👤 Hongwei An

Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which can be identified by immunohistochemistry in the senile plaques and neurofibrillary tangles of Alzheimer's disease (AD) patients. Growing evidence suggests that AGEs are important risk factors for the development and progression of AD. 1,8-cineole (CIN) is a monoterpenoid compound which exists in many plant essential oils and has been proven to have neuroprotective activity, but its specific effect and molecular mechanisms are not clear. In this study, AGEs-induced neuronal injury and intracerebroventricular-AGE animals as the possible models for AD were employed to investigate the effects of CIN on AD pathology as well as the molecular mechanisms involved both in vivo and in vitro. Our study demonstrated that CIN could ameliorate tau phosphorylation by down-regulating the activity of GSK-3β and reducing Aβ production by inhibiting the activity of BACE-1 both in vivo and in vitro. It is suggested that CIN has certain therapeutic value in the treatment of AD. Show less

The prognosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) remained unsatisfactory currently, more anti-HER2 agents are needed. Here we report a phase I study that evaluated the safety, activity, and biomarkers of LZM005, a HER2 antibody, used as a monotherapy or in combination with trastuzumab plus docetaxel in patients with HER2-positive MBC. From October 2017 to December 2019, 34 patients received LZM005 (14 monotherapy, 20 combination therapy). No DLT was observed. The common adverse events (AEs) in phase Ia included diarrhea (21.4%), infusion reaction (21.4%), and hypertriglyceridemia (21.4%), while those in phase Ib were leukopenia (85.0%), neutropenia (75.0%), anemia (60.0%), diarrhea (60.0%), and rash/pruritus (50.0%). All AEs were manageable. In phase Ia, partial response (PR) was achieved in one case (1/14, overall response rate [ORR]: 7.1%); the disease control rate was 42.90% (6/14). In phase Ib, 11 patients (55.0%) achieved PR, and eight (40.0%) had stable disease. The ORR was 100% (6/6) in trastuzumab-naive and 35.7% (5/14) in trastuzumab-pretreated patients. Biomarker analysis showed that chromatin remodeling genes KMT2B and BRWD1 were associated with better progression-free survival. LZM005 is well tolerated and shows potent activity in patients with HER2-positive MBC. Show less

ERK1/2 are essential proteins mediating mitogen-activated protein kinase signaling downstream of RAS in pancreatic adenocarcinoma (PDAC). Our previous study reveals that ARF6 plays a positive regulatory role in ERK1/2 pathway in a feedback loop manner. A significant part of the literature on ARF6 has emphasized its oncogenic effect as an essential downstream molecule of ERK1/2, and no research has been done on the regulation mechanisms of the feedback loop between ARF6 and the ERK1/2 signaling pathway. In the present study, we explore the gene network downstream of Show less

Diabetes is a serious disease that could greatly increase the risk of cardiovascular complications, whereas the underlying pathology of DN is still unknown. GPRC5B is a member of the RAIG subfamily of type 3 (family C) GPCR, and its role in DN is still unclear. To unveil the role of GPRC5B in diabetic nephropathy (DN) progression and investigate the potential signaling pathway. Podocytes were stimulated with high glucose and expression of GPRC5B was analyzed by qPCR and western blot. Then the level of GPRC5B was depleted by siRNA transfection and inflammatory cytokine level was monitored by ELISA assay. The ECM depostion and the activation of NF-κB pathway were detected by Immunoblot. We investigated the possible role of GPRC5B in the pathology of diabetic nephropathy. We found GPRC5B was highly expressed in high glocuse (HG) induced podocytes. The depletion of GPRC5B inhibited HG induced cell inflammation. In addition, the ablation of GPRC5B suppressed the HG induced ECM deposition. We further found GPRC5B could alleviate the inflammation and extracellular matrix deposition of HG-induced podocytes through NF-κB pathway. We therefore thought GPRC5B could serve as a promising target for the treatment of diabetic nephropathy. G-protein-coupled receptors. Show less

Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attracted extensive attention. Here, we performed genomics and transcriptomics analysis to detect candidates affecting subcutaneous fat (SCF) deposition in beef cattle. The association of 770K SNPs with the backfat thickness captured nine significant SNPs within or near 11 genes. Additionally, 13 overlapping genes regarding fat deposition were determined via the analysis of differentially expressed genes and weighted gene co-expression network analysis (WGCNA). We then calculated the correlations of these genes with BFT and constructed their interaction network. Finally, seven biomarkers including ACACA, SCD, FASN, ACOX1, ELOVL5, HACD2, and HSD17B12 were screened. Notably, ACACA, identified by the integration of genomics and transcriptomics, was more likely to exert profound effects on SCF deposition. These findings provided novel insights into the regulation mechanism underlying bovine fat accumulation. Show less

Viruses are the most common and abundant organisms in the marine environment. To better understand how cetaceans have adapted to this virus-rich environment, we compared cetacean virus-responsive genes to those from terrestrial mammals. We identified virus-responsive gene sequences in seven species of cetaceans, which we compared with orthologous sequences in seven terrestrial mammals. As a result of evolution analysis using the branch model and the branch-site model, 21 genes were selected using at least one model. IFN-ε, an antiviral cytokine expressed at mucous membranes, and its receptor IFNAR1 contain cetacean-specific amino acid substitutions that might change the interaction between the two proteins and lead to regulation of the immune system against viruses. Cetacean-specific amino acid substitutions in IL-6, IL-27, and the signal transducer and activator of transcription (STAT)1 are also predicted to alter the mucosal immune response of cetaceans. Since mucosal membranes are the first line of defense against the external environment and are involved in immune tolerance, our analysis of cetacean virus-responsive genes suggests that genes with cetacean-specific mutations in mucosal immunity-related genes play an important role in the protection and/or regulation of immune responses against viruses. Show less

The Lauren classification of gastric tumors strongly correlates with prognosis. The purpose of this study was to explore the specific molecular mechanism of Lauren classification of gastric cancer and provide a possible theoretical basis for the treatment of gastric cancer. We standardized the gene expression data of five Gene Expression Omnibus gastric cancer databases and constructed a Weighted Co-expression Network Analysis (WGCNA) model based on clinicopathological information. The overall survival (OS) and disease-free survival (DFS) curves were extracted from the Cancer Genome Atlas (TCGA) and GSE62254 databases. Western blotting was used to measure protein expression in cells and tissues. Scratch and transwell experiments were used to test the migration ability of tumor cells. Immunohistochemistry was used to measure tissue protein expression in clinical tissue samples to correlate to survival data. The WGCNA model demonstrated that blue cyan was highly correlated with the Lauren classification of the tumor (r = 0.24, P = 7 × 10 LMOD1 is an oncogene associated with diffuse gastric cancer and can affect the occurrence and development of EMT by regulating the FAK-Akt/mTOR pathway. LMOD1 can therefore promote peritoneal metastasis of gastric cancer cells and can be used as a novel therapeutic target for gastric cancer. Show less

The centrosome is composed of a pair of centrioles and serves as the major microtubule-organizing center (MTOC) in cells. Centrosome dysfunction has been linked to autosomal recessive primary microcephaly (MCPH), which is a rare human neurodevelopmental disorder characterized by small brain size with intellectual disability. Recently, several mouse models carrying mutated genes encoding centrosomal proteins have been generated to address the genotype-phenotype relationships in MCPH. However, several human-specific features were not observed in the mouse models during brain development. Herein, we generated isogenic hiPSCs carrying the gene encoding centrosomal CPAP-E1235V mutant protein using the CRISPR-Cas9 genome editing system, and examined the phenotypic features of wild-type and mutant hiPSCs and their derived brain organoids. Our results showed that the CPAP-E1235V mutant perturbed the recruitment of several centriolar proteins involved in centriole elongation, including CEP120, CEP295, CENTROBIN, POC5, and POC1B, onto nascent centrioles, resulting in the production of short centrioles but long cilia. Importantly, our wild-type hiPSC-derived brain organoid recapitulated many cellular events seen in the developing human brain, including neuronal differentiation and cortical spatial lamination. Interestingly, hiPSC-CPAP-E1235V-derived brain organoids induced p53-dependent neuronal cell death, resulting in the production of smaller brain organoids that mimic the microcephaly phenotype. Furthermore, we observed that the CPAP-E1235V mutation altered the spindle orientation of neuronal progenitor cells and induced premature neuronal differentiation. In summary, we have shown that the hiPSC-derived brain organoid coupled with CRISPR/Cas9 gene editing technology can recapitulate the centrosome/centriole-associated MCPH pathological features. Possible mechanisms for MCPH with centriole/centrosome dysfunction are discussed. Show less

Metabolic reprogramming is a major feature of many tumors including non-small cell lung cancer (NSCLC). Branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in diabetes, obesity, and other diseases. However, the function of BCKDK in NSCLC is unclear. This study aimed to explore the function of BCKDK in NSCLC. Metabolites in the serum of patients with NSCLC and the supernatant of NSCLC cell cultures were detected using nuclear magnetic resonance (NMR) spectroscopy. Colony formation, cell proliferation, and cell apoptosis were assessed to investigate the function of BCKDK in the progression of NSCLC. Glucose uptake, lactate production, cellular oxygen consumption rate, extracellular acidification rate, and reactive oxygen species (ROS) were measured to examine the function of BCKDK in glucose metabolism. The expression of BCKDK was measured using reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemical assay. Compared with healthy controls and postoperative NSCLC patients, increased branched-chain amino acid (BCAA) and decreased citrate were identified in the serum of preoperative NSCLC patients. Upregulation of BCKDK affected the metabolism of BCAAs and citrate in NSCLC cells. Knockout of BCKDK decreased the proliferation and exacerbated apoptosis of NSCLC cells ex vivo, while increased oxidative phosphorylation and, ROS levels, and inhibited glycolysis. BCKDK may influence glycolysis and oxidative phosphorylation by regulating the degradation of BCAA and citrate, thereby affecting the progression of NSCLC. Show less

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with Show less

To investigate whether an exercise intervention using the VIVIFRAIL© protocol has benefits for inflammatory and functional parameters in different frailty status. This is a randomized clinical trial in an outpatient geriatrics clinic including older adults ≥60 years. For each frailty state (frail, pre-frail and robust), forty-four volunteers will be randomly allocated to the control group (n = 22) and the intervention group (n = 22) for 12 weeks. In the control group, participants will have meetings of health education while those in the intervention group will be part of a multicomponent exercise program (VIVIFRAIL©) performed five times a week (two times supervised and 3 times of home-based exercises). The primary outcome is a change in the inflammatory profile (a reduction in inflammatory interleukins [IL-6, TNF- α, IL1beta, IL-17, IL-22, CXCL-8, and IL-27] or an increase in anti-inflammatory mediators [IL-10, IL1RA, IL-4]). Secondary outcomes are change in physical performance using the Short Physical Performance Battery, handgrip strength, fatigue, gait speed, dual-task gait speed, depressive symptoms, FRAIL-BR and SARC-F scores, and quality of life at the 12-week period of intervention and after 3 months of follow-up. We expect a reduction in inflammatory interleukins or an increase in anti-inflammatory mediators in those who performed the VIVIFRAIL© protocol. The results of the study will imply in a better knowledge about the effect of a low-cost intervention that could be easily replicated in outpatient care for the prevention and treatment of frailty, especially regarding the inflammatory and anti-inflammatory pathways involved in its pathophysiology. Brazilian Registry of Clinical Trials (RBR-9n5jbw; 01/24/2020). Registred January 2020. http://www.ensaiosclinicos.gov.br/rg/RBR-9n5jbw/ . Show less

To investigate the relationship between the fatty acid-binding protein 4 (FABP4) and colorectal cancer (CRC). Using an enzyme-linked immunosorbent assay (ELISA), we measured the expression of FABP4 in plasma of 50 patients who underwent surgery for CRC from October 2017 to May 2018 and 50 healthy controls. The content of the visceral fat area (VFA) as seen with abdominal computed tomography (CT) scanning was measured by ImageJ software. The expression levels of FABP4, E-cadherin, and Snail proteins in CRC and adjacent tissues were determined by immunohistochemistry. The mean concentration of plasma FABP4 of CRC patients was higher than that of the control group (22.46 vs. 9.82 ng/mL; High LPA and VFA were risk factors for increased plasma FABP4 in CRC patients. FABP4 protein was highly expressed in CRC tissues and associated with TNM stage, differentiation, and lymph node metastasis of CRC. The level of FABP4 in CRC tissue was correlated with E-cadherin and Snail expression, suggesting that FABP4 may promote CRC progression related to epithelial-mesenchymal transition (EMT). 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, 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

Uterine carcinosarcoma (UCS) is a type of rare and aggressive tumor. The standard treatment for UCS involves surgical treatment followed by radiochemotherapy. Clinical outcomes of UCS patients are poor due to high metastasis and relapse rate. Therefore, new targeted therapy strategies for UCS are needed. Because UCS is highly heterogenous, it is critical to identify and develop prognostic biomarkers to distinguish molecular subtypes of UCS for better treatment guidance. Using gene expression profiles and clinical follow-up data, we developed an online consensus survival analysis tool named OSucs. This web tool allows researchers to conveniently analyze the prognostic abilities of candidate genes in UCS. To test the reliability of this server, we analyzed five previously reported prognostic biomarkers, all of which showed significant prognostic impacts. In addition, ETV4 (ETS variant transcription factor 4), ANGPTL4 (Angiopoietin-like protein 4), HIST1H1C (Histone cluster 1 H1 family member c) and CTSV (Cathepsin V) showed prognostic potential in a molecular subtype-specific manner. We built a platform for researchers to analyze if genes have prognostic potentials in UCS. Show less

The aim of the present research is to study the roles of miR-203a-3p on cell proliferation, migration, invasion, and epithelial-mesenchymal transition in pancreatic cancer. Transcription profiles were acquired from Gene Expression Omnibus database, which was used to screen out the differentially expressed microRNAs and messenger RNAs in pancreatic cancer. Pancreatic cancer tissues were used to verify the bioinformatics results by quantitative real-time polymerase chain reaction. The relationship between miR-203a-3p and SLUG was examined by TargetScan software, dual-luciferase reporter assay, and RNA immunoprecipitation. The Cell Counting Kit-8, wound healing, and transwell assays were conducted to investigate the proliferation, migration, and invasion capability of pancreatic cancer cells, respectively. The expression of epithelial-mesenchymal transition-related proteins was determined by the Western blot assay. Xenograft assay was performed to verify findings from Bioinformatic analysis found that a total of 113 microRNAs and 1749 messenger RNAs expressed differentially in pancreatic cancer tissues. Among these microRNAs, the expression of miR-203a-3p was significantly decreased in both pancreatic cancer tissues and cells. On the other hand, the SLUG expression was remarkably upregulated in pancreatic cancer tissues and cells in comparison with normal tissues and cells. Moreover, TargetScan software, dual-luciferase reporter assay, and RNA immunoprecipitation revealed that SLUG was a target of miR-203a-3p. The upregulation of miR-203a-3p expression inhibited the proliferation, migration, and invasion ability of pancreatic cancer cells by suppressing the epithelial-mesenchymal transition process via sponging SLUG. These findings indicate that downregulation of miR-203a-3p in pancreatic cancer cells leads to high expression of SLUG, which promotes epithelial-mesenchymal transition process and induces cancer progression. Show less

Hepatocellular carcinoma (HCC), the sixth most common malignancy worldwide, is characterized by a dismal prognosis due to high recurrence and metastasis rates. Thus, the need for the development of novel chemotherapeutic drugs is urgent. Cyclovirobuxine D (CVB-D), a steroidal alkaloid extracted from Show less

Telmisartan (TLM), a highly selective angiotensin II type 1 receptor blocker (ARB) and partial PPAR-γ agonist, has versatile beneficial effects against oxidative stress, apoptosis, inflammatory responses and epithelial-mesenchymal transition (EMT). However, its underlying mechanism of inhibiting oxalate and calcium oxalate (CaOx) crystal-induced EMT by activating the PPAR-γ pathway remains unclear. CCK-8 assays were used to evaluate the effects of TLM on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were measured by the cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate (DCFH-DA). Wound-healing and Transwell assays were used to evaluate the migration ability of HK2 cells exposed to oxalate. Moreover, immunofluorescence, immunohistochemistry and western blotting were used to examine the expression of E-cadherin, N-cadherin, vimentin and α-SMA and explore the underlying molecular mechanisms in HK2 cells and a stone-forming rat model. Our results showed that TLM treatment could protect HK2 cells from oxalate-induced cytotoxicity and oxidative stress injury. Additionally, TLM prevented EMT induction by oxalate and CaOx crystals via the PPAR-γ-AKT/STAT3/p38 MAPK-Snail pathway in vitro and in vivo. However, knockdown of PPAR-γ with small interfering RNA or the PPAR-γ-specific antagonist GW9662 abrogated these protective effects of TLM. As a PPAR-γ agonist, TLM can ameliorate oxalate and CaOx crystal-induced EMT by exerting an antioxidant effect through the PPAR-γ-AKT/STAT3/p38 MAPK-Snail signaling pathway. Therefore, TLM can block EMT progression and could be a potential therapeutic agent for preventing and treating calcium oxalate urolithiasis formation and recurrence. Show less

Transposable elements (TEs) make up > 50% of the human genome, and the majority of retrotransposon insertions are truncated and many are located in introns. However, the effects of retrotransposition on the host genes remain incompletely known. We report here that insertion of a chimeric L1 (cL1), but not IAP solo LTR, into intron 6 of The mechanism for Show less

Microbial fuel cells (MFCs) are eco-friendly bio-electrochemical reactors that use exoelectrogens as biocatalyst for electricity harvest from organic biomass, which could also be used as biosensors for long-term environmental monitoring. Glucose and xylose, as the primary ingredients from cellulose hydrolyzates, is an appealing substrate for MFC. Nevertheless, neither xylose nor glucose can be utilized as carbon source by well-studied exoelectrogens such as Show less

Female sex steroid hormones, including estradiol (E2) and progesterone (P4), serve significant physiological roles in pregnancy. In particular, E2 and P4 influence placenta formation, maintain pregnancy and stimulate milk production. These hormones are produced by ovaries, adrenal glands and the placenta, of which the latter is a major endocrine organ during pregnancy. However, the mechanism of hormone production during pregnancy remains unclear. In the present study, the regulation of steroid hormones and steroidogenic enzymes was examined in human placenta according to gestational age. In human placental tissues, expression levels of steroidogenic enzymes were determined with reverse transcription‑quantitative polymerase chain reaction and western blotting. The mRNA and protein expression of CYP17A1, HSD17B3 and CYP19A1, which are associated with the synthesis of dehydroepiandrosterone (DHEA) and E2, was elevated at different gestational ages in human placenta. In addition, to evaluate the correlation between serum and placental‑produced hormones, steroid hormone levels, including pregnenolone (PG), DHEA, P4, testosterone (T) and E2, were examined in serum and placenta. Serum and placenta expression of DHEA and E2 increased with gestational age, whereas T and P4 were differently regulated in placenta and serum. To confirm the mechanism of steroidogenesis in vitro, placental BeWo cells were treated with E2 and P4, which are the most important hormones during pregnancy. The mRNA and protein expression of steroidogenic enzymes was significantly altered by E2 in vitro. These results demonstrated that concentration of steroid hormones was differently regulated by steroidogenic enzymes in the placenta depending on the type of the hormones, which may be critical to maintain pregnancy. Show less

Panax ginseng (P. ginseng C.A. Meyer, Araliaceae) is used as a therapeutic agent for various diseases. P. ginseng saponins, known as ginsenosides, are the main bioactive compounds responsible for its pharmacological activities. In this work, we have developed a new method of P. ginseng root processing termed solid-state fermentation and examined its effects compared with nonfermented P. ginseng. Mice were fed a high-fat diet (HFD) to induce hyperlipidemia and then received 100 mg·kg bw Show less

Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription polymerase chain reaction assays to measure expression levels of LINC01503. We collected clinical data from patients and compared expression levels with survival times. LINC01503 was knocked down using small interfering RNAs and oligonucleotides in TE7, TE5, and KYSE510 cell lines and overexpressed in KYSE30 cells. Cells were analyzed by chromatin immunoprecipitation sequencing, luciferase reporter assays, colony formation, migration and invasion, and mass spectrometry analyses. Cells were injected into nude mice and growth of xenograft tumors was measured. LINC01503 interaction with proteins was studied using fluorescence in situ hybridization, RNA pulldown, and RNA immunoprecipitation analyses. We identified a lncRNA, LINC01503, which is regulated by a super enhancer and is expressed at significantly higher levels in esophageal and head and neck SCCs than in non-tumor tissues. High levels in SCCs correlated with shorter survival times of patients. The transcription factor TP63 bound to the super enhancer at the LINC01503 locus and activated its transcription. Expression of LINC01503 in ESCC cell lines increased their proliferation, colony formation, migration, and invasion. Knockdown of LINC01503 in SCC cells reduced their proliferation, colony formation, migration, and invasion, and the growth of xenograft tumors in nude mice. Expression of LINC01503 in ESCC cell lines reduced ERK2 dephosphorylation by DUSP6, leading to activation of ERK signaling via MAPK. LINC01503 disrupted the interaction between EBP1 and the p85 subunit of PI3K, increasing AKT signaling. We identified an lncRNA, LINC01503, which is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients. Show less

Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity. Show less

During mouse preimplantation development, blastomeres are equipotent until polarity establishment at compacted 8-cell stage. The intrinsic nature of polarity is the asymmetric distribution of polarity proteins between inside and outside blastomeres along the direction of apical-basal axis. This study investigated the early developmental temporal and spatial expression of the main CRUMBS polarity complex proteins in the mouse preimplantation embryo. We observed that Crb3, Pals1, Patj and Mpdz are transcribed in the mouse preimplantation embryo. However, the asymmetric distribution of these polarity proteins is not established until the compacted 8-cell stage. From compaction and thereafter, CRB3 and PALS1 are progressively enriched in the apical membrane, while PATJ and MPDZ are discretely localized at both tight junctions and the apical membrane adjacent to tight junctions. These temporal and spatial distribution patterns suggest that CRUMBS polarity complex might be involved in the cell polarity establishment in the early mouse embryo and reinforce the viewpoint that developmentally spatial asymmetries are first set up at the compaction stage. The present study provides a foundation for further investigation on the functions of CRUMBS polarity complex in trophectoderm specification and blastocyst morphogenesis. Show less

The molecular mechanism of stress-induced hepatic steatosis is not well known. Human leucine zipper protein (LZIP) regulates the expression of genes involved in inflammation, cell migration, and stress response. The aim of this study was to determine the regulatory role of LZIP in stress-induced hepatic steatosis. We used a microarray analysis to identify LZIP-induced genes involved in hepatic lipid metabolism. LZIP increased the expression of apolipoprotein A-IV (APOA4) mRNA. In the presence of stress inducer, APOA4 promoter analysis was performed, and LZIP-induced lipid accumulation was monitored in mouse primary cells and human tissues. Under Golgi stress conditions, LZIP underwent proteolytic cleavage and was phosphorylated by AKT to protect against proteasome degradation. The stabilized N-terminal LZIP was translocated to the nucleus, where it directly bound to the APOA4 promoter, leading to APOA4 induction. LZIP-induced APOA4 expression resulted in increased absorption of surrounding free fatty acids. LZIP also promoted hepatic steatosis in mouse liver. Both LZIP and APOA4 were highly expressed in human steatosis samples. Our findings indicate that LZIP is a novel modulator of APOA4 expression and hepatic lipid metabolism. LZIP might be a therapeutic target for developing treatment strategies for hepatic steatosis and related metabolic diseases.-Kang, M., Kim, J., An, H.-T., Ko, J. Human leucine zipper protein promotes hepatic steatosis Show less

Blood lipids are associated with cardiovascular disease (CVD) risk. Moreover, circulating lipid and fatty acid levels vary between men and women, and evidence demonstrates these traits may be influenced by single nucleotide polymorphisms (SNP). Sex-genotype interactions related to blood lipids and fatty acids have been poorly investigated and may help elucidate sex differences in CVD risk. The goal of this study was to investigate if the influence of SNPs previously associated with blood lipids and fatty acids varies in a sex-specific manner. Lipids and fatty acids were measured in serum and red blood cells (RBC), respectively, in 94 adults (18-30 years) from the GONE FISHIN' cohort and 118 age-matched individuals from the GOLDN cohort. HDL-c levels were higher and the total cholesterol/HDL-c (TC/HDL-c) ratio was lower in women versus men (p < 0.01). RBC palmitoleic acid and the stearoyl-CoA desaturase index were both higher in women (p < 0.01). Fatty acid desaturase (FADS) pathway activity (estimated using the ratio of eicosapentaenoic acid/alpha-linolenic acid) was higher in men (p < 0.01). The AA genotype for rs1800775 in CETP had a lower TC/HDL-c ratio in men, but not women (p Show less

Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors. Show less

Low density lipoprotein (LDL) receptor-related protein-6 (LRP6) is an important co-receptor of Wnt pathway, which plays a predominant role in development and progression of colorectal cancer. Recently, dysregulation of LRP6 has proved to be involved in the progression of cancers, but its biological role and clinical significance in colorectal cancer remain unclear. In present study, we revealed that phosphorylation of LRP6 was aberrantly upregulated in colorectal carcinoma correlating with TNM or Dukes staging and worse prognosis. In addition, phosphorylated LRP6 was positively correlated with nuclear accumulation of β-catenin. Overexpression or activation of LRP6 could activate Wnt signaling and promote tumor cell migration Show less