Ischemic stroke is a disease with a very high incidence in the clinic, and hypertension is the most important variable risk factor of ischemic stroke. Studies have shown that intestinal microbes are i Show more
Ischemic stroke is a disease with a very high incidence in the clinic, and hypertension is the most important variable risk factor of ischemic stroke. Studies have shown that intestinal microbes are involved in the occurrence and development of various diseases. This study aims to explore whether intestinal microbes play an important role in the pathogenesis of ischemic stroke in a hypertensive population. In this study, the inpatients in the Department of Neurology and Cardiology of the Second Affiliated Hospital of Shandong First Medical University in April 2021 were selected, including seven patients with hypertension complicated with ischemic stroke and only seven patients with hypertension. After collecting the stool samples of patients, the gene sequence of the samples was detected by 16S rRNA sequencing technology, and the double-ended 2 × 150 bp sequencing was carried out. After sequencing, the results were analyzed by diversity analysis, species difference analysis, species function difference analysis, and other bioinformatics tests. According to the test results, serum proteomics and biochemical blood tests were carried out to verify. There was no significant difference in α diversity and β diversity between hypertension complicated with the cerebral infarction and hypertension groups. LEfSe analysis showed that at the genus level, compared with the hypertension group, Bacteroides, UCG₀₀₉, and Eisenbergiella had significantly increased relative abundance. The genera with relatively significantly reduced abundance are Ruminococcus_gnavus_group, Sutterellaceae, Burkholderia, and Prevotella and the LDA score of Prevotella is < - 4, which indicates that there are significant differences. Compared with the blood biochemical indexes, the results showed that the level of APOA1 in hypertensive patients with ischemic stroke was significantly higher than that in hypertensive patients (p < 0.05), but there was no significant difference in total cholesterol (CHOL), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein B (APOB), and free fatty acid (NEFA). Proteomic analysis showed that there were 89 up-regulated genes and 51 down-regulated genes in the serum of the two groups, and the expression of APOC2 and APOC3 in the cerebral infarction group with hypertension was significantly higher than that in the hypertension group (p < 0.05). The intestinal diversity of patients with hypertension complicated with stroke is similar to that of patients with hypertension, but there are differences in microbiota, among which Prevotella is the most significant. Prevotella could affect lipid metabolism so that APOC2 and APOC3 in the blood are significantly increased, leading to cerebral artery atherosclerosis and, finally, ischemic stroke. This provides a new idea for preventing and treating ischemic stroke in patients with hypertension, but the mechanism of Prevotella acting on apolipoprotein needs further verification by basic medical research. Show less
The level of serum interleukin-27 (IL-27) was significantly decreased in the obesity group. After injection of IL-27, obese mice showed significant weight loss,reduced fat accumulation, improved insul Show more
The level of serum interleukin-27 (IL-27) was significantly decreased in the obesity group. After injection of IL-27, obese mice showed significant weight loss,reduced fat accumulation, improved insulin resistance and hepatic steatosis.IL-27 plays a key role in the regulation of metabolic processes, but there are scarce data on circulating IL-27 levels in hypothyroidism. The purpose of this study was to assess the serum levels of IL-27 in patients with hypothyroidism and its relationship with NAFLD. 185 participants were included in this cross-sectional survey. According to thyroid function, the subjects were classified into three groups: euthyroidism (n = 55), subclinical hypothyroidism (n = 53), and hypothyroidism (n = 77). Serum IL-27 concentrations were measured by ELISA. Serum IL27 levels were significantly higher in subclinical hypothyroidism and hypothyroidism groups than in the euthyroidism group. Serum IL27 levels had a negative correlation with HOMA-IR,FBG,TG, subcutaneous fat,and visceral fat, and had a positive correlation with HDL-C ( Serum IL-27 levels demonstrated a compensatory increase in patients with subclinical hypothyroidism or hypothyroidism and showed an independent association with NAFLD. Circulating IL-27 levels could predict the occurrence of NAFLD in hypothyroidism. These results suggested that altering the circulating levels of IL-27 may be a potential therapeutic target for NAFLD. Show less
Recently, there has been growing interest among researchers in exploring the effects of epithelial-mesenchymal transformation (EMT) or N6-Methyladenosine (m6A) modification regulators on tumor develop Show more
Recently, there has been growing interest among researchers in exploring the effects of epithelial-mesenchymal transformation (EMT) or N6-Methyladenosine (m6A) modification regulators on tumor development. However, the synergistic efficiency of these regulators in relation to ovarian cancer development remains unclear. This study aims to explore the transcription patterns of main regulators, including 19 EMT and 22 m6A, in ovarian cancer samples from TCGA datasets and normal samples from GTEx datasets. After conducting a LASSO regression analysis, ten prognostic signatures were identified, namely KIAA1429, WTAP, SNAI1, AXL, IGF2BP1, ELAVL1, CBLL1, CDH2, NANOG and ALKBH5. These signatures were found to have a comprehensive effect on immune infiltrating signatures and the final prognostic outcome. Next, utilizing the ssGSEA algorithm and conducting overall survival analyses, we have identified the key prognosis-related immunological signatures in ovarian cancer to be ALKBH5, WTAP, ELAVL1, and CDH2 as the regulators. The characteristic immune response and related genetic expression have revealed a significant correlation between the alteration of m6A regulators and EMT regulators, indicating a synergistic effect between these two factors in the development of ovarian cancer. In summary, our research offers a novel perspective and strategy to enhance the occurrence, progression, and prognosis of ovarian cancer. Show less
Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually resul Show more
Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually results in major adverse cardiovascular events. The C1q/TNF-related protein (C1QTNF) family is closely associated with cardiovascular disease. Notably, C1QTNF4 has unique two C1q domains. However, the role of C1QTNF4 in vascular diseases remains unclear. C1QTNF4 expression was detected in human serum and artery tissues using ELISA and multiplex immunofluorescence (mIF) staining. Scratch assay, transwell assay and confocal microscopy were used to investigate C1QTNF4 effects on VSMC migration. EdU incorporation, MTT assay and cell counting experiment revealed C1QTNF4 effects on VSMC proliferation. C1QTNF4-transgenic, C1QTNF4 Serum C1QTNF4 levels were decreased in patients with arterial stenosis. C1QTNF4 shows colocalisation with VSMC in human renal arteries. In vitro, C1QTNF4 inhibits VSMC proliferation and migration and alters VSMC phenotype. In vivo, an adenovirus-infected rat balloon injury model, C1QTNF4-transgenic and C1QTNF4 Our study demonstrated that C1QTNF4 is a novel inhibitor of VSMC proliferation and migration that acts by downregulating the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation. These results provide new insights into promising potent treatments for vascular stenosis diseases. Show less
Alzheimer's disease presents an abnormal cognitive behavior. TgCtwh6 is one of the predominant T. gondii strains prevalent in China. Although T. gondii type II strain infection can cause host cognitiv Show more
Alzheimer's disease presents an abnormal cognitive behavior. TgCtwh6 is one of the predominant T. gondii strains prevalent in China. Although T. gondii type II strain infection can cause host cognitive behavioral abnormalities, we do not know whether TgCtwh6 could also cause host cognitive behavioral changes. So, in this study, we will focus on the effect of TgCtwh6 on mouse cognitive behavior and try in vivo and in vitro to explore the underlying mechanism by which TgCtwh6 give rise to mice cognitive behavior changes at the cellular and molecular level. C57BL/6 mice were infected orally with TgCtwh6 cysts. From day 90 post-infection on, all mice were conducted through the open field test and then Morris water maze test to evaluate cognitive behavior. The morphology and number of cells in hippocampus were examined with hematoxylin-eosin (H&E) and Nissl staining; moreover, Aβ protein in hippocampus was determined with immunohistochemistry and thioflavin S plaque staining. Synaptotagmin 1, apoptosis-related proteins, BACE1 and APP proteins and genes from hippocampus were assessed by western blotting or qRT-PCR. Hippocampal neuronal cell line or mouse microglial cell line was challenged with TgCtwh6 tachyzoites and then separately cultured in a well or co-cultured in a transwell device. The target proteins and genes were analyzed by immunofluorescence staining, western blotting and qRT-PCR. In addition, mouse microglial cell line polarization state and hippocampal neuronal cell line apoptosis were estimated using flow cytometry assay. The OFT and MWMT indicated that infected mice had cognitive behavioral impairments. The hippocampal tissue assay showed abnormal neuron morphology and a decreased number in infected mice. Moreover, pro-apoptotic proteins, as well as BACE1, APP and Aβ proteins, increased in the infected mouse hippocampus. The experiments in vitro showed that pro-apoptotic proteins and p-NF-κBp65, NF-κBp65, BACE1, APP and Aβ proteins or genes were significantly increased in the infected HT22. In addition, CD80, pro-inflammatory factors, notch, hes1 proteins and genes were enhanced in the infected BV2. Interestingly, not only the APP and pro-apoptotic proteins in HT22, but also the apoptosis rate of HT22 increased after the infected BV2 were co-cultured with the HT22 in a transwell device. Neuron apoptosis, Aβ deposition and neuroinflammatory response involved with microglia polarization are the molecular and cellular mechanisms by which TgCtwh6 causes mouse cognitive behavioral abnormalities. Show less
Melanocortin 4 receptor (MC4R), the most important monogenetic cause of human metabolic disorders, has been of great interest to many researchers in the field of energy homeostasis and public health. Show more
Melanocortin 4 receptor (MC4R), the most important monogenetic cause of human metabolic disorders, has been of great interest to many researchers in the field of energy homeostasis and public health. Because MC4R is a vital pharmaceutical target for maintaining controllable appetite and body weight for professional athletes, previous studies have mainly focused on the central, rather than the peripheral, roles of MC4R. Thus, the local expression of MC4R and its behavioral regulation remain unclear. In an attempt to shed light on different directions for future studies of MC4R signaling, we review a series of recent and important studies exploring the peripheral functions of MC4R and the direct physiological interaction between peripheral organs and central MC4R neurons in this article. Show less
Changes in kidney function and the progression of chronic kidney disease (CKD) are associated with the risk of cardiovascular disease (CVD) and influenced by genetic factors. However, the association Show more
Changes in kidney function and the progression of chronic kidney disease (CKD) are associated with the risk of cardiovascular disease (CVD) and influenced by genetic factors. However, the association between genetic variants and kidney function in patients treated with antihypertensive drugs remains uncertain. This study aimed to examine the association between 30 variants locating at the 22 genes and the risk of kidney function evaluated by the estimated glomerular filtration rate (eGFR) in 1911 patients with hypertension from a Chinese community-based longitudinal cohort (including 1220 participants with CKD and 691 without CKD at baseline). By using multivariate linear regression analysis after adjustment for age, sex, traditional cardiovascular risk factors, and the use of antihypertensive drugs, as well as after correction for multiple comparison, patients with rs10767873T allele of the metallophosphoesterase domain containing 2 (MPPED2) gene were associated with higher level of eGFR (β = 0.041, p = 0.01) and lower levels of serum creatinine (β = -0.068, p = 0.001) and serum uric acid (β = -0.047, p = 0.02). But variant rs10767873 was not found to be associated with the risk of CKD, regardless of the types of antihypertensive drugs used. During a median 2.25-year follow-up, 152 CVD events were documented. Interestingly, patients with the rs10767873TT genotype had an increased risk of CVD events (hazard ratio, 1.74, 95% confidence interval, 1.11 to 2.73; p = 0.02) compared with patients carrying the wild-type genotype of rs10767873CC. In conclusion, our findings suggest variant rs10767873 of the MPPED2 gene is associated with kidney function and risk of CVD in Chinese hypertensive patients. Show less
Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European anc Show more
Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P Show less
Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes Show more
Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC). We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes. Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155. Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities. Show less
Spermatogenesis is a highly complex developmental process that typically consists of mitosis, meiosis, and spermiogenesis. DNA/RNA helicase DHX36, a unique guanine-quadruplex (G4) resolvase, plays cru Show more
Spermatogenesis is a highly complex developmental process that typically consists of mitosis, meiosis, and spermiogenesis. DNA/RNA helicase DHX36, a unique guanine-quadruplex (G4) resolvase, plays crucial roles in a variety of biological processes. We previously showed that DHX36 is highly expressed in male germ cells with the highest level in zygotene spermatocytes. Here, we deleted Dhx36 in advanced germ cells with Stra8-GFPCre and found that a Dhx36 deficiency in the differentiated spermatogonia leads to meiotic defects and abnormal spermiogenesis. These defects in late stages of spermatogenesis arise from dysregulated transcription of G4-harboring genes, which are required for meiosis. Thus, this study reveals that Dhx36 plays crucial roles in late stages of spermatogenesis. Show less
Fibroblast growth factor 21 (FGF21) regulates glycolipid metabolism and insulin homeostasis and acts as a cardioprotective factor by protecting against myocardial ischemia/reperfusion injury, hyperten Show more
Fibroblast growth factor 21 (FGF21) regulates glycolipid metabolism and insulin homeostasis and acts as a cardioprotective factor by protecting against myocardial ischemia/reperfusion injury, hypertension, and vascular dysfunction. FGF21 has been reported to prevent Doxorubicin (Dox)-induced cardiotoxicity, and the related signaling pathway is worthy of further study. Connexin43 (Cx43) protein was reduced by Dox treatment, especially low phosphorylated form of Cx43. Thus the aim of study is to explore the protection effect of FGF21 on Dox induced cardiotoxicity by improving the expression of Cx43 and the involved signaling pathway. FGF21 inhibited apoptosis in Dox-treated mice and cardiomyocytes. FGF21 increased the levels of connexin43 phosphorylated at serine (S) 282 (p-Cx43 S282) and total Cx43 to inhibit Dox-induced apoptosis. By RNA sequencing, we found that deubiquitinase monocyte chemoattractant protein-induced protein 1 (MCPIP1) expression was increased by FGF21. We further found that FGF21 induced the phosphorylation of fibroblast growth factor receptor 1 (FGFR1), extracellular signal-regulated kinase 1 and 2 (Erk1/2), and Elk. Phosphorylated Elk translocated to the nucleus and increased the expression of MCPIP1. Then, MCPIP1 bound neural precursor cell expressed developmentally downregulated protein 4 (Nedd4), an E3 ubiquitination ligase, as shown by co-immunoprecipitation (Co-IP), and suppressed Cx43 ubiquitination and degradation, competitively inhibiting the binding of Cx43 with Nedd4. Thus Nedd4 could not bind and ubiquitinate Cx43, leading to the up-regulation of Cx43 and phosphorylation of Cx43 at S282. FGF21 inhibited the effects of Dox on cardiomyocytes by elevating the phosphorylation of Cx43 at S282 and total Cx43 expression. This study suggests a previously unknown mechanism for the FGF21-mediated enhancement of cardiomyocyte survival and provides an effective approach to protect against the adverse cardiac effects of Dox. Show less
Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, incl Show more
Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, including gastric cancer (GC) cells. However, the mechanism by which the functional stability of LATS1 is modulated has yet to be elucidated. Online prediction tools, immunohistochemistry and western blotting assays were used to explore the expression of WW domain-containing E3 ubiquitin ligase 2 (WWP2) in GC cells and tissues. Gain- and loss-of-function assays, as well as rescue experiments were performed to determine the role of the WWP2-LATS1 axis in cell proliferation and invasion. Additionally, the mechanisms involving WWP2 and LATS1 were assessed by coimmunoprecipitation (Co-IP), immunofluorescence, cycloheximide and in vivo ubiquitination assays. Our results demonstrate a specific interaction between LATS1 and WWP2. WWP2 was markedly upregulated and correlated with disease progression and a poor prognosis in GC patients. Moreover, ectopic WWP2 expression facilitated the proliferation, migration and invasion of GC cells. Mechanistically, WWP2 interacts with LATS1, resulting in its ubiquitination and subsequent degradation, leading to increased transcriptional activity of YAP1. Importantly, LATS1 depletion abolished the suppressive effects of WWP2 knockdown on GC cells. Furthermore, WWP2 silencing attenuated tumor growth by regulating the Hippo-YAP1 pathway in vivo. Our results define the WWP2-LATS1 axis as a critical regulatory mechanism of the Hippo-YAP1 pathway that promotes GC development and progression. Video Abstract. Show less
As a novel polyfluoroalkyl substance, Nafion by-product 2 (Nafion BP2) has been detected widely in environmental matrix as well as human samples. However, its toxicity remains poorly recognized. Here, Show more
As a novel polyfluoroalkyl substance, Nafion by-product 2 (Nafion BP2) has been detected widely in environmental matrix as well as human samples. However, its toxicity remains poorly recognized. Here, we investigated the toxic effects of Nafion BP2 by use of zebrafish model and highlighted its toxicity on lipid homeostasis. Large sized-lipid droplets (LDs) have been revealed to gather in pericardium and anterior yolk sac region of zebrafish larvae by Oil Red O staining after a 120 h Nafion BP2 exposure. Meanwhile, the total cholesterol (TC) concentrations were significantly disrupted. Lipidomic analysis uncovered a dramatical alterations on lipid profiles. Significant reductions were observed for a set of lipids including phosphatidylinositol (PI), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingolipid (SM) and triglyceride (TG) in zebrafish. Transcriptome analyses further confirmed genes involved in LDs biosynthesis, lipid transportation and lipid metabolism, were significantly disrupted. Especially for APOA4 and CIDEC genes, fold changes (Log2 FC) of gene expression level by up to 17.8 and 3.5, respectively, were observed. Together, these findings demonstrated the disturbance of Nafion BP2 on lipid homeostasis of zebrafish and provided an unprecedented insight into the health risk assessments of emerging fluorochemicals. Show less
Neuropathic pain (NP) is a chronic pain state with a complex etiology that currently lacks effective treatment in clinical practice. Studies have found that exercise training can alleviate NP hyperalg Show more
Neuropathic pain (NP) is a chronic pain state with a complex etiology that currently lacks effective treatment in clinical practice. Studies have found that exercise training can alleviate NP hyperalgesia, but the specific mechanism remains unclear. Here, we sought to identify proteins and signaling pathways critical for mediating the effects of treadmill training on NP in a mouse model of spared nerve injury (SNI). We used Tandem Mass Tag (TMT) technology for proteins and signaling pathways identification. Functional enrichment analyses were conducted using DAVID and Metascape software. Ingenuity pathway analysis was used to conduct functional annotation and analyze alterations in canonical pathways and molecular networks. Reverse transcription quantitative PCR (RT-qPCR) was used to confirm the results of proteomics analysis. A total of 270 differentially expressed proteins were screened in the detrained and trained groups ( Our results suggest that treadmill training may alleviate nociceptive hyperalgesia in NP mice by modulating the autophagic pathway, providing unique mechanistic insights into the analgesic effects of exercise. Show less
Estrogen deficiency causes mitochondrial defects that precede pathological changes related to Alzheimer's disease (AD) in the mouse model of postmenopause. The aim of this study was to investigate in Show more
Estrogen deficiency causes mitochondrial defects that precede pathological changes related to Alzheimer's disease (AD) in the mouse model of postmenopause. The aim of this study was to investigate in such a mouse model whether and how estrogen receptor β (ERβ) was involved in prevention of mitochondrial damage and protection of neurons in the hippocampus. A mouse model of postmenopausal AD was created by ovariectomizing female 3xTg-AD mice, some of which were subcutaneously injected for six weeks with the non-steroidal ERβ agonist diarylpropionitrile. ERβ expression in female C57BL/6J mice was knocked down using shRNA interference. The different groups of animals were compared in terms of cognitive function using the Y-maze test, new object recognition test, and Morris water maze test, expression of numerous proteins related to mitochondrial biogenesis, mitophagy, apoptosis, and mitochondrial membrane potential, as well as deposition of amyloid β and neurofibrillary tangles. To complement these in vivo studies, we probed the effects of diarylpropionitrile on ERβ expression, apoptosis, and mitochondrial homeostasis in primary rat hippocampal neurons treated with amyloid β. ERβ knockdown in C57BL/6J mice produced cognitive impairment, reduced mitochondrial biogenesis by downregulating PGC-1α, NRF1, mtTFA, and TOM20, and decreased mitophagy by downregulating Pink1, Parkin, and LC3B while upregulating PARIS and p62. ERβ knockdown promoted neuronal apoptosis by upregulating Cleaved-Caspase 9, Cleaved-Caspase 3, and Bax, while downregulating Bcl2 in hippocampus. Diarylpropionitrile mitigated cognitive decline in ovariectomized 3xTg-AD mice, which was associated with downregulation of BACE1, reduction of Aβ deposition, neurofibrillary tangles, and tau hyperphosphorylation, and upregulation of ERβ, increases in mitochondrial biogenesis and mitophagy, and decreases in apoptosis. The effects of diarylpropionitrile in mice were recapitulated in Aβ-injured primary rat hippocampal neurons. ERβ activation can support learning and memory and alleviate AD symptoms in the postmenopausal AD model, which may involve regulation of neuronal mitochondrial biogenesis and mitophagy via NRF1/PGC-1α. This study supports further research on ERβ as a therapeutic target for postmenopausal women with AD. Show less
We previously demonstrated that heat shock factor protein 4 (HSF4) facilitates colorectal cancer (CRC) progression. DNA methylation, a major modifier of gene expression and stability, is involved in C Show more
We previously demonstrated that heat shock factor protein 4 (HSF4) facilitates colorectal cancer (CRC) progression. DNA methylation, a major modifier of gene expression and stability, is involved in CRC development and outcome. To investigate the correlation between Differences in β values of A total of 19 CpG methylation loci were identified in HSF4 is highly methylated in CRC, but there is no significant correlation between it and the prognosis and diagnosis of CRC. Show less
Persistent inflammation and epithelial-mesenchymal transition are essential pathophysiological processes in chronic obstructive pulmonary disease (COPD) and involve airway remodeling. m6A methylation Show more
Persistent inflammation and epithelial-mesenchymal transition are essential pathophysiological processes in chronic obstructive pulmonary disease (COPD) and involve airway remodeling. m6A methylation modification was discovered to play an important role in various diseases. Nevertheless, the regulatory role of m6A methylation has not yet been investigated in cigarette smoking-induced COPD. The study aims to explore the regulatory role of m6A methylation in cigarette smoking-induced COPD. In this study, two Gene Expression Omnibus (GEO) datasets were first utilized to analyze the expression profiles of m6A RNA methylation regulators in COPD. We then established a cell model of COPD by exposing human bronchial epithelial cells (HBECs) to cigarette smoke extract (CSE) in vitro and detected the expression of m6A writer Mettl3 and EMT phenotype markers. RNA interference, cycloleucine, RT-qPCR, western blot, MeRIP-sequencing, and cell migration assay were performed to investigate the potential effect of Mettl3 on the EMT process in CSE-induced HBECs. Our results showed that Mettl3 expression was significantly elevated in cigarette smoking-induced COPD patients and in a cellular model of COPD. Furthermore, Mettl3 silence and cycloleucine treatment inhibited the EMT process of HBECs caused by CSE. Mechanically, Mettl3 silence weakens the m6A methylation of SOCS3 mRNA to enhance the protein expression of SOCS3, inhibiting CSE-induced SOCS3/STAT3/SNAI1 signaling and EMT processes in HBECs. Our study inferred that Mettl3-mediated m6A RNA methylation modification modulates CSE-induced EMT by targeting SOCS3 mRNA and ultimately serves as a crucial regulator in the emergence of COPD. This conclusion reinforces the regulatory role of m6A methylation in COPD. Show less
Previous studies have revealed that there existed epidemic associations between Alzheimer's disease (AD) and many types of tumors, however, the inner biological mechanism connecting these diseases was Show more
Previous studies have revealed that there existed epidemic associations between Alzheimer's disease (AD) and many types of tumors, however, the inner biological mechanism connecting these diseases was not clear currently. In this study, we explored the transcriptome associations between AD and glioblastoma multiforme (GBM) that both originate in the brain, using microglia as a bridge, from gene and network levels. Firstly, we extracted human scRNA sequencing datasets from Gene Expression Omnibus (GEO) database, and identified differentially expressed genes within microglia after cell annotation. It was observed that there were 11 common genes shared by AD and GBM dys-regulated genes. Next, we utilized DIAMOnD and Flow Centrality algorithms to identify microglia modules and mediating pathways connecting these two diseases based on global network topology. Among these candidate pathways, the mediating genes FURIN and BACE1 (from SPIKN5 to CSNK1A1) were not only related to the formation of amyloid beta plaques that accumulate in the brain of AD patients, but also involved in cancer biology. Furthermore, the biological explorations of mediating pathways connecting AD and GBM modules reveal inflammatory response, lipid metabolism disorder, and cell proliferation terms. Finally, novel signatures for early AD detection as well as risk models for glioma prognosis were identified based on mediating genes involved in these pathways. In conclusion, this study provided a novel network-based strategy for exploring microglia mediation between AD and GBM and identified candidate signatures for disease detection and prognosis. Show less
This study aimed to explore the effect of miR-23b-3p on the differentiation of goat intramuscular preadipocytes, and to confirm whether miR-23b-3p plays its roles
Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Show more
Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and PDT effectiveness remains awaited. The influencing factors of two-photon excited PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline ligand containing Show less
DNAJ heat shock protein family (Hsp40) member C1(DNAJC1) is a member of the DNAJ family. Some members of the DNAJ gene family had oncogenic properties in many cancers. However, the role of DNAJC1 in h Show more
DNAJ heat shock protein family (Hsp40) member C1(DNAJC1) is a member of the DNAJ family. Some members of the DNAJ gene family had oncogenic properties in many cancers. However, the role of DNAJC1 in hepatocellular carcinoma (HCC) was unclear. In this study, expression and prognostic value of DNAJC1 in HCC were analyzed by bioinformatics. Quantitative real-time PCR and Western blotting were used to verify DNAJC1 expression in liver cancer cell lines. Furthermore, immunohistochemical (IHC) was used to detect DNAJC1 expression in liver cancer tissues. Subsequently, the effect of DNAJC1 on the proliferation, migration, invasion and apoptosis of HCC cells was detected by knocking down DNAJC1. Finally, gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of DNAJC1 and was verified by Western blotting. DNAJC1 was highly expressed in HCC and was significantly associated with the prognosis of patients with HCC. Importantly, the proliferation, migration and invasion of Huh7 and MHCC97H cells were inhibited by the knockdown of DNAJC1 and the knockdown of DNAJC1 promoted Huh7 and MHCC97H cell apoptosis. Furthermore, compared to the negative control group, DNAJC1 knockdown in Huh7 and MHCC97H cells promoted the expression of p21, p53, p-p53(Ser20), Bax and E-cadherin proteins, while inhibiting the expression of PARP, MMP9, Vimentin, Snai1, Bcl-2 and N-cadherin proteins. DNAJC1 had a predictive value for the prognosis of HCC. Knockdown of DNAJC1 may inhibit HCC cell proliferation, migration and invasion and promote the HCC cell apoptosis through p53 and EMT signaling pathways. Show less
Melanoma is the most aggressive form of skin cancer with rapidly increased incidence worldwide especially in the Caucasian population. Surgical excision represents the curative treatment choice in pat Show more
Melanoma is the most aggressive form of skin cancer with rapidly increased incidence worldwide especially in the Caucasian population. Surgical excision represents the curative treatment choice in patients with early-stage disease. However, the therapeutic outcomes in patients with metastatic melanoma remains unsatisfactory. Thus, understanding molecular mechanisms contributing to metastasis and chemoresistance is critical for new improved therapies of melanoma. Snail1, an important epithelial-mesenchymal transition transcription factors (EMT-TFs), is critical to induce the EMT process, thereby contributing to cancer metastasis. However, the involvement of Snail1 in melanoma metastasis remains elusive and the underlying mechanism to regulate Snail1 in melanoma needs to be further investigated. Here, we identified OTUD4 as a novel deubiquitinase of Snail1 in melanoma. Moreover, the depletion of OTUD4 in melanoma cells markedly inhibited Snail1 stability and Snail1-driven malignant phenotypes both in vitro and in vivo. Overall, our study establishes OTUD4 as a novel therapeutic target in metastasis and chemoresistance of melanoma by stabilizing Snail1 and provides a rationale for potential therapeutic strategies of melanoma. Show less
Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammator Show more
Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammatory responses in vivo. With the development of animal models and technical tools, several studies have shown that it is also closely associated with autoimmune diseases and other immune related diseases, and is considered as an important candidate for the treatment of viral disease, autoimmune diseases, tumors and obesity. Therefore, this paper reviews recent progress on the role of IL-27 in acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, tumors and obesity, with the aim of providing new ideas for the treatment of immune related diseases. Show less
Jun Li, Ying Xia, Shumin Kong+6 more · 2023 · Journal of the European Academy of Dermatology and Venereology : JEADV · Blackwell Publishing · added 2026-04-24
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having Show more
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having the potential to progress into invasive SCC (iSCC) and metastasize, causing death. This study aimed to investigate the heterogeneity of keratinocytes and how this heterogeneity promoted AK development and progression. We employed single-cell RNA sequencing (scRNA-seq) to examine the heterogeneity of keratinocytes and dermal fibroblast clusters in AKs and adjacent normal skins. Cell clustering, pseudotime trajectory construction, gene ontology enrichment analysis, transcription factor network analysis, and cell-cell communication were used to investigate the heterogeneity of keratinocytes in AK. The cellular identity and function were verified by immunohistochemical and immunofluorescence staining. Using scRNA-seq, we revealed 13 keratinocyte subgroups (clusters 0-12) in AK tissues and characterized 2 AK-specific clusters. Cluster 9 displayed high levels of IL1R2 and WFDC2, and cluster 11 showed high levels of FADS2 and FASN. The percentages of cells in these two clusters significantly increased in AK compared with normal tissues. The existence and spatial localization of AK-specific IL1R2+WFDC2+ cluster were verified by immunohistochemical and immunofluorescence staining. Functional studies indicated that the genes identified in the IL1R2+WFDC2+ cluster were crucial for epithelial cell proliferation, migration, and angiogenesis. Further immunofluorescent staining revealed the interactions between AK-specific keratinocytes and secretory-papillary fibroblasts mainly through ANGPTL4-ITGA5 signalling pathway rarely seen in normal tissues. The findings of this study might help better understand AK pathogenesis. Show less
Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, Show more
Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with early weaning to explore the protective role of EPA in adolescent depression. We found that that ELS induced depression-like behavior rather than anxiety-like behavior in adolescent mice. RNA-sequencing results showed that ELS changed the transcription pattern in the liver, including 863 upregulated genes and 971 downregulated genes, especially those related to the biosynthesis of unsaturated fatty acids metabolism in the liver. Moreover, ELS decreased the expression of the rate-limiting enzymes, fatty acid desaturases 1/2 (FADS1/2), involved in the biosynthesis of EPA in the liver. Additionally, ELS reduced the levels of EPA in the liver, serum, and hippocampus, and EPA administration improved depression-like behavior-induced by ELS. Our results provide transcriptomic evidence that ELS increases the risk of adolescent depression by reducing the synthesis of unsaturated fatty acids in the liver, especially EPA, and suggest that supplementation with EPA should be investigated as a potential treatment for adolescent depression. 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
Muscle mass development depends on increased protein synthesis and reduced muscle protein degradation. Muscle ring-finger protein-1 (MuRF1) plays a key role in controlling muscle atrophy. Its E3 ubiqu Show more
Muscle mass development depends on increased protein synthesis and reduced muscle protein degradation. Muscle ring-finger protein-1 (MuRF1) plays a key role in controlling muscle atrophy. Its E3 ubiquitin ligase activity recognizes and degrades skeletal muscle proteins through the ubiquitin-proteasome system. The loss of Murf1, which encodes MuRF1, in mice leads to the accumulation of skeletal muscle proteins and alleviation of muscle atrophy. However, the function of Murf1 in agricultural animals remains unclear. Herein, we bred F1 generation Murf1 Show less