Biomedical subjects

Lei Zhao

Publications and source records attributed to Lei Zhao.

At least 19 recordsLinked to original sources

PubMed2026

Proteogenomic analysis of pediatric and AYA high-grade glioma reveals age-dependent biology, female-male differences, and kinase targets.

High-grade gliomas (HGGs) in children and adolescents and young adults (AYA) exhibit distinct biology across the neurodevelopmental spectrum. To dissect tumor-intrinsic molecular characteristics independent of developmental variation, we perform comprehensive proteogenomic analyses of tumors from 112 HGG patients aged 0-40 years. Our multi-omics analysis identifies two AYA subgroups-adolescents (aged 15-26 years) and young adults (aged 26-40 years)-with distinct molecular profiles and survival outcomes. Tumor-normal comparisons and survival modeling highlight roles of oxidative phosphorylation and neuronal system biology in glioma progression. Causal network analysis and cell line studies provide a rationale for personalized therapies targeting candidate kinases, such as CDK8. Survival modeling, clustering, and immune-landscape analyses identify proteins, post-translational modifications, and immune signatures linked to outcomes and reveal clinically relevant differences between male and female patients.

adolescent and young adult glioma↗

PubMed2026

CST2 promotes melanoma malignant phenotypes through the IL-6-STAT3-NF-κB signaling axis.

BACKGROUND: Melanoma is a highly aggressive malignancy with increasing incidence and mortality over recent decades. Cystatin SA (CST2) encodes a secreted cysteine protease inhibitor that is overexpressed in various cancers and promotes tumor progression; however, its role in melanoma remains unclear. This study aimed to investigate the expression and clinical significance of CST2 in melanoma as well as its biological functions and underlying molecular mechanisms in melanoma progression. METHODS: CST2 expression was analyzed in melanoma tissues using The Cancer Genome Atlas (TCGA) dataset. The prognostic value of CST2 was assessed using Kaplan-Meier analysis. In vitro gain- and loss-of-function experiments were performed to evaluate the effect of CST2 on melanoma cell proliferation, colony formation, and migration. Mechanistic studies included protein-protein docking and co-immunoprecipitation to detect the interaction between CST2 and interleukin-6 (IL-6). Western blotting was used to examine the activation status of IL-6 downstream signaling pathways. RESULTS: CST2 was significantly upregulated in melanoma tissues and was correlated with poor patient prognosis. Overexpression of CST2 promoted melanoma cell proliferation, clonogenicity, and migration, whereas CST2 knockdown suppressed these malignant behaviors. CST2 interacted with IL-6, and its knockdown reduced the expression of IL-6, phospho-STAT3, and phospho-NF-κB. These suppressive effects were reversed by IL-6 overexpression, indicating that CST2 exerted its oncogenic effects through the IL-6-STAT3-NF-κB axis. CONCLUSIONS: CST2 promotes melanoma progression by activating the IL-6-STAT3-NF-κB signaling pathway, and may serve as a potential prognostic biomarker and therapeutic target in melanoma.

CST2↗

PubMed2026

Subphenogroups of acute heart failure with preserved ejection fraction: comprehensive proteomics and pathway analysis.

BACKGROUND: Heterogeneity of heart failure with preserved ejection fraction (HFpEF) results in significant challenges for treatment development. Identifying and characterising distinct HFpEF phenogroups may aid in tailoring therapeutic strategies for these patients. The objective of this study was to assess proteomic patterns of HFpEF phenogroups identified through a machine-learning-based clustering model, with the aim of uncovering specific biological pathways associated with each phenogroup. METHODS: This study represents a post-hoc analysis of the ongoing Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a multicentre prospective observational study of hospitalised patients with acute decompensated HFpEF. Of the overall cohort (N=1238), this study analysed 198 patients with HFpEF with available proteomics data. These patients were classified into four phenogroups using the machine-learning-based clustering model. The SomaScan assay V.4.1 was used to measure levels of >7000 plasma proteins, and subsequent pathway analysis was conducted to determine the biological differences among the phenogroups. RESULTS: We identified four distinct phenogroups: Phenogroup 1 ('rhythm trouble'), Phenogroup 2 ('ventricular-arterial uncoupling'), Phenogroup 3 ('low output and systemic congestion') and Phenogroup 4 ('systemic failure'). The proteomics revealed distinct protein expression profiles among the phenogroups, with ribonuclease 4, tax1-binding protein 1, regenerating islet-derived protein 3-gamma and alpha-1-antichymotrypsin being the most significant markers to specific identified phenogroups. Pathway analysis suggested differences in immune response, autonomic activation, cellular homeostasis and tissue repair mechanisms across the phenogroups. CONCLUSIONS: Using a comprehensive plasma proteomics approach, our study identified distinct proteomic profiles of HFpEF phenogroups, which in turn suggest specific underlying biological processes. These profiles suggest the involvement of inflammatory activation, tissue injury and regenerative responses, immune modulation and systemic stress signalling as key components of HFpEF pathophysiology. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Humans↗

PubMed2007

Integral equation theory study on the structure and effective interactions in star polymer nanocomposite melts.

The polymer reference interaction site model theory is used to investigate the radial distribution function, potential of mean force, depletion force, and second virial coefficient in star polymer nanocomposite melts. The contact aggregation of nanoparticles for relatively weak nanoparticle-monomer attraction and the bridging aggregation of nanoparticles for very large nanoparticle-monomer attraction are observed. The star architecture can well suppress the organization states of direct contact and bridging structure for the moderate nanoparticle-monomer attraction, and promote the bridging-type organization for relatively large nanoparticle-monomer attraction. At constant particle volume fraction, the arm length quantitatively affects the organization states of star polymer nanocomposite melt, and larger repulsive barriers are existent to prevent the contact aggregation of larger nanoparticles. These observations provide useful information for the development of new nanocomposite materials.

Journal Article↗

PubMed2007

The relationship between gene polymorphism and CRP level in a Chinese Han population.

We investigated the relationships among the +1444C/T polymorphism in the C-reactive protein (CRP) gene and the concentration of CRP and the risk of coronary heart disease. Using polymerase chain reaction-restriction fragment length polymorphism, we analyzed the frequency distribution of genotypes and alleles of the +1444C/T polymorphism in samples from 128 patients with coronary heart disease (coronary stenosis more than 50%) and 119 unrelated normal individuals. The plasma levels of CRP and lipids in the subjects were also measured. The frequencies of the genotypes were CC 89.1%, CT 10.9%, and TT 0% in patients and CC 89.9%, CT 10.1%, and TT 0% in controls. The frequency of allele C was 94.5% in patients and 95.0% in controls, and allele T was 5.5% in patients and 5.1% in controls. The distribution of genotypes and alleles in the Chinese Han population was significantly different from that of the Caucasian population. There were no significant differences between frequencies of genotype and allele of controls and those of patients (P>0.05), but in controls the concentrations of CRP in the CC genotype subgroup were significantly higher than those in the CT genotype subgroup (P<0.05). This suggests that the +1444C/T variant in the CRP gene influences the basal CRP level in normal people. These findings imply that there may eventually be a need to establish genotype-specific risk thresholds of the CRP level.

Aged↗

PubMed2007

A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) - part I: pharmacological characterization.

We have discovered a novel small-molecule (3-phosphinoylpropionic acid) inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa), BX 528, which had an IC (50) of 2 nM in an enzymatic assay and 50 nM in an in-vitro clot lysis assay, with 3,500- to 35,000-fold selectivity against other carboxypeptidases, such as CPN, CPZ and CPD, and 5- and 12-fold selectivity against CPE (CPH) and CPB, respectively. At 10 micro M, BX 528 had no significant activity (<50% inhibition or antagonism) in a panel of 137 enzymes and receptors. It had no effects on blood coagulation and platelet aggregation up to 300 and 10 micro M, respectively. The plasma half-life following intravenous administration was 0.85 hours in rats and 4.5 hours in dogs. No significant metabolism was detected in human, dog or rabbit hepatic microsomes, and no significant inhibition of cytochrome P450 3A4 and 2D6 up to 30 micro M. No cytotoxic or cell proliferative effects were found in three hepatic and renal cell lines up to 300 micro M and no mutagenic activity was seen in the Ames II screen. There were no significant hemodynamic effects in rats and dogs up to 100 and 30 mg/kg with peak plasma drug concentrations of approximately 1,000 and 300 micro M, respectively. In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 micro M. Thus, these data demonstrate that BX 528 is a novel, potent, selective and safe TAFIa inhibitor.

Animals↗

PubMed2007

A novel inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) - part II: enhancement of both exogenous and endogenous fibrinolysis in animal models of thrombosis.

We have discovered a novel small-molecule TAFIa inhibitor, BX 528, which is potent, highly selective against other carboxypeptidases and safe. The present study was to determine if BX 528 can enhance exogenous and endogenous thrombolysis in four different animal models. In the first three models, a thrombus was induced by FeCl (2) (dogs) or laser (rats) injury of the femoral artery, or formed ex vivo and implanted in the jugular vein in rabbits. A low dose of exogenous t-PA was given to induce a low-level thrombolysis on an established thrombus. Co-treatment with BX 528 further enhanced the thrombolytic effects induced by the exogenous t-PA and, thus, reduced thrombosis in all three animal models. In a second rat model, fibrin deposition in the lungs was induced by batroxobin, which was spontaneously resolved in 30 minutes due to the activation of endogenous fibrinolysis. Pre-treatment with lipopolysaccharide (LPS) attenuated this spontaneous fibrinolysis. Co-treatment with 10 mg/kg BX 528 prevented the LPS-induced attenuation of endogenous fibrinolysis. Thus, these studies demonstrated that inhibition of TAFIa by BX 528, our newly discovered small-molecule TAFIa inhibitor, enhanced both the exogenous (induced by a low dose of t-PA) and endogenous (LPS-induced resistance) thrombolysis without increasing the bleeding risk in four different animal models of thrombosis in different species (rat, dog and rabbit) employing different thrombogenic stimuli (FeCl (2) , laser, ex vivo and batroxobin) to induce thrombus formation in different tissues (artery, vein and lung microcirculation).

Animals↗

PubMed2006

3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa).

A novel series of cyclic potent, selective, small molecule, thiol-based inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) and the crystal structures of TAFIa inhibitors bound to porcine pancreatic carboxypeptidase B are described. Three series of cyclic arginine and lysine mimetic inhibitors vary significantly in their selectivity against other human basic carboxypeptidases, carboxypeptidase N and carboxypeptidase B. (-)2a displays TAFIa IC50 = 3 nM and 600-fold selectivity against CPN. Inhibition of TAFIa with (rac)2a resulted in dose dependent acceleration of human plasma clot lysis in vitro and was efficacious as an adjunct to tPA in an in vivo rabbit jugular vein thrombolysis model.

3-Mercaptopropionic Acid↗

PubMed2006

Alterations of biliary biochemical constituents and cytokines in infantile hepatitis syndrome.

AIM: To investigate the biliary biochemical constituents and cytokines in infantile hepatitis syndrome (IHS). METHODS: From 42 IHS subjects and 21 controls, serum and biliary biochemical constituents, including total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GT), total bile acid (TBA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) both in bile and serum, were assayed. The subjects with IHS were divided into a cholestasis group (n = 21) and a hepatitis group (n = 21). RESULTS: In the cholestasis group, serum TBIL, DBIL, ALT, gamma-GT, TBA, IL-6 and TNF-alpha levels were higher than those in the control (P < 0.01); and also the biliary TBIL, DBIL, gamma-GT and TBA levels were lower than those in the control, whereas biliary IL-6 and TNF-alpha levels were higher than those in the control (P < 0.01). In the cholestasis group, serum IL-6 and TNF-alpha levels were lower than those in bile (P < 0.01). In the hepatitis group, serum DBIL, ALT, gamma-GT, TBA, IL-6 and TNF-alpha levels were higher than those in the control (P < 0.01 or 140.57 +/- 70.32 vs 79.06 +/- 35.25, P < 0.05), while biliary TBIL, DBIL, gamma-GT and TBA levels were lower than those in the control (P < 0.01), and biliary IL-6 and TNF-alpha levels were higher than those in the control (P < 0.01). In the hepatitis group, serum IL-6 and TNF-alpha levels were also lower than those in bile (P < 0.01). Serum TBIL, DBIL, gamma-GT, IL-6 and TNF-alpha levels in the cholestasis group were higher than those in the hepatitis group, while biliary IL-6 and TNF-alpha levels in the cholestasis group were higher than those in the hepatitis group. Biliary IL-6 and TNF-alpha were found to be more significantly increased than serum IL-6 and TNF-alpha in IHS (P < 0.01). The biliary IL-6 and TNF-alpha levels were positively correlated with serum DBIL, TBA and gamma-GT levels in IHS subjects. CONCLUSION: Biliary biochemical constituents alter in coincidence with pathological changes in hepatocellular injury. Cholestasis is more serious in IHS patients of cholestasis subtype. Assay of biliary IL-6 and TNF-alpha levels can be specific and sensitive to determine the inflammatory status of impaired liver in IHS.

Alanine Transaminase↗

PubMed2006

Regulation of thromboxane receptor trafficking through the prostacyclin receptor in vascular smooth muscle cells: role of receptor heterodimerization.

BACKGROUND: Prostacyclin (PGI2) and thromboxane (TxA2) effect disparate outcomes for atherogenesis and the response to vascular injury; PGI2, a vasodilator and inhibitor of platelet aggregation, limits the deleterious actions of TxA2, a vasoconstrictor and platelet activator. Dimerization of their G protein-coupled receptors, IP and TP, evokes a modified cellular response through which IP/TP counter-balance may be effected. We examined the consequence of IP/TP interaction for the regulatory pathways of both receptors. METHODS AND RESULTS: TPalpha overexpressed in HEK293 cells or expressed endogenously in aortic smooth muscle cells (ASMCs) was internalized after selective activation of either TP or IP. Homologous trafficking of TP was unaltered by coexpression of IP. Heterologous sequestration of TPalpha required the physical presence of activated IP, in transfected and native cells, but was independent of IP signaling to adenylyl cyclase. Reciprocal heterologous regulation of IP, via activated TP, was evident in both HEK293 cells and ASMCs. Homologous TP internalization led to receptor retention and degradation. In contrast, when internalization was IP-induced, TPalpha was recycled to the cell surface in coexpressing HEK293 cells, but not in ASMCs, in accord with the postendocytotic pathway of IP. CONCLUSIONS: IP/TPalpha interaction permits reciprocal regulation of receptor endocytosis via the trafficking pathway determined by the activated dimeric partner.

Animals↗

PubMed2006

[Effects of chloride channel blockers on excitatory junction potentials in smooth muscle cells of cochlear spiral modiolar artery in guinea pigs].

Chloride channels have been identified in vascular smooth muscle cells (SMCs). It has been shown that these channels are involved in myogenic tone regulation and neuromuscular transmission in various vascular beds. However, whether the chloride channels are responsible for the formation of excitatory junction potentials (EJPs) of SMCs in the spiral modiolar artery (SMA) remains unelucidated. In the present study, the effects of chloride channel blockers (niflumic acid, NFA; indanyloxyacetic acid 94, IAA-94; disodium 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonate, DIDS) on EJP were explored in guinea pigs, using intracellular recording techniques on acutely isolated SMA. It was found that EJP was evoked in the majority of the SMCs (75%, n=49) with an adequate electronic stimulation. The amplitude of the EJP was partially blocked (30% approximately 80%) by combined application of alpha(1) receptor antagonist (prazosin) and alpha(2) receptor antagonist (idazoxan) at concentration of up to 1 micromol/L, and P(2x) receptor antagonist (PPADS, 10 approximately 100 micromol/L). NFA (100 micromol/L) could further inhibit the residual EJP in the presence of alpha(1), alpha(2)-adrenergic and P(2x) receptor antagonists. IAA-94 or DIDS not only inhibited the amplitude but also shortened the duration of EJP. Decrease of extracellular chloride concentration from 135.6 mmol/L to 60 mmol/L would enhance EJP. Moreover, IAA-94 (100 micromol/L) and DIDS (200 mumol/L) could reverse the enhancement of EJP by low extracellular Cl(-). NFA (100 micromol/L) could also block the residual depolarizations evoked by norepinephrine (NE, 1 approximately 50 micromol/L). Based on these results, it is inferred that NE could activate a novel adrenoceptor to open the chloride channel on the membrane of the SMCs, leading to a transmembrane Cl(-) current. This current is involved, at least partially, in the formation of EJP.

Adrenergic alpha-Antagonists↗

PubMed2006

Modulatory effect of CCK-8S on GABA-induced depolarization from rat dorsal root ganglion.

CCK is a brain-gut peptide that is abundantly distributed in both gastrointestinal tract and mammalian brain. The sulfated octapeptide fragment of cholecystokinin (CCK-8S) has been shown to be involved in numerous physiological functions such as behavior, anxiety, learning/memory processes and neuropathic pain. CCK-8S is one of the strongest endogenous anti-opioid substances and suppresses opioid peptides-mediated 'pre-synaptic inhibition' of gamma-aminobutyric acid (GABA) release. Here we provide evidence that CCK-8S modulates GABA-evoked membrane depolarization in rat dorsal root ganglion (DRG) neurons using intracellular recording technique. Bath application CCK-8S-induced membrane depolarization in most of the rat DRG neurons. The depolarization was blocked by prolumide but not LY225910. Pretreatment with CCK-8S suppressed the GABA-evoked depolarization in a concentration-dependent manner. The CCK-8S inhibition was also time-dependent and reached the peak at about 2 min. The inhibitory effect of CCK-8S was strongly suppressed by pre-incubation of CCK-B receptor antagonist LY225910, phospholipase C inhibitor U73122, protein kinase C inhibitor chelerythrine and calcium chelator BAPTA-AM, respectively. The protein kinase A inhibitor H-89 did not affect CCK-8S effect. The results suggest that CCK-8S inhibits GABA-A receptor function by activation of CCK-B receptor followed by activation of intracellular PLC-Ca(2+)-PKC cascade. Thus, CCK-8S might enhance nociceptive information transmission through inhibition of the "pre-synaptic inhibition" evoked by GABA, which may explain its role in modulation of primary sensory information (especially pain).

Action Potentials↗

PubMed2006

[Changes in hemodynamics and oxygen metabolism of different Child-grade patients during orthotopic liver transplantation without veno-venous bypass].

OBJECTIVE: To investigate the changes in hemodynamics and oxygen metabolism of different Child-grade patients during orthotopic liver transplantation (OLT) without veno-venous bypass. METHODS: Forty patients with end-stage liver disease undergoing non veno-venous OLT under general anesthesia were enrolled in this research. Swan-Ganz catheter was placed in the pulmonary artery via right internal jugular vein and right radial artery was cannulated to monitor mean pulmonary artery pressure (mPAP) and artery blood pressure (ABP) continuously. Pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP) were also recorded. Cardiac output (CO) was recorded at several time points, such as, 30 min after induction (T1), when inferior vena cava and portal vein were clamped (T2), 30 min after portal vein was clamped (T3), 10 min after unclamping of portal vein (T4), 60 min after graft reperfusion (T5) and at the end of the operation (T6). Blood samples were taken from radial and pulmonary artery for blood gas analysis and hemodynamic parameters, such as, cardiac index (CI), stroke volume index (SVI), pulmonary vascular resistance index (PVRI), and system vascular resistance index (SVRI); oxygen delivery (DO2) and oxygen consumption (VO2) were also calculated at these time points. RESULTS: (1) The mPAP values were much higher in group C than in group A or B at all time points. CVP was significantly increased at T1 or T2 in group C as compared with those points of Child's B or C. PCWP was increased significantly after unclamping of portal vein in all three groups and was much higher at several points in Child's C than in Child's A or B. The SVRI value of T1 and the PVRI value of T3 were much lower in group C than those points in group A and the value of SVRI/PVRI was less than normal except at T3 point. And blood gas analysis elucidated that PaO2 was higher than 400 mm Hg at any points. (2) Oxygen consumption was significantly decreased during the operation due to less blood supply and was reverted to normal at the end point of the operation in all patients. Oxygen delivery was all at least 1,000 mL/min during OLT and there was no significant difference between different groups or different points. CONCLUSION: The hemodynamic state of high cardiac output with low peripheral resistance deteriorated when patients' Child-grade shifted from A to C. VO2 was less than normal value during OLT until the end point.

Adult↗

PubMed2006

Differentiation of hepatocytoid cell induced from whole-bone-marrow method isolated rat myeloid mesenchymal stem cells.

AIM: To explore the expansion and differentiation of hepatocytoid cell induced from myeloid mesenchymal stem cell (MSC) in vitro, in order to find suitable resource of hepatocytes for bioartificial liver or liver transplantation. METHODS: The rat myeloid MSC was isolated and divided into three groups which were cultured by Friedensteion method, and then were induced by culture fluid, culture fluid plus cholestatic serum and culture fluid plus hepatocyte growth factor (HGF), respectively. Hepatocytoid cell as well as expression of CK18 and AFP was observed by immunohistochemistry. RESULTS: After the induction for 21 d, hepatocytoid cell was observed, and its expression of CK18 and AFP was detected by immunohistochemistry in MSC cultured with cholestatic serum. Furthermore, on the 35th d, albumin mRNA was expressed in the cell, suggesting the inducing effect was similar to that by HGF. CONCLUSION: Rat myeloid MSC can differentiate into hepatocyte lineage under appropriate condition. This method is easy to operate.

Albumins↗

PubMed2006

Loss or retention of chloroplast DNA in maize seedlings is affected by both light and genotype.

We examined the chloroplast DNA (cpDNA) from plastids obtained from wild type maize (Zea mays L.) seedlings grown under different light conditions and from photosynthetic mutants grown under white light. The cpDNA was evaluated by real-time quantitative PCR, quantitative DNA fluorescence, and blot-hybridization following pulsed-field gel electrophoresis. The amount of DNA per plastid in light-grown seedlings declines greatly from stalk to leaf blade during proplastid-to-chloroplast development, and this decline is due to cpDNA degradation. In contrast, during proplastid-to-etioplast development in the dark, the cpDNA levels increase from the stalk to the blade. Our results suggest that DNA replication continues in the etioplasts of the upper regions of the stalk and in the leaves. The cpDNA level decreases rapidly, however, after dark-grown seedlings are transferred to light and the etioplasts develop into photosynthetically active chloroplasts. Light, therefore, triggers the degradation of DNA in maize chloroplasts. The cpDNA is retained in the leaf blade of seedlings grown under red, but not blue light. We suggest that light signaling pathways are involved in mediating cpDNA levels, and that red light promotes replication and inhibits degradation and blue light promotes degradation. For five of nine photosynthetic mutants, cpDNA levels in expanded leaves are higher than in wild type, indicating that nuclear genotype can affect the loss or retention of cpDNA.

Chloroplasts↗

PubMed2006

The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma.

We aimed to evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in 101 patients with hepatocellular carcinoma (HCC) who underwent liver resection. Plasma OPN levels were detected by ELISA. The association of plasma OPN levels of patients with clinicopathological characteristics, tumor recurrence, and survival was analyzed. The median plasma OPN level of patients was 176.90 ng/ml (range 13.73-780.00 ng/ml), which was significantly higher than that of 24 healthy volunteers (63.74 ng/ml, range 12.20-122.32 ng/ml). Plasma OPN levels were significantly different in patients with different numbers of tumor nodules (168.18 and 217.11 ng/ml for single and multiple nodules, respectively; P = 0.002), different Edmondson's grades (201.24, 168.36, and 503.58 ng/ml for grades I, II, and III/IV, respectively; P = 0.015), and different TNM stages (168.16, 167.54, and 216.18 ng/ml for stages I, II, and III/IV, respectively; P = 0.016). Significantly higher plasma OPN levels were found in patients with a recurrence of HCC after resection, compared with those without recurrence (213.55 versus 153.70 ng/ml; P = 0.0013). A higher plasma OPN level was a leading independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in univariate and multivariate Cox models. This suggests that the preoperative plasma OPN level can be used as a predictive marker for HCC recurrence and may be helpful to assess the prognosis of patients with HCC after surgery.

Adult↗

PubMed2006

Reactive oxygen species are involved in lipopolysaccharide-induced intrauterine growth restriction and skeletal development retardation in mice.

OBJECTIVE: Maternal infection is a cause of adverse developmental outcomes including embryonic resorption, intrauterine fetal death, and preterm labor. Lipopolysaccharide-induced developmental toxicity at early gestational stages has been well characterized. The purpose of the present study was to investigate the effects of maternal lipopolysaccharide exposure at late gestational stages on intrauterine fetal growth and skeletal development and to assess the potential role of reactive oxygen species in lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation. STUDY DESIGN: The timed pregnant CD-1 mice were intraperitoneally injected with lipopolysaccharide (25 to 75 microg/kg per day) on gestational day 15 to 17. To investigate the role of reactive oxygen species on lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation, the pregnant mice were injected with alpha-phenyl-N-t-butylnitrone (100 mg/kg, intraperitoneally) at 30 minutes before lipopolysaccharide (75 microg/kg per day, intraperitoneally), followed by an additional dose of alpha-phenyl-N-t-butylnitrone (50 mg/kg, intraperitoneally) at 3 hours after lipopolysaccharide. The number of live fetuses, dead fetuses, and resorption sites was counted on gestational day 18. Live fetuses in each litter were weighed. Crown-rump and tail lengths were examined and skeletal development was evaluated. RESULTS: Maternal lipopolysaccharide exposure significantly increased fetal mortality, reduced fetal weight and crown-rump and tail lengths of live fetuses, and retarded skeletal ossification in caudal vertebrae, anterior and posterior phalanges, and supraoccipital bone in a dose-dependent manner. Alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, almost completely blocked lipopolysaccharide-induced fetal death (63.2% in lipopolysaccharide group versus 6.5% in alpha-phenyl-N-t-butylnitrone + lipopolysaccharide group, P < .01). In addition, alpha-phenyl-N-t-butylnitrone significantly reversed lipopolysaccharide-induced intrauterine growth restriction and skeletal development retardation. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, had little effect. Furthermore, lipopolysaccharide-induced intrauterine fetal death, intrauterine fetal growth restriction, and skeletal development retardation were associated with lipid peroxidation and glutathione depletion in maternal liver, placenta, and fetal liver. Alpha-phenyl-N-t-butylnitrone significantly attenuated lipopolysaccharide-induced lipid peroxidation and glutathione depletion in maternal liver, placenta, and fetal liver. CONCLUSION: Maternal lipopolysaccharide exposure at late gestational stages results in intrauterine fetal growth restriction and skeletal development retardation in mice. Reactive oxygen species might be, at least in part, involved in lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation.

Animals↗

PubMed2006

[High mobility group box-1 protein activates endothelial cells to produce cytokines and has synergistic effect with lipopolysaccharide in inducing interleukin-6 release].

OBJECTIVE: To observe the effects of high mobility group box 1 (HMGB1) protein on the release of cytokines of human umbilic vein endothelial cells (HUVECs) and the expression of interleukin-6 (IL-6) induced by lipopolysaccharide (LPS). METHODS: HUVECs were cultured and then divided into the following groups. (1) Recombinant HMGB1 protein of the terminal concentration of 15 ng/ml was added into the culture fluid of HUVECs, 24 hours later the supernatant was collected to detect the levels of granulocyte/macrophage colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), and interleukin-10, IL-12, IL-1beta, IL-2, IL-4, IL-6, and IL-8, by using LiquiChip system. (2) HMGB1 protein of the terminal concentrations of 3, 15, or 75 ng/ml was added into the culture fluid of the HUVECs, 24 hours later the supernatants were collected to detect the level of IL-6. (3) HMGB1 protein of the terminal concentration of 15 ng/ml was added into the culture fluid of HUVECs, 1, 3, 6, 12, and 24 hours after the stimulation the supernatant was collected to detect the level of IL-6. (4) The culture fluid of HUVECs was added with HMGB1 protein of the terminal concentration of 15 ng/ml and/or LPS of the concentration of 10 ng/ml, 24 hours later the supernatant was collected to detect the level of IL-6. Culture fluid not added with HMGB1 protein was used as control in any kind of test. RESULTS: (1) The levels of GM-CSF, IFN-gamma, IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) secreted by the HMGB1 stimulated HUVECs were 5, 7, 4.2, 27.8, 12.8, and 5.4 times that of those control group (all P < 0.01) (2) The levels of IL-6 secreted by the HUVECs stimulated with HMGB1 protein of the concentrations of 3, 15 and 75 ng/ml respectively were 155 pg/ml +/- 33 pg/ml, 901 pg/ml +/- 184 pg/ml, and 1508 pg/ml +/- 379 pg/ml respectively, all significantly higher than that of the control group (32 pg/ml +/- 21 pg/ml, all P < 0.01). (3) Since 3 h after the stimulation of HMGB1 protein the level of IL-6 began to increase gradually. 6, 12, and 24 hours after the stimulation the levels of IL-6 secreted by the HUVEC were 75 pg/ml +/- 22 pg/ml, 453 pg/ml +/- 78 pg/ml, and 901 pg/ml +/- 184 pg/ml respectively, all significantly higher than that of the control group (32 pg/ml +/- 21 pg/ml, all P < 0.01). (4) When the HUVECs were stimulated individually by LPS (10 ng/ml) or HMGB1 (15 ng/ml), the levels of IL-6 increased to 289 pg/ml +/- 42 pg/ml and 901 pg/ml +/- 183.6 pg/ml respectively (both P < 0.01); when the HUVECs were costimulated by LPS and HMGB1, the level of IL-6 increased to 2360 pg/ml +/- 299 pg/ml, which showing that there was a synergistic effect between HMGB and LPS (F = 69.405, P < 0.001). CONCLUSION: HMGB1 activates HUVECs to produce multiple inflammatory cytokines and induces HUVEC to secret IL-6 in a dose- and time-dependent manner. HMGB1 can also act synergistically with LPS in inducing IL-6 release, which may play an important role in the development of sepsis.

Cell Line↗