BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide.Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell...BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide.Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival,growth,and evolution.Emerging evidence suggests the importance of fatty acid binding proteins(FABPs)in contribution to cancer progression and metastasis;however,how these FABPs are dysregulated in cancer cells,especially in HCC,and the roles of FABPs in cancer progression have not been well defined.AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies.METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma(LIHC)as well as patient cohorts with other cancer types in this study.We investigated genetic alterations of FABPs in various cancer types.mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome,enriched cancer hallmarks and oncogenes previously reported for patients with HCC.We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells.RESULTS We discovered that a gene cluster including five FABP family members(FABP4,FABP5,FABP8,FABP9 and FABP12)is frequently co-amplified in cancer.Amplification,in fact,is the most common genetic alteration for FABPs,leading to overexpression of FABPs.FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues.High FABP5 expression correlates well with worse patient outcomes(P<0.05).FABP5 expression highly correlates with enrichment of G2M checkpoint(r=0.33,P=1.1e-10),TP53 signaling pathway(r=0.22,P=1.7e-5)and many genes in the gene sets such as CDK1(r=0.56,P=0),CDK4(r=0.49,P=0),and TP53(r=0.22,P=1.6e-5).Furthermore,FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients(r=0.58,P=0;r=0.58,P=0;respectively).FABP5high Huh7 cells also expressed higher protein levels of p53,BIRC5,CDK1,CDK2,and CDK4 than FABP5low HepG2 cells.FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells.CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer,especially in HCC,leading to its significant elevated expression in HCC.Its high expression correlates well with worse patient outcome,enriched cancer hallmarks and oncogenes in HCC.FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells.All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.展开更多
Background:Burn shock caused by vascular leakage is one of the main causes of high mortality in severe burn injury.However,the pathophysiological mechanism of vascular leakage is still unclear.The purpose of this stud...Background:Burn shock caused by vascular leakage is one of the main causes of high mortality in severe burn injury.However,the pathophysiological mechanism of vascular leakage is still unclear.The purpose of this study was to explore the molecular mechanism of vascular leakage in the early stage of severe burn and provide a new target for the treatment of severe burns.Methods:Neutrophils were isolated from human peripheral blood by magnetic beads sorting.ELISA was used to detect neutrophil-derived granule proteins and glycocalyx injury products in plasma.The vascular leakage and neutrophil movement were assessed by in vivo laser confocal imaging in mice,and high-quality video were provided.Adhesion-related molecules were investigated by qRT-PCR.The damage to glycocalyx of mice vascular endothelial cellswas observed by transmission electron microscope and scanning electron microscope.Proteomic analysis,flow cytometry and immunofluorescence were used to further study the relationship between human peripheral blood neutrophil-derived hypochlorite(HOCl)and CD44 of human vascular endothelial cells.Results:In this study,we found that rapidly increasing activated neutrophils secrete heparin binding protein(HBP)andmyeloperoxidase(MPO)after severe burn injury.Increased HBP triggers vascular leakage with synergy of MPO,results in systemic edema and burn shock.Furthermore,we found that the MPO catalytic product HOCl but not MPO triggers CD44 extracellular domain shedding from vascular endothelial cells to damage the glycocalyx.Damage to the glycocalyx results in firm adhesion of neutrophils and increases vascular leakage.However,MPO inhibitors partially protect the glycocalyx of vascular endothelial cells.The combination of HBP and MPO inhibitors markedly reduces vascular leakage and systemic edema in the early stage of severe burns.Conclusions:Taken together,these data reveal that neutrophil-derived HBP and MPO play an important synergies role in triggering vascular leakage at the early stage of severe burns.Targeted intervention in these two biomolecules may introduce new strategies for helping to reduce large amount of fluid loss and subsequent burn shock.展开更多
After spinal cord injury(SCI),a fibroblast-and microglia-mediated fibrotic scar is formed in the lesion core,and a glial scar is formed around the fibrotic scar as a res ult of the activation and proliferation of astr...After spinal cord injury(SCI),a fibroblast-and microglia-mediated fibrotic scar is formed in the lesion core,and a glial scar is formed around the fibrotic scar as a res ult of the activation and proliferation of astrocytes.Simultaneously,a large number of neuro ns are lost in the injured area.Regulating the dense glial scar and re plenishing neurons in the injured area are essential for SCI repair.Polypyrimidine tra ct binding protein(PTB),known as an RNA-binding protein,plays a key role in neurogenesis.Here,we utilized short hairpin RNAs(shRNAs)and antisense oligonucleotides(ASOs)to knock down PTB expression.We found that reactive spinal astrocytes from mice were directly reprogrammed into motoneuron-like cells by PTB downregulation in vitro.In a mouse model of compressioninduced SCI,adeno-associated viral shRNA-mediated PTB knockdown replenished motoneuron-like cells around the injured area.Basso Mouse Scale scores and forced swim,inclined plate,cold allodynia,and hot plate tests showed that PTB knockdown promoted motor function recovery in mice but did not improve sensory perception after SCI.Furthermore,ASO-mediated PTB knockdown improved motor function resto ration by not only replenishing motoneuron-like cells around the injured area but also by modestly reducing the density of the glial scar without disrupting its overall structure.Together,these findings suggest that PTB knockdown may be a promising therapeutic strategy to promote motor function recovery during spinal cord repair.展开更多
Fidgetin,a microtubule-severing enzyme,regulates neurite outgrowth,axonal regeneration,and cell migration by trimming off the labile domain of microtubule polymers.Because maintenance of the microtubule labile domain ...Fidgetin,a microtubule-severing enzyme,regulates neurite outgrowth,axonal regeneration,and cell migration by trimming off the labile domain of microtubule polymers.Because maintenance of the microtubule labile domain is essential for axon initiation,elongation,and navigation,it is of interest to determine whether augmenting the microtubule labile domain via depletion of fidgetin serves as a therapeutic approach to promote axonal regrowth in spinal cord injury.In this study,we constructed rat models of spinal cord injury and sciatic nerve injury.Compared with spinal cord injury,we found that expression level of tyrosinated microtubules in the labile portion of microtubules continuously increased,whereas fidgetin decreased after peripheral nerve injury.Depletion of fidgetin enhanced axon regeneration after spinal cord injury,whereas expression level of end binding protein 3(EB3)markedly increased.Next,we performed RNA interference to knockdown EB3 or fidgetin.We found that deletion of EB3 did not change fidgetin expression.Conversely,deletion of fidgetin markedly increased expression of tyrosinated microtubules and EB3.Deletion of fidgetin increased the amount of EB3 at the end of neurites and thereby increased the level of tyrosinated microtubules.Finally,we deleted EB3 and overexpressed fidgetin.We found that fidgetin trimmed tyrosinated tubulins by interacting with EB3.When fidgetin was deleted,the labile portion of microtubules was elongated,and as a result the length of axons and number of axon branches were increased.These findings suggest that fidgetin can be used as a novel therapeutic target to promote axonal regeneration after spinal cord injury.Furthermore,they reveal an innovative mechanism by which fidgetin preferentially severs labile microtubules.展开更多
Hydrophobic Val derivative Schiff base copper(II) complexes and dipeptide (AlaAla, GlyGly) derivative Schiff base copper(II) complexes were introduced into egg white lysozyme. X-ray crystal structure analysis revealed...Hydrophobic Val derivative Schiff base copper(II) complexes and dipeptide (AlaAla, GlyGly) derivative Schiff base copper(II) complexes were introduced into egg white lysozyme. X-ray crystal structure analysis revealed amino acid derivative Schiff base copper(II) complexes were obtained. Herein we discuss primarily on the binding mode of copper(II) of the complexes obtained with egg white lysozyme. The electron density of copper(II) ions was confirmed by X-ray crystal structure analysis. The Val derivative Schiff base copper(II) complex was weakly bound at Arg114 of egg white lysozyme. In other copper(II) complexes, binding of copper(II) ions with dissociated ligands to various residues was observed. The binding sites of copper(II) ions were compared with computational scientific predictions.展开更多
This present study investigated the ability of various soy protein hydrolysates(SPHs)in binding calcium.It was demonstrated that the amount of Ca-bound depended greatly on the SPHs obtained using different proteases,w...This present study investigated the ability of various soy protein hydrolysates(SPHs)in binding calcium.It was demonstrated that the amount of Ca-bound depended greatly on the SPHs obtained using different proteases,which included:neutrase, flavourzyme,protease M and pepsin.The maximum level of Ca-bound(66.9 mg/g)occurred when protease M was used to hydrolyze soy protein.Peptide fragments exhibiting high Ca-binding capacity had molecular weights of either 14.4 or 8-9 kDa.The level of Ca-bound increased linearly with the increment of carboxyl content in SPHs,and further deamidation on SPHs from protease M improved Ca-binding of the hydrolysate.展开更多
Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue ...Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.展开更多
Background: Retinoblastoma binding protein 4 (RBBP4) plays an essential role in the development of multiple cancers. However, its relationship with prognosis in colon cancer and colon cancer hepatic metastasis has not...Background: Retinoblastoma binding protein 4 (RBBP4) plays an essential role in the development of multiple cancers. However, its relationship with prognosis in colon cancer and colon cancer hepatic metastasis has not been elucidated. The aim of this study was to explore the relationship between RBBP4 expression and prognosis of colon cancer patients and to evaluate RBBP4 as a new prognostic marker in these patients. Methods: Eighty colon cancer patients underwent surgical resection of the colon were enrolled. Among them, forty colon cancer patients suffered with hepatic metastasis. The colon cancer tissues, para-colon cancer tissues, and hepatic metastatic cancer tissues were collected from the pathological department for further analysis. The expression of RBBP4 proteins was examined by immunohistochemistry and correlated with clinicopathological parameters. The Cancer Genome Atlas (TCGA) database was used to validate the expression and explore its relationship with clinical characteristics. Results: RBBP4 was up-regulated in the colon cancer tissues compared with the para-colon cancer tissues. The analysis of TCGA database verified the upregulation of RBBP4 in the colon cancer tissues and RBBP4 overexpression was correlated with nerve invasion and poor outcomes of chemotherapy. Moreover, the positive rate of RBBP4 expression in 40 colon cancer patients with hepatic metastasis was higher in the hepatic metastatic cancer tissues (39/40, 97.5%) than in the colon cancer tissues (26/40, 65.0%). Our clinicopathological analysis showed that RBBP4 expression was significantly correlated with vascular invasion, hepatic metastasis, and lymph node involvement (all P < 0.05). Additionally, the survival analysis demonstrated that RBBP4 over-expression was correlated with poor prognosis. Conclusions: RBBP4 was upregulated in the colon cancer. RBBP4 may be a novel predictor for poor prognosis of colon cancer and colon cancer hepatic metastasis.展开更多
AIM: To study the contribution of tonicity response element binding protein(Ton EBP) in retinal ganglion cell(RGC) death of diabetic retinopathy(DR).METHODS: Diabetes was induced in C57BL/6 mice by five consecutive in...AIM: To study the contribution of tonicity response element binding protein(Ton EBP) in retinal ganglion cell(RGC) death of diabetic retinopathy(DR).METHODS: Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin(STZ). Control mice received vehicle(phosphate-buffered saline). All mice were killed 2mo after injections, and the extent of cell death and the protein expression levels of Ton EBP and aldose reductase(AR) were examined.RESULTS: The Ton EBP and AR protein levels and the death of RGC were significantly increased in the retinas of diabetic mice compared with controls 2mo after the induction of diabetes. Terminal deoxynucleotidyl transferase(Td T)-mediated d UTP nick end labeling(TUNEL)-positive signals co-localized with Ton EBP immunoreactive RGC. These changes were increased in the diabetic retinas compared with controls.CONCLUSION: The present data show that AR and Ton EBP are upregulated in the DR and Ton EBP may contribute to apoptosis of RGC in the DR.展开更多
Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose ...Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomainhelicase-DNA binding protein 5, chromodomain-helicaseDNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation,and should be validated in future studies.展开更多
The stereoselective hydrolysis of esmolol in whole blood and in its separated components from rat,rabbit and human was investigated.Blood esterase activities were variable in different species in the order of rat>r...The stereoselective hydrolysis of esmolol in whole blood and in its separated components from rat,rabbit and human was investigated.Blood esterase activities were variable in different species in the order of rat>rabbit>human.Rat plasma showed the high esterase activity and had no stereoselectivity to enantiomers.Rabbit red blood cell(RBC) membrane,RBC cytosol and plasma all hydrolyzed esmolol but with different esterase activity,whereas the hydrolysis in RBC membrane and cytosol showed significant stereoselectivity towards R-(+)-esmolol.Esterase in RBC cytosol from human blood mainly contributed to the esmolol hydrolysis,which was demonstrated with no stereoselctivity.Esterase in human plasma showed a low activity,but a remarkable stereoselectivity with R-(+)-esmolol.In addition,the protein concentration affected the hydrolysis behavior of esmolol in RBC suspension.Protein binding of esmolol enantiomers in human plasma,human serum albumin(HSA) and α_1-acid glycoprotein(AGP) revealed that there was a significant difference in bound fractions between two enantiomers,especially for AGP.Our results indicated that the stereoselective protein binding might play a role in the different hydrolysis rates of esmolol enantiomers in human plasma.展开更多
BACKGROUND:We previously showed that insulin-like growth factor binding protein-related protein 1(IGFBPrP1) is a novel mediator in liver fibrosis.Transforming growth factor beta 1(TGFβ1) is known as the strongest eff...BACKGROUND:We previously showed that insulin-like growth factor binding protein-related protein 1(IGFBPrP1) is a novel mediator in liver fibrosis.Transforming growth factor beta 1(TGFβ1) is known as the strongest effector of liver fibrosis.Therefore,we aimed to investigate the detailed interaction between IGFBPrP1 and TGFβ1 in primary hepatic stellate cells(HSCs).METHODS:We overexpressed TGFβ1 or IGFBPrP1 and inhibited TGFβ1 expression in primary HSCs for 6,12,24,48,72,and 96 hours to investigate their interaction and observe the accompanying expressions of α-smooth muscle actin(α-SMA),collagen I,fibronectin,and phosphorylated-mothers against decapentaplegic homolog 2/3(p-Smad2/3).RESULTS:We found that the adenovirus vector encoding the TGFβ1 gene(Ad TGFβ1) induced IGFBPrP1 expression while that of α-SMA,collagen I,fibronectin,and TGFβ1 increased gradually.Concomitantly,Ad IGFBPrP1 upregulated TGFβ1,α-SMA,collagen I,fibronectin,and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours.Inhibition of TGFβ1 expression reduced the IGFBPrP1-stimulated expression of α-SMA,collagen I,fibronectin,and p-Smad2/3.CONCLUSIONS:These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGFβ1,which likely accelerates liver fibrosis progression.Furthermore,IGFBPrP1 likely participates in liver fibrosis in a TGFβ1-depedent manner,and may act as an upstream regulatory factor of TGFβ1 in the Smad pathway.展开更多
BACKGROUND Liver cirrhosis is a major risk factor for hepatocellular carcinoma(HCC)development in chronic hepatitis B(CHB). Serum Mac-2 binding protein glycosylation isomer(M2 BPGi) is a novel serological marker for f...BACKGROUND Liver cirrhosis is a major risk factor for hepatocellular carcinoma(HCC)development in chronic hepatitis B(CHB). Serum Mac-2 binding protein glycosylation isomer(M2 BPGi) is a novel serological marker for fibrosis. The role of M2 BPGi in prediction of HCC is unknown.AIM To examine the role of serum M2 BPGi in predicting HCC development in hepatitis B e antigen(HBeAg)-negative patients.METHODS Treatment-naive CHB patients with documented spontaneous HBeAg seroconversion were recruited. Serum M2 BPGi was measured at baseline(within3 years from HBeAg seroconversion), at 5 years and 10 years after HBeAg seroconversion and expressed as cut-off index(COI). Multivariate cox regression was performed to identify predictors for HCC development. ROC analysis was used to determine the cut-off value of M2 BPGi.RESULTS Among 207 patients(57% male, median age at HBeAg seroconversion 40 years old) with median follow-up of 13.1(11.8-15.5) years, the cumulative incidence of HCC at 15 years was 7%. Median M2 BPGi levels were significantly higher in patients with HCC compared to those without HCC(baseline: 1.39 COI vs 0.38 COI, P < 0.001; 5-year: 1.45 COI vs 0.47 COI, P < 0.001; 10-year: 1.20 COI vs 0.55 COI, P = 0.001). Multivariate analysis revealed age at HBeAg seroconversion[odds ratio(OR) = 1.196, 95% confidence interval(CI): 1.034-1.382, P = 0.016] and baseline M2 BPGi(OR = 4.666, 95%CI: 1.296-16.802, P = 0.018) were significant factors predictive of HCC. Using a cut-off value of 0.68 COI, baseline M2 BPGi yielded AUROC of 0.883 with 91.7% sensitivity and 80.8% specificity.CONCLUSION High serum M2 BPGi within 3 years after HBeAg seroconversion was a strong predictor for subsequent HCC development in treatment-naive HBeAg-negative CHB patients.展开更多
BACKGROUND Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma(HCC).Y-box binding protein 1(YB-1)is closely correlated with tumors and drug resistance.However,the relationship bet...BACKGROUND Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma(HCC).Y-box binding protein 1(YB-1)is closely correlated with tumors and drug resistance.However,the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.AIM To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.METHODS The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues.Next,we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib.Then,we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling,flow cytometry and Western blotting assays.We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo.Moreover,we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing(DGE-seq).RESULTS YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues.YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis.Consistently,the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down.Furthermore,KEGG pathway enrichment analysis of DGEseq demonstrated that the phosphoinositide-3-kinase(PI3K)/protein kinase B(Akt)signaling pathway was essential for the sorafenib resistance induced by YB-1.Subsequently,YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway(Akt1 and PIK3R1)as shown by searching the BioGRID and HitPredict websites.Finally,YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib,and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.CONCLUSION Overall,we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene,which is of great significance for the application of sorafenib in advanced-stage HCC.展开更多
BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occu...BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occurrence and development of diabetic atheroscerosis have not been fully elucidated.AIM To summarize the potential role of retinol binding protein 4(RBP4) in the pathogenesis of diabetic atheroscerosis,particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.METHODS Male Wistar rats were randomly divided into three groups,including a control group(NC group),diabetic rat group(DM group),and diabetic atherosclerotic rat group(DA group).The contents of total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), triglycerides(TG), low-density lipoprotein cholesterol(LDLc), fasting insulin(FINS),fasting plasma glucose,and hemoglobin A1 c(HbA1 c)were measured.Moreover,the adipose and serum levels of RBP4,along with the expression levels of JAK2, phosphorylated JAK2(p-JAK2), STAT3,phosphorylated STAT3(p-STAT3), B-cell lymphoma-2(Bcl-2), and Cyclin D1 in aortic tissues were also measured.Besides,homeostasis model assessment of insulin resistance(HOMA-IR) and atherogenic indexes(AI) were calculated.RESULTS Compared with the NC and DM groups,the levels LDL-c,TG,TC,FINS,HOMAIR,RBP4,and AI were upregulated,whereas that of HDL-c was downregulated in the DA group(P <0.05);the mRNA levels of JAK2,STAT3,Cyclin D1,and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group;P-JAK2,p-JAK2/JAK2 ratio,p-STAT3,p-STAT3/STAT3 ratio,Cyclin D1,and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group.In addition,as shown by Pearson analysis,serum RBP4 had a positive correlation with TG,TC,LDL-c,FINS,HbA1 C,p-JAK2,p-STAT3,Bcl-2,Cyclin D1,AI,and HOMA-IR but a negative correlation with HDL-c.In addition,multivariable logistic regression analysis showed that serum RBP4,p-JAK2,p-STAT3,and LDL-c were predictors of the presence of diabetic atherosclerosis.CONCLUSION RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.展开更多
The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane pr...The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.展开更多
The full-length sequence of the odorant binding protein 5 gene,HarmOBP5,was obtained from an antennae cDNA library of cotton bollworm,Helicoverpa armigera (Hübner).The cDNA contains a 444 bp open reading frame,en...The full-length sequence of the odorant binding protein 5 gene,HarmOBP5,was obtained from an antennae cDNA library of cotton bollworm,Helicoverpa armigera (Hübner).The cDNA contains a 444 bp open reading frame,encoding a protein with 147 amino acids,namely HarmOBP5.HarmOBP5 was expressed in Escherichia coli and the recombinant protein was purified by affinity chromatography.SDS-PAGE and Western blot analysis demonstrated that the purified protein can be used for further investigation of its binding characteristics.Competitive binding assays with 113 odorant chemicals indicated that HarmOBP5 has strong affinity to some special plant volatiles,including (E)-β-farnesene,ethyl butyrate,ethyl heptanoate,and acetic acid 2-methylbutyl ester.Based on three-dimensional (3D) model of AaegOBP1 from Aedes aegypti,a 3D model of HarmOBP5 was predicted.The model revealed that some key binding residues in HarmOBP5 may play important roles in odorant perception of H.armigera.This study provides clues for better understanding physiological functions of OBPs in H.armigera and other insects.展开更多
AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhos...AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.展开更多
Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute t...Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused synapses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.展开更多
Heart fatty acid-binding protein (H-FABP) is supposed to be the most sensitive biomarker of early acute myocardial infarction (AMI). To evaluate the diagnostic value of H-FABP for AMI in the early stage, the plasma le...Heart fatty acid-binding protein (H-FABP) is supposed to be the most sensitive biomarker of early acute myocardial infarction (AMI). To evaluate the diagnostic value of H-FABP for AMI in the early stage, the plasma levels of H-FABP were measured by sandwich ELISA in 93 patients with suspected AMI at admission within 6 h after onset of chest pain and 69 normal healthy subjects. The plasma concentrations of cardiac troponin-I (cTnI), creatine kinase-MB (CK-MB) and myoglobin (Mb) were assayed at the same time by using corpuscle chemiluminescence for those patients. The patients were classified as AMI group (n=32) and non-AMI group (n=61) retrospectively. The diagnostic validity was evaluated in terms of sensitivity, specificity and receiver operating characteristic (ROC) curve analysis. The results showed the cutoff value of H-FABP for AMI was 16.8 ng/ml, and its diagnostic sensitivity for AMI was 64.29 % within 3 h and 84.38 % within 6 h after onset of chest pain, and the diagnostic specificity for non-AMI was 100 % within 3 h and 91.8 % within 6 h. H-FABP had higher sensitivity than that of cTnI and CK-MB at all time points (P<0.05), whereas there was no significant difference in specificity among the four markers. But the area under the ROC curve of H-FABP was significantly greater than that of cTnI, CK-MB and Mb within 3 h. These results revealed that H-FABP possessed high diagnostic sensitivity and specificity for AMI in early stage, especially within 3 h after onset of persistent angina pectoris. In conclusion, H-FABP can be used as a sensitive marker for AMI in the early stage.展开更多
基金Tianjin Key Medical Discipline Construction Project,No.TJYXZDXK-034A.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide.Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival,growth,and evolution.Emerging evidence suggests the importance of fatty acid binding proteins(FABPs)in contribution to cancer progression and metastasis;however,how these FABPs are dysregulated in cancer cells,especially in HCC,and the roles of FABPs in cancer progression have not been well defined.AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies.METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma(LIHC)as well as patient cohorts with other cancer types in this study.We investigated genetic alterations of FABPs in various cancer types.mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome,enriched cancer hallmarks and oncogenes previously reported for patients with HCC.We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells.RESULTS We discovered that a gene cluster including five FABP family members(FABP4,FABP5,FABP8,FABP9 and FABP12)is frequently co-amplified in cancer.Amplification,in fact,is the most common genetic alteration for FABPs,leading to overexpression of FABPs.FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues.High FABP5 expression correlates well with worse patient outcomes(P<0.05).FABP5 expression highly correlates with enrichment of G2M checkpoint(r=0.33,P=1.1e-10),TP53 signaling pathway(r=0.22,P=1.7e-5)and many genes in the gene sets such as CDK1(r=0.56,P=0),CDK4(r=0.49,P=0),and TP53(r=0.22,P=1.6e-5).Furthermore,FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients(r=0.58,P=0;r=0.58,P=0;respectively).FABP5high Huh7 cells also expressed higher protein levels of p53,BIRC5,CDK1,CDK2,and CDK4 than FABP5low HepG2 cells.FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells.CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer,especially in HCC,leading to its significant elevated expression in HCC.Its high expression correlates well with worse patient outcome,enriched cancer hallmarks and oncogenes in HCC.FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells.All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.
基金supported by the National Natural Science Founda-tion of China,No.82072217,81772135the Jiangsu Natural Science Foundation,No.BK20201178。
文摘Background:Burn shock caused by vascular leakage is one of the main causes of high mortality in severe burn injury.However,the pathophysiological mechanism of vascular leakage is still unclear.The purpose of this study was to explore the molecular mechanism of vascular leakage in the early stage of severe burn and provide a new target for the treatment of severe burns.Methods:Neutrophils were isolated from human peripheral blood by magnetic beads sorting.ELISA was used to detect neutrophil-derived granule proteins and glycocalyx injury products in plasma.The vascular leakage and neutrophil movement were assessed by in vivo laser confocal imaging in mice,and high-quality video were provided.Adhesion-related molecules were investigated by qRT-PCR.The damage to glycocalyx of mice vascular endothelial cellswas observed by transmission electron microscope and scanning electron microscope.Proteomic analysis,flow cytometry and immunofluorescence were used to further study the relationship between human peripheral blood neutrophil-derived hypochlorite(HOCl)and CD44 of human vascular endothelial cells.Results:In this study,we found that rapidly increasing activated neutrophils secrete heparin binding protein(HBP)andmyeloperoxidase(MPO)after severe burn injury.Increased HBP triggers vascular leakage with synergy of MPO,results in systemic edema and burn shock.Furthermore,we found that the MPO catalytic product HOCl but not MPO triggers CD44 extracellular domain shedding from vascular endothelial cells to damage the glycocalyx.Damage to the glycocalyx results in firm adhesion of neutrophils and increases vascular leakage.However,MPO inhibitors partially protect the glycocalyx of vascular endothelial cells.The combination of HBP and MPO inhibitors markedly reduces vascular leakage and systemic edema in the early stage of severe burns.Conclusions:Taken together,these data reveal that neutrophil-derived HBP and MPO play an important synergies role in triggering vascular leakage at the early stage of severe burns.Targeted intervention in these two biomolecules may introduce new strategies for helping to reduce large amount of fluid loss and subsequent burn shock.
基金supported by the National Natural Science Foundation of China,Nos.82101455(to RYY),31872773(to GC),82001168(to JYP)the Key Research and Development Program(Social Development)of Jiangsu Province,No.BE2020667(to GC)+3 种基金the Foundation of Jiangsu Province,333 Project High-level Talents",No.BRA2020076(to GC)the Nantong Civic Science and Technology Project of China,No.JC2020028(to RYY)the Natural Science Research of Jiangsu Higher Education Institutions of China,No.19KJB310012(to RYY)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘After spinal cord injury(SCI),a fibroblast-and microglia-mediated fibrotic scar is formed in the lesion core,and a glial scar is formed around the fibrotic scar as a res ult of the activation and proliferation of astrocytes.Simultaneously,a large number of neuro ns are lost in the injured area.Regulating the dense glial scar and re plenishing neurons in the injured area are essential for SCI repair.Polypyrimidine tra ct binding protein(PTB),known as an RNA-binding protein,plays a key role in neurogenesis.Here,we utilized short hairpin RNAs(shRNAs)and antisense oligonucleotides(ASOs)to knock down PTB expression.We found that reactive spinal astrocytes from mice were directly reprogrammed into motoneuron-like cells by PTB downregulation in vitro.In a mouse model of compressioninduced SCI,adeno-associated viral shRNA-mediated PTB knockdown replenished motoneuron-like cells around the injured area.Basso Mouse Scale scores and forced swim,inclined plate,cold allodynia,and hot plate tests showed that PTB knockdown promoted motor function recovery in mice but did not improve sensory perception after SCI.Furthermore,ASO-mediated PTB knockdown improved motor function resto ration by not only replenishing motoneuron-like cells around the injured area but also by modestly reducing the density of the glial scar without disrupting its overall structure.Together,these findings suggest that PTB knockdown may be a promising therapeutic strategy to promote motor function recovery during spinal cord repair.
基金the National Natural Science Foundation of China,Nos.32070725(to ML),82001295(to RHW),31970412(to YL)the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions。
文摘Fidgetin,a microtubule-severing enzyme,regulates neurite outgrowth,axonal regeneration,and cell migration by trimming off the labile domain of microtubule polymers.Because maintenance of the microtubule labile domain is essential for axon initiation,elongation,and navigation,it is of interest to determine whether augmenting the microtubule labile domain via depletion of fidgetin serves as a therapeutic approach to promote axonal regrowth in spinal cord injury.In this study,we constructed rat models of spinal cord injury and sciatic nerve injury.Compared with spinal cord injury,we found that expression level of tyrosinated microtubules in the labile portion of microtubules continuously increased,whereas fidgetin decreased after peripheral nerve injury.Depletion of fidgetin enhanced axon regeneration after spinal cord injury,whereas expression level of end binding protein 3(EB3)markedly increased.Next,we performed RNA interference to knockdown EB3 or fidgetin.We found that deletion of EB3 did not change fidgetin expression.Conversely,deletion of fidgetin markedly increased expression of tyrosinated microtubules and EB3.Deletion of fidgetin increased the amount of EB3 at the end of neurites and thereby increased the level of tyrosinated microtubules.Finally,we deleted EB3 and overexpressed fidgetin.We found that fidgetin trimmed tyrosinated tubulins by interacting with EB3.When fidgetin was deleted,the labile portion of microtubules was elongated,and as a result the length of axons and number of axon branches were increased.These findings suggest that fidgetin can be used as a novel therapeutic target to promote axonal regeneration after spinal cord injury.Furthermore,they reveal an innovative mechanism by which fidgetin preferentially severs labile microtubules.
文摘Hydrophobic Val derivative Schiff base copper(II) complexes and dipeptide (AlaAla, GlyGly) derivative Schiff base copper(II) complexes were introduced into egg white lysozyme. X-ray crystal structure analysis revealed amino acid derivative Schiff base copper(II) complexes were obtained. Herein we discuss primarily on the binding mode of copper(II) of the complexes obtained with egg white lysozyme. The electron density of copper(II) ions was confirmed by X-ray crystal structure analysis. The Val derivative Schiff base copper(II) complex was weakly bound at Arg114 of egg white lysozyme. In other copper(II) complexes, binding of copper(II) ions with dissociated ligands to various residues was observed. The binding sites of copper(II) ions were compared with computational scientific predictions.
文摘This present study investigated the ability of various soy protein hydrolysates(SPHs)in binding calcium.It was demonstrated that the amount of Ca-bound depended greatly on the SPHs obtained using different proteases,which included:neutrase, flavourzyme,protease M and pepsin.The maximum level of Ca-bound(66.9 mg/g)occurred when protease M was used to hydrolyze soy protein.Peptide fragments exhibiting high Ca-binding capacity had molecular weights of either 14.4 or 8-9 kDa.The level of Ca-bound increased linearly with the increment of carboxyl content in SPHs,and further deamidation on SPHs from protease M improved Ca-binding of the hydrolysate.
基金supported by grants from National Natural Science Foundation of China(81670559)Key Research and Development Project of Shanxi Province(201603D421023)+2 种基金Youth Fund of Shanxi Medical University(02201514)Graduate Student Education Innovation Project of Shanxi(2016BY077)Youth Fund of Ap-plied Basic Research Program of Shanxi(201701D221175)
文摘Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.
基金supported by grants from Project of Zhejiang Education Department(Y201430659)Zhejiang Provincial Natural Science Foundation of China(LQ18H160011)
文摘Background: Retinoblastoma binding protein 4 (RBBP4) plays an essential role in the development of multiple cancers. However, its relationship with prognosis in colon cancer and colon cancer hepatic metastasis has not been elucidated. The aim of this study was to explore the relationship between RBBP4 expression and prognosis of colon cancer patients and to evaluate RBBP4 as a new prognostic marker in these patients. Methods: Eighty colon cancer patients underwent surgical resection of the colon were enrolled. Among them, forty colon cancer patients suffered with hepatic metastasis. The colon cancer tissues, para-colon cancer tissues, and hepatic metastatic cancer tissues were collected from the pathological department for further analysis. The expression of RBBP4 proteins was examined by immunohistochemistry and correlated with clinicopathological parameters. The Cancer Genome Atlas (TCGA) database was used to validate the expression and explore its relationship with clinical characteristics. Results: RBBP4 was up-regulated in the colon cancer tissues compared with the para-colon cancer tissues. The analysis of TCGA database verified the upregulation of RBBP4 in the colon cancer tissues and RBBP4 overexpression was correlated with nerve invasion and poor outcomes of chemotherapy. Moreover, the positive rate of RBBP4 expression in 40 colon cancer patients with hepatic metastasis was higher in the hepatic metastatic cancer tissues (39/40, 97.5%) than in the colon cancer tissues (26/40, 65.0%). Our clinicopathological analysis showed that RBBP4 expression was significantly correlated with vascular invasion, hepatic metastasis, and lymph node involvement (all P < 0.05). Additionally, the survival analysis demonstrated that RBBP4 over-expression was correlated with poor prognosis. Conclusions: RBBP4 was upregulated in the colon cancer. RBBP4 may be a novel predictor for poor prognosis of colon cancer and colon cancer hepatic metastasis.
基金Supported by the Basic Research Program of the Korea Science & Engineering Foundation (No. 2009-0068732)the Basic Research Program of the National Research Foundation of Korea (No.2011-0020163)+1 种基金the Bio-Industry Technology Development Program funded by the Korea Institute of Planning & Evaluation for Technology in Food, Agriculture Forestry & Fisheries (No.112005-3)the BK21 Program and by the MRC program of KRF (R13-2005-012-01001-1)
文摘AIM: To study the contribution of tonicity response element binding protein(Ton EBP) in retinal ganglion cell(RGC) death of diabetic retinopathy(DR).METHODS: Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin(STZ). Control mice received vehicle(phosphate-buffered saline). All mice were killed 2mo after injections, and the extent of cell death and the protein expression levels of Ton EBP and aldose reductase(AR) were examined.RESULTS: The Ton EBP and AR protein levels and the death of RGC were significantly increased in the retinas of diabetic mice compared with controls 2mo after the induction of diabetes. Terminal deoxynucleotidyl transferase(Td T)-mediated d UTP nick end labeling(TUNEL)-positive signals co-localized with Ton EBP immunoreactive RGC. These changes were increased in the diabetic retinas compared with controls.CONCLUSION: The present data show that AR and Ton EBP are upregulated in the DR and Ton EBP may contribute to apoptosis of RGC in the DR.
基金Supported by The National Center for Advancing Translational Sciences of the National Institutes of Health under award numbers ULl TR000454 previously awarded to Dr.Colbert and Dr.Fisher and TLlT R000456 to Dr.ColbertPancreatic Cancer Action Network(Pan-CAN)&sol American Association for Cancer Research(AACR)award 16982+1 种基金Department of Defense(DOD)/Peer Reviewed Cancer Research Program(PRCRP)award CA110535Georgia Cancer Coalition award 11072,all to Dr.Yu
文摘Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomainhelicase-DNA binding protein 5, chromodomain-helicaseDNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation,and should be validated in future studies.
基金supported by National Major Projects of Ministry Science and Technology of China(2011CB710800,2012ZX09506001-004)Zhejiang Education Department(Y200909571)
文摘The stereoselective hydrolysis of esmolol in whole blood and in its separated components from rat,rabbit and human was investigated.Blood esterase activities were variable in different species in the order of rat>rabbit>human.Rat plasma showed the high esterase activity and had no stereoselectivity to enantiomers.Rabbit red blood cell(RBC) membrane,RBC cytosol and plasma all hydrolyzed esmolol but with different esterase activity,whereas the hydrolysis in RBC membrane and cytosol showed significant stereoselectivity towards R-(+)-esmolol.Esterase in RBC cytosol from human blood mainly contributed to the esmolol hydrolysis,which was demonstrated with no stereoselctivity.Esterase in human plasma showed a low activity,but a remarkable stereoselectivity with R-(+)-esmolol.In addition,the protein concentration affected the hydrolysis behavior of esmolol in RBC suspension.Protein binding of esmolol enantiomers in human plasma,human serum albumin(HSA) and α_1-acid glycoprotein(AGP) revealed that there was a significant difference in bound fractions between two enantiomers,especially for AGP.Our results indicated that the stereoselective protein binding might play a role in the different hydrolysis rates of esmolol enantiomers in human plasma.
基金supported by a grant from the Shanxi Province Foundation for Returness(2012-4)
文摘BACKGROUND:We previously showed that insulin-like growth factor binding protein-related protein 1(IGFBPrP1) is a novel mediator in liver fibrosis.Transforming growth factor beta 1(TGFβ1) is known as the strongest effector of liver fibrosis.Therefore,we aimed to investigate the detailed interaction between IGFBPrP1 and TGFβ1 in primary hepatic stellate cells(HSCs).METHODS:We overexpressed TGFβ1 or IGFBPrP1 and inhibited TGFβ1 expression in primary HSCs for 6,12,24,48,72,and 96 hours to investigate their interaction and observe the accompanying expressions of α-smooth muscle actin(α-SMA),collagen I,fibronectin,and phosphorylated-mothers against decapentaplegic homolog 2/3(p-Smad2/3).RESULTS:We found that the adenovirus vector encoding the TGFβ1 gene(Ad TGFβ1) induced IGFBPrP1 expression while that of α-SMA,collagen I,fibronectin,and TGFβ1 increased gradually.Concomitantly,Ad IGFBPrP1 upregulated TGFβ1,α-SMA,collagen I,fibronectin,and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours.Inhibition of TGFβ1 expression reduced the IGFBPrP1-stimulated expression of α-SMA,collagen I,fibronectin,and p-Smad2/3.CONCLUSIONS:These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGFβ1,which likely accelerates liver fibrosis progression.Furthermore,IGFBPrP1 likely participates in liver fibrosis in a TGFβ1-depedent manner,and may act as an upstream regulatory factor of TGFβ1 in the Smad pathway.
文摘BACKGROUND Liver cirrhosis is a major risk factor for hepatocellular carcinoma(HCC)development in chronic hepatitis B(CHB). Serum Mac-2 binding protein glycosylation isomer(M2 BPGi) is a novel serological marker for fibrosis. The role of M2 BPGi in prediction of HCC is unknown.AIM To examine the role of serum M2 BPGi in predicting HCC development in hepatitis B e antigen(HBeAg)-negative patients.METHODS Treatment-naive CHB patients with documented spontaneous HBeAg seroconversion were recruited. Serum M2 BPGi was measured at baseline(within3 years from HBeAg seroconversion), at 5 years and 10 years after HBeAg seroconversion and expressed as cut-off index(COI). Multivariate cox regression was performed to identify predictors for HCC development. ROC analysis was used to determine the cut-off value of M2 BPGi.RESULTS Among 207 patients(57% male, median age at HBeAg seroconversion 40 years old) with median follow-up of 13.1(11.8-15.5) years, the cumulative incidence of HCC at 15 years was 7%. Median M2 BPGi levels were significantly higher in patients with HCC compared to those without HCC(baseline: 1.39 COI vs 0.38 COI, P < 0.001; 5-year: 1.45 COI vs 0.47 COI, P < 0.001; 10-year: 1.20 COI vs 0.55 COI, P = 0.001). Multivariate analysis revealed age at HBeAg seroconversion[odds ratio(OR) = 1.196, 95% confidence interval(CI): 1.034-1.382, P = 0.016] and baseline M2 BPGi(OR = 4.666, 95%CI: 1.296-16.802, P = 0.018) were significant factors predictive of HCC. Using a cut-off value of 0.68 COI, baseline M2 BPGi yielded AUROC of 0.883 with 91.7% sensitivity and 80.8% specificity.CONCLUSION High serum M2 BPGi within 3 years after HBeAg seroconversion was a strong predictor for subsequent HCC development in treatment-naive HBeAg-negative CHB patients.
基金Supported by National Natural Science Foundation of China,No.81770601,No.81702324,and No.81602529Natural Science Foundation of Hebei Province,No.H2018206176 and No.H2017206141Post-graduate’s Innovation Fund Project of Hebei Province,No.CXZZBS2019121.
文摘BACKGROUND Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma(HCC).Y-box binding protein 1(YB-1)is closely correlated with tumors and drug resistance.However,the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.AIM To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.METHODS The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues.Next,we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib.Then,we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling,flow cytometry and Western blotting assays.We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo.Moreover,we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing(DGE-seq).RESULTS YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues.YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis.Consistently,the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down.Furthermore,KEGG pathway enrichment analysis of DGEseq demonstrated that the phosphoinositide-3-kinase(PI3K)/protein kinase B(Akt)signaling pathway was essential for the sorafenib resistance induced by YB-1.Subsequently,YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway(Akt1 and PIK3R1)as shown by searching the BioGRID and HitPredict websites.Finally,YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib,and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.CONCLUSION Overall,we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene,which is of great significance for the application of sorafenib in advanced-stage HCC.
基金Supported by National Natural Science Foundation of China,No.81800713 and No.81971264The Project of Natural Science Foundation of Anhui Province,No.1808085QH292Fundamental Research Funds for the Central Universities,No.WK9110000041。
文摘BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occurrence and development of diabetic atheroscerosis have not been fully elucidated.AIM To summarize the potential role of retinol binding protein 4(RBP4) in the pathogenesis of diabetic atheroscerosis,particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.METHODS Male Wistar rats were randomly divided into three groups,including a control group(NC group),diabetic rat group(DM group),and diabetic atherosclerotic rat group(DA group).The contents of total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), triglycerides(TG), low-density lipoprotein cholesterol(LDLc), fasting insulin(FINS),fasting plasma glucose,and hemoglobin A1 c(HbA1 c)were measured.Moreover,the adipose and serum levels of RBP4,along with the expression levels of JAK2, phosphorylated JAK2(p-JAK2), STAT3,phosphorylated STAT3(p-STAT3), B-cell lymphoma-2(Bcl-2), and Cyclin D1 in aortic tissues were also measured.Besides,homeostasis model assessment of insulin resistance(HOMA-IR) and atherogenic indexes(AI) were calculated.RESULTS Compared with the NC and DM groups,the levels LDL-c,TG,TC,FINS,HOMAIR,RBP4,and AI were upregulated,whereas that of HDL-c was downregulated in the DA group(P <0.05);the mRNA levels of JAK2,STAT3,Cyclin D1,and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group;P-JAK2,p-JAK2/JAK2 ratio,p-STAT3,p-STAT3/STAT3 ratio,Cyclin D1,and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group.In addition,as shown by Pearson analysis,serum RBP4 had a positive correlation with TG,TC,LDL-c,FINS,HbA1 C,p-JAK2,p-STAT3,Bcl-2,Cyclin D1,AI,and HOMA-IR but a negative correlation with HDL-c.In addition,multivariable logistic regression analysis showed that serum RBP4,p-JAK2,p-STAT3,and LDL-c were predictors of the presence of diabetic atherosclerosis.CONCLUSION RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.
文摘The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.
基金supported by the National Basic Research Program of China(2012CB114104)the National Natural Science Foundation of China(30871640,31071694)+1 种基金the National High-Tech R&D Program of China(2008AA02Z307)the International Cooperation and Exchange Foundation of NSFC-RS of China(31111130203).
文摘The full-length sequence of the odorant binding protein 5 gene,HarmOBP5,was obtained from an antennae cDNA library of cotton bollworm,Helicoverpa armigera (Hübner).The cDNA contains a 444 bp open reading frame,encoding a protein with 147 amino acids,namely HarmOBP5.HarmOBP5 was expressed in Escherichia coli and the recombinant protein was purified by affinity chromatography.SDS-PAGE and Western blot analysis demonstrated that the purified protein can be used for further investigation of its binding characteristics.Competitive binding assays with 113 odorant chemicals indicated that HarmOBP5 has strong affinity to some special plant volatiles,including (E)-β-farnesene,ethyl butyrate,ethyl heptanoate,and acetic acid 2-methylbutyl ester.Based on three-dimensional (3D) model of AaegOBP1 from Aedes aegypti,a 3D model of HarmOBP5 was predicted.The model revealed that some key binding residues in HarmOBP5 may play important roles in odorant perception of H.armigera.This study provides clues for better understanding physiological functions of OBPs in H.armigera and other insects.
文摘AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.
基金supported by a grant from the Heart and Stroke Foundation of Canada(HHC,AFRS)a grant from the Natural Science&Engineering Research Council of Canada(HHC,AFRS)a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario,Canada(HHC)
文摘Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused synapses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.
文摘Heart fatty acid-binding protein (H-FABP) is supposed to be the most sensitive biomarker of early acute myocardial infarction (AMI). To evaluate the diagnostic value of H-FABP for AMI in the early stage, the plasma levels of H-FABP were measured by sandwich ELISA in 93 patients with suspected AMI at admission within 6 h after onset of chest pain and 69 normal healthy subjects. The plasma concentrations of cardiac troponin-I (cTnI), creatine kinase-MB (CK-MB) and myoglobin (Mb) were assayed at the same time by using corpuscle chemiluminescence for those patients. The patients were classified as AMI group (n=32) and non-AMI group (n=61) retrospectively. The diagnostic validity was evaluated in terms of sensitivity, specificity and receiver operating characteristic (ROC) curve analysis. The results showed the cutoff value of H-FABP for AMI was 16.8 ng/ml, and its diagnostic sensitivity for AMI was 64.29 % within 3 h and 84.38 % within 6 h after onset of chest pain, and the diagnostic specificity for non-AMI was 100 % within 3 h and 91.8 % within 6 h. H-FABP had higher sensitivity than that of cTnI and CK-MB at all time points (P<0.05), whereas there was no significant difference in specificity among the four markers. But the area under the ROC curve of H-FABP was significantly greater than that of cTnI, CK-MB and Mb within 3 h. These results revealed that H-FABP possessed high diagnostic sensitivity and specificity for AMI in early stage, especially within 3 h after onset of persistent angina pectoris. In conclusion, H-FABP can be used as a sensitive marker for AMI in the early stage.
