In eukaryotic cells, both alternative splicing and alternative polyadenylation (APA) play essential roles in the gene regulation network. U1 small ribonucleoprotein particle (U1 snRNP) is a major comp Show more
In eukaryotic cells, both alternative splicing and alternative polyadenylation (APA) play essential roles in the gene regulation network. U1 small ribonucleoprotein particle (U1 snRNP) is a major component of spliceosome, and U1 snRNP complex can suppress proximal APA sites through crosstalking with 3' end processing factors. However, here we show that both knockdown and overexpression of SNRPA, SNRPC, SNRNP70, and SNRPD2, the U1 snRNP proteins, promote the usage of proximal APA sites at the transcriptome level. SNRNP70 can drive the phase transition of PABPN1 from droplet to aggregate, which may reduce the repressive effects of PABPN1 on the proximal APA sites. Additionally, SNRNP70 can also promote the proximal APA sites by recruiting CPSF6, suggesting that the function of CPSF6 on APA is related with other RNA-binding proteins and cell context-dependent. Consequently, these results reveal that, on the contrary to U1 snRNP complex, the free proteins of U1 snRNP complex can promote proximal APA sites through the interaction with 3' end processing machinery. Show less
Bone marrow-derived mesenchymal stem cells (BMSCs) and their exosomes are of great significance for the recovery of cardiac function in patients with myocardial infarction (MI). However, the underlyin Show more
Bone marrow-derived mesenchymal stem cells (BMSCs) and their exosomes are of great significance for the recovery of cardiac function in patients with myocardial infarction (MI). However, the underlying mechanisms of BMSCs applied to MI treatment remain unclear. Fluorescence-activated cell sorting (FACs) are performed to assess the apoptosis, reactive oxygen species levels and glucose uptake capacity of BMSCs. Reverse transcription polymerase chain reaction is conducted to detect the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), transforming growth factor-beta 1, connective tissue growth factor, and platelet-derived growth factor. The levels of apoptosis-related proteins were detected by Western blot. The levels of VEGF, bFGF, HGF, and IGF were assessed by enzyme-linked immunosorbent assay. The biochemical kits are applied to detect the levels of malondialdehyde, superoxide dismutase, and adenosine triphosphate/adenosine diphosphate. 2,3,5-triphenyltetrazolium and Masson staining and immunofluorescence are performed to assess myocardial function of rats. Angiopoietin-like protein 4 (ANGPTL4) alleviates apoptosis and oxidative stress of BMSCs induced by serum deprivation and hypoxia; ANGPTL4 activates paracrine and accelerate metabolic energy of BMSCs; and ANGPTL4 treated-BMSCs alleviate myocardial injury of rats with MI. ANGPTL4 treated-BMSCs alleviate myocardial injury in rats with MI, indicating the combination therapy of ANGPTL4 and BMSCs may alleviate myocardial injury in rats with MI. Show less
Heterogeneous nuclear ribonucleoprotein (HnRNP) F is a member of HnRNP family proteins that participate in splicing of cellular newly synthesized mRNAs by specifically recognizing tandem guanine-tract Show more
Heterogeneous nuclear ribonucleoprotein (HnRNP) F is a member of HnRNP family proteins that participate in splicing of cellular newly synthesized mRNAs by specifically recognizing tandem guanine-tracts (G-tracts) RNA sequences. Whether HnRNP F could recognize viral-derived tandem G-tracts and affect virus replication remain poorly defined. The effect of HnRNP F on porcine reproductive and respiratory syndrome virus (PRRSV) propagation was evaluated by real-time PCR, western blotting, and plaque-forming unit assay. The association between HnRNP F and PRRSV guanine-rich segments (GRS) were analyzed by RNA pulldown and RNA immunoprecipitation. The expression pattern of HnRNP F was investigated by western blotting and nuclear and cytoplasmic fractionation. Knockdown of endogenous HnRNP F effectively blocks the synthesis of viral RNA and nucleocapsid (N) protein. Conversely, overexpression of porcine HnRNP F has the opposite effect. Moreover, RNA pulldown and RNA immunoprecipitation assays reveal that the qRMM1 and qRRM2 domains of HnRNP F recognize the GRS in PRRSV antigenomic RNA. Finally, HnRNP F is redistributed into the cytoplasm and forms a complex with guanine-quadruplex (G4) helicase DHX36 during PRRSV infection. These findings elucidate the potential functions of HnRNP F in regulating the proliferation of PRRSV and contribute to a better molecular understanding of host-PRRSV interactions. Show less
Radiotherapy (RT) is one of the most important treatments for patients with colorectal cancer (CRC). Radioresistance is the crucial cause of poor therapeutic outcomes in colorectal cancer. However, th Show more
Radiotherapy (RT) is one of the most important treatments for patients with colorectal cancer (CRC). Radioresistance is the crucial cause of poor therapeutic outcomes in colorectal cancer. However, the underlying mechanism of radioresistance in colorectal cancer is still poorly defined. Herein we established a radioresistant colorectal cancer cell line and performed transcriptomics analyses to search for the underlying genes that contribute to radioresistance and investigate its association with the prognosis of CRC patients. The radioresistant cell line was developed from the parental HCT116 cell by a stepwise increased dose of irradiation. Differential gene analysis was performed using cellular transcriptome data to identify genes associated with radioresistance, from which extracellular matrix (ECM) and cell adhesion-related genes were screened. Survival data from a CRC cohort in the TCGA database were used for further model gene screening and validation. The correlation between the risk score model and tumor microenvironment, clinical phenotype, drug treatment sensitivity, and tumor mutation status were also investigated. A total of 493 different expression genes were identified from the radioresistant and wild-type cell line, of which 94 genes were associated with ECM and cell adhesion-related genes. The five model genes The risk score model built with five radioresistance genes in this study, including Show less
Sheng Li, Lin Cao · 2022 · Bioengineered · Taylor & Francis · added 2026-04-24
N6-Methyladenosine (m6A) is the most abundant modifications in human messenger RNAs (mRNAs). This study aimed at investigating the function and mechanism of demethyltransferase fat mass and obesity-as Show more
N6-Methyladenosine (m6A) is the most abundant modifications in human messenger RNAs (mRNAs). This study aimed at investigating the function and mechanism of demethyltransferase fat mass and obesity-associated protein (FTO) in prostate cancer(PCa). The expression level of FTO in PCa was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Besides, the impacts of FTO on the proliferation, migration and invasion of PCa cells were also detected by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. Furthermore, we also explored the potential mechanism of FTO in PCa. The results showed that FTO expression was decreased in PCa, and the low expression of FTO showed an obvious relevance to the clinical characteristics. Downregulation of FTO facilitated the proliferation, migration, invasion and tumor growth of PCa cells. Besides, MC4R displayed a remarkably high expression in PCa tissues, whose expression and m6A level were regulated by FTO. Meanwhile, the in vitro experiments revealed that highly expressed FTO partially reversed the facilitating effect of highly expressed MC4R on the malignant phenotype of PCa cells. Overall, FTO was downregulated in PCa and its expression level showed a relevance to the prognosis of PCa patients. Additionally, FTO could regulate the proliferation, migration and invasion of PCa via regulating the expression level of MC4R. Show less
Obesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and m Show more
Obesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and mitochondrial respiration. We aimed to investigate the ferroptosis- and autophagy-related differentially expressed genes (DEGs) that might be potential targets for MI progression. GSE116250 was analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis- and autophagy-related DEGs. The enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors, and drugs with the hub genes interactions were also predicted. The MI mice model was constructed, and qPCR analysis and single-cell sequencing were used to validate the hub genes. Utilizing the limma package and the Venn diagram, 26 ferroptosis-related and 29 autophagy-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in the cellular response to a toxic substance, cellular oxidant detoxification, and the IL-17 signaling pathway. The list of autophagy-related DEGs was involved in the regulation of autophagy, the regulation of JAK-STAT signaling pathway, and the regulation of MAPK cascade. In the protein-protein interaction network, the hub DEGs, such as IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, were obtained. After validation using qPCR analysis in the MI mice model and single-cell sequencing, the 10 hub genes can be the potential targets for MI deterioration. The screened hub genes, IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, may be therapeutic targets for patients with MI and may prevent adverse cardiovascular events. Show less
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial Show more
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial-mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3' UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC. Show less
Cardiomyocyte dysfunction and apoptosis induced by ischemia-hypoxia are common features of many acute and chronic heart diseases. WW domain-containing E3 ubiquitin ligase (WWP2) has been identified as Show more
Cardiomyocyte dysfunction and apoptosis induced by ischemia-hypoxia are common features of many acute and chronic heart diseases. WW domain-containing E3 ubiquitin ligase (WWP2) has been identified as an important regulator in pathogenesis of some health-threatening diseases. Although a couple of recent reports prompted the potential role of WWP2 in heart dysfunction, however, its exact role and how its expression was regulated in ischemic-hypoxic cardiomyocytes are still elusive. Here, we found that WWP2 protein level was induced in anoxia/reoxygenation (A/R) treated cardiomyocytes in a time-dependent manner, accompanied by synchronous expression of LINC01588 and HNRNPL. Knockdown of LINC01588 increased cardiomyocyte apoptosis, the level of oxidative stress, and expression of pro-inflammatory cytokine genes, down-regulated the expression of WWP2 and promoted expression of SEPT4 gene that contributed to cardiomyocyte dysfunction and was a target gene of WWP2. LINC01588 overexpression improved the functions of A/R treated cardiomyocytes, up-regulated WWP2 and reduced SEPT4 expression. In the mechanism exploration, we found that LINC01588 could directly bind with HNRNPL protein that could interact with WWP2, suggesting that WWP2 was involved in the regulation of LINC01588 in A/R treated cardiomyocytes. Moreover, WWP2 inhibition declined the protective role of LINC01588 in cardiomyocyte dysfunction induced by A/R. Finally, we demonstrated that LINC01588 overexpression improved acute myocardial infarction in mice in vivo. In conclusion, LINC01588 improved A/R-induced cardiomyocyte dysfunction by interacting with HNRNPL and promoting WWP2-mediated degradation of SEPT4. Show less
Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure a Show more
Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure and function of hippocampal neurons, and is closely implicated to the deterioration of Alzheimer's disease (AD). Oxidative stress and neuroinflammation play an important role in the occurrence and development of AD. However, it is still unclear whether chronic GC exposure promotes beta-amyloid (Aβ) accumulation and neuronal injury by increasing oxidative stress and neuroinflammation. In this study, we investigated the effects of chronic GC exposure on NOX2-NLRP1 inflammasome activation and the protective effects of NLRP1-siRNA against GC-induced neuronal injury in primary hippocampal neurons of APP/PS1 mice. The results showed that chronic dexamethasone (DEX, 1 µM) exposure 72 h had no significant effect on the primary hippocampal neurons of WT mice, but significantly increased Aβ Show less
Yunan is a crossed lean meat pig breed in China. Backfat thickness is the gold standard for carcass quality grading. However, over 14 years after breed registration, the backfat of Yunan thickened and Show more
Yunan is a crossed lean meat pig breed in China. Backfat thickness is the gold standard for carcass quality grading. However, over 14 years after breed registration, the backfat of Yunan thickened and the consistency of backfat thickness decreased. Meanwhile, no genetic study has been ever performed on Yunan population. So, in this study we collected all the 120 nucleus individuals of Yunan and recorded six backfat traits of them, carried out population genetic structure analysis, selection signals analysis and genome-wide association study of Yunan pigs with the help of their founder population Duroc and Chinese native Huainan pigs, to determine the genomic loci on backfat of Yunan. Genetic diversity indexes suggested Yunan pigs had no inbreeding risk while population genetic structure showed they had few molecular pedigrees and were stratified. A total of 71 common selection signals affecting growth and fat deposition were detected by F Show less
Hereditary multiple exostosis (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple cartilage-covered tumors on the external surfaces of bones (osteochondromas) Show more
Hereditary multiple exostosis (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple cartilage-covered tumors on the external surfaces of bones (osteochondromas). Most of HME cases result from heterozygous loss-of-function mutations in EXT1 or EXT2 gene. Clinical examination was performed to diagnose the patients: Whole exome sequencing (WES) was used to identify pathogenic mutations in the proband, which is confirmed by Sanger sequencing and co-segregation analysis: qRT-PCR was performed to identify the mRNA expression level of EXT1 in patient peripheral blood samples: minigene splicing assay was performed to mimic the splicing process of EXT1 variants in vitro. We evaluated the pathogenicity of EXT1 c.1056 + 1G > T in a Chinese family with HME. The clinical, phenotypic, and genetic characterization of patients in this family were described. The variant was detected by whole-exome sequencing (WES) and confirmed by Sanger sequencing. Sequencing of the RT-PCR products from the patient's blood sample identified a large deletion (94 nucleotides), which is the whole exome 2 of the EXT1 cDNA. Splicing assay indicated that the mutated minigene produced alternatively spliced transcripts, which cause a frameshift resulting in an early termination of protein expression. Our study establishes the pathogenesis of the splicing mutation EXT1 c.1056 + 1G > T to HME and provides scientific foundation for accurate diagnosis and precise medical intervention for HME. Show less
Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use Show more
Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Show less
IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells tr Show more
IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. Here, we show that the activation of mast cells is negatively regulated by IL-27 signaling. We found that mice lacking IL-27Rα (WSX-1) displayed increased sensitivity to IgE-mediated skin allergic response and chronic airway inflammation. The bone marrow-derived mast cells (BMMCs) of IL-27Rα-deficient mouse showed greater high-affinity receptor Fc epsilon RI (FcεRI)-mediated activation with significantly enhanced degranulation and cytokine production. Mechanistically, the dysregulated signaling in IL-27Rα Show less
Traditional interventions can play a certain role in attenuating ulcerative colitis (UC), known as one type of inflammatory bowel diseases, but sometimes are not effective. Endometrial regenerative ce Show more
Traditional interventions can play a certain role in attenuating ulcerative colitis (UC), known as one type of inflammatory bowel diseases, but sometimes are not effective. Endometrial regenerative cells (ERCs) have been shown to exert immunosuppressive effects in different models of inflammation, and stem cell-derived conditioned media (CM) have advantages over cell therapy in terms of easy access and direct action. However, whether ERC-CM could alleviate colitis remains unclear and will be explored in this study. Menstrual blood was collected from healthy female volunteers to obtain ERCs and ERC-CM. Acute colitis was induced by 3% dextran sodium sulfate (DSS), and ERC-CM was injected on days 4, 6, and 8, respectively, after induction. The disease activity index was calculated through the record of weight change, bleeding, and fecal viscosity during the treatment process. Histological features, macrophage and CD4 ERC-CM treatment significantly improved the symptoms and histological changes in colitis mice. ERC-CM increased the percentage of Tregs in the spleen and colon but decreased the percentages of M1 macrophages and Th1 and Th17 cells in the spleen and decreased the population of Th17 cells in the colon. In addition, ERC-CM treatment decreased the local expression of TNF- The results suggest that ERC-CM can exert similar therapeutic effects as ERCs and could be explored for future application of cell-free therapy in the treatment of colitis. Show less
Directed evolution is a widely-used engineering strategy for improving the stabilities or biochemical functions of proteins by repeated rounds of mutation and selection. A protein of interest is selec Show more
Directed evolution is a widely-used engineering strategy for improving the stabilities or biochemical functions of proteins by repeated rounds of mutation and selection. A protein of interest is selected as the template and expressed on a molecular display platform such as a bacteriophage for engineering. Initially, the surface-displayed protein template needs to be checked against the desired target Show less
Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hyp Show more
Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1 Show less
To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of Show more
To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of GAgP group and control group was (27.5±5.2) years and (28.8±7.1) years respectively. There was significant difference in age between the two groups ( Show less
Oral squamous cell carcinoma (OSCC), the most common type of primary malignant tumor in the oral cavity, is a lethal disease with high recurrence and mortality rates. Butyrate, a metabolite produced b Show more
Oral squamous cell carcinoma (OSCC), the most common type of primary malignant tumor in the oral cavity, is a lethal disease with high recurrence and mortality rates. Butyrate, a metabolite produced by periodontal pathogens, has been linked to oral diseases. The purpose of this study was to evaluate the effect of sodium butyrate (NaB) on the proliferation, migration, and invasion of OSCC cells Two OSCC cell lines (HSC-4 and SCC-9) were treated with NaB at different concentrations. The cell proliferation was assayed by CCK-8, ethylene deoxyuridine (EdU), and flow cytometry. Wound healing and transwell assay were performed to detect cell migration and invasion. Changes in epithelial-mesenchymal transition (EMT) markers, including E-cadherin, Vimentin, and SNAI1, were evaluated by quantitative real-time PCR (qRT-PCR), western blot, and immunofluorescent staining. The expression levels of matrix metalloproteinases (MMPs) were analyzed by qRT-PCR and gelatin zymography. Our results showed that NaB inhibited the proliferation of OSCC cells and induced cell cycle arrest at G1 phase, but NaB significantly enhanced cell migration and invasion compared with the control group. Further mechanistic investigation demonstrated that NaB induced EMT by increasing the expression of Vimentin and SNAI1, decreasing the expression of membrane-bound E-cadherin, and correspondingly promoting E-cadherin translocation from the membrane to the cytoplasm. In addition, the overexpression of MMP1/2/9/13 was closely related to NaB treatment. Our study conclude that butyrate may promote the migration and invasion of OSCC cells by inducing EMT. These findings indicate that butyrate may contribute to OSCC metastasis. Show less
To identify the pathogenic gene variation in a Chinese family with Hereditary Multiple Exostoses (HME). By examining blood-sourced DNA and clinical manifestations of the proband and his family members Show more
To identify the pathogenic gene variation in a Chinese family with Hereditary Multiple Exostoses (HME). By examining blood-sourced DNA and clinical manifestations of the proband and his family members, the whole exome sequencing (WES) and Sanger sequencing were used to detect possibly pathogenic mutations. A novel heterozygous mutation (c.325dup) was identified in exon 1 of the Show less
The pro-inflammatory factor interleukin-8 (IL-8) is related to poor prognosis in hepatocellular carcinoma (HCC) patients. Interleukin-8 enhanced HCC invasion by upregulating Snail and Twist1, whether Show more
The pro-inflammatory factor interleukin-8 (IL-8) is related to poor prognosis in hepatocellular carcinoma (HCC) patients. Interleukin-8 enhanced HCC invasion by upregulating Snail and Twist1, whether this modulation relies on microRNAs (miR) is unclear. In this study, hsa-miR-370-3p was screened as candidate miRNA targeting Snail and Twist1, and its expression was downregulated by IL-8. Luciferase assays and RNA electrophoretic mobility shift assays were used to evaluate the interaction between miR-370-3p and targeted mRNAs. Coimmunoprecipitation, luciferase, and ChIP assays were undertaken to investigate the mechanisms underlying IL-8-mediated modification of miR-370-3p. Gain- and loss-of-function studies, Transwell assays, and a xenograft nude mouse model were used to investigate pro- and antitumor activities. Interleukin-8 and miR-370-3p levels were analyzed for clinical relevance in HCC patients. Our results showed that HCC patients with high levels of IL-8 experienced more metastasis and shorter survival. Interleukin-8 induced epithelial-mesenchymal transition and promoted liver cancer cell migration, invasion, and metastasis both in vitro and in vivo. MicroRNA-370-3p interacted with its cognate mRNA within the 3'-UTR regions of Twist1 and Snail mRNA directly and specifically and attenuated IL-8 protumoral effects on liver cancer cells. Interleukin-8 negatively modulated miR-370-3p through signal transducer and activator of transcription 3 (STAT3) activation by recruiting histone deacetylase 1 (HDAC1) to miR-370-3p promoter. The STAT3 and HDAC antagonists inhibited liver cancer cell migration and invasion. Patients with high miR-370-3p and low IL-8 levels had longer overall survival. In conclusion, our study elucidated a novel axis IL-8/STAT3/miR-370-3p/Twist1 and Snail relying on HDAC1 recruitment, which showed both diagnostic and therapeutic potentials of miR-370-3p in HCC metastasis. Show less
The Apolipoprotein A5 (APOA5) rs662799 was significantly associated with blood lipid level at genome-wide significance level. Whether dynamic changes of adiposity influence the effect of lipid loci on Show more
The Apolipoprotein A5 (APOA5) rs662799 was significantly associated with blood lipid level at genome-wide significance level. Whether dynamic changes of adiposity influence the effect of lipid loci on long-term blood lipid profile remains unclear. We assessed interactions of 5-year body mass index (BMI) change and rs662799 genotypes with risk of incident dyslipidemia and longitudinal changes in serum lipids in a prospective cohort. We included 4329 non-dyslipidemia participants aged ≥ 40 years at baseline from a well-defined community-based cohort and followed up for an average of 5 years. BMI and blood lipids were measured at baseline and follow-up. The association of each rs662799 A-allele with risk of incident dyslipidemia was stronger along with the increase in BMI change level, with the odds ratios (OR) increasing from 1.03 in the lowest tertile of BMI change (< 0.02 kg/m BMI changes significantly modulate rs662799 genetic contribution to dyslipidemia and long-term lipid profile, which provide new evidence for personalized clinical management of lipids according to individual genetic background. Show less
Pleural effusion is a common clinical condition caused by several respiratory diseases, including tuberculosis and malignancy. However, rapid and accurate diagnoses of tuberculous pleural effusion (TP Show more
Pleural effusion is a common clinical condition caused by several respiratory diseases, including tuberculosis and malignancy. However, rapid and accurate diagnoses of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remain challenging. Although monocytes have been confirmed as an important immune cell in tuberculosis and malignancy, little is known about the role of monocytes subpopulations in the diagnosis of pleural effusion. Pleural effusion samples and peripheral blood samples were collected from 40 TPE patients, 40 MPE patients, and 24 transudate pleural effusion patients, respectively. Chemokines (CCL2, CCL7, and CX3CL1) and cytokines (IL-1β, IL-17, IL-27, and IFN-γ) were measured by ELISA. The monocytes phenotypes were analyzed by flow cytometry. The chemokines receptors (CCR2 and CX3CR1) and cytokines above in different monocytes subsets were analyzed by real-time PCR. Receiver operating characteristic curve analysis was performed for displaying differentiating power of intermediate and nonclassical subsets between tuberculous and malignant pleural effusions. CCL7 and CX3CL1 levels in TPE were significantly elevated in TPE compared with MPE and transudate pleural effusion. Cytokines, such as IL-1β, IL-17, IL-27, and IFN-γ, in TPE were much higher than in other pleural effusions. Moreover, CD14 CD14 and CD16 markers on monocytes could be potentially used as novel diagnostic markers for diagnosing TPE and MPE. Show less
Exploration of lead compounds against Parkinson's disease (PD), a neurodegenerative disease, is of great important. Dioscin, a bioactive natural product, shows various pharmacological effects. However Show more
Exploration of lead compounds against Parkinson's disease (PD), a neurodegenerative disease, is of great important. Dioscin, a bioactive natural product, shows various pharmacological effects. However, the activities and mechanisms of dioscin against PD have not been well investigated. In this study, the tests on 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats were carried out. The results showed that dioscin dramatically improved cell viability, decreased reactive oxygen species (ROS) levels, improved motor behavior and tyrosine hydroxylase(TH) levels and restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats. Mechanism investigation showed that dioscin not only markedly increased the expression level of dual- specificity phosphatase 6 (DUSP6) by 1.87-fold in cells and 2.56-fold in rats, and decreased phospho-extracellular regulated protein kinases (p-ERK) level by 2.12-fold in cells and 2.34-fold in rats, but also increased the levels of nuclear factor erythroid2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), superoxide dismutase (SOD) and decreased the levels of kelch-1ike ECH-associated protein l (Keap1) in vitro and in vivo. Furthermore, DUSP6 siRNA transfection experiment in PC12 cells validated the protective effects of dioscin against PD via regulating DUSP6 to adjust the Keap1/Nrf2 pathway. Our data supported that dioscin has protection against PD in regulating oxidative stress via DUSP6 signal, which should be considered as an efficient candidate for the treatment of PD in the future. Show less
As one of the common birth defects worldwide, nonsyndromic microtia is a complex disease that results from interactions between environmental and genetic factors. However, the underlying causes of non Show more
As one of the common birth defects worldwide, nonsyndromic microtia is a complex disease that results from interactions between environmental and genetic factors. However, the underlying causes of nonsyndromic microtia are currently not well understood. The present study determined transcriptomic and proteomic profiles of auricular cartilage tissues in 10 patients with third-degree nonsyndromic microtia and five control subjects by RNA microarray and tandem mass tag-based quantitative proteomics technology. Relative mRNA and protein abundances were compared and evaluated for their function and putative involvement in nonsyndromic microtia. A total of 3971 differentially expressed genes and 256 differentially expressed proteins were identified. Bioinformatics analysis demonstrated that some of these genes and proteins showed potential associations with nonsyndromic microtia. Thirteen proteins with the same trend at the mRNA level obtained by the integrated analysis were validated by parallel reaction monitoring analysis. Several key genes, namely, Show less
Rab21 is a GTPase protein that is functional in intracellular trafficking and involved in the pathologies of many diseases, such as Alzheimer's disease (AD), glioma, cancer, etc. Our previous work has Show more
Rab21 is a GTPase protein that is functional in intracellular trafficking and involved in the pathologies of many diseases, such as Alzheimer's disease (AD), glioma, cancer, etc. Our previous work has reported its interaction with the catalytic subunit of gamma-secretase, PS1, and it regulates the activity of PS1 via transferring it from the early endosome to the late endosome/lysosome. However, it is still unknown how Rab21 protein itself is regulated. This work revealed that Rab21 protein, either endogenously or exogenously, can be degraded by the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. It is further observed that the ubiquitinated Rab21 is increased, but the total protein is unchanged in AD model mice. We further observed that overexpression of Rab21 leads to increased expression of a series of genes involved in the autophagy-lysosome pathway. We speculated that even though the ubiquitinated Rab21 is increased due to the impaired proteasome function in the AD model, the autophagy-lysosome pathway functions in parallel to degrade Rab21 to keep its protein level in homeostasis. In conclusion, understanding the characters of Rab21 protein itself help explore its potential as a target for therapeutic strategy in diseases. Show less
Protein complexes mediated by various post-translational modifications (PTMs) play important roles in almost every aspect of biological processes. PTM-mediated protein complexes often have weak and tr Show more
Protein complexes mediated by various post-translational modifications (PTMs) play important roles in almost every aspect of biological processes. PTM-mediated protein complexes often have weak and transient binding properties, which limit their unbiased profiling especially in complex biological samples. Here, we developed a plug-and-play chemical proteomic approach for high-throughput analyis of PTM-mediated protein complexes. Taking advantage of the glutathione-S-transferase (GST) tag, which is the gold standard for protein purification and has wide access to a variety of proteins of interest (POIs), a glutathione (GSH) group- and photo-cross-linking group-containing trifunctional chemical probe was developed to tag POIs and assembled onto a streptavidin-coated 96-well plate for affinity purification, photo-cross-linking, and proteomics sample preparation in a fully integrated manner. Compared with the previously developed photo-pTyr-scaffold strategy, by assembling the tyrosine phosphorylation (pTyr) binding domain through covalent NHS chemistry, the new plug-and-play strategy using a noncovalent GST-GSH interaction has comparable enrichment efficiency for EGF stimulation-dependent pTyr protein complexes. To further prove its feasibility, we additionally assembled four pTyr-binding domains in the 96-well plate and selectively identified their pTyr-dependent interacting proteins. Importantly, we systematically optimized and applied the plug-and-play approach for exploring protein methylation-mediated protein complexes, which are difficult to be characterized due to their weak binding affinity and the lack of efficient enrichment strategies. We explored a comprehensive protein methylation-mediated interaction network assembled by five protein methylation binding domains including the chromo domain of MPP8, tandem tudor domain of KDM4A, full-length CBX1, PHD domain of RAG2, and tandem tudor domain of TP53BP1 and validated the chromo domain- and tudor domain-mediated interaction with histone H3. Collectively, this plug-and-play approach provides a convenient and generic strategy for exploring PTM-dependent protein complexes for any POIs with the GST tag. Show less