To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then us Show more
To investigate associations of genetic and environmental factors with coronary artery disease (CAD), we collected medical reports, lifestyle details, and blood samples of 2113 individuals, and then used the polymerase chain reaction (PCR)-ligase detection reaction (LDR) to genotype the targeted 102 SNPs. We adopted elastic net algorithm to build an association model that considered simultaneously genetic and lifestyle/clinical factors associated with CAD in Chinese Han population. In this study, we developed an all covariates-based model to explain the risk of CAD, which incorporated 8 lifestyle/clinical factors and a gene-score variable calculated from 3 significant SNPs (rs671, rs6751537 and rs11641677), attaining an area under the curve (AUC) value of 0.71. It was found that, in terms of genetic variants, the AA genotype of rs671 in the additive (adjusted odds ratio (OR) = 2.51, p = 0.008) and recessive (adjusted OR = 2.12, p = 0.021) models, the GG genotype of rs6751537 in the additive (adjusted OR = 3.36, p = 0.001) and recessive (adjusted OR = 3.47, p = 0.001) models were associated with increased risk of CAD, while GG genotype of rs11641677 in additive model (adjusted OR = 0.39, p = 0.044) was associated with decreased risk of CAD. In terms of lifestyle/clinical factors, the history of hypertension (unadjusted OR = 2.37, p < 0.001) and dyslipidemia (unadjusted OR = 1.82, p = 0.007), age (unadjusted OR = 1.07, p < 0.001) and waist circumference (unadjusted OR = 1.02, p = 0.05) would significantly increase the risk of CAD, while height (unadjusted OR = 0.97, p = 0.006) and regular intake of chicken (unadjusted OR = 0.78, p = 0.008) reduced the risk of CAD. A significantinteraction was foundbetween rs671 and dyslipidemia (the relative excess risk due to interaction (RERI) = 3.36, p = 0.05). In this study, we constructed an association model and identified a set of SNPs and lifestyle/clinical risk factors of CAD in Chinese Han population. By considering both genetic and non-genetic risk factors, the built model may provide implications for CAD pathogenesis and clues for screening tool development in Chinese Han population. 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
Investigation of associated risk factors of valproic acid (VPA)-induced tremor helped in increasing tolerance and optimizing treatment scheme individually. To determine the risk factors of VPA-induced Show more
Investigation of associated risk factors of valproic acid (VPA)-induced tremor helped in increasing tolerance and optimizing treatment scheme individually. To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations. Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. One hundred and eighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p = 0.014), family history of tremor (OR = 7.595, p = 0.003), treatment duration (> 24 months; OR = 3.294, p = 0.002), and daily dosage (> 1,000 mg/d; OR = 19.801, p = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER (p = 0.030) and carbamazepine combination (p = 0.040) reduced the incidence of tremor. One hundred and seventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values (p > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p = 0.001), reduced cerebellar hemisphere thickness (p = 0.025), and right cerebellar hemisphere longitudinal diameter (p = 0.047). Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000 mg and treatment duration > 24 months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor. Show less
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
Senile osteoporosis is one of the major health problems in an aging society. Decreased bone formation due to osteoblast dysfunction may be one of the causes of aging-related bone loss. With increasing Show more
Senile osteoporosis is one of the major health problems in an aging society. Decreased bone formation due to osteoblast dysfunction may be one of the causes of aging-related bone loss. With increasing evidence suggesting that multiple microRNAs (miRNAs) play important roles in osteoblast function, the relationship between miRNAs and senile osteoporosis has become a popular research topic. Previously, we confirmed that mechanoresponsive miR-138-5p negatively regulated bone anabolic action. In this study, the miR-138-5p level was found to be negatively correlated with BMD and osteogenic markers in bone specimens of senile osteoporotic patients by bioinformatic analysis and experimental verification. Furthermore, high miR-138-5p levels aggravated the decrease of aged osteoblast differentiation Show less
HMO (Hereditary Multiple Osteochondroma), an uncommon autosomal dominant disorder, is characterized by the development of multiple osteochondromas, which are nonmalignant cartilage-capped bone tumors Show more
HMO (Hereditary Multiple Osteochondroma), an uncommon autosomal dominant disorder, is characterized by the development of multiple osteochondromas, which are nonmalignant cartilage-capped bone tumors growing outwards from long bone metaphyses. The present work retrospectively analyzed seven children with HMO who were enrolled for routine clinical diagnosis and treatment, including X-ray examination. Subsequent genetic detection was carried out using whole exome sequencing (WES). In addition, this work applied Sanger sequencing to be the validation approach. Moreover, this work also examined amino acid (AA) evolutionary conservatism under the influence of certain missense variants. The clinical indications of all seven patients and their family members were thoroughly indexed. WES identified diagnostic variants in the Our results expanded HMO variation spectrum, and laid certain foundations for the precise counseling of those affected families. 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
Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiac disorder characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. Sorbin Show more
Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiac disorder characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. Sorbin and SH3 domain-containing protein 2 (SORBS2) converges on the actin and microtubule cytoskeleton. Here, we investigated the proteins interacting with SORBS2 to elucidate the pathogenic mechanism of LVNC. As reported in previous studies, SORBS2 enhances the occurrence of LVNC by potentiating heart failure, but the specific mechanism remains unclear. Building from our previous finding of elevated SORBS2 levels in LVNC hearts, we screened for proteins interacting with SORBS2 by proteomics and conducting IP experiments. Co-IP and immunofluorescence were used to verify the effects. We selected several proteins with high scores and high coverage that could be closely related to SORBS2 according to earlier reports showing a correlation with LVNC for verification. We finally obtained several proteins that were related to the pathogenesis of LVNC and also interacted with SORBS2, such as α-actinin, β-tubulin, MYH7, FLNA, MYBPC3, YWHAQ and DES, and YWHAQ was the most associated. We focused on the YWHAQ protein, and we identified a novel mechanism through which SORBS2 interacts with YWHAQ, having a negative effect on the cell cycle, potentially leading to LVNC. Show less
Hepatocellular carcinoma (HCC) is a malignancy with a dismal survival rate. The novel autoantibodies panel may provide new insights for the diagnosis of HCC. Biomarkers screened by two methods (bioinf Show more
Hepatocellular carcinoma (HCC) is a malignancy with a dismal survival rate. The novel autoantibodies panel may provide new insights for the diagnosis of HCC. Biomarkers screened by two methods (bioinformatics and the antigen-antibody system) were taken as candidate tumor-associated antigens (TAAs). Enzyme-linked immunosorbent assay was used to detect the corresponding autoantibodies in 888 samples of verification and validation cohorts. The verification cohort was used to verify the autoantibodies. Samples in the validation cohort were randomly divided into a train set and a test set with the ratio of 6:4. A diagnostic model was established by support vector machines within the train set. The test set further verified the model. Eleven TAAs were selected (AAGAB, C17orf75, CDC37L1, DUSP6, EID3, PDIA2, RGS20, PCNA, TAF7L, TBC1D13, and ZIC2). The titer of six autoantibodies (PCNA, AAGAB, CDC37L1, TAF7L, DUSP6, and ZIC2) had a significant difference in any of the pairwise comparisons among the HCC, liver cirrhosis, and normal control groups. The titer of these autoantibodies had an increasing tendency. Finally, an optimum diagnostic model was constructed with the six autoantibodies. The AUCs were 0.826 in the train set and 0.773 in the test set. The area under the curve (AUC) of this panel for diagnosing early HCC was 0.889. The diagnostic ability of the panel reduced with the progress of HCC. The positive rate of the panel in diagnosing alpha-fetoprotein (AFP)-negative patients was 75.6%. For early HCC, the sensitivity of the combination of AFP with the panel was 90.9% and superior to 53.2% of AFP alone. The novel immunodiagnosis panel combining AFP may be a new approach for the diagnosis of HCC, especially for early-HCC cases. Show less
To investigate the aqueous levels of angiogenic factors in nonproliferative diabetic retinopathy (NPDR) patients with diabetic macular edema (DME) and to ascertain their association with optical coher Show more
To investigate the aqueous levels of angiogenic factors in nonproliferative diabetic retinopathy (NPDR) patients with diabetic macular edema (DME) and to ascertain their association with optical coherence tomography angiography (OCTA) metrics. This study enrolled 21 NPDR eyes with DME (NPDR/DME+), 17 NPDR eyes without DME (NPDR/DME-), and 16 diabetic eyes without retinopathy (DWR). Luminex bead-based multiplex array was used to measure the levels of 25 cytokines. OCTA system with a scan area of 3 × 3 mm was used to measure retinal thickness (RT), retinal volume (RV), superficial vessel density (SVD), deep vessel density (DVD), foveal avascular zone (FAZ) area, perimeter and acircularity index. The levels of ANGPTL4 were significantly different among the three groups ( The level of ANGPTL4 in aqueous humor of NPDR patients with DME was significantly increased and ANGPTL4 might predict RT, RV, and parafoveal DVD of DME in NPDR patients. Show less
Betaine is more efficient than choline and methionine methyl donors, as it can increase nitrogen storage, promote fat mobilisation and fatty acid oxidation and change body fat content and distribution Show more
Betaine is more efficient than choline and methionine methyl donors, as it can increase nitrogen storage, promote fat mobilisation and fatty acid oxidation and change body fat content and distribution. Lipid is absorbed primarily in the small intestine after consumption, which is also the basis of lipid metabolism. This study was conducted to establish a mouse model of obesity in Kunming mice of the same age and similar body weight, and to assess the effect of betaine on the intestinal protein expression profile of mice using a proteomic approach. Analysis showed that betaine supplementation reversed the reduction in expression of proteins related to lipid metabolism and transport in the intestine of mice induced by a high-fat diet (HFD). For example, the addition of betaine resulted in a significant upregulation of microsomal triglyceride transfer protein (Mttp), apolipoprotein A-IV (Apoa4), fatty-acid-binding protein 1 (Fabp1) and fatty-acid-binding protein 2 (Fabp2) expression compared to the HFD group (p < 0.05), which exhibited accelerated lipid absorption and then translocation from the intestine into the body’s circulation, in addition to a significant increase in Acetyl-CoA acyltransferase (Acaa1a) protein expression, hastening lipid metabolism in the intestine (p < 0.05). Simultaneously, a significant reduction in protein expression of alpha-enolase 1 (Eno1) as the key enzyme for gluconeogenesis in mice in the betaine-supplemented group resulted in a reduction in lipid synthesis in the intestine (p < 0.05). These findings provide useful information for understanding the changes in the protein profile of the small intestine in response to betaine supplementation and the potential physiological regulation of diets’ nutrient absorption. 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
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
The molecular mechanism of in hyperlipidemia-induced renal injury has not been elucidated. Angiogenin-like protein 4 (ANGPTL4) is a key regulator of lipid metabolism. The role of ANGPTL4 hyperlipidemi Show more
The molecular mechanism of in hyperlipidemia-induced renal injury has not been elucidated. Angiogenin-like protein 4 (ANGPTL4) is a key regulator of lipid metabolism. The role of ANGPTL4 hyperlipidemia-induced renal injury has not been reported. Wild type C57 mice and gene angptl4 knockout mice were fed with 60% high fat diet or normal diet respectively. The serum lipid, urinary albumin and renal pathology were tested at the 9th, 13th, 17th and 21st week with high fat diet. Elevated blood lipids in the wild-type mice with high-fat diet were found at 9th week. At the 17th week, the level of urinary albumin in high-fat fed wild type mice were significantly higher than which with normal diet, correspondingly, segmental fusion of podocyte foot process in kidney could be observed in these hyperlipidemia mice. IHC showed that the expression of ANGPTL4 in glomeruli of high-fat fed wild type mice began significant elevated since the 9th week. When given high fat diet, compared to the wild type, the gene angptl4 knockout mice showed significantly alleviated the levels of hyperlipidemia, proteinuria and effacement of podocyte foot process. Finally, the expression of ACTN4 showed remarkably lower in glomeruli podocyte of wild type mice fed high fat diet than that of wild type mice with normal diet at each time-point (P < 0.01). Differently, the expression of ACTN4 in gene angptl4 knockout mice did not happen significantly weaken when given the same dose of high fat diet. ANGPTL4 could play a role in hyperlipidemic-induced renal injury via down-regulating the expression of ACTN4 in kidney podocyte. Show less
Adiponectin is a potent vascular protective molecule. Recent findings have suggested adiponectin resistance during early diabetes. However, the molecular mechanisms responsible remain unidentified. He Show more
Adiponectin is a potent vascular protective molecule. Recent findings have suggested adiponectin resistance during early diabetes. However, the molecular mechanisms responsible remain unidentified. Here, we took an unbiased approach to identify whether hyperlipidemic plasma molecules exist that bind and inhibit adiponectin function, contributing to adiponectin resistance and diabetic vascular injury. Adult rats were randomly assigned to receive either a normal or a high-fat diet for 8 weeks. Plasma was co-immunoprecipitated with anti-APN antibody and analyzed by mass spectrometry. The APN binding molecules and their effect upon APN biological activity were determined. As expected, the high-fat-diet increased plasma triglyceride, total cholesterol, and low-density lipoprotein. Importantly, the circulating APN level was significantly increased at this time point. Mass spectrometry identified 18 proteins with increased APN binding in hyperlipidemic plasma, among which four proteins critical in lipid metabolism, including apolipoprotein A1 (APOA1), APOA4, APOC1, and paraoxonase 1, were further investigated. Incubating recombinant APN with APOA1 markedly (P < 0.01), and incubating with APOC1 significantly (P < 0.05), inhibited APN activity as evidenced by the reduced AMPK activation in HUVECs. APOA4 and paraoxonase 1 incubation had no effect upon APN activity. Finally, plasma APOA1 was significantly increased (P < 0.05) in hyperlipidemic plasma compared with the control plasma. It was demonstrated for the first time that increased APOA1 and APOC1 in hyperlipidemic plasma binds and inhibits APN activity. This result not only identifies a novel molecular mechanism responsible for adiponectin resistance during early stage diabetes, but also provides additional new insight into the diverse/controversial (protective and harmful) functions of high-density lipoprotein. Show less
IL-17D is a new member of the IL-17 family. Currently, it is believed that IL-17D can directly act on immune cells or may indirectly modulate immune responses by regulating cytokine expression. Herein Show more
IL-17D is a new member of the IL-17 family. Currently, it is believed that IL-17D can directly act on immune cells or may indirectly modulate immune responses by regulating cytokine expression. Herein, we hypothesized that IL-17D regulates the expression of chemokines in intestinal epithelial cells, in turn modulating the immune response within intestinal mucosa under hyperoxia. To explore this notion, newborn rats were divided into a hyperoxia group (85 % O Show less
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are majo Show more
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated Show less
The Chromobox (CBX) family members were involved in a variety of physiological and oncological processes through the regulation of the epigenetic modification of chromatin. However, the comprehensive Show more
The Chromobox (CBX) family members were involved in a variety of physiological and oncological processes through the regulation of the epigenetic modification of chromatin. However, the comprehensive analysis of the CBX family in head and neck squamous cell carcinoma (HNSC) is lacking. In this work, we used multiple online databases and tools to investigate the roles of CBX family in aspects of gene expression, prognostic evaluation, genetic alteration, immune micro-environment of tumor, and status of methylation. The mRNA expression levels of CBX1, CBX3, and CBX5 were aberrantly increased in patients with HNSC, while CBX7 was aberrantly decreased. Higher expression of CBX7 was significantly associated with longer OS. Within the 5-11% of genetic alteration rate of CBXs, CBX3 ranked the highest and CBX5/7 ranked the lowest. SPRR1B, S100A7, CASP14, CDSN, LCE3D were the top 5 neighbor genes with the strongest association with CBXs in HNSC patients. Signaling pathways such as epidermal cell differentiation, cornification, and peptide cross-linking were demonstrated to have a strong association with CBX genes. The profiles of immune cell infiltration had high similarity for the group of HNSC patients stratified by expression of CBXs. The methylation levels of CBX1 and CBX5 significantly decreased, while that of CBX7 significantly increased in HNSC samples when compared with normal tissue. In conclusion, the CBX family showed its valuation for further investigation in HNSC. Our research highlighted that CBX7 had the potential to be a novel diagnostic and prognostic biomarker for patients with HNSC. Show less
Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present Show more
Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50 mg/kg per day, i.g.) for 28 days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Abeta (Aβ) generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases. Show less
Minghui Bao, Haotong Li, Jianping Li · 2022 · Journal of cellular and molecular medicine · Blackwell Publishing · added 2026-04-24
Aldosterone-producing adenoma (APA) is a common cause of secondary hypertension. This study aimed to explore the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network to uncover molecular mecha Show more
Aldosterone-producing adenoma (APA) is a common cause of secondary hypertension. This study aimed to explore the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network to uncover molecular mechanism underlying APA. The mRNA and lncRNA expression data of APA and adjacent adrenal gland (AAG) from GSE60044, GSE64957 and GSE101894 were obtained from the Gene Expression Omnibus (GEO) database to analyse differentially expressed genes (DEGs) and lncRNAs (DElncs). Hub genes were identified by robust rank aggregation (RRA) and protein-protein interaction (PPI) network analysis. The miRcode and miRWalk network tools were used to construct the ceRNA network. 1526 upregulated and 1512 downregulated DEGs were identified, which are mainly enriched in extracellular matrix and Ca Show less
Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural Show more
Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 μM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP Show less
Ovarian cancer (OC) is the most fatal gynecologic cancer. The branched-chain First, the expression level of BCKDK in OC cell lines or tissues was determined using tissue microarray- (TMA-) based immun Show more
Ovarian cancer (OC) is the most fatal gynecologic cancer. The branched-chain First, the expression level of BCKDK in OC cell lines or tissues was determined using tissue microarray- (TMA-) based immunohistochemistry or western blotting. Then, growth curve analysis, anchorage-independent cell transformation assays, wound healing assays, cell migration assays, and tumor xenografts were used to test whether BCKDK could promote cell transformation or metastasis. Finally, the signaling pathways involved in this process were investigated by western blotting or immunoprecipitation. We found that the expression of BCKDK was upregulated in OC tissues and the high expression of BCKDK was correlated with an advanced pathological grade in patients. The ectopic overexpression of BCKDK promoted the proliferation and migration of OC cells, and the knockdown of BCKDK with shRNAs inhibited the proliferation and migration of OC ex vivo and Our results demonstrate that BCKDK promotes OC proliferation and migration by activating the MEK/ERK signaling pathway. Targeting the BCKDK-MEK axis may provide a new therapeutic strategy for treating patients with OC. Show less
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic traffi Show more
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy. Show less
Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sit Show more
Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis. Show less
Early diagnosis and prognosis evaluation are of great significance to hepatitis E virus (HEV)-related acute liver failure (HEV-ALF) patients. We collected serum samples from 200 health controls (HCs), Show more
Early diagnosis and prognosis evaluation are of great significance to hepatitis E virus (HEV)-related acute liver failure (HEV-ALF) patients. We collected serum samples from 200 health controls (HCs), 200 patients with acute hepatitis E (AHE), and 200 HEV-ALF patients to evaluate serum exosome-derived carbamoyl phosphate synthase 1 (CPS1) levels and determine its diagnostic and prognostic value. The exosome-derived CPS1 levels in the HEV-ALF group were significantly higher than those in the AHE and HCs groups. The AUC of exosome-derived CPS1 to predict the occurrence of HEV-ALF was 0.850 (0.811-0.883). Both logistical regression and orthogonal partial least squares discriminant analysis (OPLS-DA) showed that exosome-derived CPS1 is an independent risk factor for HEV-ALF. The exosome-derived CPS1 levels were positively correlated with organ failure and the outcomes in HEV-ALF patients. The exosome-derived CPS1 levels in the worsening group were significantly higher than those in the fluctuating and the improving groups. The AUC of serum exosome-derived CPS1 to predict 30-day mortality was 0.829 (0.770-0.879), which was significantly greater than that of the Child-Pugh, KCH, and MELD models. The level of serum exosome-derived CPS1 might serve as a promising diagnostic and prognostic biomarker for HEV-ALF patients, which may provide better guidance for the diagnosis, prognosis, and treatment of HEV-ALF patients. Show less