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
Background Post-weaning diarrhea(PWD)in piglets,often caused by F4^(+)enterotoxigenic Escherichia coli(ETEC),poses significant challenges in pig production.Traditional solutions like antibiotics and zinc oxide face in...Background Post-weaning diarrhea(PWD)in piglets,often caused by F4^(+)enterotoxigenic Escherichia coli(ETEC),poses significant challenges in pig production.Traditional solutions like antibiotics and zinc oxide face increasing restrictions due to growing concerns over antibiotic resistance and environmental sustainability.This study investigates the application of bivalent heavy chain variable domain(V_(H)H)constructs(BL1.2 and BL2.2)targeting ETEC virulence factors,administered in feed to mitigate ETEC-induced PWD in weaned piglets.Results The supplementation of BL1.2 and BL2.2 in both mash and pelleted feed significantly reduced the diarrhea incidence and fecal shedding of F4^(+)ETEC in challenged piglets.Pelleted feed containing V_(H)H constructs helped to preserve gut barrier integrity by maintaining levels of the tight junction protein occludin in the small intestine.Additionally,the constructs maintained blood granulocyte counts at a similar level to the non-challenged control group,including neutrophils,and ameliorated the acute phase protein response after challenge.Notably,even at low feed intake immediately after weaning,V_(H)H constructs helped maintain piglet health by mitigating ETEC-induced inflammation and the resulting diarrhea.Conclusions Our findings demonstrated that using V_(H)H constructs as feed additives could serve as an effective strategy to help manage ETEC-associated PWD,by reducing F4^(+)ETEC gut colonization and supporting gut barrier function of weaned piglets.The high stability of these V_(H)H constructs supports their incorporation into industrial feed manufacturing processes,offering a more sustainable preventive strategy compared to traditional antimicrobial interventions,which could contribute to sustainable farming practices.展开更多
Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
Host-derived small RNAs are emerging as critical regulators in the dynamic interactions between host tissues and the microbiome,with implications for microbial pathogenesis and host defense.Among these,transfer RNA-de...Host-derived small RNAs are emerging as critical regulators in the dynamic interactions between host tissues and the microbiome,with implications for microbial pathogenesis and host defense.Among these,transfer RNA-derived small RNAs(tsRNAs)have garnered attention for their roles in modulating microbial behavior.However,the bacterial factors mediating tsRNA interaction and functionality remain poorly understood.In this study,using RNA affinity pull-down assay in combination with mass spectrometry,we identified a putative membrane-bound protein,annotated as P-type ATPase transporter(PtaT)in Fusobacterium nucleatum(Fn),which binds Fn-targeting tsRNAs in a sequence-specific manner.Through targeted mutagenesis and phenotypic characterization,we showed that in both the Fn type strain and a clinical tumor isolate,deletion of ptaT led to reduced tsRNA intake and enhanced resistance to tsRNA-induced growth inhibition.Global RNA sequencing and label-free Raman spectroscopy revealed the phenotypic differences between Fn wild type and PtaT-deficient mutant,highlighting the functional significance of PtaT in purine and pyrimidine metabolism.Furthermore,AlphaFold 3 prediction provides evidence supporting the specific binding between PtaT and Fn-targeting tsRNA.By uncovering the first RNA-binding protein in Fn implicated in growth modulation through interactions with host-derived small RNAs(sRNAs),our study offers new insights into sRNA-mediated host-pathogen interplay within the context of microbiome-host interactions.展开更多
BACKGROUND The Mac-2 binding protein glycosylated isomer(M2BPGi)is a serum marker for fibrosis that correlates with the fibrosis stages in various liver diseases.AIM To examine the M2BPGi’s threshold for staging fibr...BACKGROUND The Mac-2 binding protein glycosylated isomer(M2BPGi)is a serum marker for fibrosis that correlates with the fibrosis stages in various liver diseases.AIM To examine the M2BPGi’s threshold for staging fibrosis in patients with chronic hepatitis B(CHB),and its changes during treatment.METHODS This was a prospective,longitudinal study.A total of 348 eligible patients were recruited from the Hepatology Department,Medic Medical Center between March 2020 and December 2023.Liver enzyme tests,platelet counts,M2BPGi levels,and FibroScan were conducted at baseline and at 3-month intervals until six months post-treatment.Correlation plots of M2BPGi,FibroScan,and the other parameters were generated.Receiver operating characteristic curves were constructed for M2BPGi and the other parameters to evaluate their performance.RESULTS M2BPGi levels correlated well with FibroScan results and increased as the fibrosis stage advanced.The median M2BPGi levels at the different stages of fibrosis showed statistically significant differences.The cut-off values of M2BPGi for diagnosing significant fibrosis(F≥2),advanced fibrosis(F3),and cirrhosis(F4)were determined to be 1.08,1.4,and 1.52,respectively.In the context of fibrosis regression in CHB patients during the first 6-month of treatment,M2BPGi levels appeared to decrease before this pattern occurred in the FibroScan results.CONCLUSION M2BPGi levels were strongly correlated with FibroScan.M2BPGi can be used to assess liver fibrosis,and to serve as a tool for monitoring fibrosis regression in CHB patients undergoing treatment.展开更多
BACKGROUND Cirrhosis is a progressive condition characterized by fibrosis that can lead to severe complications and increased mortality.The mac-2 binding protein glyco-sylation isomer(M2BPGi)is a prominent biomarker f...BACKGROUND Cirrhosis is a progressive condition characterized by fibrosis that can lead to severe complications and increased mortality.The mac-2 binding protein glyco-sylation isomer(M2BPGi)is a prominent biomarker for predicting hepatocellular carcinoma(HCC)and cirrhosis-induced esophageal varices(EV).AIM To investigate thresholds of M2BPGi associated with HCC,EV,and decomp-ensation in patients with cirrhosis.METHODS This was a prospective study.A total of 153 patients with cirrhosis who met the inclusion criteria were enrolled.The patients were diagnosed with HCC and EV according to the Baveno VII and European Association for the Study of the Liver guidelines.Baseline serum M2BPGi levels were assessed along with other routine tests.The data analysis aimed to determine the cutoff values of M2BPGi for pre-dicting EV and HCC.RESULTS In the study 85.6%of patients were Child-Pugh B and C.M2BPGi mean cutoff index was 7.1±3.7,showing no significant etiological differences.However,M2BPGi levels varied significantly among Child-Pugh classes,EV classifications,and between patients with and without HCC(P<0.01).M2BPGi cutoff values for predicting HCC,EV,and decompensated cirrhosis were 6.50,6.64,and 5.25,respectively.Mul-tivariate analysis confirmed M2BPGi as an independent risk factor for EV[adjusted odds ratio(aOR):1.3,95%CI:1.08-1.64]and liver decompensation(aOR:2.11,95%CI:1.37-3.83).Area under the curve of M2BPGi for HCC differ-entiation was 0.71.An algorithm combining alpha-fetoprotein(AFP)and M2BPGi detected 26 of 28 HCC cases with 98.04%accuracy vs 10 cases by AFP alone.CONCLUSION Serum M2BPGi predicted cirrhosis complications,including decompensation and varices,especially in HCC.Combined with AFP,it enhanced HCC detection.Future liver biopsy studies are needed for tissue confirmation.展开更多
BACKGROUND Mac-2 binding protein glycosylation isomer(M2BPGi)serves as a marker of activated hepatic stellate cells and as such holds potential as a biomarker for liver fibrosis.In Viet Nam,metabolic dysfunction-assoc...BACKGROUND Mac-2 binding protein glycosylation isomer(M2BPGi)serves as a marker of activated hepatic stellate cells and as such holds potential as a biomarker for liver fibrosis.In Viet Nam,metabolic dysfunction-associated steatotic liver disease(MASLD)is rising in prevalence and there is an urgent need for better clinical management,particularly in early detection methods that will improve overall prognosis.AIM To examine M2BPGi cut-off values for staging liver fibrosis in patients with MASLD and risk factors associated with disease progression.METHODS A total of 301 individuals with ultrasound-confirmed or FibroScan-confirmed diagnosis of fatty liver were enrolled in the study.The participants were stratified according to fibrosis stage,measured via magnetic resonance elastography.M2-BPGi,Fibrosis-4(FIB-4)Index score,and routine parameters of liver function were assessed to statistically investigate the correlation of M2BPGi levels in various fibrosis stages and to identify risk factors associated with fibrosis severity.RESULTS M2BPGi levels positively correlated with fibrosis stages,with cut-off indexes of 0.57 for F0-1,0.68 for F2-3,and 0.78 for F4.M2BPGi levels in the F0-1 group were significantly different from those in both the F2-3 group(P=0.038)and the F4 group(P=0.0051);the F2-3 and F4 groups did not show a significant difference(P=0.39).Females exhibited significantly higher M2BPGi levels than males for all fibrosis stages,particularly in the F2-3 group(P=0.01)and F4 group(P=0.0006).In the F4(cirrhosis)group,individuals with diabetes had significantly higher M2BPGi levels than those without.M2BPGi,hemoglobin A1c,and FIB-4 score were identified as independent risk factors for greater fibrosis and cirrhosis.CONCLUSION M2BPGi levels varied significantly throughout fibrosis progression,from early MASLD to cirrhosis,with sex correlation.M2BPGi holds promise as an early biomarker for fibrosis characterization in MASLD adult patient populations.展开更多
[Objective] The research aimed to find the extracellular binding proteins of CR4.[Method] The extracellular domain of OsCR4 was as the bait protein,and the yeast two-hybrid was used to screen cDNA library of seedling ...[Objective] The research aimed to find the extracellular binding proteins of CR4.[Method] The extracellular domain of OsCR4 was as the bait protein,and the yeast two-hybrid was used to screen cDNA library of seedling which was cultivated 14 d.[Result] A lot of proteins which included a peroxide B（D26484）,a methionine thioredoxin reductase（ABF96078）and an unknown function protein were gained.[Conclusion] It provided the theory basis for studying the signal transduction mechanism of CR4.展开更多
OBJECTIVE: To study the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) levels in differential diagnosis of growth hormone deficiency (GHD). METHODS: To measure serum IGFBP-3 levels by RIA in nor...OBJECTIVE: To study the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) levels in differential diagnosis of growth hormone deficiency (GHD). METHODS: To measure serum IGFBP-3 levels by RIA in normal children and adolescents, GHD children and short-stature children without GHD. RESULTS: Serum level of IGFBP-3 in 129 children with untreated GHD and with no pubertal development was 1.6 +/- 0.9 mg/L, which was less than that in normal group of the same age, but overlapped with the normal children in Tanner stage I. After six-month treatment with recombinant human growth hormone (rhGH), serum level of IGFBP-3 in 59 GHD significantly increased from 1.3 +/- 0.7 mg/L to 2.7 +/- 0.9 mg/L, accompanied by an increase of body heights, growth velocities and serum level of IGF-1. Serum level of IGFBP-3 in 55 short-stature children without GHD was 3.3 +/- 2.2 mg/L, which was not significantly different from that in normal group. CONCLUSION: Serum IGFBP-3 level can reflect the status of GH secretion in children with GHD and is a useful marker for differential diagnosis of GHD.展开更多
BACKGROUND The Mac-2 binding protein glycosylation isomer(M2BPGi),a fibrosis marker in various liver diseases,is reportedly a prognostic marker in patients with hepatocellular carcinoma(HCC)who underwent hepatectomy.A...BACKGROUND The Mac-2 binding protein glycosylation isomer(M2BPGi),a fibrosis marker in various liver diseases,is reportedly a prognostic marker in patients with hepatocellular carcinoma(HCC)who underwent hepatectomy.AIM To evaluate whether the M2BPGi value,M2BP,and pre-sarcopenia before radiofrequency ablation(RFA)could be useful recurrence and prognostic markers in patients with early-stage HCC.METHODS In total,160 patients with early-stage primary HCC treated with RFA were separately analyzed as hepatitis C virus(HCV)-positive and HCV-negative.Factors contributing to recurrence and liver-related death,including M2BP,M2BPGi,and skeletal muscle mass index,were statistically analyzed.Eighty-three patients were HCV-positive and 77 were HCV-negative.RESULTS In HCV-positive patients,only des-γ-carboxy-prothrombin≥23 mAU/mL was a significant poor prognostic factor affecting survival after RFA.In HCV-negative patients,M2BPGi≥1.86 cutoff index was significantly associated with tumor recurrence,while M2BP was not.M2BPGi≥1.86 cutoff index(hazard ratio,4.89;95%confidence interval:1.97-12.18;P<0.001)and pre-sarcopenia(hazard ratio,3.34,95%confidence interval:1.19-9.37;P=0.022)were independent significant poor prognostic factors in HCV-negative patients.CONCLUSION In HCV-negative patients with primary HCC treated with RFA,lower M2BPGi contributed to a lower tumor recurrence rate and longer survival period.Pre-sarcopenia contributed to the poor prognosis independently in HCV-negative patients.These factors might be useful recurrence and prognostic markers for early-stage primary HCC.展开更多
Cysteine residues found in proteins have various functions such as metal binding, nitrosylation, and stabilization of structure. We have done a comparative, computational structural analysis of the cysteine residues i...Cysteine residues found in proteins have various functions such as metal binding, nitrosylation, and stabilization of structure. We have done a comparative, computational structural analysis of the cysteine residues in two proteins from bacteria to get some insight into the differences between metal binding cysteine residues and those involved in structure stabilization. The two target proteins in this study are the periplasmic mercury binding protein （MerP） and the 1-1eucine binding protein （LBP）. Both are periplasmic binding proteins from E. coli. We have shown key phenomenon that define cysteines as metal binding or structural in nature.展开更多
The association of retinol binding protein 4 （RBP4） with atherosclerosis of the carotid artery in type 2 diabetes mellitus （T2DM） remains undefined. We aimed to investigate the correlation of RBP4 expression with ...The association of retinol binding protein 4 （RBP4） with atherosclerosis of the carotid artery in type 2 diabetes mellitus （T2DM） remains undefined. We aimed to investigate the correlation of RBP4 expression with atherosclerosis of the carotid artery in T2DM. A total of 1,076 subjects were investigated for intima-media thickness of the bilateral common carotid arteries, and they were divided into three groups： in group Ⅰ, patients had normal neck vascular ultra- sound, in group Ⅱ, intimal carotid artery media thickness was equal to or more than 1 mm, and in group Ⅲ, carotid artery plaque was present. Height, weight, blood pressure （BP）, fasting plasma glucose （FPG）, hemoglobin Alc （HbA1c）, total cholesterol （TC）, triglyceride （TG）, low-density lipoprotein cholesterol （LDL-C）, high-density lipopro- tein cholesterol （HDL-C）, apolipoprotein A-1 （apoA-1）, apolipoprotein B （apoB） and lipoprotein （a） [Lp（a）] were determined by routine laboratory methods. RBP4 and high sensitivity C reactive protein （HsCRP） were measured by an enzyme-linked immuno-sorbent assay, and insulin concentration was measured by an electrochemiluminescence sandwich immunoassay. Duration of diabetes, waist and BP, FPG, HbAlc, TG, TC, LDL-C, APOB, Lp（a）, HsCRP, RBP4 and homeostasis model assessment insulin resistance index （HOMA-IR） were significantly lower in group I than in the other two groups （P〈0.01, P〈0.01）. Plasma levels of HbAlc, RBP4, LDL-C, TC, HOMA-IR, HsCRP and Lp（a）, waist and BP were significantly increased in group III than in group II （P〈0.01）. Multivariate logistic regression analysis showed that there were seven factors associated with the occurrence of carotid artery atherosclero- sis and its risks in descending order were： high LDL-C, high waist, high HsCRP, duration of diabetes, high HOMA-IR, HbAlc and high RBP4. Our finding supported that RBP4 was positively correlated with carotid atherosclerosis in patients with T2DM and could be used as an early predictor of cardiovascular 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,...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
Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactiv...Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactive transcription despite heavy translational requirements for continued growth and differentiation. Hence, spermatogenesis is highly reliant on mechanisms of posttranscriptional regulation of gene expression, facilitated by RNA binding proteins （RBPs）, which remain abundantly expressed throughout this process. One such group of proteins is the Musashi family, previously identified as critical regulators of testis germ cell development and meiosis in Drosophila, and also shown to be vital to sperm development and reproductive potential in the mouse. This review describes the role and function of RBPs our recent knowledge of the Musashi proteins in spermatogenesis. within the scope of male germ cell development, focusing on The functional mechanisms utilized by RBPs within the cell are outlined in depth, and the significance of sub-cellular localization and stage-specific expression in relation to the mode and impact of posttranscriptional regulation is also highlighted. We emphasize the historical role of the Musashi family of RBPs in stem cell function and cell fate determination, as originally characterized in Drosophila and Xenopus, and conclude with our current understanding of the differential roles and functions of the mammalian Musashi proteins, Musashi-1 and Musashi-2, with a primary focus on our findings in spermatogenesis. This review highlights both the essential contribution of RBPs to posttranscriptional regulation and the importance of the Musashi family as master regulators of male gamete development.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
To assess the relationship between serum levels of insulin-like growth factor-1(IGF1)/IGF-binding protein-3(IGFBP3)and the risk of esophageal carcinoma.METHODSWe assessed the relationship between the serum levels of t...To assess the relationship between serum levels of insulin-like growth factor-1(IGF1)/IGF-binding protein-3(IGFBP3)and the risk of esophageal carcinoma.METHODSWe assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective,nested case-control study of participants from the Japan Collaborative Cohort Study.A baseline survey was conducted from 1988 to 1990.Of the 110585 enrolled participants,35%donated blood samples.Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies.A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels.RESULTSThirty-one cases and 86 controls were eligible for the present assessment.The molar ratio of IGF1/IGFBP3,which represents the free and active form of IGF1,was not correlated with the risk of esophageal carcinoma.A higher molar difference between IGFBP3 and IGF1,which estimates the free form of IGFBP3,was associated with a decreased risk of esophageal carcinoma(P=0.0146),and people in the highest tertile had the lowest risk(OR=0.107,95%CI:0.017-0.669).After adjustment for body mass index,tobacco use,and alcohol intake,the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma(P=0.0150).CONCLUSIONThe free form of IGFBP3,which is estimated by this molar difference,may be inversely associated with esophageal cancer incidence.展开更多
Background:In sepsis,vitamin D binding protein(VDBP)has been shown to be low-expressed.The current study examined the relationship between serum VDBP level and liver injury in sepsis patients,as well as in a mouse mod...Background:In sepsis,vitamin D binding protein(VDBP)has been shown to be low-expressed.The current study examined the relationship between serum VDBP level and liver injury in sepsis patients,as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide(LPS).Methods:The human study included 78 sepsis patients and 50 healthy volunteers.Sepsis patients were categorized into sepsis survivor group(n=43)and sepsis non-survivor group(n=35)based on 28-day mortality for data analysis.Adult male C57BL/6 mice were subjected to cecal ligation and puncture(CLP).Serum samples were collected on day 1,3,5 and 7 to determine the levels of VDBP,25-hydroxyvitamin D[25(OH)D_(3)],1,25-dihydroxyvitamin D[1,25(OH)_(2)D_(3)],interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α).Potential protective effects of VDBP overexpression against LPS-induced liver damage were examined in cultured THLE2 cells.Results:Serum levels of VDBP,25(OH)D_(3),and 1,25(OH)_(2)D_(3)were significantly lower in sepsis patients vs.the healthy control(P<0.001),as well as in the sepsis non-survivor group vs.the sepsis survivor group(P<0.001,P=0.0338,or P=0.0013,respectively).Lower serum VDBP level was associated with higher Acute Physiology and Chronic Health Evaluation(APACHE)II score(r=−0.2565,P=0.0234)and Sequential Organ Failure Assessment score(r=−0.3522,P=0.0016),but lower serum albumin(ALB,r=0.4628,P<0.001)and total protein(TP,r=0.263,P=0.02).In CLP mice,there was a 5-day period of serum VDBP reduction,followed by return towards the baseline on day 7.VDBP was also decreased in LPS-treated THLE2 cells(P<0.001).VDBP overexpression reduced LPS-induced THLE2 damage.Reduced damage was associated with decreased oxidative stress and inactivation of the c-Jun N-terminal kinase signaling pathway.Conclusion:VDBP may be protective against sepsis-induced liver injury.展开更多
BACKGROUND： Neural stem cell （NSC） survival is closely associated with cell apoptosis in ischemic-hypoxic regions following transplantation. Numerous studies have revealed that X-box binding protein 1 （XBP1） is a...BACKGROUND： Neural stem cell （NSC） survival is closely associated with cell apoptosis in ischemic-hypoxic regions following transplantation. Numerous studies have revealed that X-box binding protein 1 （XBP1） is a transcription factor during endoplasmic reticulum unfolded protein response and is essential for cell survival, differentiation, and anti-apoptotic effects. OBJECTIVE： To determine the effects of the XBP1 gene on NSC proliferation and apoptosis under hypoxic conditions following XBP1 gene transfection into rat embryonic hippocampal NSCs using recombinant adenovirus vector. DESIGN, TIME AND SETTING： In vitro experiments were performed at the Laboratory of Cell Biology of Jilin University and Laboratory of Proteomics, Department of Neurology, Jilin University China from September 2008 to November 2009. MATERIALS： Recombinant adenovirus package XBP1 gene and Ad-XBPl-enhanced green fluorescent protein plasmid （Guangzhou Easywin BioMed Technology, China）, rabbit anti-XBP1 and its target gene estrogen receptor degradation-enhancing a-mannosidase-like protein （EDEM） glucose-regulated protein 78 （GRP78）, anti-apoptotic molecule Bcl-2 and proapoptotic molecule Bax polyclonal antibody （Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA）, and COCI2 （Sigma, St. Louis, MO, USA） were used in the present study. METHODS： Hippocampi from embryonic, Sprague Dawley rats on gestational day 16 were harvested for NSC isolation and cloning, followed by immunofluorescence for Nestin and sub-culturing. The recombinant adenovirus Ad-XBPl-enhanced green fluorescent protein plasmid was transfected into rat embryonic hippocampal NSCs, and then CoCl2 was applied to induce hypoxia. MAIN OUTCOME MEASURES： Cell quantification and 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide colorimetric assay were utilized to detect proliferation in XBPl-transfected NSCs for 7 consecutive days. Western blot assay was utilized to quantify XBP1 GRP78, EDEM, Bcl-2, and Bax expression. Flow cytometry was used to measure apoptosis. RESULTS： NSC proliferation was significantly enhanced following XBP1 gene transfection （P 〈 0.05）. Under hypoxic conditions, GRP78, EDEM, and Bcl-2 levels increased, but Bax levels decreased. In addition, NSC apoptosis decreased following transfection （P 〈 0.05）. CONCLUSION： The XBP1 gene was successfully transfected into rat embryonic hippocampal NSCs using a recombinant adenovirus vector. NSC proliferation following transfection, as well as anti-apoptotic effects under hypoxia, was significantly increased.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
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
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financially supported by the Green Development and Demonstration Programme(GUDP)(case number 34009-19-1585)。
文摘Background Post-weaning diarrhea(PWD)in piglets,often caused by F4^(+)enterotoxigenic Escherichia coli(ETEC),poses significant challenges in pig production.Traditional solutions like antibiotics and zinc oxide face increasing restrictions due to growing concerns over antibiotic resistance and environmental sustainability.This study investigates the application of bivalent heavy chain variable domain(V_(H)H)constructs(BL1.2 and BL2.2)targeting ETEC virulence factors,administered in feed to mitigate ETEC-induced PWD in weaned piglets.Results The supplementation of BL1.2 and BL2.2 in both mash and pelleted feed significantly reduced the diarrhea incidence and fecal shedding of F4^(+)ETEC in challenged piglets.Pelleted feed containing V_(H)H constructs helped to preserve gut barrier integrity by maintaining levels of the tight junction protein occludin in the small intestine.Additionally,the constructs maintained blood granulocyte counts at a similar level to the non-challenged control group,including neutrophils,and ameliorated the acute phase protein response after challenge.Notably,even at low feed intake immediately after weaning,V_(H)H constructs helped maintain piglet health by mitigating ETEC-induced inflammation and the resulting diarrhea.Conclusions Our findings demonstrated that using V_(H)H constructs as feed additives could serve as an effective strategy to help manage ETEC-associated PWD,by reducing F4^(+)ETEC gut colonization and supporting gut barrier function of weaned piglets.The high stability of these V_(H)H constructs supports their incorporation into industrial feed manufacturing processes,offering a more sustainable preventive strategy compared to traditional antimicrobial interventions,which could contribute to sustainable farming practices.
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
基金supported by NSF 2333230 (J.L.),NIH National Institute of Dental and Craniofacial Research (NIDCR) awards,DE030943 (X.H.),DE023810 (X.H.) and DE031329 (J.L.),T90 DE026110,and K99 DE033794 (to P.-T.D.)
文摘Host-derived small RNAs are emerging as critical regulators in the dynamic interactions between host tissues and the microbiome,with implications for microbial pathogenesis and host defense.Among these,transfer RNA-derived small RNAs(tsRNAs)have garnered attention for their roles in modulating microbial behavior.However,the bacterial factors mediating tsRNA interaction and functionality remain poorly understood.In this study,using RNA affinity pull-down assay in combination with mass spectrometry,we identified a putative membrane-bound protein,annotated as P-type ATPase transporter(PtaT)in Fusobacterium nucleatum(Fn),which binds Fn-targeting tsRNAs in a sequence-specific manner.Through targeted mutagenesis and phenotypic characterization,we showed that in both the Fn type strain and a clinical tumor isolate,deletion of ptaT led to reduced tsRNA intake and enhanced resistance to tsRNA-induced growth inhibition.Global RNA sequencing and label-free Raman spectroscopy revealed the phenotypic differences between Fn wild type and PtaT-deficient mutant,highlighting the functional significance of PtaT in purine and pyrimidine metabolism.Furthermore,AlphaFold 3 prediction provides evidence supporting the specific binding between PtaT and Fn-targeting tsRNA.By uncovering the first RNA-binding protein in Fn implicated in growth modulation through interactions with host-derived small RNAs(sRNAs),our study offers new insights into sRNA-mediated host-pathogen interplay within the context of microbiome-host interactions.
文摘BACKGROUND The Mac-2 binding protein glycosylated isomer(M2BPGi)is a serum marker for fibrosis that correlates with the fibrosis stages in various liver diseases.AIM To examine the M2BPGi’s threshold for staging fibrosis in patients with chronic hepatitis B(CHB),and its changes during treatment.METHODS This was a prospective,longitudinal study.A total of 348 eligible patients were recruited from the Hepatology Department,Medic Medical Center between March 2020 and December 2023.Liver enzyme tests,platelet counts,M2BPGi levels,and FibroScan were conducted at baseline and at 3-month intervals until six months post-treatment.Correlation plots of M2BPGi,FibroScan,and the other parameters were generated.Receiver operating characteristic curves were constructed for M2BPGi and the other parameters to evaluate their performance.RESULTS M2BPGi levels correlated well with FibroScan results and increased as the fibrosis stage advanced.The median M2BPGi levels at the different stages of fibrosis showed statistically significant differences.The cut-off values of M2BPGi for diagnosing significant fibrosis(F≥2),advanced fibrosis(F3),and cirrhosis(F4)were determined to be 1.08,1.4,and 1.52,respectively.In the context of fibrosis regression in CHB patients during the first 6-month of treatment,M2BPGi levels appeared to decrease before this pattern occurred in the FibroScan results.CONCLUSION M2BPGi levels were strongly correlated with FibroScan.M2BPGi can be used to assess liver fibrosis,and to serve as a tool for monitoring fibrosis regression in CHB patients undergoing treatment.
文摘BACKGROUND Cirrhosis is a progressive condition characterized by fibrosis that can lead to severe complications and increased mortality.The mac-2 binding protein glyco-sylation isomer(M2BPGi)is a prominent biomarker for predicting hepatocellular carcinoma(HCC)and cirrhosis-induced esophageal varices(EV).AIM To investigate thresholds of M2BPGi associated with HCC,EV,and decomp-ensation in patients with cirrhosis.METHODS This was a prospective study.A total of 153 patients with cirrhosis who met the inclusion criteria were enrolled.The patients were diagnosed with HCC and EV according to the Baveno VII and European Association for the Study of the Liver guidelines.Baseline serum M2BPGi levels were assessed along with other routine tests.The data analysis aimed to determine the cutoff values of M2BPGi for pre-dicting EV and HCC.RESULTS In the study 85.6%of patients were Child-Pugh B and C.M2BPGi mean cutoff index was 7.1±3.7,showing no significant etiological differences.However,M2BPGi levels varied significantly among Child-Pugh classes,EV classifications,and between patients with and without HCC(P<0.01).M2BPGi cutoff values for predicting HCC,EV,and decompensated cirrhosis were 6.50,6.64,and 5.25,respectively.Mul-tivariate analysis confirmed M2BPGi as an independent risk factor for EV[adjusted odds ratio(aOR):1.3,95%CI:1.08-1.64]and liver decompensation(aOR:2.11,95%CI:1.37-3.83).Area under the curve of M2BPGi for HCC differ-entiation was 0.71.An algorithm combining alpha-fetoprotein(AFP)and M2BPGi detected 26 of 28 HCC cases with 98.04%accuracy vs 10 cases by AFP alone.CONCLUSION Serum M2BPGi predicted cirrhosis complications,including decompensation and varices,especially in HCC.Combined with AFP,it enhanced HCC detection.Future liver biopsy studies are needed for tissue confirmation.
文摘BACKGROUND Mac-2 binding protein glycosylation isomer(M2BPGi)serves as a marker of activated hepatic stellate cells and as such holds potential as a biomarker for liver fibrosis.In Viet Nam,metabolic dysfunction-associated steatotic liver disease(MASLD)is rising in prevalence and there is an urgent need for better clinical management,particularly in early detection methods that will improve overall prognosis.AIM To examine M2BPGi cut-off values for staging liver fibrosis in patients with MASLD and risk factors associated with disease progression.METHODS A total of 301 individuals with ultrasound-confirmed or FibroScan-confirmed diagnosis of fatty liver were enrolled in the study.The participants were stratified according to fibrosis stage,measured via magnetic resonance elastography.M2-BPGi,Fibrosis-4(FIB-4)Index score,and routine parameters of liver function were assessed to statistically investigate the correlation of M2BPGi levels in various fibrosis stages and to identify risk factors associated with fibrosis severity.RESULTS M2BPGi levels positively correlated with fibrosis stages,with cut-off indexes of 0.57 for F0-1,0.68 for F2-3,and 0.78 for F4.M2BPGi levels in the F0-1 group were significantly different from those in both the F2-3 group(P=0.038)and the F4 group(P=0.0051);the F2-3 and F4 groups did not show a significant difference(P=0.39).Females exhibited significantly higher M2BPGi levels than males for all fibrosis stages,particularly in the F2-3 group(P=0.01)and F4 group(P=0.0006).In the F4(cirrhosis)group,individuals with diabetes had significantly higher M2BPGi levels than those without.M2BPGi,hemoglobin A1c,and FIB-4 score were identified as independent risk factors for greater fibrosis and cirrhosis.CONCLUSION M2BPGi levels varied significantly throughout fibrosis progression,from early MASLD to cirrhosis,with sex correlation.M2BPGi holds promise as an early biomarker for fibrosis characterization in MASLD adult patient populations.
基金Supported by Science Technology Research and Development Project in Shijiazhuang City in2010(10120803)Scientific Research Starting Fund Project of Shijiazhuang University in2007(2007012),Education Reform Research Item of Shijiazhuang University in2008(2008006)~~
文摘[Objective] The research aimed to find the extracellular binding proteins of CR4.[Method] The extracellular domain of OsCR4 was as the bait protein,and the yeast two-hybrid was used to screen cDNA library of seedling which was cultivated 14 d.[Result] A lot of proteins which included a peroxide B（D26484）,a methionine thioredoxin reductase（ABF96078）and an unknown function protein were gained.[Conclusion] It provided the theory basis for studying the signal transduction mechanism of CR4.
文摘OBJECTIVE: To study the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) levels in differential diagnosis of growth hormone deficiency (GHD). METHODS: To measure serum IGFBP-3 levels by RIA in normal children and adolescents, GHD children and short-stature children without GHD. RESULTS: Serum level of IGFBP-3 in 129 children with untreated GHD and with no pubertal development was 1.6 +/- 0.9 mg/L, which was less than that in normal group of the same age, but overlapped with the normal children in Tanner stage I. After six-month treatment with recombinant human growth hormone (rhGH), serum level of IGFBP-3 in 59 GHD significantly increased from 1.3 +/- 0.7 mg/L to 2.7 +/- 0.9 mg/L, accompanied by an increase of body heights, growth velocities and serum level of IGF-1. Serum level of IGFBP-3 in 55 short-stature children without GHD was 3.3 +/- 2.2 mg/L, which was not significantly different from that in normal group. CONCLUSION: Serum IGFBP-3 level can reflect the status of GH secretion in children with GHD and is a useful marker for differential diagnosis of GHD.
文摘BACKGROUND The Mac-2 binding protein glycosylation isomer(M2BPGi),a fibrosis marker in various liver diseases,is reportedly a prognostic marker in patients with hepatocellular carcinoma(HCC)who underwent hepatectomy.AIM To evaluate whether the M2BPGi value,M2BP,and pre-sarcopenia before radiofrequency ablation(RFA)could be useful recurrence and prognostic markers in patients with early-stage HCC.METHODS In total,160 patients with early-stage primary HCC treated with RFA were separately analyzed as hepatitis C virus(HCV)-positive and HCV-negative.Factors contributing to recurrence and liver-related death,including M2BP,M2BPGi,and skeletal muscle mass index,were statistically analyzed.Eighty-three patients were HCV-positive and 77 were HCV-negative.RESULTS In HCV-positive patients,only des-γ-carboxy-prothrombin≥23 mAU/mL was a significant poor prognostic factor affecting survival after RFA.In HCV-negative patients,M2BPGi≥1.86 cutoff index was significantly associated with tumor recurrence,while M2BP was not.M2BPGi≥1.86 cutoff index(hazard ratio,4.89;95%confidence interval:1.97-12.18;P<0.001)and pre-sarcopenia(hazard ratio,3.34,95%confidence interval:1.19-9.37;P=0.022)were independent significant poor prognostic factors in HCV-negative patients.CONCLUSION In HCV-negative patients with primary HCC treated with RFA,lower M2BPGi contributed to a lower tumor recurrence rate and longer survival period.Pre-sarcopenia contributed to the poor prognosis independently in HCV-negative patients.These factors might be useful recurrence and prognostic markers for early-stage primary HCC.
文摘Cysteine residues found in proteins have various functions such as metal binding, nitrosylation, and stabilization of structure. We have done a comparative, computational structural analysis of the cysteine residues in two proteins from bacteria to get some insight into the differences between metal binding cysteine residues and those involved in structure stabilization. The two target proteins in this study are the periplasmic mercury binding protein （MerP） and the 1-1eucine binding protein （LBP）. Both are periplasmic binding proteins from E. coli. We have shown key phenomenon that define cysteines as metal binding or structural in nature.
文摘The association of retinol binding protein 4 （RBP4） with atherosclerosis of the carotid artery in type 2 diabetes mellitus （T2DM） remains undefined. We aimed to investigate the correlation of RBP4 expression with atherosclerosis of the carotid artery in T2DM. A total of 1,076 subjects were investigated for intima-media thickness of the bilateral common carotid arteries, and they were divided into three groups： in group Ⅰ, patients had normal neck vascular ultra- sound, in group Ⅱ, intimal carotid artery media thickness was equal to or more than 1 mm, and in group Ⅲ, carotid artery plaque was present. Height, weight, blood pressure （BP）, fasting plasma glucose （FPG）, hemoglobin Alc （HbA1c）, total cholesterol （TC）, triglyceride （TG）, low-density lipoprotein cholesterol （LDL-C）, high-density lipopro- tein cholesterol （HDL-C）, apolipoprotein A-1 （apoA-1）, apolipoprotein B （apoB） and lipoprotein （a） [Lp（a）] were determined by routine laboratory methods. RBP4 and high sensitivity C reactive protein （HsCRP） were measured by an enzyme-linked immuno-sorbent assay, and insulin concentration was measured by an electrochemiluminescence sandwich immunoassay. Duration of diabetes, waist and BP, FPG, HbAlc, TG, TC, LDL-C, APOB, Lp（a）, HsCRP, RBP4 and homeostasis model assessment insulin resistance index （HOMA-IR） were significantly lower in group I than in the other two groups （P〈0.01, P〈0.01）. Plasma levels of HbAlc, RBP4, LDL-C, TC, HOMA-IR, HsCRP and Lp（a）, waist and BP were significantly increased in group III than in group II （P〈0.01）. Multivariate logistic regression analysis showed that there were seven factors associated with the occurrence of carotid artery atherosclero- sis and its risks in descending order were： high LDL-C, high waist, high HsCRP, duration of diabetes, high HOMA-IR, HbAlc and high RBP4. Our finding supported that RBP4 was positively correlated with carotid atherosclerosis in patients with T2DM and could be used as an early predictor of cardiovascular 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Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactive transcription despite heavy translational requirements for continued growth and differentiation. Hence, spermatogenesis is highly reliant on mechanisms of posttranscriptional regulation of gene expression, facilitated by RNA binding proteins （RBPs）, which remain abundantly expressed throughout this process. One such group of proteins is the Musashi family, previously identified as critical regulators of testis germ cell development and meiosis in Drosophila, and also shown to be vital to sperm development and reproductive potential in the mouse. This review describes the role and function of RBPs our recent knowledge of the Musashi proteins in spermatogenesis. within the scope of male germ cell development, focusing on The functional mechanisms utilized by RBPs within the cell are outlined in depth, and the significance of sub-cellular localization and stage-specific expression in relation to the mode and impact of posttranscriptional regulation is also highlighted. We emphasize the historical role of the Musashi family of RBPs in stem cell function and cell fate determination, as originally characterized in Drosophila and Xenopus, and conclude with our current understanding of the differential roles and functions of the mammalian Musashi proteins, Musashi-1 and Musashi-2, with a primary focus on our findings in spermatogenesis. This review highlights both the essential contribution of RBPs to posttranscriptional regulation and the importance of the Musashi family as master regulators of male gamete development.
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.
基金Supported by the Ministry of Education,Culture,Sports,Science,and Technology and from the Ministry of Health,Labour and Welfare,Japan
文摘To assess the relationship between serum levels of insulin-like growth factor-1(IGF1)/IGF-binding protein-3(IGFBP3)and the risk of esophageal carcinoma.METHODSWe assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective,nested case-control study of participants from the Japan Collaborative Cohort Study.A baseline survey was conducted from 1988 to 1990.Of the 110585 enrolled participants,35%donated blood samples.Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies.A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels.RESULTSThirty-one cases and 86 controls were eligible for the present assessment.The molar ratio of IGF1/IGFBP3,which represents the free and active form of IGF1,was not correlated with the risk of esophageal carcinoma.A higher molar difference between IGFBP3 and IGF1,which estimates the free form of IGFBP3,was associated with a decreased risk of esophageal carcinoma(P=0.0146),and people in the highest tertile had the lowest risk(OR=0.107,95%CI:0.017-0.669).After adjustment for body mass index,tobacco use,and alcohol intake,the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma(P=0.0150).CONCLUSIONThe free form of IGFBP3,which is estimated by this molar difference,may be inversely associated with esophageal cancer incidence.
基金the Clinical Research Support Fund of Chinese PLA General Hospital(2018FC-WJFWZX-1-03)Youth Talents Promotion Project of China(17-JCJQ-QT-036)Natural Science Foundation of Beijing(7214254).
文摘Background:In sepsis,vitamin D binding protein(VDBP)has been shown to be low-expressed.The current study examined the relationship between serum VDBP level and liver injury in sepsis patients,as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide(LPS).Methods:The human study included 78 sepsis patients and 50 healthy volunteers.Sepsis patients were categorized into sepsis survivor group(n=43)and sepsis non-survivor group(n=35)based on 28-day mortality for data analysis.Adult male C57BL/6 mice were subjected to cecal ligation and puncture(CLP).Serum samples were collected on day 1,3,5 and 7 to determine the levels of VDBP,25-hydroxyvitamin D[25(OH)D_(3)],1,25-dihydroxyvitamin D[1,25(OH)_(2)D_(3)],interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α).Potential protective effects of VDBP overexpression against LPS-induced liver damage were examined in cultured THLE2 cells.Results:Serum levels of VDBP,25(OH)D_(3),and 1,25(OH)_(2)D_(3)were significantly lower in sepsis patients vs.the healthy control(P<0.001),as well as in the sepsis non-survivor group vs.the sepsis survivor group(P<0.001,P=0.0338,or P=0.0013,respectively).Lower serum VDBP level was associated with higher Acute Physiology and Chronic Health Evaluation(APACHE)II score(r=−0.2565,P=0.0234)and Sequential Organ Failure Assessment score(r=−0.3522,P=0.0016),but lower serum albumin(ALB,r=0.4628,P<0.001)and total protein(TP,r=0.263,P=0.02).In CLP mice,there was a 5-day period of serum VDBP reduction,followed by return towards the baseline on day 7.VDBP was also decreased in LPS-treated THLE2 cells(P<0.001).VDBP overexpression reduced LPS-induced THLE2 damage.Reduced damage was associated with decreased oxidative stress and inactivation of the c-Jun N-terminal kinase signaling pathway.Conclusion:VDBP may be protective against sepsis-induced liver injury.
文摘BACKGROUND： Neural stem cell （NSC） survival is closely associated with cell apoptosis in ischemic-hypoxic regions following transplantation. Numerous studies have revealed that X-box binding protein 1 （XBP1） is a transcription factor during endoplasmic reticulum unfolded protein response and is essential for cell survival, differentiation, and anti-apoptotic effects. OBJECTIVE： To determine the effects of the XBP1 gene on NSC proliferation and apoptosis under hypoxic conditions following XBP1 gene transfection into rat embryonic hippocampal NSCs using recombinant adenovirus vector. DESIGN, TIME AND SETTING： In vitro experiments were performed at the Laboratory of Cell Biology of Jilin University and Laboratory of Proteomics, Department of Neurology, Jilin University China from September 2008 to November 2009. MATERIALS： Recombinant adenovirus package XBP1 gene and Ad-XBPl-enhanced green fluorescent protein plasmid （Guangzhou Easywin BioMed Technology, China）, rabbit anti-XBP1 and its target gene estrogen receptor degradation-enhancing a-mannosidase-like protein （EDEM） glucose-regulated protein 78 （GRP78）, anti-apoptotic molecule Bcl-2 and proapoptotic molecule Bax polyclonal antibody （Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA）, and COCI2 （Sigma, St. Louis, MO, USA） were used in the present study. METHODS： Hippocampi from embryonic, Sprague Dawley rats on gestational day 16 were harvested for NSC isolation and cloning, followed by immunofluorescence for Nestin and sub-culturing. The recombinant adenovirus Ad-XBPl-enhanced green fluorescent protein plasmid was transfected into rat embryonic hippocampal NSCs, and then CoCl2 was applied to induce hypoxia. MAIN OUTCOME MEASURES： Cell quantification and 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide colorimetric assay were utilized to detect proliferation in XBPl-transfected NSCs for 7 consecutive days. Western blot assay was utilized to quantify XBP1 GRP78, EDEM, Bcl-2, and Bax expression. Flow cytometry was used to measure apoptosis. RESULTS： NSC proliferation was significantly enhanced following XBP1 gene transfection （P 〈 0.05）. Under hypoxic conditions, GRP78, EDEM, and Bcl-2 levels increased, but Bax levels decreased. In addition, NSC apoptosis decreased following transfection （P 〈 0.05）. CONCLUSION： The XBP1 gene was successfully transfected into rat embryonic hippocampal NSCs using a recombinant adenovirus vector. NSC proliferation following transfection, as well as anti-apoptotic effects under hypoxia, was significantly increased.
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 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.
