👤 A Reum Han

MicroRNA-205 (miR-205) is believed to be related to the progress of tumors. HOXD9 has been proved to be expressed abnormally in several kinds of cancers. However, the role of miR-205 and HOXD9 in breast cancer remains unclear. The biological role of miR-205 in breast cancer cell proliferation and chemoresistance was investigated. The expression of miR-205 in clinical tissues and breast cancer cell lines were analyzed using quantitative real-time PCR test (qRT-PCR). Overexpression and knockdown models of miR-205 were established to study cell proliferation and chemotherapy-resistant. Moreover, the potential relationships between miR-205 and HOXD9/Snail1 were measured using qRT-PCR, western blot, and chemotherapy-resistant study. miR-205 was lowly expressed in breast cancer tissues and cell lines. Overexpression of miR-205 could inhibit cell proliferation and chemotherapy-resistance. Moreover, we proved that miR-205 could target the HOXD9-Snail1 axis to suppress triple negative breast cancer cell proliferation and chemoresistance. The activation of Snail1 gene by HOXD9 was also proved in this study. The present study may provide a novel insight for the therapeutic strategies of breast cancer through targeting miR-205/HOXD9/Snail1. Show less

Parthenolide has been demonstrated to have anticancer effects against various types of cancer. However, the functional role of parthenolid has yet to be clearly reported in renal cell carcinoma (RCC). The aim of the present study was to investigate the effect of parthenolide in RCC 786‑O and ACHN cells. CCK‑8 and colony‑formation assays were used to observe the proliferation of RCC 786‑O and ACHN cells. Migration and invasion abilities were assessed through Transwell assays. The stem cell‑like properties of RCC cell lines were evaluated by mammosphere formation assay. Western blot analysis was used to investigate the metastasis and epithelial‑mesenchymal transition (EMT) induced by parthenolide on the expression levels of MMP2, MMP9, E‑cadherin, N‑cadherin, vimentin and snail. The results revealed that when the cells were treated with various concentrations of parthenolide, the rate of proliferation and growth was decreased in 786‑O and ACHN cells. The number of invasive cells in a field was approximately 170, 90, 40 and 190, 150, 70 in 786‑O and ACHN cells with 0, 4 and 8 µM of parthenolide treatment. MMP‑2/‑9 expression (P<0.05) was inhibited by parthenolide. The protein levels of E‑cadherin were increased (P<0.05) and N‑cadherin, vimentin and snail were decreased (P<0.05) by parthenolide treatment. In addition, Parthenolide inhibited the expression of cancer stem cell markers and the PI3K/AKT pathway. The present study confirmed that parthenolide inhibited RCC cell proliferation and metastasis and suppressed the stem cell‑like properties of RCC cell lines, which could be a potential strategy to treat RCC. However, further molecular mechanisms of parthenolide in RCC should be observed and reported in the future. Show less

Inflammatory reactions induced by alveolar macrophages and excessive fibroblast activation lead to pulmonary fibrosis in silicosis. The endothelial-mesenchymal transition (EndoMT) is a key source of myofibroblasts. ZC3H4 is a member of the CCCH zinc finger protein family that participates in macrophage activation and epithelial mesenchymal transition (EMT). However, whether ZC3H4 is involved in EndoMT in silicosis has not yet been elucidated. Therefore, we conducted further studies into the role of ZC3H4 in silica-induced EndoMT in pulmonary vessels. Western blotting and immunofluorescence staining were used to detect the regulatory influences of SiO 1) SiO ZC3H4 greatly affects the progression of SiO Show less

Intestinal microorganisms have been shown to be important factors affecting the growth performance of pigs. Therefore, to investigate the effect of the intestinal microflora structure on the growth performance of pigs, samples from Duroc (n = 10), Landrace (n = 9) and Yorkshire (n = 21) pigs under the same diet and feeding conditions were collected. The fecal microbial composition was profiled via 16S ribosomal RNA (rRNA) gene sequencing. We also analyzed their growth performance. We found that Duroc and Landrace pigs had significant differences in average daily gain (ADG), feed efficiency ratio (FER), growth index (GI), and number of days taken to reach 100 kg (P < 0.05). Moreover, through analysis of the intestinal flora, we also identified 18 species of intestinal flora with significant differences between Duroc and Landrace pigs (P < 0.05). To eliminate the influence of genetic background, the differential intestinal flora of 21 Yorkshire pigs with differences in growth performance was analyzed. The results showed that there were significant correlations between Barnesiella, Dorea, Clostridium and Lactobacillus and pig growth performance. To explore the effect of the intestinal flora on the growth performance of pigs at the molecular level, Lactobacillus, which is the most abundant in the intestine, was selected for isolation and purification and cocultured with intestinal epithelial cells. qPCR was used to determine the effect of Lactobacillus on MC4R gene expression in intestinal epithelial cells. The results showed that Lactobacillus inhibited MC4R gene expression in these cells. The results provide a useful reference for further study of the relationship between the intestinal flora and pig growth performance. 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-angstrom resolution. Ca Show less

In early childhood, individuals with Prader-Willi syndrome (PWS) experience excess weight gain and severe hyperphagia with food compulsivity, which often leads to early onset morbid obesity. Effective treatments for appetite suppression and weight control are currently unavailable for PWS. Our aim to further understand the pathogenesis of PWS led us to carry out a comprehensive search of the current and emerging therapies for managing hyperphagia and extreme weight gain in PWS. A literature search was performed using PubMed and the following keywords: "PWS" AND "therapy" OR "[drug name]"; reference lists, pharmaceutical websites, and the ClinicalTrials.gov registry were also reviewed. Articles presenting data from current standard treatments in PWS and also clinical trials of pharmacological agents in the pipeline were selected. Current standard treatments include dietary restriction/modifications, exercise, and growth hormone replacement, which appear to have limited efficacy for appetite and weight control in patients with PWS. The long-term safety and effectiveness of bariatric surgery in PWS remains unknown. However, many promising pharmacotherapies are in development and, if approved, will bring much needed choices into the PWS pharmacological armamentarium. With the progress that is currently being made in our understanding of PWS, an effective treatment may not be far off. Show less

Obesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits. This study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers. This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci. This study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing. Show less

Colorectal cancer, is the growth of cancer cells in the part of the colon. Angiopeptin is one of the growth factors in the human body that is particularly effective in the regulatory process. In this research, the regulatory role and its mechanism of Angiopoietin-like protein 4 (ANGPTL4) in colorectal cancer (CRC) metastasis, has been studied. Protein expression of ANGPLT4 was analyzed by immunohistochemistry in tumor samples and adjacent normal specimens of 40 patients with CRC cancer of various phases. A gene knockout test was conducted, two effective siRNA of ANGPTL4, named siRNA1 and siRNA2, were constructed and transfected into two CRC cell lines SW480 and HT-29 to block the expression of ANGPTL4. QRT-PCR and western blotting were used to validate the knockdown efficiency of the mRNA and proteins. Based on the results, the protein expression of ANGPTL4 was increased in human CRC tissues with the development of CRC. Knockdown of ANGPTL4 by siRNA in SW480 and HT-29 cells in vitro inhibited cell proliferation, promoted cell apoptosis, and suppressed the ability of cell migration and invasion. Besides, the sensitivity of CRC cells to Cisplatin was increased in the low ANGPTL4 expression group. ANGPTL4 might be a new potential therapeutic target for patients with CRC. Show less

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis. Show less

Fish intestine is an important constituent of the mucosal immune system. The gut and gut-associated lymphoid tissue construct a local immune environment. A Shewanella algae strain was previously reported to be a pathogen causing ascitic disease accompanied with intestinal inflammation in Cynoglossus semilaevis. This study aimed to investigate the intestine immune response in C. semilaevis to S. algae infection at the protein level. Two-dimensional electrophoresis coupled with mass spectrometry proteomics was utilized to compare protein expression in the intestines from normal and S. algae-infected C. semilaevis. A total of 70 differentially expressed proteins (DEPs), consisting of 16 upregulated and 54 downregulated proteins, were identified in the intestine tissue of C. Semilaevis. These protein expression changes were further validated using western blot analysis and quantitative real-time PCR. Gene ontology enrichment analysis showed that these 70 DEPs could be assigned across three categories: "cellular components", "molecular function", and "biological process". Forty-one DEPs (six up-regulated and 35 down-regulated proteins) related to metabolic processes were identified. In addition, 20 DEPs (eight up-regulated and 12 down-regulated proteins) related to stress and immune responses were identified. A protein-protein interaction network generated by the STRING (Search Tool for the Retrieval of Interacting Genes/protein) revealed that 30 DEPs interacted with one another to form an integrated network. Among them, 29 DEPs were related to stress, immune, and metabolism processes. In the network, some of the immune related proteins (C9, FGB, KNG1, apolipoprotein A-IV-like, and PDIA3) were up-regulated and most DEPs involved in metabolism processes were down-regulated. These results indicate that the immune defense response of the intestine was activated and the intestinal function associated with metabolism processes was disturbed. This study provides valuable information for further research into the functions of these DEPs in fish. Show less

Immunosuppression with glucocorticoids is a common treatment for autoimmune liver diseases and after liver transplant, which is however associated with severe side-effects. Targeted delivery of glucocorticoids to inflammatory cells, e.g. liver macrophages and Kupffer cells, is a promising approach for minimizing side effects. Herein, we prepare core-shell silica nanocapsules (SiO Show less

Olanzapine is commonly used to treat schizophrenia. However, long-term administration of olanzapine causes metabolic side effects, such as insulin resistance (IR), which seriously affects patients' quality of life. Both diagnostic and prognostic markers are urgently needed to increase patient compliance. We applied isobaric tags for relative and absolute quantitation (iTRAQ) labeling combined with 2D LC/MS/MS technology to identify the differentially expressed proteins in olanzapine-induced IR rats. A total of 3194 proteins were identified from rat adipose tissues, and 270 differentially expressed proteins were screened out with a ratio threshold >1.5-fold or <0.67-fold. Based on a bioinformatics analysis and literature search, we selected six candidates (MYH1, MYL2, Cp, FABP4, apoA-IV, and Ywhaz) from a set of 270 proteins and verified these proteins by western blot; the expression of these proteins coincided with the LC-MS/MS results. Finally, the biological roles of FABP4 and apoA-IV, which are two novel IR-related proteins identified in the present study, were verified in 3T3-L1 cells. These data suggest that these two proteins acted on olanzapine-induced IR via the IRS-1/AKT signaling pathway. Our results provide a dataset of potential targets to explore the mechanism in olanzapine-induced IR and reveal the new roles of FABP4 and apoA-IV in olanzapine-induced IR. SIGNIFICANCE: The proteomic analysis of this study revealed the target associated with olanzapine-induced IR and provided relevant insights into the molecular functions, biological processes, and signaling pathways in these targets. Protein MYH1, MYL2, Cp, FABP4, apoA-IV, and Ywhaz may be potential biomarkers, and protein FABP4 and apoA-IV were considered as promising targets in olanzapineinduced IR. Therefore, if the performance of the proposed biomarkers is further confirmed, these proteins can provide powerful targets for exploring the mechanism of olanzapine-induced IR. Show less

Hypertriglyceridaemia is a very rare disorder caused by the mutations of LPL gene, with an autosomal recessive mode of inheritance. Here, we identified two unrelated Chinese patients manifested with severe hypertriglyceridaemia and acute pancreatitis. The clinical symptoms of proband 1 are more severe than proband 2. Whole exome sequencing and Sanger sequencing were performed. Functional analysis of the identified mutations has been done. Whole exome sequencing identified two pairs of variants in LPL gene in the proband 1 (c.162C>A and c.1322+1G>A) and proband 2 (c.835C>G and c.1322+1G>A). The substitution (c.162C>A) leads to the formation of a truncated (p.Cys54*) LPL protein. The substitution (c.835C>G) leads to the replacement of leucine to valine (p.Leu279Val). The splice donor site mutation (c.1322+1G>A) leads to the formation of alternative transcripts with the loss of 134 bp in exon 8 of the LPL gene. The proband 1 and his younger son also harbouring a heterozygous variant (c.553G>T; p.Gly185Cys) in APOA5 gene. The relative expression level of the mutated LPL mRNA (c.162C>A, c.835C>G and c.1322+1G>A) showed significant differences compared to wild-type LPL mRNA, suggesting that all these three mutations affect the transcription of LPL mRNA. These three mutations (c.162C>A, c.835C>G and c.1322+1G>A) showed noticeably decreased LPL activity in cell culture medium but not in cell lysates. Here, we identified three mutations in LPL gene which causes severe hypertriglyceridaemia with acute pancreatitis in Chinese patients. We also described the significance of whole exome sequencing for identifying the candidate gene and disease-causing mutation in patients with severe hypertriglyceridaemia and acute pancreatitis. 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. 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

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang's distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia. Show less

Circular RNAs (circRNAs), highly expressed in the central nervous system, are involved in various regulatory processes and implicated in some pathophysiology. However, the potential role of circRNAs in psychiatric diseases, particularly major depressive disorder (MDD), remains largely unknown. Here, we demonstrated that circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of patients with MDD and in the two depressive-like mouse models: the chronic unpredictable stress (CUS) and lipopolysaccharide (LPS) models. Restoration of circDYM expression significantly attenuated depressive-like behavior and inhibited microglial activation induced by CUS or LPS treatment. Further examination indicated that circDYM functions as an endogenous microRNA-9 (miR-9) sponge to inhibit miR-9 activity, which results in a downstream increase of target-HECT domain E3 ubiquitin protein ligase 1 (HECTD1) expression, an increase of HSP90 ubiquitination, and a consequent decrease of microglial activation. Taken together, the results of our study demonstrate the involvement of circDYM and its coupling mechanism in depression, providing translational evidence that circDYM may be a novel therapeutic target for depression. Show less

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy. Show less

Gram-negative bacterial infection causes an excessive inflammatory response and acute organ damage or dysfunction due to its outer membrane component, lipopolysaccharide (LPS). Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenous lipid mediator, exerts fundamental anti-inflammation and pro-resolution during infection. In the present study, we examined the properties of PCTR1 on the systemic inflammatory response, organic morphological damage and dysfunction, and serum metabolic biomarkers in an LPS-induced acute inflammatory mouse model. The results show that PCTR1 reduced serum inflammatory factors and ameliorated morphological damage and dysfunction of the lung, liver, kidney, and ultimately improved the survival rate of LPS-induced acute inflammation in mice. In addition, metabolomics analysis and high performance liquid chromatography-mass spectrometry revealed that LPS-stimulated serum linoleic acid (LA), arachidonic acid (AA), and prostaglandin E2 (PGE2) levels were significantly altered by PCTR1. Moreover, PCTR1 upregulated LPS-inhibited fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongase of very long chain fatty acids 2 (ELOVL2) expression, and downregulated LPS-stimulated phospholipase A2 (PLA2) expression to increase the intrahepatic content of AA. However, these effects of PCTR1 were partially abrogated by a lipoxin A4 receptor (ALX) antagonist (BOC-2). In summary, via the activation of ALX, PCTR1 promotes the conversion of LA to AA through upregulation of FADS1, FADS2, and ELOVL2 expression, and inhibits the conversion of bound AA into free AA through downregulation of PLA2 expression to decrease the serum AA and PGE2 levels. Show less

Lung adenocarcinoma (LUAD) is the most common and lethal cancer worldwide. Radiotherapy (RT) is widely used at all stages of LUAD, and the development of immunotherapy substantially enhances the survival of LUAD patients. Although the emerging treatments for LUAD have improved prognosis, only a small fraction of patients can benefit from clinical therapies. Thereby, approaches assessing responses to RT and immunotherapy in LUAD patients are essential. After integrating the analysis of RT, immunization, mRNA, and clinical information, we constructed a signature based on 308 tumor-infiltrating B lymphocyte-specific genes (TILBSig) using a machine learning method. TILBSig was composed of 6 B cell-specific genes (PARP15, BIRC3, RUBCNL, SP110, TLE1, and FADS3), which were highly associated with the overall survival as independent factors. TILBSig was able to differentiate better survival compared with worse survival among different patients, and served as an independent factor for clinical characteristics. The low-risk TILBSig group was correlated with more immune cell infiltration (especially B lineages) and lower cancer stem cell characteristics than the high-risk group. The patients with lower risk scores were more likely to respond to RT and immunotherapy. TILBSig served as an excellent predicator for prognosis and response to immunotherapy and RT in LUAD patients. Show less

Arterial marker genes EphrinB2 and HEY2 are essential for cardiovascular development and postnatal neovascularization. Our previous study confirmed that E2F1 could activate the transcription of EphrinB2 and HEY2 in human mesenchymal stem cells; however, the detailed mechanism has not been resolved yet. In this study, we focused on the interaction between E2F1 and DNMT3A, a de novo DNA methyltransferase, on regulating the expression of EphrinB2 and HEY2, and explored the potential mechanisms. Gain- and loss-of-function experiments implicated the positive effect of E2F1 on the expression of EphrinB2 and HEY2 and tube formation in human umbilical artery endothelial cells. Accumulation of DNMT3A decreased the levels of EphrinB2 and HEY2, and impaired tube formation induced by E2F1, while inhibiting DNMT3A by RNA interference augmented their expression and angiogenesis in E2F1-trasfected cells. We then asked whether the low expressions of EphrinB2 and HEY2 induced by DNMT3A are related to the methylation status of their promoters. Surprisingly, the methylation status of the CpG islands in the promoter region was not significantly affected by overexpression of exogenous DNMT3A. Furthermore, the interaction between E2F1 and DNMT3A was confirmed by co-immunoprecipitation. DNMT3A could inhibit the transcription of EphrinB2 and HEY2 promoters by affecting the binding of E2F1 to its recognition sequences as revealed by luciferase reporter assay and chromatin immunoprecipitation. These results identified a novel mechanism underlying the cooperation of DNMT3A with E2F1 on regulating target gene expression, and revealed their roles in the angiogenic process. Show less

The aim of this study was to screen the leading compounds of natural origin with anti-angiogenic potential and to investigate their anti-angiogenic mechanism preliminarily. An initial screening of 240 compounds from the Natural Products Collection of MicroSource was performed using the transgenic zebrafish strain Five compounds were identified with potential anti-angiogenic activity on the zebrafish embryogenesis. Among them, deoxysappanone B 7.4'-dimethyl ether (Deox B 7,4) showed anti-angiogenic activity on the formation of ISVs in a dose-dependent manner. The inhibition of ISV formation reached up to 99.64% at 5 μM Deox B 7,4. The expression of delta-like ligand 4 ( Deox B 7,4 has a therapeutic potential for the treatment of angiogenesis-dependent diseases and may exert anti-angiogenic activities by suppressing the slit2/robo1/2, slit3/robo4, cox2/ptp-rb/pik3r2, and dll4/hey2/efnb2a signaling pathways as well as activation of vegfr-2/fgfr1/mmp9. Show less

Starch is an important substance that supplies energy to ruminants. To provide sufficient energy for high-yielding dairy ruminants, they are typically fed starch-enriched diets. However, starch-enriched diets have been proven to increase the risk of milk fat depression (MFD) in dairy cows. The starch present in ruminant diets could be divided into rumen-degradable starch (RDS) and rumen escaped starch (RES) according to their different degradation sites (rumen or intestine). Goats and cows have different sensitivities to MFD. Data regarding the potential roles of RDS in milk fat synthesis in the mammary tissue of dairy goats and in regulating the occurrence of MFD are limited. Eighteen Guanzhong dairy goats (day in milk = 185 ± 12 d) with similar parity, weight, and milk yield were selected and randomly assigned to one of three groups ( HRDS-induced goat MFD resulted from the downregulation of genes involved in lipogenesis, particularly, Show less

The Jianchang duck is mainly distributed in Southwest China, and has the characteristics of fast growth rate and strong abilities in lipid deposition in the liver. In order to investigate the effects of domestication process on formation of the unique characteristics of Jianchang duck, the whole genome of sixteen individuals and three pooling of Jianchang duck were re-sequenced, and genome data of 70 mallards and 83 domestic ducks from thirteen different places in China were obtained from NCBI. The population stratification and evolution analysis showed gene exchanges existed between the Jianchang and other domestic duck populations, as well as Jianchang ducks and mallards. Genomic comparison between mallards and Jianchang ducks showed genes, including Show less

Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP Show less

Chronic overconsumption of a high-carbohydrate diet leads to steatosis and its associated metabolic disorder and, eventually, to non-alcoholic fatty liver disease. Carbohydrate-responsive element binding protein (ChREBP) and insulin regulate de novo lipogenesis from glucose. Herein, we studied the effect of reticulon-4 (Nogo) expression on diet-induced metabolic disorders in mice. Nogo-deficient (Nogo HGD/HFrD induced steatosis and its associated metabolic disorders in WT mice by activating ChREBP and impairing insulin sensitivity. They also activated Nogo-B expression, which in turn inhibited insulin activity. In response to HGD/HFrD feeding, Nogo deficiency enhanced insulin sensitivity and energy metabolism to reduce the expression of ChREBP and lipogenic molecules, activated AMP-activated catalytic subunit α, peroxisome proliferator activated receptor α and fibroblast growth factor 21, and reduced endoplasmic reticulum (ER) stress and inflammation, thereby blocking HGD/HFrD-induced hepatic lipid accumulation, insulin resistance and other metabolic disorders. Injection of Nogo siRNA protected C57BL/6J mice against HFrD-induced metabolic disorders by ameliorating insulin sensitivity, ChREBP activity, ER stress and inflammation. Our study identified Nogo as an important mediator of insulin sensitivity and ChREBP activity. Reduction of Nogo expression is a potential strategy for the treatment of high-carbohydrate diet-induced metabolic complications. Nogo deficiency blocks high-carbohydrate diet-induced glucose intolerance and insulin resistance, while increasing glucose/lipid utilisation and energy expenditure. Thus, reduction of Nogo expression protects against high-carbohydrate diet-induced body-weight gain, hepatic lipid accumulation and the associated metabolic disorders, indicating that approaches inhibiting Nogo expression can be applied for the treatment of diseases associated with metabolic disorders. Show less

Dose-dependent lipid accumulation was induced by glucose in HepG2 cells. GlcN also exerted a promotory effect on lipid accumulation in HepG2 cells under normal glucose conditions (NG, 5 mM) and liver of normal fed zebrafish larvae. High glucose (HG, 25 mM)-induced lipid accumulation was suppressed by l-glutamine-d-fructose 6-phosphate amidotransferase inhibitors. ER stress inhibitors did not suppress HG or GlcN-mediated lipid accumulation. HG and GlcN stimulated protein expression, DNA binding and O-GlcNAcylation of carbohydrate-responsive element-binding protein (ChREBP). Furthermore, both HG and GlcN increased nuclear sterol regulatory element-binding protein-1 (SREBP-1) levels in HepG2 cells. In contrast to its stimulatory effect under NG, GlcN suppressed lipid accumulation in HepG2 cells under HG conditions. Similarly, GlcN suppressed lipid accumulation in livers of overfed zebrafish. In addition, GlcN activity on DNA binding and O-GlcNAcylation of ChREBP was stimulatory under NG and inhibitory under HG conditions. Moreover, GlcN enhanced ChREBP, SREBP-1c, ACC, FAS, L-PK and SCD-1 mRNA expression under NG but inhibited HG-induced upregulation in HepG2 cells. The O-GlcNAc transferase inhibitor, alloxan, reduced lipid accumulation by HG or GlcN while the O-GlcNAcase inhibitor, PUGNAc, enhanced lipid accumulation in HepG2 cells and liver of zebrafish larvae. GlcN-induced lipid accumulation was inhibited by the AMPK activator, AICAR. Phosphorylation of AMPK (p-AMPK) was suppressed by GlcN under NG while increased by GlcN under HG. PUGNAc downregulated p-AMPK while alloxan restored GlcN- or HG-induced p-AMPK inhibition. Our results collectively suggest that GlcN regulates lipogenesis by sensing the glucose or energy states of normal and excess fuel through AMPK modulation. Show less

Atrial fibrillation (AF), known as the most common arrhythmia in the developed world, affects 1.5-2.0% of the population. Numerous basic studies have been carried out to identify the roles of electric and structural remodeling in the pathophysiological changes of AF, but more explorations are required to further understand the mechanisms of AF development. Proteomics enables researchers to identify protein alterations responsible for the pathological developing progresses of diseases. Compared to the genome, the proteome is closely related to the disease phenotype and can better manifest the progression of diseases. In this study, AF patients proteomically analyzed to identify possible mechanisms. Totally 20 patients undergoing cardiac surgery (10 with paroxysmal AF and 10 with persistent AF) and 10 healthy subjects were recruited. The differentially expressed proteins identified here included AKR1A1, LYZ, H2AFY, DDAH1, FGA, FGB, LAMB1, LAMC1, MYL2, MYBPC3, MYL5, MYH10, HNRNPU, DKK3, COPS7A, YWHAQ, and PAICS. These proteins were mainly involved in the development of structural remodeling. The differently expressed proteins may provide a new perspective for the pathological process of AF, and may enable useful targets for drug interference. Nevertheless, more research in terms of multi-omics is required to investigate possible implicated molecular pathways of AF development. Show less