The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present Show more
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non-muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co-immunoprecipitation, GST pull-down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non-muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin-specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co-expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10-MYH9-snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. Show less
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progressi Show more
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progression of DKD. The public transcriptomic datasets of the alloxan-induced DKD model and the streptozotocin-induced DKD model were retrieved to perform an integrative bioinformatic analysis of differentially expressed genes (DEGs) shared by two experimental animal models. The dominant biological processes and pathways associated with DEGs were identified through enrichment analysis. The expression changes of the key DEGs were validated in the classic db/db DKD mouse model. The downregulated and upregulated genes in DKD models were uncovered from GSE139317 and GSE131221 microarray datasets. Enrichment analysis revealed that metabolic process, extracellular exosomes, and hydrolase activity are shared biological processes and molecular activity is altered in the DEGs. Importantly, Hmgcs2, angptl4, and Slco1a1 displayed a consistent expression pattern across the two DKD models. In the classic db/db DKD mice, Hmgcs2 and angptl4 were also found to be upregulated while Slco1a1 was downregulated in comparison to the control animals. In summary, we identified the common biological processes and molecular activity being altered in two DKD experimental models, as well as the novel gene factors (Hmgcs2, Angptl4, and Slco1a1) which may be implicated in DKD. Future works are warranted to decipher the biological role of these genes in the pathogenesis of DKD. Show less
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (P Show more
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory. Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively. Fifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m The meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease. https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543. Show less
Bicuspid aortic valve (BAV) is the most common congenital heart defect in human beings, with an estimated prevalence in the general population of between 0.5 and 2%. Moreover, BAV is the most common c Show more
Bicuspid aortic valve (BAV) is the most common congenital heart defect in human beings, with an estimated prevalence in the general population of between 0.5 and 2%. Moreover, BAV is the most common cause of aortic stenosis in the pediatric population. Patients with BAV may have no symptoms for life, and some of them may progress to aortic stenosis. Genetic factors increase the susceptibility and development of BAV. However, the pathogenesis and BAV are still unclear, and more genetic variants are still needed for elucidating the molecular mechanism and stratification of patients. The present study carried out screening of variants implicated in disease in BAV patients. The whole-exome sequencing (WES) was performed in 20 BAV patients and identified 40 different heterozygous missense mutations in 36 genes (MIB2, FAAH, S100A1, RGS16, MAP3K19, NEB, TTN, TNS1, CAND2, CCK, KALRN, ATP10D, SLIT3, ROS1, FABP7, NUP205, IL11RA, NPR2, COL5A1, CUBN, JMJD1C, ANXA7, TRIM8, LGR4, TPCN2, APOA5, GPR84, LRP1, NCOR2, AKAP11, ESRRB, NGB, AKAP13, WWOX, KCNJ12, ARHGEF1). The mutations in these genes were identified as recurrent variants implicated in disease by in silico prediction tool analysis. Nine genes (MIB2, S100A1, TTN, CCK, NUP205, LGR4, NCOR2, ESRRB, and WWOX) among the 36 genes were identified as variants implicated in disease via unanimous agreement of in silico prediction tool analysis and sequenced in an independent cohort of 137 BAV patients to validate the results of WES. BAV patients carrying these variants demonstrated reduced left ventricular ejection fractions (LVEF) (63.8 ± 7.5% vs. 58.4 ± 5.2%, P < 0.001) and larger calcification volume [(1129.3 ± 154) mm Show less
The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic targets for DCM. We do Show more
The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic targets for DCM. We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results. FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments. These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM. 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
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
Koolen-de Vries syndrome (KdVS) is a genomic disorder characterized by intellectual disability, heart failure, hypotonia and congenital malformations, which is caused by haploinsufficiency of
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
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
Procymidone (PCM) is a low toxicity fungicide, and an endocrine-disrupting chemical (EDC) that particularly damages the reproductive system of male vertebrates. In present study, adolescent mice in co Show more
Procymidone (PCM) is a low toxicity fungicide, and an endocrine-disrupting chemical (EDC) that particularly damages the reproductive system of male vertebrates. In present study, adolescent mice in control, low-, medium-, and high-dose groups were orally administered 0 (equal volume of soybean oil), 50, 100, and 200 mg/kg/day PCM, respectively, for 21 days. Additionally, a three-dimensional culture of mouse testes was performed in vitro, and the control, low dose (0.33 × 10 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
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
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
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
Polyunsaturated fatty acid (PUFA) in breast milk provides physiological benefits for offspring and is closely related to endogenous biosynthesis in lactating women. Few studies have addressed the asso Show more
Polyunsaturated fatty acid (PUFA) in breast milk provides physiological benefits for offspring and is closely related to endogenous biosynthesis in lactating women. Few studies have addressed the association between fatty acid desaturase ( Show less
Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumi Show more
Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumin, a major ingredient of traditional Chinese medicine, Curcuma Longa, has various pharmacological activities. Therefore, exploring clinical drugs based on the inhibition of AD pathological features is imperative. First, we utilized the HERB database and Swisstarget Prediction database to get the related targets of curcumin and intersected with the AD targets. The intersection targets were used to construct the protein-protein interaction network and performed gene ontology and kyoto encyclopedia of genes and genomes analyses. Further, we obtained targets of curcumin against AD-related tau and aβ pathology via the AlzData database. These targets were applied to perform GEO and receiver operating characteristic analyses. Finally, the reliability of the core targets was evaluated using molecular docking technology. We identified 49 targets of curcumin against AD, and kyoto encyclopedia of genes and genomes pathway enrichment analysis demonstrated that the Alzheimer disease pathway (has05010) was significantly enriched. Even more, we obtained 16 targets of curcumin-related Aβ and tau pathology. Among these targets, 8 targets involved the Alzheimer disease pathway and the biological process analyses showed that positive regulation of cytokine production (GO:0001819) was significantly enriched. Bioinformatic analyses indicated that HMOX1, CSF1R, NFKB1, GSK3B, BACE1, AR, or PTGS1 expression was significantly different compared to the control group in the AD patients. Finally, molecular docking studies suggested these genes have a good binding force with curcumin. In this study, we identified curcumin exerted the effect of treating AD by regulating multitargets and multichannels through the method of network pharmacology. Show less
The characterization of immortalized canine osteosarcoma (OS) cell lines used for research has historically been based on phenotypic features such as cellular morphology and expression of bone specifi Show more
The characterization of immortalized canine osteosarcoma (OS) cell lines used for research has historically been based on phenotypic features such as cellular morphology and expression of bone specific markers. With the increasing use of these cell lines to investigate novel therapeutic approaches prior to in vivo translation, a much more detailed understanding regarding the genomic landscape of these lines is required to ensure accurate interpretation of findings. Here we report the first whole genome characterization of eight canine OS cell lines, including single nucleotide variants, copy number variants and other structural variants. Many alterations previously characterized in primary canine OS tissue were observed in these cell lines, including TP53 mutations, MYC copy number gains, loss of CDKN2A, PTEN, DLG2, MAGI2, and RB1 and structural variants involving SETD2, DLG2 and DMD. These data provide a new framework for understanding how best to incorporate in vitro findings generated using these cell lines into the design of future clinical studies involving dogs with spontaneous OS. Show less
Systemic amyloidosis is classified according to the deposited amyloid fibril protein (AFP), which determines its best therapeutic scheme. The most common type of AFP found are immunoglobulin light cha Show more
Systemic amyloidosis is classified according to the deposited amyloid fibril protein (AFP), which determines its best therapeutic scheme. The most common type of AFP found are immunoglobulin light chains. The laser microdissection combined with mass spectrometry (LMD-MS) technique is a promising approach for precise typing of amyloidosis, however, the major difficulty in interpreting the MS data is how to accurately identify the precipitated AFP from background. The objective of the present study is to establish a complete data interpretation procedure for LMD-MS based amyloidosis typing. Formalin-fixed paraffin-embedded specimens from patients with renal amyloidosis and non-amyloid nephropathies (including diabetic nephropathy, fibrillary glomerulonephritis, IgA nephropathy, lupus nephritis, membranous nephropathy, and normal tissue adjacent to tumors) were analyzed by LMD-MS. Forty-two specimens were used to train the data interpretation procedure, which was validated by another 50 validation specimens. Area under receiver operating curve (AUROC) analysis of amyloid accompanying proteins (AAPs, including apolipoprotein A-IV, apolipoprotein E and serum amyloid P-component) for discriminating amyloidosis from non-amyloid nephropathies was performed. A stepwise data interpretation procedure that includes or excludes the types of amyloidosis group by group was established. The involvement of AFPs other than immunoglobulin was determined by P-score, as well as immunoglobulin light chain by variable of λ-κ, and immunoglobulin heavy chain by H-score. This achieved a total of 88% accuracy in 50 validation specimens. The AAPs showed significantly different expression levels between amyloidosis specimens and non-amyloid nephropathies. Each of the single AAP had a AUROC value more than 0.9 for diagnosis of amyloidosis from non-amyloid control, and the averaged level of the three AAPs showed the highest AUROC (0.966), which might be an alternative indicator for amyloidosis diagnosis. The proteomic data interpretation procedure for LMD-MS based amyloidosis typing was established successfully that has a high practicability in clinical application. 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
The early diagnosis of tuberculous pleural effusion (TPE) is challenging due to the difficulty of isolating A total of 48 children with TPE and 64 children with severe The level of p-IL-27 in TPE show Show more
The early diagnosis of tuberculous pleural effusion (TPE) is challenging due to the difficulty of isolating A total of 48 children with TPE and 64 children with severe The level of p-IL-27 in TPE showed statistically no significant difference when compared with SMPPE ( Pleural fluid IL-27 alone was not accurate in distinguishing pediatric TPE from SMPPE, which was different from the diagnostic value of IL-27 in adult studies due to the different disease spectra between children and adults. Our results implied that the p-IL-27/s-IL-27 ratio had a potential value in distinguishing TPE from SMPPE. However, the specificity of IL-27 was relatively lower and it is necessary to find a more specific marker in tuberculous pleurisy of children. Show less