mech Show more
In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-β-peptide (Aβ) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKβ specifically in neurons, and observed that IKKβ deficiency reduced cerebral Aβ and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKβ decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKβ deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKβ in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKβ deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aβ production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKβ deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aβ and p-tau, before IKKβ/NF-κB can be targeted for AD therapies. Show less
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophag Show more
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycan on Aβ Show less
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and Show more
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate Show less
Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expres Show more
Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expression patterns and molecular bases underlying thermo-resistant heterosis in Crassostrea gigas ♀ × Crassostrea angulata ♂ (GA) and C. angulata ♀ × C. gigas ♂ (AG). About 505 million clean reads were obtained, and 38,210 genes were identified, of which 3779 genes were differentially expressed between the reciprocal hybrids and purebreds. The global gene expression levels were toward the C. gigas genome in the reciprocal hybrids. In GA and AG, 95.69% and 92.00% of the differentially expressed genes (DEGs) exhibited a non-additive expression pattern, respectively. We observed all gene expression modes, including additive, partial dominance, high and low dominance, and under- and over-dominance. Of these, 77.52% and 50.00% of the DEGs exhibited under- or over-dominance in GA and AG, respectively. The over-dominance DEGs common to reciprocal hybrids were significantly enriched in protein folding, protein refolding, and intrinsic apoptotic signaling pathway, while the under-dominance DEGs were significantly enriched in cell cycle. As possible candidate genes for thermo-resistant heterosis, GRP78, major egg antigen, BAG, Hsp70, and Hsp27 were over-dominantly expressed, while MCM6 and ANAPC4 were under-dominantly expressed. This study extends our understanding of the thermo-resistant heterosis in oysters. Show less
EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior o Show more
EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore the mechanism of miR-BART1-3p transmission through the exosome pathway and its influence on tumor cell proliferation and invasion. Exosomes of EBV-positive and EBV-negative gastric cancer cells were characterized by transmission electron microscopy. NanoSight and Western blotting, and miRNA expression profiles in exosomes were sequenced with high throughput. Exosomes with high or low expression of miR-BART1-3p were co-cultured with AGS cells to study the effects on proliferation, invasion, and migration of gastric cancer cells. The target genes of EBV-miR-BART1-3p were screened and predicted by PITA, miRanda, RNAhybrid, virBase, and DIANA-TarBase v.8 databases, and the expression of the target genes after co-culture was detected by qPCR. The exosomes secreted by EBV-positive and negative gastric cancer cells range in diameter from 30 nm to 150 nm and express the exosomal signature proteins CD9 and CD63. Small RNA sequencing showed that exosomes expressed some human miRNAs, among which hsa-miR-23b-3p, hsa-miR-320a-3p, and hsa-miR-4521 were highly expressed in AGS-exo; hsa-miR-21-5p, hsa-miR-148a-3p, and hsa-miR-7-5p were highly expressed in SNU-719-exo. All EBV miRNAs were expressed in SNU-719 cells and their exosomes, among which EBV-miR-BART1-5p, EBV-miR-BART22, and EBV-miR-BART16 were the highest in SNU-719 cells; EBV-miR-BART1-5p, EBV-miR-BART10-3p, and EBV-miR-BART16 were the highest in SNU-719-exo. After miR-BART1-3p silencing in gastric cancer cells, the proliferation, healing, migration, and invasion of tumor cells were significantly improved. Laser confocal microscopy showed that exosomes could carry miRNA into recipient cells. After co-culture with miR-BART1-3p silenced exosomes, the proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved. The target gene of miR-BART1-3p was FAM168A, MACC1, CPEB3, ANKRD28, and USP37 after screening by a targeted database. CPEB3 was not expressed in all exosome co-cultured cells, while ANKRD28, USP37, MACC1, and FAM168A were all expressed to varying degrees. USP37 and MACC1 were down-regulated after up-regulation of miR-BART1-3p, which may be the key target genes for miR-BART1-3p to regulate the proliferation of gastric cancer cells through exosomes. miR-BART1-3p can affect the growth of tumor cells through the exosome pathway. The proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved after co-culture with exosomes of miR-BART1-3p silenced expression. USP37 and MACC1 may be potential target genes of miR-BART1-3p in regulating cell proliferation. Show less
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations bet Show more
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies. Show less
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflamm Show more
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA. Show less
The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/β-catenin is a frequently dysregulated sig Show more
The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/β-catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/β-catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and β-catenin and supports the phase transition of β-catenin. Both processes suppress Wnt/β-catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/β-catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation. Show less