👤 Xuejun Jiang

Succinate dehydrogenase (SDH) deficiency is associated with gastrointestinal stromal tumor (GIST) oncogenesis, but the underlying molecular mechanism remains to be further investigated. Here, we show that succinate accumulation induced by SDHB loss of function increased the expression of zinc finger protein 148 (ZNF148, also named ZBP-89) in GIST cells. Meanwhile, ZNF148 is found to be phosphorylated by ERK at Ser306, and this phosphorylation results in ZNF148 binding to Forkhead box M1 (FOXM1). Through the complex formation at the promoter, ZNF148 facilitates Histone H3 acetylation and FOXM1-mediated Snail transcription, which eventually promotes cell invasion and tumor growth. The clinical analysis indicates that SDHB deficiency is associated with elevated ZNF148 levels, and ZNF148-S306 phosphorylation level displays a positive correlation with poor prognosis in GIST patients. These findings illustrate an unidentified molecular mechanism underlying FOXM1-regulated gene transcription related to GIST cell invasion, which highlights the physiological effects of SDHB deficiency on the invasiveness of GIST. Show less

Cholangiocarcinoma (CCA) is a serious malignant tumor. Long non-coding RNA NNT-AS1 (NNT-AS1) takes crucial roles in several tumors. So, we planned to research the roles and underlying mechanism of NNT-AS1 in CCA. NNT-AS1 overexpression was appeared in CCA tissues and cell lines. Proliferation was promoted by NNT-AS1 overexpression in CCLP1 and TFK1 cells. Besides, NNT-AS1 overexpression reduced E-cadherin level and raised levels of N-cadherin, vimentin, Snail and Slug. However, the opposite trend was occurred by NNT-AS1 knockdown. Further, NNT-AS1 overexpression promoted phosphatidylinositol 3 kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. MiR-203 was sponged by NNT-AS1 and miR-203 mimic reversed the above promoting effects of NNT-AS1. Additionally, insulin-like growth factor type 1 receptor (IGF1R) and zinc finger E-box binding homeobox 1 (ZEB1) were two potential targets of miR-203. NNT-AS1 promoted proliferation, EMT and PI3K/AKT and ERK1/2 pathways in CCLP1 and TFK1 cells through down-regulating miR-203. CCLP1 and TFK1 cells were co-transfected with pcDNA-NNT-AS1 and miR-203 mimic. Bromodeoxyuridine (BrdU), flow cytometry, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were employed to detect roles and mechanism of NNT-AS1. Interaction between NNT-AS1 and miR-203 or miR-203 and target genes was examined through luciferase activity experiment. Show less

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease. Show less

SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of dehydroepiandrosterone (DHEA), the precursor for 5α-dihydrotestosterone (DHT) biosynthesis. The aldo-keto reductase (AKR)1C3 regulates androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by promoting tumor tissue androgen biosynthesis from adrenal DHEA and also by functioning as an AR-selective coactivator. Herein we report that SULT2B-depleted CRPC cells, arising from stable RNA interference or gene knockout (KO), are markedly upregulated for AKR1C3, activated for ERK1/2 survival signal, and induced for epithelial-to-mesenchymal (EMT)-like changes. EMT was evident from increased mesenchymal proteins and elevated EMT-inducing transcription factors SNAI1 and TWIST1 in immunoblot and single-cell mass cytometry analyses. SULT2B KO cells showed greater motility and invasion in vitro; growth escalation in xenograft study; and enhanced metastatic potential predicted on the basis of decreased cell stiffness and adhesion revealed from atomic force microscopy analysis. While AR and androgen levels were unchanged, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several-fold higher in SULT2B-silenced cells. AKR1C3 silencing prevented ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells. SULT2B was undetectable in nearly all CRPC metastases from 50 autopsy cases. Primary tumors showed variable and Gleason score (GS)-independent SULT2B levels. CRPC metastases lacking SULT2B expressed AKR1C3. Since AKR1C3 is frequently elevated in advanced prostate cancer, the inhibitory influence of SULT2B on AKR1C3 upregulation, ERK1/2 activation, EMT-like induction, and on cell motility and invasiveness may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for targeting SULT2B-deficient prostate cancer. Show less

To investigate the effect of propofol on the migration and invasion of oral squamous cell carcinoma (OSCC) cells and explore the underlying mechanism. Cal-27 and SCC-25 cells treated with or without propofol, then the cells metastasis were determined. The levels of SNAI1 mRNA and protein were detected by real-time PCR and western blot. Cell migration ability was evaluated by wound healing assay, and the invasion of cells was measured using transwell assay. Propofol treatment significantly promoted cell migration and invasion of OSCC. Further mechanistic studies of the stimulating effects of propofol on OSCC cell metastasis revealed that propofol treatment dose-dependently upregulated the expression of SNAI1, a member of the Snail superfamily of zinc-finger transcription factors. Additionally, the inhibition of endogenous SNAI1 expression reversed the effect of propofol on cell migration and invasion in Cal-27 and SCC-25 cells. Our results demonstrate that propofol at clinically relevant concentrations facilitates cell migration and invasion through up-regulation of SNAI1 in OSCC cells, and suggest propofol may not be suitable for anesthesia management in OSCC patients. Show less

Although accumulating evidence has indicated the intimate association between epithelial-mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlying mechanisms remain elusive. Herein, we reported that Snail, a crucial EMT controller, was upregulated in CRC tissues. Colorectal cancer cells overexpressing Snail were found to be more resistant to 5-fluorouracil (5-Fu). Mechanistic studies reveal that Snail could increase the expression of ATP-binding cassette subfamily B member 1 (ABCB1) rather than the other 23 chemoresistance-related genes. Additionally, knockdown of ABCB1 significantly attenuated Snail-induced 5-Fu resistance in CRC cells. Oxaliplatin increased Snail and ABCB1 expression in CRC cells. Snail and ABCB1 were upregulated in 5-Fu-resistant HCT-8 (HCT-8/5-Fu) cells and inhibition of Snail decreased ABCB1 in HCT-8/5-Fu cells. These results confirm the vital role played by ABCB1 in Snail-induced chemoresistance. Further investigation into the relevant molecular mechanism revealed Snail-mediated ABCB1 upregulation was independent of β-catenin, STAT3, PXR, CAR and Foxo3a, which are commonly involved in modulating ABCB1 transcription. Instead, Snail upregulated ABCB1 transcription by directly binding to its promoter. Clinical analysis confirms that increased Snail expression correlated significantly with tumor size (P = .018), lymph node metastasis (P = .033), distant metastasis (P = .025), clinical stage grade (P = .024), and poor prognosis (P = .045) of CRC patients. Moreover, coexpression of Snail and ABCB1 was observed in CRC patients. Our study revealed that direct regulation of ABCB1 by Snail was critical for conferring chemoresistance in CRC cells. These findings unraveled the mechanisms underlying the association between EMT and chemoresistance, and provided potential targets for CRC clinical treatment. Show less

Breast cancer is one of the most common types of cancer in women. Although the mortality rate of breast cancer has fallen over the past 10 years, effective treatments that reduce the occurrence of breast cancer metastasis remain lacking. In this study, we explored the role of receptor for hyaluronan mediated motility (RHAMM) and the associated signaling pathway in cell migration in luminal A breast cancer. We first examined RHAMM expression levels using human breast tissue microarray and patient breast tissues. We then studied the role of RHAMM in migration in luminal A breast cancer using loss-of-function and gain-of-function strategies in in vitro models and confirmed these findings in an in vivo model. Finally, we investigated signaling molecules that play a role in cell migration using western blot. Our results demonstrated the following: (a) RHAMM shows high expression levels in malignant breast tissue, (b) RHAMM shows low expression levels in luminal A breast cancer compared to other subtypes of breast cancer, (c) RHAMM inhibits cell migration in luminal A breast cancer, and (d) RHAMM inhibits cell migration via the AKT/GSK3β/Snail axis in luminal A breast cancer. This study demonstrates a novel role of RHAMM in cell migration in luminal A breast cancer and suggests that therapeutic strategies involving RHAMM should be considered for various subtypes of breast cancer. Show less

Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC. Show less

Genetic mutations associated with early-onset Parkinson's disease (EOPD) vary widely among different ethnicities. We detected the genes associated with EOPD in a Chinese cohort using next-generation sequencing (NGS) combined with multiplex ligation-dependent probe amplification (MLPA) and analyzed the phenotypic characteristics of the mutation carriers. Cohort of 23 sporadic EOPD patients (onset age ≤ 45 years) were recruited. Genetic causes were identified by a targeted NGS panel containing 136 known extrapyramidal disease-causative genes. Multiplications or deletions of PD-causing genes were detected using the MLPA method. Demographic and clinical data were obtained, analyzed, and compared between patients with and those without Parkin gene variants. We identified 14 pathogenic or likely pathogenic variants (12 in Parkin, 1 in LRRK2, and 1 in VPS13C) in 10 patients (43.5%) and 8 rare variants of uncertain significance in 9 patients (39.1%). Parkin (34.8%) was the most common causative gene among our patients cohort, and exon deletion (62.5%) was the main type of variant. Patients with Parkin mutations had a younger age of onset, longer delay in diagnosis, slower disease progression, higher frequency of hyperreflexia, fatigue, and less hyposmia compared to patients without Parkin mutations. Our results revealed a higher prevalence of Parkin mutations in Chinese sporadic EOPD patients, and notably, exon deletion was the most common type of mutation. EOPD patients with Parkin mutations showed unique clinical characteristics. Show less

The epithelial-mesenchymal transition (EMT) process is a key priming activity of fibroblasts in pulmonary fibrosis during silicosis. Ets-like protein-1 (Elk-1) is a critical modulator that promotes functional changes in cells, and the effects are mediated by oxidative stress (OS). However, whether ELK-1 is involved in EMT of silicosis remains unclear. In addition, researchers have found that Elk-1 is involved in the expression of the gene zc3h12a, which encodes the protein MCPIP1, and MCPIP1 is a member of the zinc finger Cys-Cys-Cys-His (CCCH)-type protein family. A previous study from our lab showed that ZC3H4, which is also a member of the CCCH-type protein family, critically affected the regulation of EMT during silicosis. However, it has not yet been elucidated if ELK-1 acts at the promoter for zc3h4 to increase its expression in a mechanism that is similar to that of the zc3h12a gene and whether such regulation ultimately controls EMT. Therefore, we explored the correlation between ELK-1 and ZC3H4 expression and tested the underlying mechanisms affecting ELK-1 activation induced by silica. Our study identifies that SiO Show less

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene. A second copy, SMN2, is similar to SMN1 but produces ∼10% SMN protein because of a single-point mutation that causes splicing defects. Chronic low levels of SMN cause accumulation of co-transcriptional R-loops and DNA damage leading to genomic instability and neurodegeneration in SMA. Severity of SMA disease correlates inversely with SMN levels. SMN2 is a promising target to produce higher levels of SMN by enhancing its expression. Mechanisms that regulate expression of SMN genes are largely unknown. We report that zinc finger protein ZPR1 binds to RNA polymerase II, interacts in vivo with SMN locus and upregulates SMN2 expression in SMA mice and patient cells. Modulation of ZPR1 levels directly correlates and influences SMN2 expression levels in SMA patient cells. ZPR1 overexpression in vivo results in a systemic increase of SMN levels and rescues severe to moderate disease in SMA mice. ZPR1-dependent rescue improves growth and motor function and increases the lifespan of male and female SMA mice. ZPR1 reduces neurodegeneration in SMA mice and prevents degeneration of cultured primary spinal cord neurons derived from SMA mice. Further, we show that the low levels of ZPR1 associated with SMA pathogenesis cause accumulation of co-transcriptional RNA-DNA hybrids (R-loops) and DNA damage leading to genomic instability in SMA mice and patient cells. Complementation with ZPR1 elevates senataxin levels, reduces R-loop accumulation and rescues DNA damage in SMA mice, motor neurons and patient cells. In conclusion, ZPR1 is critical for preventing accumulation of co-transcriptional R-loops and DNA damage to avert genomic instability and neurodegeneration in SMA. ZPR1 enhances SMN2 expression and leads to SMN-dependent rescue of SMA. ZPR1 represents a protective modifier and a therapeutic target for developing a new method for the treatment of SMA. Show less

Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases. Show less

α-Melanocyte-stimulating hormone (α-MSH) has been shown to be involved in nociception, but the underlying molecular mechanisms remain largely unknown. In this study, we report that α-MSH suppresses the transient outward A-type K Show less

Inducing of dental pulp stem cells (DPSCs) into endothelial cells (ECs) to prevascularize pulp tissue constructs may offer a novel and viable approach for enhancing pulp regeneration. However, there are numerous challenges in current methods for the acquisition of sufficient translational ECs. It was known that Sema4D/PlexinB1 signaling exerts profound effects on enhancing vascular endothelial growth factor (VEGF) secretion and angiogenesis. Whether Sema4D/PlexinB1 could regulate endothelial differentiation of DPSCs is not yet investigated. In this study, when DPSCs were treated with Sema4D (2 μg/mL), ECs-specific (VEGFR1, VEGFR2, CD31, and vWF), and angiogenic genes and proteins were significantly upregulated. The induced ECs exhibited similar endothelial vessel formation ability to that of human umbilical vein endothelial cells (HUVECs). Furthermore, phosphorylation of AKT increased dramatically within 5 minutes (from 0.93 to 21.8), while p-ERK1/2 was moderately elevated (from 0.94 to 2.65). In summary, our results demonstrated that Sema4D/PlexinB1 signaling induces endothelial differentiation of DPSCs. The interactions of Sema4D, VEGF, ANGPTL4, ANG1, and HIF-1α may play a crucial role in mediating the differentiation process. Show less

Obesity is a risk factor for breast cancer and also predicts poor clinical outcomes regardless of menopausal status. Contributing to the poor clinical outcomes is the suboptimal efficacy of standard therapies due to dose limiting toxicities and obesity-related complications, highlighting the need to develop novel therapeutic approaches for treating obese patients. We recently found that obesity leads to an increase in tumor-infiltrating macrophages with activated NLRC4 inflammasome and increased interleukin (IL)-1β production. IL-1β, in turn, leads to increased angiogenesis and cancer progression. Using Next Generation RNA sequencing, we identified an NLRC4/IL-1β-dependent upregulation of angiopoietin-like 4 (ANGPTL4), a known angiogenic factor in cancer, in tumors from obese mice. ANGPTL4-deficiency by genetic knockout or treatment with a neutralizing antibody led to a significant reduction in obesity-induced angiogenesis and tumor growth. At a mechanistic level, ANGPTL4 expression is induced by IL-1β from primary adipocytes in a manner dependent on NF-κB- and MAP kinase-activation, which is further enhanced by hypoxia. This report shows that adipocyte-derived ANGPTL4 drives disease progression under obese conditions and is a potential therapeutic target for treating obese breast cancer patients. Show less

A genomics approach is an effective way to understand the possible mechanisms underlying the onset and progression of disease. However, very limited results have been published regarding whole-genome expression analysis of human idiopathic membranous nephropathy (iMN) using renal tissue. In the present study, gene expression profiling using renal cortex tissue from iMN patients and healthy controls was conducted; differentially expressed genes (DEGs) were filtered out, and 167 up- and 291 down-regulated genes were identified as overlapping DEGs (ODEGs). Moreover, enrichment analysis and protein-protein network construction were performed, revealing enrichment of genes mainly in cholesterol metabolism and arachidonic acid metabolism, among others, with 38 hub genes obtained. Furthermore, we found several associations between circulating lipid concentrations and hub gene signal intensities in the renal cortex. Our findings indicate that lipid metabolism, including cholesterol metabolism and arachidonic acid metabolism, may participate in iMN pathogenesis through key genes, including apolipoprotein A1 (APOA1), apolipoprotein B (APOB), apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP), and phospholipase A2 group XIIB (PLA2G12B). Show less

Chronic HBV infection (CHB) can lead to acute-on-chronic liver failure (HBV-ACLF) characterized by high mortality. This study aimed to reveal ACLF-related proteomic alterations, from which protein based diagnostic and prognostic scores for HBV-ACLF were developed. Show less

Lung cancer is a common malignant neoplasm that is prone to distant metastasis. Gastrointestinal metastasis from lung cancer is rather rare no matter what stage. Herein, we presented a case of pulmonary adenocarcinoma six months after thoracoscopic Lobectomy isolated metastasis to sigmoid colon. Then the patient underwent radical resection of metastatic tumors of sigmoid colon. The pathologic morphology and immunohistochemistry of lung adenocarcinoma is highly consistent with the sigmoid colon tumor and their gene profiles are likely similar expect for an AXIN1 mutation in primary tumor and not in the metastatic lesion. Show less

Caveolin-1 has been reported to play an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). This study was designed to identify Caveolin-1-interacting proteins to reveal the molecular mechanisms of ARDS. Yeast two-hybrid screening was performed using Caveolin-1 as the bait, and Axin-1 was identified as a binding partner for Caveolin-1. Co-immunoprecipitation demonstrated that the binding domains were located in the N-terminal region (1-100 aa) of Caveolin-1 and the C-terminal region (710-797 aa) of Axin-1. Caveolin-1 gene knockout or Axin-1 knockdown significantly decreased the levels of TNF-α and IL-6 in the supernatants of alveolar type I (AT-I) epithelial cells treated with LPS. Disrupting the interaction between Caveolin-1 and Axin-1 using CRISPR/Cas9 technology led to a significant increase in TNF-α and IL-6 from AT-I cells, along with a significant reduction in β-catenin expression. In conclusion, Axin-1 functions as an adaptor of Caveolin-1 and affects the production of inflammatory cytokines in AT-I cells challenged with LPS via β-catenin-mediated negative regulation. Show less

Since metabolic process differs between humans and mice, studies were performed in hamsters, which are generally considered to be a more appropriate animal model for studies of obesity-related metabolic disorders. The modulation of gut microbiota, bile acids and the farnesoid X receptor (FXR) axis is correlated with obesity-induced insulin resistance and hepatic steatosis in mice. However, the interactions among the gut microbiota, bile acids and FXR in metabolic disorders remained largely unexplored in hamsters. In the current study, hamsters fed a 60% high-fat diet (HFD) were administered vehicle or an antibiotic cocktail by gavage twice a week for four weeks. Antibiotic treatment alleviated HFD-induced glucose intolerance, hepatic steatosis and inflammation accompanied with decreased hepatic lipogenesis and elevated thermogenesis in subcutaneous white adipose tissue (sWAT). In the livers of antibiotic-treated hamsters, cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative bile acid synthesis pathway was upregulated, contributing to a more hydrophilic bile acid profile with increased tauro- Show less

Cholesteryl ester transfer protein (CETP) inhibitor-mediated induction of HDL-cholesterol has no effect on the protection from cardiovascular disease (CVD). However, the mechanism is still unknown. Data on the effects of this class of drugs on subclasses of HDL are either limited or insufficient. In this study, we investigated the effect of evacetrapib, a CETP inhibitor, on subclasses of HDL in patients with atherosclerotic cardiovascular disease or diabetes. Baseline and 3-month post-treatment samples from atorvastatin 40 mg plus evacetrapib 130 mg (n = 70) and atorvastatin 40 mg plus placebo (n = 30) arms were used for this purpose. Four subclasses of HDL (large HDL, medium HDL, small HDL, and preβ-1 HDL) were separated according to their size and quantified by densitometry using a recently developed native polyacrylamide gel electrophoresis (PAGE) system. Relative to placebo, while evacetrapib treatment dramatically increased large HDL and medium HDL subclasses, it significantly reduced small HDL (27%) as well as preβ-1 HDL (36%) particles. Evacetrapib treatment reduced total LDL, but also resulted in polydisperse LDL with LDL particles larger and smaller than the LDL subclasses of the placebo group. Evacetrapib reduced preβ-1 HDL and small HDL in patients with ASCVD or diabetes on statin. Preβ-1 HDL and medium HDL are negatively interrelated. The results could give a clue to understand the effect of CETP inhibitors on cardiovascular outcomes. Show less

Bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) play important roles in host antimicrobial defense. In the present study, we identified one isoform of BPI/LBP gene from turbot (Scophthalmus maximus), designated as SmBPI/LBP1. The full-length cDNA sequence of SmBPI/LBP1 was 1826 bp, which encoding one secreted protein with 480 amino acid residues. Structurally, the SmBPI/LBP1 showed high similarity to its homologs from other vertebrates or invertebrates, which all contained a signal peptide, a BPI/LBP/CETP N-terminal with a LPS-binding domain, and a BPI/LBP/CETP C-terminal domain. The deduced amino acid sequences of SmBPI/LBP1 shared significant similarity to BPI/LBP of Seriola lalandi dorsalis (71%) and Paralichthys olivaceus (69%). Phylogentic analysis further supported that SmBPI/LBP1 act as a new member of vertebrate BPI/LBP family. SmBPI/LBP1 was ubiquitously expressed in all tested tissues, with the highest expression level in spleen tissue. The mRNA expression of SmBPI/LBP1 in spleen and kidney were significantly up-regulated after Vibrio vulnificus challenge. Finally, the recombinant SmBPI/LBP1 showed high affinity to lipopolysaccharide, followed by peptidoglycan and lipoteichoic acid, which is the ubiquitous component of Gram-negative or Gram-positive bacteria. These results indicated that SmBPI/LBP1 probably played important roles in immune response against bacteria infection. Show less

To explore the molecular mechanism of insulin on proliferation and differentiation of MC3T3-E1 cell under high glucose conditions. We first investigated the effect of different concentrations of insulin on the osteoblast cell proliferation and cell differentiation at various time points by MTT analysis, cell cycle analysis, and expression detection of differentiation genes. Then, we used 200 ng/mL of insulin to treat the osteoblast cell at different time points for identifying the common differentially expressed mRNAs among various time points by RNA sequencing. Thirdly, we performed the gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis to explore the biological function of these common differentially expressed mRNAs. The results showed that insulin promoted the cell proliferation and differentiation of osteoblast cell. In RNA sequencing, a total of 31 common differentially expressed mRNAs were identified between different time points. Mt1, Tmem135, Avp, and Dlg2 were found to be associated with the new bone formation. In addition, three important signalling pathways, namely, lysosome, glutamatergic synapse, and chemokine signalling pathways, were found in the KEGG enrichment analysis. Our work demonstrated that insulin could promote the osteoblast cell proliferation and cell differentiation, which may play a key role in bone formation. SIGNIFICANCE OF THE STUDY: Our result showed that insulin could promote the proliferation and differentiation of osteoblast at both cellular and molecular levels, which may promote the new bone formation in the osteoblasts. Show less