Melanocortins are neuropeptides exerting versatile functions in the nervous system. Melanocortin 4 receptor (MC4R) is primarily expressed in the brain and is thought to be a major mediator for melanoc Show more
Melanocortins are neuropeptides exerting versatile functions in the nervous system. Melanocortin 4 receptor (MC4R) is primarily expressed in the brain and is thought to be a major mediator for melanocortin. Brain-derived neurotrophic factor (BDNF) may be a crucial downstream molecule of MC4R activation, to yield neurite outgrowth, neuroregenerative, anorexigenic and other actions. In this study, we stimulated Neuro2a murine neuronal cells with an α-melanocyte stimulating hormone (α-MSH) analog, [Nle(4), D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH). In Neuro2a cells, NDP-MSH promoted neurite outgrowth. Upon NDP-MSH administration, BDNF expression was greatly enhanced. Furthermore, this effect was effectively reversed by the MC4R antagonist, JKC-363. We found that NDP-MSH treatment activated the ERK cascade and its downstream kinase MSK1 (mitogen- and stress-activated protein kinase-1). Antagonism of the MSK1 cascade by a specific inhibitor or overexpression of a defective MSK1 mutant interrupted the phosphorylation of the transcription factor cAMP-response element binding protein (CREB), blocking BDNF upregulation. In addition, MSK1 activation triggered an epigenetic alteration in histone H3 (Ser10), facilitating the expression of the BDNF gene. Taken together, our results showed that MSK1 kinase positively activates MC4R-induced BDNF expression via modulating the phosphorylation of CREB and histone H3 in Neuro2a neuronal cells. Show less
In humans and mice, melanocortin receptor 4 (MC4R) and melanocortin receptor accessory protein 2 (MRAP2) can form a complex and control energy balance, thus regulating body weight and obesity. In pigs Show more
In humans and mice, melanocortin receptor 4 (MC4R) and melanocortin receptor accessory protein 2 (MRAP2) can form a complex and control energy balance, thus regulating body weight and obesity. In pigs, a missense variant (p.Asp298Asn) of MC4R has been suggested to be associated with growth and fatness; however, the effect of Asp298Asn substitution on MC4R function is controversial, limiting its application in animal breeding. Here we examined the effect of this polymorphism on MC4R constitutive activity, cell surface expression and signaling, and its interaction with MRAP2 in pigs. We found that: (i) both pig MC4R Show less
The detailed molecular mechanism of orbital venous malformation (OVM) is still not clear. Using whole exome sequencing, 4 types of melanocortin 4 receptor (MC4R) mutation were detected in 7 of 27 pati Show more
The detailed molecular mechanism of orbital venous malformation (OVM) is still not clear. Using whole exome sequencing, 4 types of melanocortin 4 receptor (MC4R) mutation were detected in 7 of 27 patients with OVM, and all types of MC4R mutations resulted in the upregulation of MC4R expression. Show less
The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-an Show more
The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca Show less
Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM an Show more
Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM and provide new diagnostic and therapies for GBM. Three microarray datasets (GSE111260, GSE103227, and GSE104267) were selected from Gene Expression Omnibus (GEO) database for integrated analysis. The differential expressed genes (DEGs) between GBM and normal tissues were identified. Then, prognosis-related DEGs were screened by survival analysis, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to explore the hub genes associated with GBM. The mRNA and protein expression levels of hub genes were respectively validated in silico using The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases. Subsequently, the small molecule drugs of GBM were predicted by using Connectivity Map (CMAP) database. A total of 78 prognosis-related DEGs were identified, of which10 hub genes with higher degree were obtained by PPI analysis. The mRNA expression and protein expression levels of Our study provided 10 key genes for diagnosis, prognosis, and therapy for GBM. These findings might contribute to a better comprehension of molecular mechanisms of GBM development, and provide new perspective for further GBM research. However, specific regulatory mechanism of these genes needed further elaboration. Show less
To investigate the differentially expressed genes (DEGs) and molecular interaction in unstable atherosclerotic carotid plaques. Gene expression datasets GSE41571, GSE118481, and E-MTAB-2055 were analy Show more
To investigate the differentially expressed genes (DEGs) and molecular interaction in unstable atherosclerotic carotid plaques. Gene expression datasets GSE41571, GSE118481, and E-MTAB-2055 were analyzed. Co-regulated DEGs in at least two datasets were analyzed with the enrichment of Gene Ontology Biological Process (GO-BP), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) networks, interrelationships between miRNAs/transcriptional factors, and their target genes and drug-gene interactions. The expression of notable DEGs in human carotid artery plaques and plasma was further identified. The GO-BP enrichment analysis revealed that genes associated with inflammatory response, and extracellular matrix organization were altered. The KEGG enrichment analysis revealed that upregulated DEGs were enriched in the tuberculous, lysosomal, and chemokine signaling pathways, whereas downregulated genes were enriched in the focal adhesion and PI3K/Akt signaling pathway. Collagen type I alpha 2 chain (COL1A2), adenylate cyclase 3 (ADCY3), C-X-C motif chemokine receptor 4 (CXCR4), and TYRO protein tyrosine kinase binding protein (TYROBP) might play crucial roles in the PPI networks. In drug-gene interactions, colonystimulating factor-1 receptor had the most drug interactions. Insulin-like growth factor binding protein 6 (IGFBP6) was markedly downregulated in unstable human carotid plaques and plasma. Under a receiver operating characteristic curve analysis, plasma IGFBP6 had a significant discriminatory power (AUC, 0.894; 95% CI, 0.810-0.977), with a cutoff value of 142.08 ng/mL. The genes COL1A2, ADCY3, CXCR4, and TYROBP are promising targets for the prevention of unstable carotid plaque formation. IGFBP6 may be an important biomarker for predicting vulnerable plaques. Show less
The bHLH transcription factor Olig2 is required for sequential cell fate determination of both motor neurons and oligodendrocytes and for progenitor proliferation in the central nervous system. Howeve Show more
The bHLH transcription factor Olig2 is required for sequential cell fate determination of both motor neurons and oligodendrocytes and for progenitor proliferation in the central nervous system. However, the role of Olig2 in peripheral sensory neurogenesis remains unknown. We report that Olig2 is transiently expressed in the newly differentiated olfactory sensory neurons (OSNs) and is down-regulated in the mature OSNs in mice from early gestation to adulthood. Genetic fate mapping demonstrates that Olig2-expressing cells solely give rise to OSNs in the peripheral olfactory system. Olig2 depletion does not affect the proliferation of peripheral olfactory progenitors and the fate determination of OSNs, sustentacular cells, and the olfactory ensheathing cells. However, the terminal differentiation and maturation of OSNs are compromised in either Olig2 single or Olig1/Olig2 double knockout mice, associated with significantly diminished expression of multiple OSN maturation and odorant signaling genes, including Omp, Gnal, Adcy3, and Olfr15. We further demonstrate that Olig2 binds to the E-box in the Omp promoter region to regulate its expression. Taken together, our results reveal a distinctly novel function of Olig2 in the periphery nervous system to regulate the terminal differentiation and maturation of olfactory sensory neurons. Show less
Fructus has motivation effect on gastrointestinal tract. Hesperidin is extracts of Fructus, and we attempted to prove its effects on improving the gastrointestinal transmission function and determine Show more
Fructus has motivation effect on gastrointestinal tract. Hesperidin is extracts of Fructus, and we attempted to prove its effects on improving the gastrointestinal transmission function and determine the possible mechanisms by a loperamide-induced slow transit constipation (STC) model. Constipation phenotypes were measured in rats with Lop-induced constipation after treatment with hesperidin. The amounts and water content of stool were significantly higher in the hesperidin-treated group than the loperamide-induced model group, whereas food intake was maintained at constant levels. Moreover, intestinal transit rate was increased in the treatment group of hesperidin. Histological alteration was detected by H&E staining, we found that the colon smooth muscle cells and neuron cells of the rats were increased, and the infiltration of inflammatory cells was decreased in the hesperidin-treated group compared with the loperamide-induced model group. 5-Hydroxytryptamine (5-HT) receptor4 fluorescence intensity and intracellular-free calcium ions in colon tissue were increased, and relative protein of cAMP/PKA pathway and p-cAMP response component-binding protein (CREB) pathway were upregulated in the hesperidin-treated group compared with the loperamide-induced model group. Further, SMCs from colon tissue of rats were cultured and identified. We found hesperidin could significantly promote tegaserod-induced increase of 5-HTR4 fluorescence intensity, intracellular calcium ions, relative protein of cAMP/PKA pathway and p-CREB pathway, and cell proliferation and inhibit GR113808-induced decrease of 5-HTR4 fluorescence intensity, 5-HTR4 pathway-related proteins (ADCY3, cAMP, PKA, and p-CREB), intracellular calcium ions, and cell proliferation. The analysis of our data suggested that hesperidin could obviously improve the gastrointestinal transmission function in loperamide-induced STC rat model via increasing the 5-HTR4 and intracellular-free calcium ions to enhance the expression of relative protein of cAMP/PKA pathway and p-CREB pathway. Hesperidin could be used in the treatment of STC, and our data not only provide experimental basis for the treatment of STC in hesperidin but also provides a theoretical reference for clinical treatment. Show less
The aim of the present study was to analyze the expression levels of angiopoietin-like 4 (ANGPTL4) in breast cancer to investigate the association between ANGPTL4 and breast cancer. Immunohistochemist Show more
The aim of the present study was to analyze the expression levels of angiopoietin-like 4 (ANGPTL4) in breast cancer to investigate the association between ANGPTL4 and breast cancer. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues, including 205 invasive ductal carcinoma (IDC) of no special type, 40 normal breast, 40 atypical ductal hyperplasia (ADH) and 40 ductal carcinomas Show less
Ambient ammonia exposure has been known to perturb lipid metabolism in farm animals, but the underlying mechanism is unclear. The current study was conducted to investigate how ambient ammonia exposur Show more
Ambient ammonia exposure has been known to perturb lipid metabolism in farm animals, but the underlying mechanism is unclear. The current study was conducted to investigate how ambient ammonia exposure influences lipid metabolism in the pig model. Twelve pigs were randomly divided into two groups, either exposed to 0 or 35 mg/m Show less
Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of kidney with high mortality. The pathogenesis of ccRCC is complicated and effective prognostic predictors for clinical prac Show more
Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of kidney with high mortality. The pathogenesis of ccRCC is complicated and effective prognostic predictors for clinical practice are still limited. This study aimed to identify significant genes with prognostic influence in ccRCC via bioinformatics analysis. Four gene expression profiles were acquired from the Gene Expression Omnibus (GEO) database, including 168 ccRCC tissues and 143 normal tissues. Common differentially expressed genes (DEGs) between ccRCC tissues and normal kidney tissues were screened out. Then gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were investigated. Protein-protein interaction (PPI) network of the common DEGs was diagrammed and analyzed. Kaplan-Meier analysis was conducted to identify genes with prognostic influence in ccRCC. Gene Expression Profiling Interactive Analysis (GEPIA) was finally applied to validating differential expression of genes. Ninety-nine common DEGs between ccRCC tissues and normal kidney tissues were eventually screened out (P<0.05, |log FC| >2). GO functional analysis showed that the down-regulated genes were enriched in excretion, negative regulation of cell proliferation, heparin binding and cellular response to BMP stimulus, etc. KEGG pathway analysis indicated that the common DEGs were particularly enriched in HIF-1 signaling pathway and aldosterone-regulated sodium reabsorption. Seven core DEGs were distinguished through PPI network analysis, of which 6 core genes Our study shows that high expression of Show less
Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of Show more
Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of EGF-induced COX-2 and angiopoietin-like 4 (ANGPTL4) on HNSCC metastasis remains unclear. In this study, we revealed that the expression of ANGPTL4 is essential for COX-2-derived prostaglandin E Show less
Angiopoietin-like 4 (ANGPLT4) regulates lipid metabolism by inhibiting lipoprotein lipase. Abnormal ANGTPL4 levels are associated with metabolic syndrome, atherosclerosis, inflammation, and cancer. We Show more
Angiopoietin-like 4 (ANGPLT4) regulates lipid metabolism by inhibiting lipoprotein lipase. Abnormal ANGTPL4 levels are associated with metabolic syndrome, atherosclerosis, inflammation, and cancer. We show here that ANGPTL4-deficient mice have abnormally large numbers of macrophages in the spleen, and that these macrophages produce large amounts of TNF-α, CD86, and inducible nitric oxide synthase. However, recombinant ANGPTL4 protein did not inhibit macrophage function Show less
Angiopoietin-like-4 (ANGPTL4) is reported to mediate proteinuria in some types of glomerulonephropathy. However, the mechanism underlying the effect on podocytes of ANGPTL4 under pathologic conditions Show more
Angiopoietin-like-4 (ANGPTL4) is reported to mediate proteinuria in some types of glomerulonephropathy. However, the mechanism underlying the effect on podocytes of ANGPTL4 under pathologic conditions in diabetic nephropathy (DN) is unclear. We investigated the role of ANGPTL4 in the pathogenesis of DN. In DN rats, elevated ANGPTL4 expression was associated with increased proteinuria, glomerular hypertrophy, and ultrastructural changes in podocytes. In vitro, hyperglycemia induced the upregulation of ANGPTL4, which led to activation of integrin-β1/FAK signaling with increased apoptosis of podocytes and actin cytoskeleton derangement. These pathological changes were reversed by transfection with a lentivirus expressing short hairpin RNA against integrin-β1 or an ANGPTL4-neutralizing antibody in vitro. Furthermore, supplementation with the sialic acid precursor ManNAc reversed these pathological changes and conferred renoprotection in a mouse model of DN. Our findings suggest that ANGPTL4 mediates high glucose-induced loss of podocytes by modulating their detachment and apoptosis in vivo and in vitro. This study deepens our understanding of the mechanisms of podocyte loss in DN and shows targeting ANGPTL4-related signaling has therapeutic potential for DN. Show less
Ovarian cancer is the deadliest gynecologic cancer. Despite recent advances, clinical outcomes remain poor, necessitating novel therapeutic approaches. To investigate metabolic susceptibility, we perf Show more
Ovarian cancer is the deadliest gynecologic cancer. Despite recent advances, clinical outcomes remain poor, necessitating novel therapeutic approaches. To investigate metabolic susceptibility, we performed nutrigenetic screens on a panel of clear cell and serous ovarian cancer cells and identified cystine addiction and vulnerability to ferroptosis, a novel form of regulated cell death. Our results may have therapeutic potential, but little is known about the determinants of ferroptosis susceptibility in ovarian cancer. We found that vulnerability to ferroptosis in ovarian cancer cells is enhanced by lower cell confluency. Because the Hippo pathway effectors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are recognized as sensors of cell density, and TAZ is the predominant effector in the tested ovarian cancer cell lines, we investigated the role of TAZ in ferroptosis of ovarian cancer. TAZ removal confers ferroptosis resistance, while TAZS89A overexpression sensitizes cells to ferroptosis. In addition, we found that lower TAZ level in chemo-resistant recurrent ovarian cancer is responsible for reduced ferroptosis susceptibility. The integrative genomic analysis identified ANGPTL4 as a direct TAZ-regulated target gene that sensitizes ferroptosis by activating NOX2. Collectively, cell density-regulated ferroptosis in ovarian cancer is mediated by TAZ through the regulation of the ANGPTL4-NOX2 axis, suggesting therapeutic potentials for ovarian cancers and other TAZ-activated tumors. IMPLICATIONS: This study reveals that TAZ promotes ferroptosis in ovarian cancers by regulating ANGPTL4 and NOX, offering a novel therapeutic potential for ovarian tumors with TAZ activation. Show less
Distinguishing between different types of thyroid cancers (TC) remains challenging in clinical laboratories. As different tumor types require different clinical interventions, it is necessary to estab Show more
Distinguishing between different types of thyroid cancers (TC) remains challenging in clinical laboratories. As different tumor types require different clinical interventions, it is necessary to establish new methods for accurate diagnosis of TC. Proteomic analysis of the human serum was performed through data-independent acquisition mass spectrometry for 29 patients with TC (stages I-IV): 13 cases of papillary TC (PTC), 10 cases of medullary TC (MTC), and six cases follicular TC (FTC). In addition, 15 patients with benign thyroid nodules (TNs) and 10 healthy controls (HCs) were included in this study. Subsequently, 17 differentially expressed proteins were identified in 291 patients with TC, including 247 with PTC, 38 with MTC, and six with FTC, and 69 patients with benign TNs and 176 with HC, using enzyme-linked immunosorbent assays. In total, 517 proteins were detected in the serum samples using an Orbitrap Q-Exactive-plus mass spectrometer. The amyloid beta A4 protein, apolipoprotein A-IV, gelsolin, contactin-1, gamma-glutamyl hydrolase, and complement factor H-related protein 1 (CFHR1) were selected for further analysis. The median serum CFHR1 levels were significantly higher in the MTC and FTC groups than in the PTC and control groups ( CFHR1 may serve as a novel biomarker to distinguish PTC from MTC with high sensitivity and specificity. Show less
Gastric cancer is the third leading cause of cancer-related deaths worldwide. The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gas Show more
Gastric cancer is the third leading cause of cancer-related deaths worldwide. The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma. The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted. Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma. This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma. Show less
The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseas Show more
The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population. Show less
Diabetes, dyslipidemia and hypertension are important metabolic diseases that impose a great burden on many populations worldwide. However, certain population strata have reduced prevalence for all th Show more
Diabetes, dyslipidemia and hypertension are important metabolic diseases that impose a great burden on many populations worldwide. However, certain population strata have reduced prevalence for all three diseases, but the underlying mechanisms are poorly understood. We sought to identify the phenotypic, genomic and metabolomic characteristics of the low-prevalence population to gain insights into possible innate non-susceptibility against metabolic diseases. We performed k-means cluster analysis of 16,792 subjects using anthropometric and clinical biochemistry data collected by the Taiwan Biobank. Nuclear magnetic resonance spectra-based metabolome analysis was carried out for 217 subjects with normal body mass index, good exercise habits and healthy lifestyles. We found that the gene APOA5 was significantly associated with reduced prevalence of disease, and lesser associations included the genes HIF1A, LIMA1, LPL, MLXIPL, and TRPC4. Blood plasma of subjects belonging to the low disease prevalence cluster exhibited lowered levels of the GlycA inflammation marker, very low-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, valine and leucine compared to controls. Literature mining revealed that these genes and metabolites are biochemically linked, with the linkage between lipoprotein metabolism and inflammation being particularly prominent. The combination of phenomic, genomic and metabolomic analysis may also be applied towards the study of metabolic disease prevalence in other populations. Show less
A previous study by our group demonstrated a protective role of the neuropeptide secretoneurin (SN) in DL‑isoproterenol hydrochloride (ISO)‑induced cardiac hypertrophy in mice. To further characterize Show more
A previous study by our group demonstrated a protective role of the neuropeptide secretoneurin (SN) in DL‑isoproterenol hydrochloride (ISO)‑induced cardiac hypertrophy in mice. To further characterize the molecular mechanism of SN treatment, an isobaric tags for relative and absolute quantification (iTRAQ)‑based quantitative proteomic analysis was applied to identify putative target proteins and molecular pathways. An SN expression vector was injected into the myocardial tissues of mice, and the animals were then subcutaneously injected with ISO (5 mg/kg/day) for 7 days to induce cardiac hypertrophy. The results of echocardiography and hemodynamic measurements indicated that the function of the heart impaired by ISO treatment was significantly ameliorated via SN gene injection. The investigation of heart proteomics was performed by iTRAQ‑based liquid chromatography‑tandem mass spectrometry analysis. A total of 2,044 quantified proteins and 15 differentially expressed proteins were associated with SN overexpression in mice with cardiac hypertrophy. Functional enrichment analysis demonstrated that these effects were possibly associated with metabolic processes. A protein‑protein interaction network analysis was constructed and the data indicated that apolipoprotein C‑III (Apoc3) was associated with the positive effect of SN on the induction of cardiac hypertrophy in mice. The present study proposed a potential mechanism of SN action on Apoc3 upregulation that may contribute to the amelioration of cardiac hypertrophy. These findings can aid the clinical application of SN in patients with cardiac hypertrophy. Show less
The Wingless-type (Wnt) signaling pathway plays an important role in the development and progression of cancer. This study aimed to evaluate the relationship between single nucleotide polymorphisms (S Show more
The Wingless-type (Wnt) signaling pathway plays an important role in the development and progression of cancer. This study aimed to evaluate the relationship between single nucleotide polymorphisms (SNPs) in the Wnt pathway and the risk of bone metastasis in patients with non-small cell lung cancer (NSCLC). We collected 500 blood samples from patients with NSCLC and genotyped eight SNPs from four core genes (WNT2, AXIN1, CTNNB1 and APC) present within the WNT pathway. Moreover, we assessed the potential relationship of these genes with bone metastasis development. Our results showed that the AC/AA genotype of CTNNB1: rs1880481 was associated with a decreased risk of bone metastasis. Polymorphisms with an HR of < 1 had a cumulative protective impact on the risk of bone metastasis. Furthermore, patients with the AC/AA genotype of CTNNB1: rs1880481 was associated with Karnofsky performance status score, squamous cell carcinoma antigen and Ki-67 proliferation index. Lastly, patients with the AC/AA genotype of CTNNB1: rs1880481 had significantly longer median progression free survival time than those with the CC genotype. In conclusion, SNPs within the Wnt signaling pathway are associated with a decreased risk of bone metastasis, and may be valuable biomarkers for bone metastasis in patients with NSCLC. Show less
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate and low survival rate. This study was designed to explore a novel molecular with high sensitivity a Show more
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate and low survival rate. This study was designed to explore a novel molecular with high sensitivity and specificity, which can be applied in early diagnosis and therapeutic evaluation of HCC. The current study aims to investigate the effect and important role of Axin1 on cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma. qRT-PCR results showed lower Axin1 expression level and higher miR-650 expression level in HCC. Luciferase reporter assay was carried out to verify the negative correlation between Axin1 and miR-650 mRNA levels. CCK-8 assay results showed that the cell proliferation ability was significantly suppressed by Axin1 overexpression in SK-HEP-1 cells. The results in wound healing assay uncovered that cell migration ability was markedly suppressed by Axin1 overexpression. The results in trans-well invasion assay showed that Axin1 overexpression caused decreased invasive ability in SK-HEP-1 cells. The WB results showed that the protein level of E-cad was significantly increased and the protein levels of N-cad, vimentin and snail were obviously reduced following Axin1 overexpression. Whereas, the suppressive effects on cell proliferation, migration, invasion and EMT caused by Axin1 overexpression were abolished by miR-650 mimic. All the results in the current study confirmed the truth that Axin1 overexpression could suppress cell proliferation, migration, invasion and EMT by downregulating miR-650 expression. Show less
It is crucial to grasp the characteristics of tumour immune microenvironment to improve effects of immunotherapy. In this study, the immune and stromal scores of 371 cases were calculated for quantita Show more
It is crucial to grasp the characteristics of tumour immune microenvironment to improve effects of immunotherapy. In this study, the immune and stromal scores of 371 cases were calculated for quantitative analysis of immune and stromal cell infiltration in the tumour microenvironment of hepatocellular carcinoma (HCC). The weighted gene co-expression network analysis and protein-protein interaction network were analysed to identify immune microenvironment-related genes. The results showed that patients with high immune scores had a higher 4-year recurrence-free rate. TP53, CTNNB1, and AXIN1 mutations significantly varied with immune scores. In immune score-related modules analysis, Kyoto encyclopaedia of genes and genomes pathways and gene ontology terms were closely related to immune processes, tumorigenesis, and metastasis. Twelve new immune microenvironment-related genes were identified and had significantly positive correlations with seven immune checkpoint genes. In prognostic analysis, eleven immune microenvironment-related genes exhibited high expression, nine of which were validated in the GSE62232 dataset and were significantly associated with a good prognosis. Our findings suggest that calculating immune score and stromal score could help to determine tumour purity and immune cell infiltration in the tumour microenvironment. Nine immune microenvironment-related genes identified in this study had potential as prognostic markers for HCC. Show less
The dysregulation of ubiquitin ligase is the cause of many human diseases. Tripartite motif protein 32 (TRIM32) is an E3 ubiquitin ligase whose role in nucleus pulposus (NP) cell apoptosis is unclear. Show more
The dysregulation of ubiquitin ligase is the cause of many human diseases. Tripartite motif protein 32 (TRIM32) is an E3 ubiquitin ligase whose role in nucleus pulposus (NP) cell apoptosis is unclear. The expression of TRIM family protein and β-catenin in 40 NP tissue samples was detected by RT-PCR. Interleukin (IL)-1β or tumor necrosis factor (TNF)-α was used to treat rat NP cells. Knockdown and overexpression of Show less
Liver organoids have recently been applied as models for liver disease and drug screening, especially when combined with liver-on-a-chip technologies. Compared to hepatocyte-like cells, primary hepato Show more
Liver organoids have recently been applied as models for liver disease and drug screening, especially when combined with liver-on-a-chip technologies. Compared to hepatocyte-like cells, primary hepatocytes have high functionality but cannot maintain their function when cultured To create hepatocyte organoids by co-culturing primary hepatocytes with MSCs on a porcine liver extracellular matrix (PLECM) gel. Perfusion and enzymatic hydrolysis were used to form the PLECM gel. Rat hepatocytes and human MSCs were mixed and plated on pre-solidified PLECM gel in a 48-well plate for 48 h to generate organoids. Generated organoids were evaluated through hematoxylin and eosin, periodic acid-Schiff, immuno-histological, and immunofluorescence staining, and quantitative PCR for The whole porcine liver was perfused and enzymatically hydrolyzed to form a PLECM gel. The structural components and basement membrane composition of the ECM, such as collagen type I, collagen type IV, fibronectin, and laminin, were demonstrated to be retained. Through interaction of human MSCs with the liver-derived ECM, primary hepatocytes and human MSCs assembled together into a 3D construction and generated primary hepatocyte organoids for 48 h. The mRNAs of the gene Our new method of creating primary hepatocyte organoids by co-culturing hepatocytes with MSCs on liver-derived ECM hydrogels could be used to develop models for liver disease and for drug screening. Show less
Colorectal cancer (CRC) is a common malignancy occurring in the digestive system. Despite progress in surgery and therapy options, CRC is still a considerable cause of cancer mortality worldwide. In t Show more
Colorectal cancer (CRC) is a common malignancy occurring in the digestive system. Despite progress in surgery and therapy options, CRC is still a considerable cause of cancer mortality worldwide. In this study, a colon cancer patient-derived xenograft model was established to evaluate the antitumor activity of Shikonin. The protective effect underlying Shikonin was determined through assessing serum levels of liver enzymes (ALT, AST) and kidney functions (BuN, Scr) in PDX mice. Proteomics and metabolomics profiles were integrated to provide a systematic perspective in dynamic changes of proteins and global endogenous metabolites as well as their perturbed pathways. A total of 456 differently expressed proteins (DEPs), 32 differently expressed metabolites (DEMs) in tumor tissue, and 20 DEMs in mice serum were identified. The perturbation of arginine biosynthesis, purine metabolism, and biosynthesis of amino acids may mainly account for therapeutic mechanism of Shikonin. Furthermore, the expression of mRNAs participating in arginine biosynthesis (CPS1, OTC, Arg1) and do novo purine synthesis (GART, PAICS, ATIC) were validated through RT-qPCR. Our study provides new insights into the drug therapeutic strategies and a better understanding of antitumor mechanisms that might be valuable for further studies on Shikonin in the clinical treatment of colorectal cancer. Show less
Studies have increasingly shown that carbamoyl phosphate synthetase 1 ( Several biological databases including UALCAN, GEPIA and Oncomine were used to analyze the expression of The Oncomine platform, Show more
Studies have increasingly shown that carbamoyl phosphate synthetase 1 ( Several biological databases including UALCAN, GEPIA and Oncomine were used to analyze the expression of The Oncomine platform, UALCAN and gene expression profiling interactive analysis (GEPIA) were used and revealed that the expression levels of Our work indicated that Show less
Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpr Show more
Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology. Show less