Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target Show more
Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy. Show less
Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essenti Show more
Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essential for normal cellular activities such as cell signaling, division, and survival. Due to their vital and irreplaceable role in regulating intracellular vesicle transportation, accumulated researches have shown that the abnormalities of Rab proteins and their effectors are closely related to human diseases. Here, this review focused on Rab21, a member of the Rab family, and introduced the structures and functions of Rab21, as well as the regulatory mechanisms of Rab21 in human diseases, including neurodegenerative diseases, cancer, and inflammation. In summary, we described in detail the role of Rab21 in human diseases and provide insights into the potential of Rab21 as a therapeutic target for diseases. Show less
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the im Show more
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the impacts of BCFAs inferred from yak ghee on the expression of qualities related to lipid metabolism, natural pathways, and intestinal microbiota in mice. The treatment group (purified BCFAs from yak ghee) exhibited a decrease in cholesterol levels; a decrease in 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
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with intricate etiology. It is closely associated with metabolic syndrome, insulin resistance and endoplasmic reticulum (ER) Show more
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with intricate etiology. It is closely associated with metabolic syndrome, insulin resistance and endoplasmic reticulum (ER) stress. Exostosin1 (Ext1) is an ER-resident transmembrane glycosyltransferase, which plays an important role in ER homeostasis. Loss-of-function mutations in Ext1 link to hereditary multiple exostosis (HME). The present research was undertaken to identify the effect of Ext1 in the progress of NAFLD. High-fat-diet induced mice obesity, hepatic steatosis and decreased hepatic Ext1 expression. In consistent with evaluation of NAFLD mice possessing down-regulated Ext1 expression, free fatty acid (FFA) treatment blunted Ext1 expression in hepatocytes. In human subjects, HME patients presented elevated fasting blood glucose-one of the criteria that define insulin resistance. In vitro experiments, Ext1 deficiency promoted FFA-induced insulin resistance in hepatocytes by analysis of glycogen storage and hallmarks of gluconeogenesis, ascertaining its association with insulin resistance. Mechanically, Ext1 silencing exacerbated ER stress triggered by FFA, which severely disrupted autophagy in hepatocytes, and thereby accelerated the progression of NAFLD. In conclusion, our study demonstrates a beneficial role for Ext1 during the development of NAFLD, which establishes a novel correlation between Ext1 and ER stress-induced perturbations of autophagy during NAFLD progression. Show less
Carbon emission trading is not only a market-based instrument but also one of the government's macro-policies, which is extremely crucial to fulfilling both carbon peak attainment and carbon neutralit Show more
Carbon emission trading is not only a market-based instrument but also one of the government's macro-policies, which is extremely crucial to fulfilling both carbon peak attainment and carbon neutrality goals. For this purpose, this paper adopts a 30-region dataset for the period from 2008 to 2020 in China and employs the difference-in-difference (DID) method to quantify the effect of the carbon emission trading pilot policy (CETP) on carbon emissions on the basis of introducing industrial structure upgrading and green technology innovation as moderating variables. The results show that (1) CETP has a statistically significant dampening effect on carbon emissions, while its carbon emission reduction effect follows a significant strengthening trend as the policy year of CETP implementation is delayed. (2) CETP has a significant carbon emission reduction effect. However, its effect demonstrates a gradual decrease from the eastern to the central and finally to the western regions. (3) CETP can inhibit carbon emissions depending on industrial structure upgrading to a certain extent, and this dependence is significant in the national and eastern regions but not in the central and western regions. (4) CETP's carbon emission reduction effect is dependent on green technology innovation, which is only revealed in the western region and performs as a dampening effect in the national, eastern, and central regions, but not significantly. Show less
Neuritic plaques are one of the major pathological hallmarks of Alzheimer's disease. They are formed by the aggregation of extracellular amyloid-β protein (Aβ), which is derived from the sequential cl Show more
Neuritic plaques are one of the major pathological hallmarks of Alzheimer's disease. They are formed by the aggregation of extracellular amyloid-β protein (Aβ), which is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretase. BACE1 is the main β-secretase in the pathogenic process of Alzheimer's disease, which is believed to be a rate-limiting step of Aβ production. Presenilin 1 (PS1) is the active center of the γ-secretase that participates in the APP hydrolysis process. Mutations in the PS1 gene ( Show less
Human Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive. Mutated hTau (P301S) was ov Show more
Human Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive. Mutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co-immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor-erythroid 2-related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti-oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining. Overexpressing P301S decreased the protein levels of post-synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch-like ECH-associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S-reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin-proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S-KEAP1 interaction at K312 rescued the P301S-suppressed expression of synaptic proteins and memory deficits with anxiety efficiently. P301S-hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies. Show less
Alzheimer's disease (AD) is a common neurodegenerative disorder with progressive cognitive impairment in the elderly. Beta-amyloid (Aβ) formation and its accumulation in the brain constitute one of th Show more
Alzheimer's disease (AD) is a common neurodegenerative disorder with progressive cognitive impairment in the elderly. Beta-amyloid (Aβ) formation and its accumulation in the brain constitute one of the pathological hallmarks of AD. Until now, how to modulate Aβ formation in hippocampal neurons remains a big challenge. Herein, we investigated whether the exosomal transfer of microRNA (miR) relates to amyloid pathology in the recipient neuron cells. We isolated circulating small extracellular vesicles (sEVs) from AD patients and healthy controls, determined the miR-342-5p level in the sEVs by RT-PCR, and evaluated its diagnostic performance in AD. Then, we took advantage of biomolecular assays to estimate the role of miR-342-5p in modulating the amyloid pathway, including amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), and Aβ42. Furthermore, we subjected HT22 cells to the sEVs from the hippocampal tissues of transgenic APP mice (Exo-APP) or C57BL/6 littermates (Exo-CTL), and the Exo-APP enriched with miR-342-5p mimics or the control to assess the effect of the sEVs' delivery of miR-342-5p on Aβ formation. We observed a lower level of miR-342-5p in the circulating sEVs from AD patients compared with healthy controls. MiR-342-5p participated in Aβ formation by modulating BACE1 expression, specifically binding its 3'-untranslated region (UTR) sequence. Exo-APP distinctly promoted Aβ42 formation in the recipient cells compared to Exo-CTL. Intriguingly, miR-342-5p enrichment in Exo-APP ameliorated amyloid pathology in the recipient cells. Our study indicated that miR-342-5p was dysregulated in human circulating sEVs from AD patients; sEV transfer of miR-342-5p ameliorates Aβ formation by modulating BACE1 expression. These findings highlight the promising potential of exosomal miRNAs in AD clinical therapy. 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
Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate th Show more
Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate the role of ANGPTL4 in glucose metabolism in colorectal cancer (CRC). Immunohistochemical staining of CRC specimens classified 84 patients into two groups according to ANGPTL4 expression. Clinicopathological characteristics, gene mutation status obtained by next-generation sequencing, and fluorodeoxyglucose (FDG) uptake measured by positron emission tomography/computed tomography (PET/CT) were compared between the two groups. Furthermore, the impact of ANGPTL4 expression on cancer metabolism was investigated by a subcutaneous xenograft mouse model using the ANGPTL4 knockout CRC cell line, and glucose transporter (GLUT) expression was evaluated. There were significantly more cases of T3/4 tumours (94.3% vs. 57.1%, P < 0.001) and perineural invasion (42.9% vs. 22.4%, P = 0.046) in the ANGPTL4-high group than in the low group. Genetic exploration revealed a higher frequency of KRAS mutation (54.3% vs. 22.4%, P = 0.003) in the ANGPTL4-high tumours. All the FDG uptake parameters were significantly higher in ANGPTL4-high tumours. In vivo analysis showed a significant reduction in tumour size due to ANGPTL4 knockout with lower expression of GLUT1 and GLUT3, and suppression of AKT phosphorylation. ANGPTL4 regulates the expression of GLUTs by activating the PI3K-AKT pathway and thereby promoting glucose metabolism in CRC. These findings establish a new functional role of ANGPTL4 in cancer progression and lay the foundation for developing a novel therapeutic target. Show less
The aggregation and interaction of metabolic risk factors leads to highly heterogeneous pathogeneses, manifestations, and outcomes, hindering risk stratification and targeted management. To deconstruc Show more
The aggregation and interaction of metabolic risk factors leads to highly heterogeneous pathogeneses, manifestations, and outcomes, hindering risk stratification and targeted management. To deconstruct the heterogeneity, we used baseline data from phase II of the Fangshan Family-Based Ischemic Stroke Study (FISSIC), and a total of 4632 participants were included. A total of 732 individuals who did not have any component of metabolic syndrome (MetS) were set as a reference group, while 3900 individuals with metabolic abnormalities were clustered into subtypes using multi-trait limited mixed regression (MFMR). Four metabolic subtypes were identified with the dominant characteristics of abdominal obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariate logistic regression showed that the hyperglycemia-dominant subtype had the highest coronary heart disease (CHD) risk (OR: 6.440, 95% CI: 3.177-13.977) and that the dyslipidemia-dominant subtype had the highest stroke risk (OR: 2.450, 95% CI: 1.250-5.265). Exome-wide association studies (EWASs) identified eight SNPs related to the dyslipidemia-dominant subtype with genome-wide significance, which were located in the genes Show less
Chicken internal organs are indispensable parts of the body, but their genetic architectures have not been commonly understood. Herein, we estimated the genetic parameters for heart weight (HW), liver Show more
Chicken internal organs are indispensable parts of the body, but their genetic architectures have not been commonly understood. Herein, we estimated the genetic parameters for heart weight (HW), liver weight (LW), spleen weight (SpW), testis weight (TW), glandular stomach weight (GSW), muscular stomach weight (MSW) and identified single nucleotide polymorphisms (SNPs) and potential candidate genes associated with internal organ weights in an F Show less
Distant metastasis is the major cause of clear cell renal cell carcinoma (ccRCC)-associated mortality. However, molecular mechanisms involved in ccRCC metastasis remain to be fully understood. With th Show more
Distant metastasis is the major cause of clear cell renal cell carcinoma (ccRCC)-associated mortality. However, molecular mechanisms involved in ccRCC metastasis remain to be fully understood. With the increasing appreciation of the role of long non-coding RNAs (lncRNAs) in cancer development, progression, and treatment resistance, the list of aberrantly expressed lncRNAs contributing to ccRCC pathogenesis is expanding rapidly. Bioinformatics analysis was carried out to interrogate publicly available ccRCC datasets. In situ hybridization and qRT-PCR assays were used to test lncRNA expression in human ccRCC tissues and cell lines, respectively. Chromatin immunoprecipitation and luciferase reporter assays were used to examine transcriptional regulation of gene expression. Wound healing as well as transwell migration and invasion assays were employed to monitor ccRCC cell migration and invasion in vitro. ccRCC metastasis was also examined using mouse models in vivo. RNA pulldown and RNA immunoprecipitation were performed to test RNA-protein associations, whereas RNA-RNA interactions were tested using domain-specific chromatin isolation by RNA purification. MILIP expression was upregulated in metastatic compared with primary ccRCC tissues. The increased MILIP expression in metastatic ccRCC cells was driven by the transcription factor AP-2 gamma (TFAP2C). Knockdown of MILIP diminished the potential of ccRCC cell migration and invasion in vitro and reduced the formation of ccRCC metastatic lesions in vivo. The effect of MILIP on ccRCC cells was associated with alterations in the expression of epithelial-to-mesenchymal transition (EMT) hallmark genes. Mechanistically, MILIP formed an RNA-RNA duplex with the snail family transcriptional repressor 1 (Snai1) mRNA and bound to Y-box binding protein 1 (YBX1). This promoted the association between the YBX1 protein and the Snai1 mRNA, leading to increased translation of the latter. Snai1 in turn played an important role in MILIP-driven ccRCC metastasis. The TFAP2C-responsive lncRNA MILIP drives ccRCC metastasis. Targeting MILIP may thus represent a potential avenue for ccRCC treatment. Show less
Ulcerative colitis (UC), a long-term inflammation of the colon, is a worldwide disease. Accumulating reports have suggested the contribution of environmental pollutants to UC development. As such, the Show more
Ulcerative colitis (UC), a long-term inflammation of the colon, is a worldwide disease. Accumulating reports have suggested the contribution of environmental pollutants to UC development. As such, the identification of biomarkers to evaluate pollutant-induced UC could provide a better assessment on the world's pollution problem. In the present study, we applied the plasma proteome to profile the plasma protein changes in three models: dextran sulfate sodium (DSS)-induced colitis, bisphenol A (BPA), and BPA-severe colitis. We aimed to investigate the functional roles of plasma proteins related to colitis development and further understand the synergistic effect of BPA on colitis. In addition, we aimed to identify novel biomarkers for UC non-invasive diagnosis and assessment of BPA-induced colitis. Our results showed a significant dysregulation of plasma proteins in these three models. Bioinformatics analysis, including gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and Ingenuity Pathway Analysis, highlighted the important effects of these dysregulated plasma proteins in immune and inflammatory responses through the regulation of CCR3 signaling in eosinophils, PI3K signaling in B lymphocytes, CD28 signaling in T helper cells, and leukocyte extravasation signaling in DSS-induced colitis model. Furthermore, our data suggested that BPA exposure altered the plasma proteins involved in lipid-related metabolic processes, leukocyte cell-cell adhesion and cytokine response. More importantly, we identified plasma proteins, ALB, APOA4, C3, CFB, DPEP1, HP, LTF, and Retnlg as biomarkers for assessing BPA-induced colitis. Show less
The molecular mechanism of mechanical force regulating the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) has not been clearly elucidated. In this study, two mRNA-seqs, GSE1068 Show more
The molecular mechanism of mechanical force regulating the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) has not been clearly elucidated. In this study, two mRNA-seqs, GSE106887 and GSE109167, which contained several samples of PDLSCs under mechanical force, were downloaded from Gene Expression Omnibus. Differential expression analysis was firstly taken between GSE106887 and GSE109167, then the common 84 up-regulated genes and 26 down-regulated genes were selected. Function enrichment analysis was used to identify the key genes and pathways in PDLSCs subjected to the tension and compression force. PDLSCs were isolated from human periodontal ligament tissues. The effects of ANGPTL4 knockdown with shRNA on the osteogenic differentiation of PDLSCs were studied in vitro. Then, the orthodontic tooth movement (OTM) rat model was used to study the expression of HIF-1α and ANGPTL4 in alveolar bone remodeling in vivo. ANGPTL4 and the HIF-1 pathway were identified in PDLSCs subjected to the tension and compression force. alizarin red staining, alcian blue staining, and oil red O staining verified that PDLSCs had the ability of osteogenic, chondrogenic, and adipogenic differentiation, respectively. Verification experiment revealed that the expression of ANGPTL4 in PDLSCs significantly increased when cultured under osteogenic medium in vitro. While ANGPTL4 was knocked down by shRNA, the levels of ALPL, RUNX2, and OCN decreased significantly, as well as the protein levels of COL1A1, ALPL, RUNX2, and OCN. During the OTM, the expression of HIF-1α and ANGPTL4 in periodontal ligament cells increased on the tension and compression sides. We concluded the positive relationship between ANGPTL4 and osteogenic differentiation of PDLSCs. Show less
Fecundity in livestock is an economically important complex quantitative trait that is influenced by both genetics and the environment. However, the underlying genetic mechanism of reproductive perfor Show more
Fecundity in livestock is an economically important complex quantitative trait that is influenced by both genetics and the environment. However, the underlying genetic mechanism of reproductive performance in goats has not been well investigated. To investigate the genomic basis of fecundity in goats, genomic sequencing data of the Jining grey goat (a high prolificacy breed in China) were collected, as well as data for other commonly available goat breeds, and a mass of genomic variants were generated after variation calling. We screened the Jining grey goat (20 individuals) using a selective sweep with the Asian wild goat population (5 individuals), and potential candidate genes were proposed, such as STIM1, ESR1, LRRC14B and SLC9A3. Among, STIM1 is a most promising one associated with high reproductive capacity. When compared to Chinese domestic goats with low fecundity (17 individuals), the genes including MLLT10, SPIRE2, TCF25, ZNF276 and FANCA were screened, and the SPIRE2 gene was thought to be associated with fecundity traits. Meanwhile, the functional enrichment of these candidate genes revealed that they were involved in biological processes of mammary gland morphogenesis, uterus development, gastrulation, mesoderm morphogenesis and formation, and blood vessel development, which might undergo natural or artificial selection during reproductive trait formation in goats. Thus, our findings could enrich the genetic basis of reproductive trait selection during goat domestication, which may serve to improve goat breeding practices. Show less
Alzheimer disease (AD), a progressive neurodegenerative disorder, is mainly caused by the interaction of genetic and environmental factors. The impact of environmental factors on the genetic mutation Show more
Alzheimer disease (AD), a progressive neurodegenerative disorder, is mainly caused by the interaction of genetic and environmental factors. The impact of environmental factors on the genetic mutation in the amyloid precursor protein (APP) is not well characterized. We hypothesized that endoplasmic reticulum (ER) stress would promote disease for the patient carrying the APP D678H mutation. Therefore, we analyzed the impact of a familial AD mutation on amyloid precursor protein (APP D678H) under ER stress. Induced pluripotent stem cells (iPSCs) from APP D678H mutant carrier was differentiated into neurons, which were then analyzed for AD-like changes. Immunocytochemistry and whole-cell patch-clamp recording revealed that the derived neurons on day 28 after differentiation showed neuronal markers and electrophysiological properties similar to those of mature neurons. However, the APP D678H mutant neurons did not have significant alterations in the levels of amyloid-β (Aβ) and phosphorylated tau (pTau) compared to its isogenic wild-type neurons. Only under ER stress, the neurons with the APP D678H mutation had more Aβ and pTau via immune detection assays. The higher level of Aβ in the APP D678H mutant neurons was probably due to the increased level of β-site APP cleaving enzyme (BACE1) and decreased level of Aβ-degrading enzymes under ER stress. Increased Aβ and pTau under ER stress reduced the N-methyl-D-aspartate receptor (NMDAR) in Western blot analysis and altered electrophysiological properties in the mutant neurons. Our study provides evidence that the interaction between genetic mutation and ER stress would induce AD-like changes. Cover Image for this issue: https://doi.org/10.1111/jnc.15420. Show less
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect Show more
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects. This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed. One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10 Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality. NCT03161002. Show less
Clear cell renal cell carcinoma (ccRCC) accounts for 85% of all malignant renal tumors. Currently, the pathogenesis of ccRCC is not fully understood. Chromobox (CBX) family proteins are the major subu Show more
Clear cell renal cell carcinoma (ccRCC) accounts for 85% of all malignant renal tumors. Currently, the pathogenesis of ccRCC is not fully understood. Chromobox (CBX) family proteins are the major subunits of PcG complexes and are implicated in regulating mammalian development. The CBX family consists of eight members, namely, CBX1-8. Numerous studies have highlighted that each CBX protein exhibits distinct functions and prognostic roles in specific cancer types. In this study, in silico analysis indicated that CBX7 was downregulated in ccRCC and correlated with favorable prognosis in a ccRCC cohort. Subsequent studies showed that CBX7 inhibited cancer cell proliferation and invasion. Then, we showed that CBX7 downregulated ETS1 to inactivate the tumor necrosis factor (TNF) signaling pathway, which inhibited tumor proliferation and enhanced the sensitivity of ccRCC cells to tyrosine kinase inhibitors (TKIs). Moreover, we found that CBX7 was a bona fide substrate of RNF26. RNF26 promoted the degradation of CBX7 and enhanced ccRCC tumor growth. Therefore, our results revealed a novel RNF26/CBX7 axis that modulates the TNF signaling pathway in ccRCC. Show less
IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function Show more
IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function and underlying mechanism of IKBKE contributing to breast cancer metastasis remain largely elusive. Here, we report that depletion of Ikbke markedly decreases polyoma virus middle T antigen (PyVMT)-induced mouse mammary tumorigenesis and subsequent lung metastasis. Biologically, ectopic expression of IKBKE accelerates, whereas depletion of IKBKE attenuates breast cancer invasiveness and migration in vitro and tumor metastasis in vivo. Mechanistically, IKBKE tightly controls the stability of transcriptional factor Snail in different layers, in particular by directly phosphorylating Snail, which markedly blocks the E3 ligase β-TRCP1-mediated Snail degradation, resulting in breast cancer epithelial-mesenchymal transition (EMT) and metastasis. These findings together reveal a novel oncogenic function of IKBKE in promoting breast cancer metastasis by governing Snail abundance, and highlight the potential of targeting IKBKE for metastatic breast cancer therapies. Show less
Adult muscle stem cells, also known as satellite cells (SCs), play pivotal roles in muscle regeneration, and long non-coding RNA (lncRNA) functions in SCs remain largely unknown. Here, we identify a l Show more
Adult muscle stem cells, also known as satellite cells (SCs), play pivotal roles in muscle regeneration, and long non-coding RNA (lncRNA) functions in SCs remain largely unknown. Here, we identify a lncRNA, Lockd, which is induced in activated SCs upon acute muscle injury. We demonstrate that Lockd promotes SC proliferation; deletion of Lockd leads to cell-cycle arrest, and in vivo repression of Lockd in mouse muscles hinders regeneration process. Mechanistically, we show that Lockd directly interacts with RNA helicase DHX36 and the 5'end of Lockd possesses the strongest binding with DHX36. Furthermore, we demonstrate that Lockd stabilizes the interaction between DHX36 and EIF3B proteins; synergistically, this complex unwinds the RNA G-quadruplex (rG4) structure formed at Anp32e mRNA 5' UTR and promotes the translation of ANP32E protein, which is required for myoblast proliferation. Altogether, our findings identify a regulatory Lockd/DHX36/Anp32e axis that promotes myoblast proliferation and acute-injury-induced muscle regeneration. Show less
Hepatocellular carcinoma (HCC) stem cells are regarded as an important part of individualized HCC treatment and sorafenib resistance. However, there is lacking systematic assessment of stem-like indic Show more
Hepatocellular carcinoma (HCC) stem cells are regarded as an important part of individualized HCC treatment and sorafenib resistance. However, there is lacking systematic assessment of stem-like indices and associations with a response of sorafenib in HCC. Our study thus aimed to evaluate the status of tumor dedifferentiation for HCC and further identify the regulatory mechanisms under the condition of resistance to sorafenib. Datasets of HCC, including messenger RNAs (mRNAs) expression, somatic mutation, and clinical information were collected. The mRNA expression-based stemness index (mRNAsi), which can represent degrees of dedifferentiation of HCC samples, was calculated to predict drug response of sorafenib therapy and prognosis. Next, unsupervised cluster analysis was conducted to distinguish mRNAsi-based subgroups, and gene/geneset functional enrichment analysis was employed to identify key sorafenib resistance-related pathways. In addition, we analyzed and confirmed the regulation of key genes discovered in this study by combining other omics data. Finally, Luciferase reporter assays were performed to validate their regulation. Our study demonstrated that the stemness index obtained from transcriptomic is a promising biomarker to predict the response of sorafenib therapy and the prognosis in HCC. We revealed the peroxisome proliferator-activated receptor signaling pathway (the PPAR signaling pathway), related to fatty acid biosynthesis, that was a potential sorafenib resistance pathway that had not been reported before. By analyzing the core regulatory genes of the PPAR signaling pathway, we identified four candidate target genes, Show less
Nonalcoholic fatty liver disease (NAFLD), one of the risk factors for hepatitis, cirrhosis, and even hepatic carcinoma, has been a global public health problem. The polyphenol compound theaflavin-3,3' Show more
Nonalcoholic fatty liver disease (NAFLD), one of the risk factors for hepatitis, cirrhosis, and even hepatic carcinoma, has been a global public health problem. The polyphenol compound theaflavin-3,3'-digallate (TF3), mainly extracted from black tea, has been reported to produce an effect on hypoglycemic and antilipid deposition Show less
Recently, attention has been focused on the central role of TREM2 in diverse pathologies. However, the role of TREM2 signaling in the tumor microenvironment of hepatocellular carcinoma (HCC) remains p Show more
Recently, attention has been focused on the central role of TREM2 in diverse pathologies. However, the role of TREM2 signaling in the tumor microenvironment of hepatocellular carcinoma (HCC) remains poorly understood. Herein, we systematically investigated the single-cell transcriptomes of human HCC tissues and found that Show less
Heat stress is one of the most prevalent issues in poultry production that reduces performance, robustness, and economic gains. Previous studies have demonstrated that native chickens are more toleran Show more
Heat stress is one of the most prevalent issues in poultry production that reduces performance, robustness, and economic gains. Previous studies have demonstrated that native chickens are more tolerant of heat than commercial breeds. However, the underlying mechanisms of the heat tolerance observed in native chicken breeds remain unelucidated. Therefore, we performed a phenotypical, physiological, liver transcriptome comparative analysis and WGCNA in response to heat stress in one native (Beijing You, BY) and one commercial (Guang Ming, GM) chicken breed. The objective of this study was to evaluate the heat tolerance and identify the potential driver and hub genes related to heat stress in these two genetically distinct chicken breeds. In brief, 80 BY and 60 GM, 21 days old chickens were submitted to a heat stress experiment for 5 days (33 °C, 8 h/day). Each breed was divided into experimental groups of control (Ctl) and heat stress (HS). The results showed that BY chickens were less affected by heat stress and displayed reduced DEGs than GM chickens, 365 DEGs and 382 DEGs, respectively. The transcriptome analysis showed that BY chickens exhibited enriched pathways related to metabolism activity, meanwhile GM chickens' pathways were related to inflammatory reactions. Show less
Lysyl-oxidase-like 3 (LOXL3) was reported to be essential in epithelial-mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this Show more
Lysyl-oxidase-like 3 (LOXL3) was reported to be essential in epithelial-mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this study, we explored clinical significance, biological functions, and regulatory mechanisms of LOXL3 in HCC. Our study found that LOXL3 expression was markedly associated with the tumor size and clinical stage of HCC, and it was highly expressed in tumor tissues of metastatic HCC patients. High expression of LOXL3 predicted a poor prognosis of HCC. TGF-β1 treatment elevated LOXL3 protein expression and cell invasion, and reduced cell apoptosis in HCC cell lines (SMMC-7721 and Huh-7), while downregulation of LOXL3 reversed the promotive effects of TGF-β1 treatment on LOXL3 protein expression and cell invasion, and the inhibitory effect on cell apoptosis. Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin-specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co-IP assays. Overexpression of USP4 reversed the inhibitory effect of LOXL3 silence on EMT in HCC cells through deubiquitinating and stabilizing the expression of Snail1. Moreover, LOXL3-promoted HCC EMT through Wnt/β-catenin/Snail1 signaling pathway. In vivo study revealed that silence of LOXL3-inhibited HCC tumor growth. In conclusion, LOXL3 silence inhibited HCC invasion and EMT through Snail1/USP4-mediated circulation loop and Wnt/β-catenin signaling pathway. Show less
Lung adenocarcinoma (LUAD) is a familiar lung cancer with a very poor prognosis. This study investigated the immune- and stemness-related genes to develop model related with cancer immunity and progno Show more
Lung adenocarcinoma (LUAD) is a familiar lung cancer with a very poor prognosis. This study investigated the immune- and stemness-related genes to develop model related with cancer immunity and prognosis in LUAD. The Cancer Genome Atlas (TCGA) was utilized for obtaining original transcriptome data and clinical information. Differential expression, prognostic value, and correlation with clinic parameter of mRNA stemness index (mRNAsi) were conducted in LUAD. Significant mRNAsi-related module and hub genes were screened using weighted gene coexpression network analysis (WGCNA). Meanwhile, immune-related differential genes (IRGs) were screened in LUAD. Stem cell index and immune-related differential genes (SC-IRGs) were screened and further developed to construct prognosis-related model and nomogram. Comprehensive analysis of hub genes and subgroups, involving enrichment in the subgroup [gene set enrichment analysis (GSEA)], gene mutation, genetic correlation, gene expression, immune, tumor mutation burden (TMB), and drug sensitivity, used bioinformatics and reverse transcription polymerase chain reaction (RT-PCR) for verification. Through difference analysis, mRNAsi of LUAD group was markedly higher than that of normal group. Clinical parameters (age, gender, and T staging) were ascertained to be highly relevant to mRNAsi. MEturquoise and MEblue were found to be the most significant modules (including positive and negative correlations) related to mRNAsi The SC-IRG model and the prognostic nomogram could accurately predict LUAD survival. Our study used mRNAsi combined with immunity that may lay a foundation for the future research studies in LUAD. Show less
It is well known that hypoxia and ferroptosis are intimately connected with tumor development. The purpose of this investigation was to identify whether they have a prognostic signature. To this end, Show more
It is well known that hypoxia and ferroptosis are intimately connected with tumor development. The purpose of this investigation was to identify whether they have a prognostic signature. To this end, genes related to hypoxia and ferroptosis scores were investigated using bioinformatics analysis to stratify the risk of lung adenocarcinoma. Hypoxia and ferroptosis scores were estimated using The Cancer Genome Atlas (TCGA) database-derived cohort transcriptome profiles via the single sample gene set enrichment analysis (ssGSEA) algorithm. The candidate genes associated with hypoxia and ferroptosis scores were identified using weighted correlation network analysis (WGCNA) and differential expression analysis. The prognostic genes in this study were discovered using the Cox regression (CR) model in conjunction with the LASSO method, which was then utilized to create a prognostic signature. The efficacy, accuracy, and clinical value of the prognostic model were evaluated using an independent validation cohort, Receiver Operator Characteristic (ROC) curve, and nomogram. The analysis of function and immune cell infiltration was also carried out. Here, we appraised 152 candidate genes expressed not the same, which were related to hypoxia and ferroptosis for prognostic modeling in The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohort, and these genes were further validated in the GSE31210 cohort. We found that the 14-gene-based prognostic model, utilizing Our research found a 14-gene signature and established a nomogram that accurately predicted the prognosis in patients with lung adenocarcinoma. Clinical decision-making and therapeutic customization may benefit from these results, which may serve as a valuable reference in the future. Show less
DNA methylation plays a significant role in transducing external environmental signals to a cellular response in reptiles; however, whether the methylation patterns are conserved across species remain Show more
DNA methylation plays a significant role in transducing external environmental signals to a cellular response in reptiles; however, whether the methylation patterns are conserved across species remains unclear. Here, we examined the genome-wide DNA methylation differentiation between male and female hatchling gonads of the temperature-dependent sex determination (TSD) Mauremys mutica (M. mutica) using methylation-dependent restriction-site associated DNA sequencing (MethylRAD-seq) to test differentially methylated genes underlying sexual development. Several categories, including heat-shock genes (HSP90A, HSP30C), histone- (KDM8) and ubiquitin-related genes (TRIM39), kinases (WNK3), and gonad differentiation or gonadal-development-related genes (HSD17B8, HSD17B12), were identified as candidates for future study. Additionally, we identified several regulatory pathways potentially mediating TSD thermosensitivity such as the GnRH signaling pathway and calcium signaling pathway. These findings provide evidence that sexually dimorphic DNA methylation may be associated with sex determination or sex differentiation in TSD M. mutica. Show less