Zhen Zhang, Yun-Xin Lu, Fangzhou Liu+16 more · 2023 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing t Show more
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) Show less
To compare and analyze the molecular mechanisms of adipose deposition in subcutaneous fat (SAF)and intramuscular fat (IMF) tissues in Ningxiang pigs, differential gene expression profiles in SAF and I Show more
To compare and analyze the molecular mechanisms of adipose deposition in subcutaneous fat (SAF)and intramuscular fat (IMF) tissues in Ningxiang pigs, differential gene expression profiles in SAF and IMF tissues of Ningxiang pigs were identified and analysed using RNA-seq technology. Six healthy 250-day-old male Ningxiang pigs with similar body weights (approximately 85 kg) of intraspecific individuals were selected as experimental material and samples of SAF and IMF tissues were collected. Differential genes associated with fat deposition and lipid metabolism were obtained by sequencing two adipose tissue transcriptomes and performing GO (Gene Ontology) functional annotation and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis. To verify the reliability of the sequencing results, six differential genes were randomly selected to validate using qRT-PCR. The results showed that we identified 2406 DEGs, with 1422 up-regulated and 984 down-regulated genes in two tissues. GO functional annotation analysis revealed that the differentially expressed genes were mainly involved in lipid metabolism related pathways, such as steroid biosynthesis, unsaturated fatty acid biosynthesis, glycerophospholipid metabolism and autophagy pathway. KEGG pathway enrichment showed that the differentially expressed genes were mainly enriched in the biological processes related to lipid binding, fatty acid metabolism, glycol ester metabolism, lipid biosynthesis and other biological processes related to lipid metabolism. Genes related to lipid metabolism, such as TCAP, NR4A1, ACACA, LPL, ELOVL6, DGAT1, PRKAA1, ATG101, TP53INP2, FDFT1, ACOX1 and SCD were identified by bioinformatic analyses and verified by qRT-PCR. Our results indicated that these genes may play important roles in the regulation of fat deposition and metabolism in the SAF and IMF tissue, providing the further mechanistic investigation of fat deposition in Ningxiang pigs. Show less
Since the prognosis of patients with pancreatic cancer is very poor and there is a lack of treatment methods, this study is performed to investigate the function of PITX2 in pancreatic stellate cells Show more
Since the prognosis of patients with pancreatic cancer is very poor and there is a lack of treatment methods, this study is performed to investigate the function of PITX2 in pancreatic stellate cells (PSCs) in the progression of pancreatic cancer. Scientific hypotheses are proposed according to bioinformatics analysis and tissue microarray analysis. Stable knockdown of Show less
What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabe Show more
What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabetes in patients treated with rosuvastatin? What is the main finding and its importance? Rosuvastatin therapy reduced intraperitoneal glucose tolerance and changed the catabolism of branched-chain amino acid (BCAAs) in white adipose tissue and skeletal muscle. Protein phosphatase 2Cm knockdown completely abolished the effects of insulin and rosuvastatin on glucose absorption. This study provides mechanistic support for recent clinical data on rosuvastatin-related new-onset diabetes and underscores the logic for intervening in BCAA catabolism to prevent the harmful effects of rosuvastatin. Accumulating evidence indicates that patients treated with rosuvastatin have an increased risk of developing new-onset diabetes. However, the underlying mechanism remains unclear. In this study, we administered rosuvastatin (10 mg/kg body weight) to male C57BL/6J mice for 12 weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin-treated mice showed considerably higher serum levels of branched-chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolism-related enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of BCAT2 and protein phosphatase 2Cm (PP2Cm) and upregulated mRNA expression of branched-chain ketoacid dehydrogenase kinase (BCKDK). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin-treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels. We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 β (GSK3β) phosphorylation. These effects of insulin were prevented by co-incubation of the cells with 25 μM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3β signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin. Show less
Gui-Feng Zhou, Jing Tang, Yuan-Lin Ma+13 more · 2023 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferent Show more
Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD. Show less
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
This report presents a case of a male infant, aged 32 days, who was admitted to the hospital due to 2 days of bloody stools and 1 day of fever. Upon admission, venous blood samples were collected, whi Show more
This report presents a case of a male infant, aged 32 days, who was admitted to the hospital due to 2 days of bloody stools and 1 day of fever. Upon admission, venous blood samples were collected, which appeared pink. Blood biochemistry tests revealed elevated levels of triglycerides and total cholesterol. The familial whole genome sequencing revealed a compound heterozygous variation in the Show less
Osteoarthritis (OA) is a common degenerative joint disease and causes chronic pain and disability to the elderly. Several risk factors are involved, such as aging, obesity, genetic susceptibility, and Show more
Osteoarthritis (OA) is a common degenerative joint disease and causes chronic pain and disability to the elderly. Several risk factors are involved, such as aging, obesity, genetic susceptibility, and environmental factors. We conducted a transcriptome-wide association study (TWAS) and chemical-related gene set enrichment analysis (CGSEA) to investigate the susceptibility genes and environmental factors. TWAS analysis was conducted to identify the susceptibility genes by integrating the summary-level genome-wide association study data of knee OA (KOA) and hip OA (HOA) with the precomputed expression weights from the Genotype-Tissue Expression Project (Version 8). The FUSION software was used for both single-tissue and cross-tissue TWAS, which were combined using an aggregate Cauchy association test. The biological function and pathways of the TWAS genes were explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases, and the human cartilage mRNA expression profiles were utilized to validate the TWAS genes. CGSEA analysis was performed to scan the OA-associated chemicals by integrating the TWAS results with the chemical-related gene sets. There were 44 and 93 unique TWAS genes identified in 7 and 11 chromosomes for KOA and HOA, respectively, fourteen and four of which showed significantly differential expression in the mRNA profiles, such as CRHR1, LTBP1, WWP2, LMX1B, and PTHLH. OA-related pathways were found in the KEGG and GO analysis, such as TGF-beta signaling pathway, MAPK signaling pathway, hyaluronan metabolic process, and chondrocyte differentiation. Forty-five OA-associated chemicals were identified, including quercetin, bisphenol A, and cadmium chloride. Several candidate OA-associated genes and chemicals were identified through TWAS and CGSEA analysis, which expanded our understanding of the relationship between genes, chemicals, and their impact on OA. Show less
Environmental, genetic, and microbial factors are independently associated with childhood asthma. We sought to determine the roles of environmental exposures and 17q12-21 locus genotype in the maturat Show more
Environmental, genetic, and microbial factors are independently associated with childhood asthma. We sought to determine the roles of environmental exposures and 17q12-21 locus genotype in the maturation of the early-life microbiome in childhood asthma. We analyzed fecal 16s rRNA sequencing at age 3 to 6 months and age 1 year to characterize microbial maturation of offspring of participants in the Vitamin D Antenatal Reduction Trial. We determined associations of microbial maturation and environmental exposures in the mediation of asthma risk at age 3 years. We examined 17q12-21 genotype and microbial maturation associations with asthma risk in Vitamin D Antenatal Reduction Trial and the replication cohort Copenhagen Prospective Studies on Childhood Asthma 2010. Accelerated fecal microbial maturation at age 3 to 6 months and delayed maturation at age 1 year were associated with asthma (P < .001). Fecal Bacteroides was reduced at age 3 to 6 months in association with subsequent asthma (P = .006) and among subjects with lower microbial maturation at age 1 year (q = 0.009). Sixty-one percent of the association between breast-feeding and asthma was mediated by microbial maturation at age 3 to 6 months. Microbial maturation and 17q12-21 genotypes exhibited independent, additive effects on childhood asthma risk. The intestinal microbiome and its maturation mediates associations between environmental exposures including breast-feeding and asthma. The intestinal microbiome and 17q12-21 genotype appear to exert additive and independent effects on childhood asthma risk. Show less
Nanoplastics and di(2-ethylhexyl) phthalate (DEHP) are ubiquitous emerging contaminants that are transferred among organisms through food chain in the ecosystem. This study evaluated the trophic trans Show more
Nanoplastics and di(2-ethylhexyl) phthalate (DEHP) are ubiquitous emerging contaminants that are transferred among organisms through food chain in the ecosystem. This study evaluated the trophic transfer of polystyrene nanoplastics (PSNPs) and DEHP in a food chain including Chlorella pyrenoidosa, Daphnia magna and Micropterus salmoides (algae-crustacean-fish) and lipid metabolism at a higher trophic level in fish. Our results showed that the PSNPs and DEHP accumulated in C. pyrenoidosa or D. magna were transferred to the M. salmoides, of which the DEHP were not biomagnified, while the PSNPs were trophically amplified by the food chain. It is suggested that more PSNPs might be accumulated by higher level consumers in a longer food chain. Additionally, the trophic transfer of PSNPs and DEHP resulted in antioxidant response and histopathological damage in M. salmoides. Moreover, the lipid biochemical parameters and lipid metabolism related genes (fasn, hsl, cpt1a, atgl, apob, fabp1, lpl, cetp) of M. salmoides were significantly affected, which indicated disturbance of lipid metabolism. This study offers great insight into the transfer of contaminants by trophic transfer and their negative effects on organisms at higher trophic levels, which cause human exposure to MNPs and organic contaminants in the ecosystem. Show less
The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain uncl Show more
The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing. Show less
The purpose of this study was to investigate genetic factors associated with metabolic syndrome (MetS) by conducting a large-scale genome-wide association study (GWAS) in Taiwan, addressing the limite Show more
The purpose of this study was to investigate genetic factors associated with metabolic syndrome (MetS) by conducting a large-scale genome-wide association study (GWAS) in Taiwan, addressing the limited data on Asian populations compared to Western populations. Using data from the Taiwan Biobank, comprehensive clinical and genetic information from 107,230 Taiwanese individuals was analyzed. Genotyping data from the TWB1.0 and TWB2.0 chips, including over 650,000 single nucleotide polymorphisms (SNPs), were utilized. Genotype imputation using the 1000 Genomes Project was performed, resulting in more than 9 million SNPs. MetS was defined based on a modified version of the Adult Treatment Panel III criteria. Among all participants (mean age: 50 years), 23% met the MetS definition. GWAS analysis identified 549 SNPs significantly associated with MetS, collectively mapping to 10 genomic risk loci. Notable risk loci included rs1004558, rs3812316, rs326, rs4486200, rs2954038, rs10830963, rs662799, rs62033400, rs183130, and rs34342646. Gene-set analysis revealed 22 associated genes: Show less
The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state accor Show more
The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state according to their respective environment. Show less
Proline-rich coiled-coil 2C ( The Cancer Genome Atlas (TCGA) RNA-sequencing datasets of 371 cases of primary liver cancer and 50 normal liver tissue specimens were obtained to analyze correlation betw Show more
Proline-rich coiled-coil 2C ( The Cancer Genome Atlas (TCGA) RNA-sequencing datasets of 371 cases of primary liver cancer and 50 normal liver tissue specimens were obtained to analyze correlation between Analysis of TCGA data sets revealed that patients with high Show less
A major consequence of acute myocardial infarction is myocardial ischemia-reperfusion (I/R) injury. Collecting proof demonstrates that AXIN1 assume a basic part in different disease; however, the role Show more
A major consequence of acute myocardial infarction is myocardial ischemia-reperfusion (I/R) injury. Collecting proof demonstrates that AXIN1 assume a basic part in different disease; however, the role of AXIN1 in I/R injury remains to a great extent obscure. The I/R injury model on AC16 cells was constructed. siRNA transfection was used to knockdown AXIN1. The qRT-PCR assays and western blot assays were used to detect the expression level of AXIN1 and other key proteins. CCK-8 assays and cell apoptosis assays were used to detect cell proliferation and cell apoptosis. AXIN1 was significantly overexpressed in an in vitro model of I/R injury. Knockdown of AXIN1 significantly restored the cell proliferation inhibition caused by IR injury, while inhibiting apoptosis and inflammation. Further mechanistic studies revealed that the transcription factor c-Myc could regulate the expression of AXIN1. The effects of I/R injury on AC16 cells after overexpression of c-Myc were reversed by knockdown of AXIN1. Meanwhile, AXIN1 could regulate the SIRT1/p53/Nrf 2 pathway. Our results show an important role for AXIN1 and provide new targets for avoiding and treating I/R injury. Show less
LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated ca Show more
LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated cardiomyopathy(LMNA-DCM) is one of the more common laminopathy which characterized by progressive heart failure and arrhythmia. However, the mutation features of LMNA-DCM are yet to be elucidated. Herein we described a dilated cardiomyopathy family carrying novel variant c.467G > C(p.Arg156Pro) of LMNA as heterozygous pathogenic variant identified by whole-exome sequencing. With the help of Alphafold2, we predicted mutant protein structure and found an interrupted α-helix region in lamin A/C. In the analysis of 49 confirmed pathogenic missense of laminopathies, Chi-square test showed the DCM phenotype was related to the α-helix region mutation (p < 0.017). After screening the differentially expressed genes (DEGs) in both mice models and human patients in Gene Expression Omnibus database, we found the variation of α-helix-coding region in LMNA caused abnormal transcriptomic features in cell migration, collagen-containing extracellular matrix, and PI3K-Akt signaling pathway. Subsequently we constructed (TF)-mRNA-microRNA (miRNA) regulatory network and identified 7 key genes (FMOD, CYP1B1, CA3, F2RL1, HAPLIN1, SNAP91, and KANSL1) as potential biomarkers or therapeutic targets in LMNA-DCM patients. Show less
Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression o Show more
Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression of FGFR1 due to gene amplification, chromosome rearrangement, point mutation, and epigenetic deregulations, have been reported in various cancers. FGFR1 overexpression has also been reported in prostate cancer (PCa), but the underlining mechanisms are not clear. Here we report a novel circular RNA, circFGFR1 Show less
Senescence is significantly associated with cancer prognosis. This study aimed to construct a senescence-related prognostic model for colorectal cancer (CRC) and to investigate the influence of senesc Show more
Senescence is significantly associated with cancer prognosis. This study aimed to construct a senescence-related prognostic model for colorectal cancer (CRC) and to investigate the influence of senescence on the tumor microenvironment. Transcriptome and clinical data of CRC cases were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Senescence-related prognostic genes detected by univariate Cox regression were included in Least Absolute Shrinkage and Selection Operator (LASSO) analysis to construct a model. The efficacy of the model was validated using the receiver operating characteristic (ROC) curve and survival analysis. Differentially expressed genes (DEGs) were identified and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed. CIBERSORT and Immuno-Oncology Biological Research (IOBR) were used to investigate the features of the tumor microenvironment. Single-cell RNA-seq data were used to investigate the expression levels of model genes in various cell types. Immunofluorescence staining for p21, SPP1, and CD68 was performed with human colon tissues. A seven-gene (PTGER2, FGF2, IGFBP3, ANGPTL4, DKK1, WNT16 and SPP1) model was finally constructed. Patients were classified as high- or low-risk using the median score as the threshold. The area under the ROC curve (AUC) for the 1-, 2-, and 3-year disease-specific survival (DSS) were 0.731, 0.651, and 0.643, respectively. Survival analysis showed a better 5-year DSS in low-risk patients in the construction and validation cohorts. GO and KEGG analyses revealed that DEGs were enriched in extracellular matrix (ECM)-receptor interactions, focal adhesion, and protein digestion and absorption. CIBERSORT and IOBR analyses revealed an abundance of macrophages and an immunosuppressive environment in the high-risk subgroup. Low-risk patients had higher response rates to immunotherapy than high-risk patients. ScRNA-seq data revealed high expression of SPP1 in a subset of macrophages with strong senescence-associated secretory phenotype (SASP) features. Using CRC tumor tissues, we discovered that SPP1 Our study presents a novel model based on senescence-related genes that can identify CRC patients with a poor prognosis and an immunosuppressive tumor microenvironment. SPP1 Show less
Hepatocellular carcinoma (HCC) ranks the third leading cause of cancer deaths with a dismal 5-year survival rate. The mitogen-activated protein kinase (MAPK) signaling pathway is abnormally activated Show more
Hepatocellular carcinoma (HCC) ranks the third leading cause of cancer deaths with a dismal 5-year survival rate. The mitogen-activated protein kinase (MAPK) signaling pathway is abnormally activated in HCC to promote growth and aggressive metastatic potential of cancer cells. Therefore, genetic variants in the MAPK signaling pathway may serve as potential predictors of Hepatitis B virus (HBV)-related HCC survival. In the present study, we performed a two-stage survival analysis to evaluate the associations between 10,912 single nucleotide polymorphisms (SNPs) in 79 MAPK signaling pathway genes and the overall survival (OS) of 866 HBV-related HCC patients, followed by functional annotation. In combined datasets, we identified two novel and potential functional SNPs (RPS6KA4 rs600377 T>G and MAP2K5 rs17300363 A>C) as prognostic factors for HBV-related HCC, with adjusted allelic hazards ratios of 1.24 (95% confidence interval [CI] = 1.05-1.46, p = 0.010) and 1.48 (1.15-1.91, p = 0.001), respectively. Furthermore, their combined risk genotypes also predicted a poor survival in a dose-response manner in the combined data set (P Show less
Epidemiological evidence suggests that comorbidity of obesity and depression is extremely common and continues to grow in prevalence. However, the mechanisms connecting these two conditions are unknow Show more
Epidemiological evidence suggests that comorbidity of obesity and depression is extremely common and continues to grow in prevalence. However, the mechanisms connecting these two conditions are unknown. In this study, we explored how treatment with K Mice were fed with HFD for 12 weeks and then treated with recombinant FGF21 protein by infusion for 2 weeks, followed by intraperitoneal injection of 3 mg/kg recombinant FGF21 once per day for 4 days. Measurements were made of catecholamine levels, energy expenditure, biochemical endpoints and behavior tests, including sucrose preference and forced swim tests were. Alternatively, animals were infused with GB into brown adipose tissue (BAT). The WT-1 brown adipocyte cell line was used for molecular studies. Compared to HFD controls, HFD + FGF21 mice exhibited less severe metabolic disorder symptoms, improved depressive-like behaviors, and more extensive mesolimbic dopamine projections. FGF21 treatment also rescued HFD-induced dysregulation of FGF21 receptors (FGFR1 and co-receptor β-klotho) in the ventral tegmental area (VTA), and it altered dopaminergic neuron activity and morphology in HFD-fed mice. Importantly, we also found that FGF21 mRNA level and FGF21 release were increased in BAT after administration of GB, and GB treatment to BAT reversed HFD-induced dysregulation of FGF21 receptors in the VTA. GB administration to BAT stimulates FGF21 production in BAT, corrects HFD-induced dysregulation of FGF21 receptor dimers in VTA dopaminergic neurons, and attenuates depression-like symptoms. Show less
Glioblastoma (GBM) is one of the most common malignant brain tumors in adults and is characterized by high aggressiveness and rapid progression, poor treatment, high recurrence rate, and poor prognosi Show more
Glioblastoma (GBM) is one of the most common malignant brain tumors in adults and is characterized by high aggressiveness and rapid progression, poor treatment, high recurrence rate, and poor prognosis. Although super-enhancer (SE)-driven genes haven been recognized as prognostic markers for several cancers, whether it can be served as effective prognostic markers for patients with GBM has not been evaluated. We first combined histone modification data with transcriptome data to identify SE-driven genes associated with prognosis in patients with GBM. Second, we developed a SE-driven differentially expressed genes (SEDEGs) risk score prognostic model by univariate Cox analysis, KM survival analysis, multivariate Cox analysis and least absolute shrinkage and selection operator (LASSO) regression. Its reliability in predicting was verified by two external data sets. Third, through mutation analysis, immune infiltration, we explored the molecular mechanisms of prognostic genes. Next, Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map (cMap) database were employed to assess different sensitivities to chemotherapeutic agents and small-molecule drug candidates between high- and low-risk patients. Finally, SEanalysis database was chosen to identify SE-driven transcription factors (TFs) regulating prognostic markers which will reveal a potential SE-driven transcriptional regulatory network. First, we developed a 11-gene risk score prognostic model (NCF2, MTHFS, DUSP6, G6PC3, HOXB2, EN2, DLEU1, LBH, ZEB1-AS1, LINC01265, and AGAP2-AS1) selected from 1,154 SEDEGs, which is not only an independent prognostic factor for patients, but also can effectively predict the survival rate of patients. The model can effectively predict 1-, 2- and 3-year survival of patients and was validated in external Chinese Glioma Genome Atlas (CGGA) and Gene Expression Omnibus (GEO) datasets. Second, the risk score was positively correlated with the infiltration of regulatory T cell, CD4 memory activated T cell, activated NK cell, neutrophil, resting mast cell, M0 macrophage, and memory B cell. Third, we found that high-risk patients showed higher sensitivity than low-risk patients to both 27 chemotherapeutic agents and 4 small-molecule drug candidates which might benefit further precision therapy for GBM patients. Finally, 13 potential SE-driven TFs imply how SE regulates GBM patient's prognosis. The SEDEG risk model not only helps to elucidate the impact of SEs on the course of GBM, but also provides a bright future for prognosis determination and choice of treatment for GBM patients. Show less
Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study Show more
Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS). Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice. The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS. Show less
Dihydrxytetraphenylmethane, also known as Bisphenol BP (BPBP), has been increasingly used in industrial production and more frequently detected in the environment as an alternative plasticizer of BPA. Show more
Dihydrxytetraphenylmethane, also known as Bisphenol BP (BPBP), has been increasingly used in industrial production and more frequently detected in the environment as an alternative plasticizer of BPA. However, there are no reports about BPBP in food safety or its effects on cellular lipogenesis. The purpose of this research was to investigate the influence and potential mechanisms of BPBP on adipogenesis in 3T3-L1 cells. Cells were treated with 4 concentrations (0.01, 0.1, 1, and 10 μM) of BPBP and the results showed that treatment with at low concentrations (0.01 μM) promoted cell fat differentiation and triglyceride accumulation. RNA-seq data showed that a total of 370 differentially expressed genes between control and the low-dose BPBP-treated group were determined, including 227 upregulated genes and 143 downregulated genes. Some key genes related to adipocyte differentiation and adipogenesis were significantly enriched after BPBP treatment, including Show less
Müller cells play a critical role in the closure of macular holes, and their proliferation and migration are facilitated by the internal limiting membrane (ILM). Despite the importance of this process Show more
Müller cells play a critical role in the closure of macular holes, and their proliferation and migration are facilitated by the internal limiting membrane (ILM). Despite the importance of this process, the underlying molecular mechanism remains underexplored. This study investigated the effects of ILM components on the microRNA (miRNA) profile of Müller cells. Rat Müller cells (rMC-1) were cultured with a culture insert and varying concentrations of ILM component coatings, namely, collagen IV, laminin, and fibronectin, and cell migration was assessed by measuring cell-free areas in successive photographs following insert removal. MiRNAs were then extracted from these cells and analyzed. Mimics and inhibitors of miRNA candidates were transfected into Müller cells, and a cell migration assay and additional cell viability assays were performed. The results revealed that the ILM components promoted Müller cell migration ( Show less
African swine fever virus (ASFV) causes a devastating viral hemorrhagic disease in domestic pigs and Eurasian wild boars, posing a foremost threat to the swine industry and pig farming. The developmen Show more
African swine fever virus (ASFV) causes a devastating viral hemorrhagic disease in domestic pigs and Eurasian wild boars, posing a foremost threat to the swine industry and pig farming. The development of an effective vaccine is urgently needed, but has been hampered by the lack of an in-depth, mechanistic understanding of the host immune response to ASFV infection and the induction of protective immunity. In this study, we report that immunization of pigs with Semliki Forest Virus (SFV) replicon-based vaccine candidates expressing ASFV p30, p54, and CD2v, as well as their ubiquitin-fused derivatives, elicits T cell differentiation and expansion, promoting specific T cell and humoral immunity. Due to significant variations in the individual non-inbred pigs in response to the vaccination, a personalized analysis was conducted. Using integrated analysis of differentially expressed genes (DEGs), Venn, KEGG and WGCNA, Toll-like receptor, C-type lectin receptor, IL17 receptor, NOD-like receptor and nucleic acid sensor-mediated signaling pathways were demonstrated to be positively correlated to the antigen-stimulated antibody production and inversely correlated to the IFN-γ secreting cell counts in peripheral blood mononuclear cells (PBMCs). An up-regulation of CIQA, CIQB, CIQC, C4BPA, SOSC3, S100A8 and S100A9, and down-regulation of CTLA4, CXCL2, CXCL8, FOS, RGS1, EGR1 and SNAI1 are general in the innate immune response post-the second boost. This study reveals that pattern recognition receptors TLR4, DHX58/DDX58 and ZBP1, and chemokines CXCL2, CXCL8 and CXCL10 may play important roles in regulating this vaccination-stimulated adaptive immune response. Show less
MicroRNAs (miRNAs) play an essential role in cancer therapy, but the disadvantages of its poor inherent stability, rapid clearance, and low delivery efficiency affect the therapeutic efficiency. Loadi Show more
MicroRNAs (miRNAs) play an essential role in cancer therapy, but the disadvantages of its poor inherent stability, rapid clearance, and low delivery efficiency affect the therapeutic efficiency. Loading miRNAs by nanoformulations can improve their bioavailability and enhance therapeutic efficiency, which is an effective miRNA delivery strategy. In this study, we synthesized layered double hydroxides (LDH), which are widely used as carriers of drugs or genes due to the characteristics of good biocompatibility, high loading capacity, and pH sensitivity. We loaded the suppressor oncogene miR-30a on LDH nanomaterials (LDH@miR-30a) and determined the mass ratio of miRNA binding to LDH by agarose gel electrophoresis. LDH@miR-30a was able to escape the lysosomal pathway and was successfully phagocytosed by breast cancer SKBR3 cells and remained detectable in the cells after 24 h of co-incubation. In vitro experiments showed that LDH@miR-30a-treated SKBR3 cells showed decreased proliferation and cell cycle arrest in the G0/G1 phase and LDH@miR-30a was able to regulate the epithelial-mesenchymal transition (EMT) process and inhibit cell migration and invasion by targeting SNAI1. Meanwhile, in vivo experiments showed that nude mice treated with LDH@miR-30a showed a significant reduction in their solid tumors and no significant impairment of vital organs was observed. In conclusion, LDH@miR-30a is an effective drug delivery system for the treatment of breast cancer. Show less
Amyloid-β (Aβ) accumulation caused by an imbalance of the production and clearance of Aβ in the brain is associated with the development of Alzheimer's disease (ad). Apolipoprotein E (ApoE) (the stron Show more
Amyloid-β (Aβ) accumulation caused by an imbalance of the production and clearance of Aβ in the brain is associated with the development of Alzheimer's disease (ad). Apolipoprotein E (ApoE) (the strongest genetic risk factor) enhances Aβ clearance, preventing Aβ deposition. Sirtuin 2 (Sirt2) is an NAD+-dependent histone deacetylase and its inhibition has been reported to ameliorate memory impairment in ad-like model mice. However, the role of Sirt2 in ApoE secretion is unknown. Here, we found that inhibition of Sirt2 activity in primary cultured astrocytes and BV2 cells decreased ApoE secretion, resulting in the accumulation of intracellular ApoE and inhibiting extracellular Aβ degradation. However, the reduction of Sirt2 protein level by Sirt2 siRNA decreased ApoE protein level, which ultimately reduces ApoE secretion. In addition, the knockdown of Sirt2 in the HEK293-APP cells also decreased levels of intracellular ApoE leading to reduction of its secretion, which is accompanied by increased Aβ levels without altering APP and APP processing enzymes. Our findings provide a novel role of Sirt2 in ApoE secretion. Show less
Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune e Show more
Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8 Show less