Cytokines are associated with postembolization fever and survival in hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization

Objective

Cytokines play important roles in angiogenesis, inflammation, and cell growth. The present study aimed to investigate the correlation between cytokine changes and clinical characteristics in hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE).

Methods

Forty-one TACE-näive HCC patients receiving 73 sessions of TACE and 30 healthy controls were studied. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, epidermal growth factor (EGF), epidermal growth factor receptor, and transforming growth factor β1 (TGF-β1) before and at 1, 3, 5, 7, and 14 days after TACE as well as clinical parameters were analyzed.

Results

Baseline serum levels of VEGF, bFGF, IL-6, IL-8, and TNF-α in HCC patients were significantly elevated, whereas EGF and TGF-β1 levels were lower compared to those in healthy controls (p < 0.05 for all). Serum IL-6 increased rapidly and peaked on day 1 after TACE administration, whereas VEGF increased more slowly and peaked on day 14 after TACE administration. Patients with post-TACE fever had higher serum IL-6 levels on days 1, 3, and 5 (p < 0.005 for all). Patients with pre-TACE serum VEGF < 200 pg/ml had a longer survival than those with pre-TACE serum VEGF levels ≥ 200 pg/ml (22.2 months vs. 11.6 months, p = 0.014). Cox multivariate analysis showed that baseline serum VEGF significantly predicted survival for HCC patients receiving TACE.

Conclusions

TACE is associated with the modulation of serum angiogenic, inflammatory, and cell growth cytokines in HCC patients. Serum IL-6 correlates with post-TACE fever, and baseline serum VEGF independently predicts patient survival.     

Serum Level of Selenium,IL-4, IL-10 & IFN-g in Patients with Allergic Asthma,Allergic Rhinitis and Healthy Controls

Background: Allergic diseases have increased during the past decade worldwide. Th2 type lymphocyte response is known to play an important role in the process of allergic inflammation. IL-4, a mediator of type II cytokine response increases IgE synthesis and Interferon gamma, a cytokine of type I response interferes with IL-4 and inhibits IgE production. Selenium is an essential component of glutathione peroxides and changes in its plasma level has been proposed to be associated with allergic diseases. Materials and Methods: This study comprised of 21 cases of allergic asthma (AA), 33 cases of allergic rhinitis (AR) whose age and sex were matched with 28 healthy controls. IL-4, IL-10, IFN-g levels were tested by ELISA assay, and serum selenium was measured by atomic absorption spectorphotometery method. Results: Mean serum selenium level of AA and AR groups were lower than controls. Mean serum IL-4 level of AA was higher than the AR group. Mean serum IL-4 level of AA and AR group were higher than controls. Conclusion: The results of this study indicate that low selenium level may have a role in the pathogenesis of allergic diseases.     

克山病病区粮饲养大鼠血栓素前列环素水平及其与硒维生素E的关系

研究了硒和维生素Ｅ（ＶＥ）对大鼠血浆和心肌血栓素（ＴＸＡ２）、前列环素（ＰＧＩ２）水平及ＴＸＡ２／ＰＧＩ２比值的影响。发现饲低硒、ＶＥ的克山病病区粮组动物在谷胱甘肽过氧化物酶降低和自由基净含量、脂质过氧化物（ＬＰＯ）浓度增高的同时，ＴＸＡ２水平增高、ＰＧＩ２水平降低、ＴＸＡ２／ＰＧＩ２比值增高；加硒或／和ＶＥ对纠正上述变化有相似而又不尽相用的效果，而以联合补充效果量佳。本研究结果提示硒和ＶＥ缺乏通过影响花生四烯酸代谢参与克山病缺血缺氧性心肌坏死的发生发展，其机制可能与二者缺乏，抗氧化能力降低，生成过量自由基和ＬＰＯ，抑制了ＰＧＩ２合成酶的作用并促进ＴＸＡ２形成有关。     

Selenium and interleukins in persons infected with human immunodeficiency virus type 1

An important role for selenium in human immunodeficiency virus (HIV) disease has been proposed. Decreased selenium levels, as found in persons with HIV infection or AIDS, are sensitive markers of disease progression. Selenium deficiency, an independent predictor of mortality in both HIV-1-infected adults and children, is an essential micronutrient that is associated with an improvement of T cell function and reduced apoptosis in animal models. In addition, adequate selenium may enhance resistance to infections through modulation of interleukin (IL) production and subsequently the Th1/Th2 response. Selenium supplementation up-regulates IL-2 and increases activation, proliferation, differentiation, and programmed cell death of T helper cells. Moreover, selenium supplementation may down-regulate the abnormally high levels of IL-8 and tumor necrosis factor-alpha observed in HIV disease, which has been associated with neurologic damage, Kaposi's sarcoma, wasting syndrome, and increased viral replication. Together, these findings suggest a new mechanism through which selenium may affect HIV-1 disease progression.     

Gastrointestinal glutathione peroxidase prevents transport of lipid hydroperoxides in CaCo-2 cells

BACKGROUND & AIMS: Gastrointestinal glutathione peroxidase (GI-GPx), 1 of the 4 types of selenium-dependent glutathione peroxidases, is expressed exclusively in the gastrointestinal system and has therefore been suggested to function as a barrier against the absorption of dietary hydroperoxides. METHODS: The selenium-dependent expression of GI-GPx and cytosolic GPx (cGPx) was analyzed by Western blotting. Transport of 13-hydroperoxy octadecadienoic acid (13-HPODE) was investigated in a CaCo-2 cell monolayer modulated in GI-GPx and cGPx by selenium restriction or repletion. Localization of GI-GPx in rat intestine was visualized by immunohistochemistry. RESULTS: Low but significant GI-GPx levels were detected in selenium-deficient CaCo-2 cells and in the gastrointestinal tract of selenium-deficient rats, whereas cGPx was completely absent. Selenium supplementation of CaCo-2 cells resulted in a 5-fold increase of GI-GPx protein, whereas total GPx activity increased by a factor of 13, with most of the GPx activity under selenium-adequate conditions being cGPx. Irrespective of the selenium status, 13-HPODE did not reach the basolateral side of an intact CaCo-2 cell monolayer. Depending on the selenium status, hydroperoxides damaged the monolayer as evidenced by loss of transepithelial resistance and paracellular diffusion of lucifer yellow. Only under these conditions was unmetabolized 13-HPODE detectable at the basolateral side. CONCLUSIONS: Low GI-GPx levels, as present in selenium deficiency, suffice to prevent transport of 13-HPODE. GI-GPx may thus function as a barrier against hydroperoxide absorption. cGPx contributes to balance major oxidative challenge.     

原发性肝癌患者细胞免疫功能变化及其与转归的关系

目的了解原发性肝癌(肝癌)患者细胞免疫功能变化及与临床转归的关系。方法应用流式细胞术检测22例肝癌患者T淋巴细胞亚群及CD8 T淋巴细胞CD28共刺激分子表达，酶联免疫吸附试验及放射免疫法检测血清白细胞介素-2(IL-2)、转化生长因子β1(TGFβ1)及白细胞介素-6(IL-6)水平，并与慢性乙型肝炎、肝硬化及正常对照比较。结果肝癌患者CD8 CD28-T淋巴细胞较正常增高，CD8 CD28 T淋巴细胞显著降低。肝癌、肝硬化及慢性乙型肝炎患者CD4 T淋巴细胞、CD4 ／CD8 比值、IL-2水平较正常明显降低，CD8 T淋巴细胞、IL-6、TGFβ1水平升高；肝癌患者CD4 T淋巴细胞、CD4 ／CD8 比值、IL-2水平低于慢性乙型肝炎，IL-6、TGFβ1水平高于慢性乙型肝炎及肝硬化患者；血清IL-6及TGFβ1水平与肝癌分期相关。结论肝癌患者存在明显的细胞免疫功能紊乱和抗肿瘤免疫功能低下，观察这些指标的变化对估价肝癌患者的抗肿瘤免疫功能以及预后将有帮助。【     

Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) often lacks curative treatment; therefore new efficient therapies are needed. In this work we aimed at evaluating the antitumor effect of interleukin-12 (IL-12)-based gene therapy on HCC occurring spontaneously in mice. METHODS: A plasmid-vector expressing IL-12 in a liver-specific and doxycycline (Dox)-inducible manner was transferred by hydrodynamic injection to the liver of L-PK/c-myc mice with HCC. IL-12 expression was induced by administering Dox (3 cycles of 1 month duration separated by 1 month rest). RESULTS: Dox administration increased serum IL-12 and IFN-gamma and induced tumor lymphocytic infiltration in all treated mice which was accompanied by tumor stabilization or regression in 40% of animals. The antitumor effect did not correlate with levels of IL-12 or IFN-gamma nor with the intensity of tumor mononuclear infiltration. However, tumors from non-responder mice showed more abundance of Foxp3+ regulatory T cells and higher expression of the immunosuppressive molecules PD-1, PD-L1, VEGF, CTLA-4, IDO, and IL-10 than those that responded to therapy. CONCLUSIONS: Although long-term induction of IL-12 expression in the liver can inhibit HCC growth, the efficacy of the treatment appears to be limited by the activation of immunosuppressive mechanisms.     

红霉素对4-羟基壬烯醛引起的支气管上皮细胞白细胞介素-8和谷氨酰半胱氨酸合成酶变化的影响

目的 探讨红霉素对4-羟基千烯醛(4-HNE)引起的支气管上皮细胞(16-HBE细胞)前乙炎因子白细胞介素-8(IL-8)和谷氨酰半胱氨酸合成酶(γ-GCS)升高的影响.方法 将16-HBE细胞分为4-HNE组(10 μmol/L)和健康对照组,每组样本量为4个培养皿,4-HNE刺激细胞0.5、2、4、8及12 h后,检测磷酸化c-Jun氨基末端激酶(JNK)、p38丝裂素活化蛋白激酶(MAPK)、细胞外信号调节蛋白激酶(ERK)-1及转录激活蛋白-1(AP-1)活性的变化,观察细胞外信号调节激酶活化激酶-1(MEK-1)抑制剂PD98059对4-HNE引起的AP-1结合活性的影响;观察两组IL-8、γ-GCS和IL-8 mRNA、γ-GCS mRNA表达水平的变化;观察PD98059和红霉索对4-HNE引起的IL8、γ-GCS和γ-GCS mRNA表达及红霉素 对4-HNE引起的AP-1结合活性的影响.结果 (1)4-HNE组在0.5、2、4、8及12 h各时间段ERK-1分别为110.4±1.6、106.1±2.1、104.4±3.4、96.3±9.6和86.3±2.9,对照组分别为114.6±2.4、110.2±2.0、112.8±2.4、113.1±2.0和115.4±3.8,两组比较差异有统计学意义(均P<0.05);4-HNE组各时间段AP-1结合活性表达分别为90.6±2.0、85.7±2.2、78.2±2.6、70.6±1.8和64.9±4.8,对照组分别为98.6±2.1、98.7±3.4、100.1±3.8、101.3±4.2和97.4±3.6,两组比较差异有统计学意义(均P<0.05);PD98059可降低4-HNE引起的AP-1结合活性.(2)4-HNE组IL-8水平在2、4、8及12 h分别为(87±4)、(98±4)、(102±6)及(117±6)μg/L,对照组分别为(64±4)、(65±6)、(65±5)及(64±7)μg/L,两组比较差异有统计学意义(均P<0.05);4-HNE组γ-GCS水平在4、8及12 h分别为5.43±0.23、5.41±0.27及5.54±0.53,对照组分别为4.78±0.26、4.03±0.34及3.22±0.31,两组比较差异有统计学意义(均P<0.05).4-HNE组比对照组IL-8 mRNA及γ-GCS mRNA表达水平高.(3)PD98059和红霉素可降低4-HNE引起的IL-8和AP-1结合活性,增加4-HNE引起的γ-GCS表达.结论 4-HNE可通过ERK-1途径增强AP*1转录活性,促进支气管上皮细胞IL-8表达;红霉素通过抑制AP-1活性,减少4-HNE引起的支气管上皮细胞IL-8的合成.红霉素及PD98059可上调4-HNE对γ-GCS的合成作用,阻断AP-1途径并不能减少支气管上皮细胞γ-GCS的合成.     

Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3

Interleukin-22 (IL-22), one of the cytokines secreted by T helper 17 (Th17) cells, was recently reported to be a novel inflammation driver through STAT3 signaling activation. We aimed to investigate the role of IL-22 expression in hepatocellular carcinoma (HCC). We demonstrated significant up-regulation of IL-22 in human HCC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, IL-22 expression was significantly higher in Edmondson Grade III-IV HCC patients versus Grade I-II, confirmed by both real-time polymerase chain reaction and immunohistochemistry. Both IL-22 receptor α and IL-23 were highly expressed in HCC and adjacent cirrhotic tissues compared to normal controls. Enhanced tumor growth and metastasis was found in mice that underwent subrenal transplantation of MHCC-97H cells cotransplanted with IL-22+ TILs cells. STAT3 phosphorylation and up-regulation of downstream genes Bcl-2, Bcl-XL, CyclinD1, and vascular endothelial growth factor (VEGF) promoted tumor growth and metastasis. In vitro studies confirmed the tumor-promoting and antiapoptotic effect of IL-22, as well as IL-6. In the mouse chronic hepatitis and HCC model, sustained and increased IL-22 expression and STAT3 activation were found in liver tissues. A linear correlation was demonstrated between IL-22 expression and hepatic complementary proliferation. An in vivo diethyl-nitrosamine-induced mouse HCC model verified that tumor formation was significantly decreased in IL-22 knockout mice. Conclusion: Excessive IL-22 can be found in the HCC microenvironment, leading to tumor growth, inhibition of apoptosis, and promotion of metastasis due to STAT3 activation.     

A molecular cascade showing nitric oxide-heme oxygenase-1-vascular endothelial growth factor-interleukin-8 sequence in human endothelial cells

Heme oxygenase (HO)-1 has been shown to be an important biological target of nitric oxide (NO). NO can induce HO-1 expression and IL-8 production, particularly, in endothelial cells. Interestingly, HO-1 tends to induce the production of vascular endothelial growth factor (VEGF) that is involved in endothelial IL-8 syntheses. Whether HO-1 expression by NO may provide a link with IL-8 or VEGF synthesis was investigated in human umbilical vein endothelial cells (HUVECs). The NO donor S-nitroso-N-acetyl-penicillamine (SNAP) dose-dependently increased IL-8 and VEGF productions and HO-1 expression in HUVECs. Transfection with either HO-1 small interfering RNA or HO-1 antisense oligodeoxynucleotide abrogated the ability of SNAP to induce HO-1 expression and IL-8 and VEGF productions. Both pharmacological induction and gene transfer of HO-1 directly induced IL-8 and VEGF productions. Anti-VEGF neutralizing antibody blocked SNAP-mediated IL-8 production and VEGF itself induced IL-8 production, whereas anti-IL-8 neutralizing antibody had no effect on VEGF production in SNAP-treated HUVECs. Neither anti-VEGF nor anti-IL-8 antibodies influenced SNAP-induced HO-1 expression. Moreover, neither VEGF nor IL-8 showed an additive effect on SNAP-induced HO-1 expression. HO-1 transfection had no significant effect on productions of other CXC chemokines, such as growth-related oncogen-alpha and epithelial neutrophil activation peptide-78. Taken together, these results provide a molecular cascade showing NO-HO-1-VEGF-IL-8 sequence in human endothelial cells.     

Selenium supplementation prevents the increase in atherogenic electronegative LDL (LDL minus) in the postprandial phase

Evidence is accumulating that postprandial phenomena play a role in atherogenesis. Dietary lipid hydroperoxides that escape from the gastrointestinal barrier can be incorporated into plasma lipoproteins, leading to a modified form of LDL (LDL minus).The present human study was designed to investigate the effect of selenium supplementation on the formation of LDL minus in the postprandial phase. Fourteen healthy subjects ate the same test meal, high in lipid hydroperoxides, at baseline and after 10-day selenium supplementation (110 μg/day). Plasma selenium, LDL minus, LDL resistance to oxidative modification, plasma antioxidants (ascorbic acid, GSH and GPx activity) and MDA were measured in preprandial (time 0) and postprandial (3 h) phases. Supplementation did not induce changes in the concentration of selenium in fasting plasma, but, at the same time, it induced a significant decrease in preprandial plasma GPx activity and inhibited the meal-induced increase in GPx activity. Selenium supplementation fully prevented the meal-induced increase in both LDL minus level and LDL susceptibility to oxidation.This study demonstrated the efficacy of selenium in preventing postprandial oxidative stress. The results, obtained on subjects adequately supplied with selenium, suggest that a non-limiting selenium availability counteracts the postprandial formation of the atherogenic form of LDL and provide a rationale for the epidemiological evidence of the inverse correlation between selenium intake and the incidence of chronic and degenerative diseases.     

Insulin enhances vascular endothelial growth factor, interleukin-8, and plasminogen activator inhibitor 1 but not interleukin-6 release by human adipocytes

The present studies were designed to investigate the hormonal regulation of vascular endothelial growth factor (VEGF) release by human subcutaneous adipose tissue explants and adipocytes incubated in primary culture for 48 hours. Vascular endothelial growth factor and IL-8 release by adipocytes were less than 10% of that by tissue explants, whereas that of leptin in adipocytes was comparable to that by tissue. Dexamethasone inhibited VEGF formation by both adipose tissue explants and isolated adipocytes, whereas insulin stimulated VEGF release only in isolated adipocytes. Insulin also enhanced the formation of IL-8 and plasminogen activation inhibitor 1 (PAI-1), but not that of IL-6 by adipocytes although having little effect on that of IL-6 or PAI-1 by adipose tissue explants. Pertussis toxin stimulated lipolysis and inhibited leptin release by human adipose tissue or adipocytes but did not affect release of IL-8 or VEGF. Isoproterenol also stimulated lipolysis by human adipocytes, but this was not accompanied by any significant changes in VEGF, IL-8, IL-6, or PAI-1 release. In contrast, insulin stimulated VEGF release by human adipocytes, and this stimulation was enhanced in the presence of isoproterenol. Insulin stimulated VEGF formation as well as that of PAI-1 by human adipocytes, but not by explants under conditions where it had little effect on that of IL-6. The ability of insulin to stimulate VEGF formation by adipocytes suggests that the elevated circulating levels of insulin in obesity promote angiogenesis in adipose tissue as well as the enhanced accumulation of fat in human adipocytes.     

Selenium and antioxidant defenses as major mediators in the development of chronic heart failure

Increased oxidative stress is involved in the pathogenesis of chronic heart failure (CHF), the common end result of most cardiac diseases. Selenium is an “essential” trace element, which means that it must be supplied by our daily diet and that its blood and tissue concentrations are extremely low. Selenium has a variety of functions. It is a key component of several functional selenoproteins required for normal health. The best known of these are the antioxidant glutathione peroxidase (GPx) enzymes, which remove hydrogen peroxide and the harmful lipid hydroperoxides generated in vivo by oxygen-derived species. GPx deficiency exacerbates endothelial dysfunction, a major contributing factor in the severity of CHF symptoms, in various conditions such as hyperhomocysteinemia. This suggests that homocysteine may be involved in the CHF associated endothelial dysfunction through a peroxide-dependent oxidative mechanism. Selenium also plays a role in the control of thyroid hormone metabolism and in protection against organic and inorganic mercury. One possible additional mechanism by which low selenium may compromise cardiovascular condition may be through the effect of selenium on the synthesis and activity of deiodinases, enzymes converting thyroxin into the biologically active triiodothyronine. Selenium and iodine actually interact in cardiovascular physiology, and further studies are needed to examine their role, in isolation and in association, in the development of CHF. Thus, selenium (through its role in selenoenzymes, thyroid hormones, and interactions with homocysteine and endothelial function) appears to be a major mediator in several pathways potentially contributing to CHF development.     

Levels of angiogenic proteins in plasma and platelets are not different between patients with hepatitis B/C-related cirrhosis and patients with cirrhosis and hepatocellular carcinoma

Increasing evidence suggests that levels of angiogenic proteins within blood platelets change at the earliest stages of cancer development and may thus provide a promising diagnostic and prognostic tool. Patients with cirrhosis have increased risk of developing hepatocellular carcinoma (HCC). We aimed to study whether development of HCC in hepatitis-related cirrhosis results in changes in platelet levels of angiogenic proteins. We studied the intraplatelet levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), endostatin, platelet factor 4 (PF4) and thrombospondin type 1 (TSP-1) in 38 consecutive patients with hepatitis B- or C-related liver cirrhosis with or without HCC in addition to plasma levels of the same proteins. Twenty healthy volunteers were included to establish reference values for the various tests. Intraplatelet levels of VEGF, bFGF, HGF and endostatin were significantly higher in patients compared to controls. Intraplatelet levels of PDGF, PF4 and TSP-1 were comparable between patients and controls. Plasma levels of VEGF, bFGF and endostatin were comparable between patients and controls. Plasma levels of PDGF, PF4 and TSP-1 were decreased in patients, but this difference disappeared when levels were corrected for platelet count. Intraplatelet and plasma levels of all proteins assessed were comparable between patients with and without HCC. In conclusion, the intraplatelet levels of some angiogenic proteins are elevated in cirrhosis, but do not discriminate between patients with and without HCC. Thus, intraplatelet levels of angiogenic proteins do not seem useful as diagnostic or prognostic biomarker of HCC in cirrhotic patients.     

Serum selenium and glutathione peroxidase concentrations in Iranian patients with angiography-defined coronary artery disease

This study investigated the relationship between serum selenium (Se) and glutathione peroxidase (GPx) levels and the presence of coronary artery disease (CAD) among Iranian patients. Three groups were compared: patients undergoing angiography with angiographically defined CAD, individuals with a normal angiogram, and apparently healthy controls with no evidence of overt CAD. Anthropometric measurements, blood pressure, fasting blood glucose and lipid profiles, serum Se and GPx measurements, and angiographic assessment were carried out using standard protocols. Mean serum Se concentrations were not significantly different between patients with and without CAD and the control group. The mean value of serum GPx in the control group was significantly higher than in patients with or without CAD. Selenium status did not differentiate between patients with and without CAD, which may be related to the fact that angiography is not a very sensitive index of global atherosclerosis, and it is possible that patients who were CAD negative by angiogram still have significant disease. It may also be that Se is not a good marker of CAD.     

CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling

A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133(+) liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133(+) cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133(+) liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133(+) liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133(+) liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133(+) liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. CONCLUSION: CD133(+) liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade.     

Redox side reactions of haemoglobin and cell signalling mechanisms

Cell-free chemically modified or recombinant haemoglobins developed as oxygen therapeutics are designed to correct oxygen deficit caused by ischaemia in a variety of clinical settings. Oxidative processes, which are in some cases enhanced when modifications are introduced that lower oxygen affinity, can limit the safety of these proteins. Direct cytotoxic effects associated with haemoglobins have been ascribed to the redox reactions between haemoglobin and biological peroxides [i.e. hydrogen peroxide (H2O2), lipid peroxides (LOOH) and peroxynitrite (ONOO-)]. Biochemical changes at the cellular, tissue and organ levels have been documented to occur in response to haemoglobin oxidative reactions. These peroxides have been implicated as regulators of redox sensitive cell signalling pathways. The effects of reactions between haemoglobin and biologically relevant peroxides may be more subtle than oxidative damage and may thus involve perturbation of redox sensitive signalling pathways. In this review, a brief outline of the role of cell-free haemoglobin in oxidative and cell-signalling pathways and the implications of these reactions on the safety and efficacy evaluation of haemoglobin-based oxygen carries are presented.