The effect of recombinant human erythropoietin on serum selenium levels in hemodialysis patients

Successful results in the treatment of anemia, one of the main complications of chronic renal failure, can be achieved by the use of recombinant human erythropoietin (RhEPO), which is available almost fifteen years in clinics. On the other hand, as both chronic renal failure and maintenance hemodialysis reduce the levels of trace elements, this study was designed to evaluate the interaction potential of RhEPO with serum concentrations of selenium (Se) during four months. Thirty one adult hemodialysis outpatients participated in the study. Ten of them, not on any drug therapy to interact with RhEPO, recruited as “Control Group”, and the remainder, on RhEPO therapy, as “RhEPO Group”. Blood was drawn from the Control Group at the beginning of the study, and from the RhEPO Group at every month for four months. Serum erythropoietin levels were measured by a radioimmunoassay method and Se status by a spectrofluorometric method. It was found that Se levels were not affected by RhEPO treatment during 3 months of therapy, while an increase was seen on the fourth month. The observation indicates that the increase in serum Se levels would be significant in longer than three-month RhEPO treatment.     

乳酸杆菌的分离、鉴定及对肠上皮细胞分泌IL-8调节作用的研究

目的探讨分离益生菌及对益生菌进行鉴定的方法,将益生菌与肠上皮细胞共培养,进一步探讨益生菌对炎症状态时肠上皮细胞分泌促炎细胞因子的调节作用。方法对自正常儿童大便分离出的乳酸杆菌进行表型特征鉴定,并进行培养。将乳酸杆菌(1×108CFU/ml)与HT29细胞共培养,1h后加入TNFα(10ng/ml)。3h后,收集上清,ELISA法测IL8;提取细胞RNA,经RTPCR检测IL8的表达。结果经表型特征鉴定,分离出的乳酸杆菌为保加利亚乳酸杆菌。与保加利亚乳酸杆共培养后,HT29细胞IL8mRNA表达降低,培养液IL8浓度也明显降低。结论自正常儿童大便分离益生菌是获得益生菌有效的方法;保加利亚乳酸杆菌能明显抑制炎症状态时肠上皮细胞分泌IL8。     

Triggering the immune response by proinflammatory cytokines

What determines whether or not an immune response takes place? The older view that it is only the presence or absence of T cells bearing appropriate receptors that matters has been replaced by one which lays at least equal emphasis on inflammation: whether or not antigenpresenting cells become activated and secrete proinflammatory cytokines. The evidence for this view comes partly from older work on animal models of autoimmunity and tolerance, partly signs of “immunological neglect” in transgenic mice akin to “immunological privilege”, and partly from some remarkably supportive genetics. The genetics includes genome scanning for quantitative trait loci determining disease susceptibility and case/control disease associations. Migration inhibitory factor is an interesting proinflammatory cytokine which does not yet fit into this scheme. We ask but do not answer the question whether protective T cell populations are subject to the same rules of activation.     

Synthetic melanin suppresses production of proinflammatory cytokines

An overproduction of proinflammatory cytokines mediates the damaging sequelae of inflammation in pathologic conditions such as rheumatoid arthritis, graft-vs-host reaction, cachexia, and sepsis syndrome. We examined the cytokine regulatory activity of synthetic melanin, exemplified by biosynthetic l-glycine-l-tyrosine-based polymer (ME-1) and chemosynthetic dihydroxyphenylalanine-based polymer (MC-1). At nontoxic concentrations, both compounds effectively (>/=60%) and reversibly suppressed the production of tumor necrosis factor (TNF), even when applied after stimulation of human peripheral blood monocytes with lipopolysaccharide (LPS). The inhibitory activity of melanin was selective with regard to cytokine response but not inducer- or cell-type-specific. In addition to TNF, melanin inhibited production of interleukin (IL)-1beta, IL-6, and IL-10 but not granulocyte-macrophage colony-stimulating factor by the LPS-stimulated monocytes. Melanin was equally effective in inhibiting production of TNF by monocytes stimulated with the purified protein derivative of Mycobacterium tuberculosis and production of IL-6 by IL-1alpha-stimulated human fibroblasts and endothelial cells. Northern blot analysis, mRNA stability determination, immunoprecipitation studies on metabolically labeled intracellular TNF, and pulse chase experiments revealed that melanin reduced efficiency of mRNA translation. The finding that melanin arrests ongoing cytokine synthesis suggests that this compound may be useful as an adjunct therapy for conditions showing involvement of proinflammatory cytokines.     

Regulation of airway tight junctions by proinflammatory cytokines

Epithelial tight junctions (TJs) provide an important route for passive electrolyte transport across airway epithelium and provide a barrier to the migration of toxic materials from the lumen to the interstitium. The possibility that TJ function may be perturbed by airway inflammation originated from studies reporting (1) increased levels of the proinflammatory cytokines interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and IL-1beta in airway epithelia and secretions from cystic fibrosis (CF) patients and (2) abnormal TJ strands of CF airways as revealed by freeze-fracture electron microscopy. We measured the effects of cytokine exposure of CF and non-CF well-differentiated primary human airway epithelial cells on TJ properties, including transepithelial resistance, paracellular permeability to hydrophilic solutes, and the TJ proteins occludin, claudin-1, claudin-4, junctional adhesion molecule, and ZO-1. We found that whereas IL-1beta treatment led to alterations in TJ ion selectivity, combined treatment of TNF-alpha and IFN-gamma induced profound effects on TJ barrier function, which could be blocked by inhibitors of protein kinase C. CF bronchi in vivo exhibited the same pattern of expression of TJ-associated proteins as cultures exposed in vitro to prolonged exposure to TNF-alpha and IFN-gamma. These data indicate that the TJ of airway epithelia exposed to chronic inflammation may exhibit parallel changes in the barrier function to both solutes and ions.     

Acute exercise effect on postabsorptive serum leptin.

We postulated that high circulating cortisol levels during intense exercise would lead to increased serum leptin concentrations. Young, lean men ate a small meal and then exercised on a cycle ergometer for 41 min or rested on a control day. Serum leptin concentration was 10% greater during exercise than in the control condition (P < 0.05). Directly after exercise, serum leptin dropped to approximately 10% less than the control level (P < 0.05) but had recovered to the nonexercised level after approximately 2 h of recovery. Rapid exercise effects on circulating leptin were related to changes in hemoconcentration rather than changes in leptin mass. When serum leptin was normalized to serum protein, leptin increased by 10% in the exercise condition compared with control by the end of recovery (P < 0.05). Although exercise increased serum cortisol concentration threefold, there was no relation between differences in cortisol and exercise vs. control differences in normalized leptin. The increased leptin mass after exercise may have been related to greater plasma glucose concentration during recovery after exercise compared with the control condition.     

Effect of selenium on pancreatic proinflammatory cytokines in streptozotocin-induced diabetic mice

To investigate the effects of selenium on mRNA expressions of proinflammatory cytokines and inducible nitric oxide synthase (iNOS) in the pancreas of streptozotocin-induced diabetic mice, the animals were divided into three groups in this study: a normal control group, an untreated diabetes mellitus group and a selenite-treated diabetes mellitus group. Selenite was administered to the diabetic mice in selenite-treated diabetes mellitus group for 2 weeks with an oral dose of 2 mg/kg body weight per day by gavage. The results showed that pancreatic selenium content and glutathione peroxidase mRNA expression and activity were decreased by 16.0%, 63.9% (P<.01) and 31.2 % (P<.01), respectively, in untreated diabetes mellitus group compared with normal control group, and they were significantly increased by 51.0% (P<.001), 79.7% (P<.05) and 21.0% (P<.05), respectively, in selenite-treated diabetes mellitus group compared with untreated diabetes mellitus group. Meanwhile, pancreatic mRNA expressions of proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma; mRNA expression and activity of iNOS and content of nitric oxide were significantly increased by 133.0% (P<.01), 164.0% (P<.001), 111.0% (P<.01), 101.0% (P<.001), 73.2% (P<.001) and 37.6% (P<.01), respectively, in untreated diabetes mellitus group compared with normal control group, and they were decreased by 43.2% (P<.01), 37.5% (P<.01), 33.9 % (P<.05), 35.5% (P<.01), 34.9% (P<.01) and 18.1% (P<.05), respectively, in selenite-treated diabetes mellitus group compared with untreated diabetes mellitus group. In conclusion, the chosen pharmacological dose of selenium provides partial correction of these effects towards control values. Moreover, the results suggested that the hypoglycemic role of selenium may relate with its inhibiting effect on augmentation of proinflammatory cytokines and reactive oxygen species/reactive nitrogen species by streptozotocin inducing in the pancreas of diabetic mice.     

Maternal serum proinflammatory cytokines in preterm labor with intact membranes: neonatal outcome and histological associations

Our aim was to compare maternal serum concentrations of interleukin(IL)-1alpha IL-1beta, IL-6 and IL-8 in pregnancies complicated by preterm labor (PTL), with the levels in healthy controls at comparable gestational age, and to determine if these assays have any value in the prediction of early-onset neonatal infection or histological chorioamnionitis. The study population consisted of 65 women with new-onset PTL, and 31 healthy controls. Maternal serum concentrations of IL-6 (8.40 versus 3.30 pg/mL; p = 0.002) and IL-1beta (2.20 versus 0.50 pg/mL; p = 0.003) were significantly higher in patients with PTL as compared to healthy pregnant women. The IL-1beta concentration (13.60 versus 1.20 pg/mL; p = 0.02) was significantly higher in the serum of mothers whose babies developed early-onset infections, than in mothers of newborns that were healthy. However, its predictive value, and the value of the other cytokines studied, was poor. In addition, IL-1beta levels (28.79 versus 5.19 pg/mL; p = 0.001) were significantly higher in patients with histological chorionamnionitis, than in those without the condition,. The cut-off value of >or= 14 pg/mL predicted inflammatory changes with a sensitivity of 80%, specificity of 86%, PPV of 80% and NPV of 86%. IL-1beta seems to be of moderate value in the prediction of histological chorioamnionitis.     

Production of recombinant human interleukin-38 and its inhibitory effect on the expression of proinflammatory cytokines in THP-1 cells

Interleukin (IL)-38 is the latest member of the IL-1 cytokine family. However, as a result of lacking efficient method to generate relatively large quantity of IL-38, its precise functions are poorly understood. In the present study, the cloning, expression, purification, and activity analysis of recombinant human IL-38 was described. Human IL-38 cDNA was cloned into the prokaryotic expression vector pET-44. The recombinant IL-38 containing a C-hexahistidine tag was expressed in Escherichia coli BL21 (DE3) which induced by isopropyl-β-D-thiogalactoside. The expressed fusion protein was purified by Ni-NTA affinity chromatography. IL-38 protein was largely found in the soluble fraction. The purified IL-38 appeared a single band on SDS-PAGE, the yield of IL-38 was 4 mg from 1 L of bacterial culture, and the purity was more than 98% with low endotoxin level (<0.1 EU/μg). Western blotting confirmed the identity of the purified protein. Activity analysis showed that IL-38 can inhibit effectively the expression of proinflammatory cytokines, such as tumor necrosis factor-α, IL-1β, IL-17, and monocyte chemoattractant protein-1 in lipopolysaccharide-activated THP-1 cells. The production and characterization of biologically active IL-38 will be beneficial for its potential role in clinical applications.     

Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology

Cholangiocytes, the epithelial cells lining the bile ducts, are an important subset of liver cells. They are involved in the modification of bile volume and composition, and respond to endogenous and exogenous stimuli. Along the biliary tree, two different kinds of cholangiocytes exist: small and large cholangiocytes. Each type has different features and biological role in physiologic and pathologic conditions, and their immunobiology is important for understanding biliary diseases. Cholangiocytes provide the first line of defence against luminal microbes in the hepatobiliary system. Indeed, they express a variety of pattern recognition receptors and may start an antimicrobial defence activating a set of intracellular signalling cascades. In response to injury, cholangiocytes that are normally quiescent become reactive and acquire a neuroendocrine-like phenotype with the release of proinflammatory mediators and antimicrobial peptides, which support biliary epithelial integrity. These molecules act in an autocrine/paracrine manner to modulate cholangiocyte biology and determine the evolution of biliary damage. Failure or dysregulation of such mechanisms may influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. In this review, we focus on the response of cholangiocytes in inflammatory conditions, with a particular focus on the mechanism driving cholangiocytes adaptation to damage. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Royal jelly inhibits the production of proinflammatory cytokines by activated macrophages

In this study, we have examined the anti-inflammatory actions of royal jelly (RJ) at a cytokine level. When supernatants of RJ suspensions were added to a culture of mouse peritoneal macrophages stimulated with lipopolysaccharide and IFN-gamma, the production of proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-1, was efficiently inhibited in a dose-dependent manner without having cytotoxic effects on macrophages. This suggests that RJ contains factor(s) responsible for the suppression of proinflammatory cytokine secretion. We named the factor for honeybees RJ-derived anti-inflammatory factor (HBRJ-AIF), and further investigated the molecular aspects of it. Size fractionation study showed that HBRJ-AIF is composed of substances of low (< 5 kDa) and high (> 30 kDa) molecular weights, with the former being a major component. Chromatographic analysis showed that MRJP3 is one candidate for the HBRJ-AIF with high molecular weights. Thus, our results suggest that RJ has anti-inflammatory actions through inhibiting proinflammatory cytokine production by activated macrophages.     

白头翁汤对炎症性肠病中促炎细胞因子表达的影响

目的：探讨白头翁汤治疗炎症性肠病的分子机制。方法：40只Wistar雄性大鼠随机分为5组（n=8）：正常对照组、模型组、模型＋阳性药物对照组（美沙拉嗪）、模型＋白头翁中、高剂量治疗组。阳性对照组、中药治疗组分别灌胃给药。疗程结束后取大鼠结肠组织提取RNA,利用realtimePCR的方法检测白介素-1β（IL-1β）、白介素-6（IL-6）YL肿瘤坏死因子-α（TNF-α）在各组中的表达变化。结果：相对于模型组,阳性药物及白头翁汤治疗组尤其是高剂量组可有效抑制IL-1β、IL-6及TNF-α的表达。结论：白头翁汤可通过抑制促炎因子的表达从而发挥了在炎症性肠病中的治疗作用。     

Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 1

We investigated proinflammatory cytokine TNFα production inhibitors in order to develop novel anti-inflammatory agents. According to the results, we found that 17, a pyrrole derivative possessing a tetrahydropyridine group at the β-position, showed potent inhibitory activity in vitro (inhibition of lipopolysaccharide (LPS) induced TNFα production in human whole blood, IC₅₀ = 1.86 μM) and in vivo (inhibition of LPS induced TNFα production in mice, ID₅₀ = 5.98 mg/kg).     

Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 3

In order to develop a new class of anti-rheumatic drug which inhibits production of proinflammatory cytokines such as TNFα, IL-1β, IL-6, and IL-8, a series of 3-pyridylpyrrole derivatives possessing a bicyclic tetrahydropyridine moiety at the 4-position of the pyrrole ring were synthesized and their pharmacological activities were evaluated. The derivatives were found to have potent inhibitory activities on the production of the cytokines both in vitro and in vivo. Among them, compound 4a, (S)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole (R-132811), achieved the most promising results in various in vitro and in vivo tests including several rheumatoid arthritis models ((i) inhibition of p38α, p38β, p38γ, and p38δ MAP kinases: IC₅₀ = 0.034, 0.572, >10, and >10 μM, respectively; (ii) inhibition of TNFα, IL-1β, IL-6, and IL-8 production in human whole blood: IC₅₀ = 0.026, 0.020, 0.88, and 0.016 μM, respectively; (iii) inhibition of LPS induced TNFα, IL-1β and IL-6 production in mice: ID₅₀ = 0.93, 8.63, and 0.11 mg/kg, po, respectively; (iv) inhibition of anti-collagen antibody-induced arthritis in mice: ID₅₀ = 2.22 mg/kg, po; (v) inhibition of collagen-induced arthritis in mice: ID₅₀ = 2.38 mg/kg, po; (vi) prophylactic effect on adjuvant-induced arthritis in rats: ID₅₀ = 3.1 mg/kg, po; (vii) therapeutic effect on adjuvant-induced arthritis in rats: ID₅₀ = 4.9 mg/kg, po; (viii) analgesic effect on adjuvant-induced arthritic pain in rats: ID₅₀ = 2.9 mg/kg, po). As a result, compound 4a was chosen as a candidate for further pre-clinical studies.     

七氟醚对宫颈癌患者围术期炎性应激反应的影响

目的 研究七氟醚麻醉对宫颈癌患者围术期血清相关细胞因子的影响.方法 将组织学诊断为宫颈癌的患者90例,按手术时采用的麻醉药物的不同随机分为三组:第Ⅰ组患者为异丙酚组(Ⅰ组,n=30);第Ⅱ组患者为七氟醚组(Ⅱ组,n=30);第Ⅲ组患者为异丙酚+七氟醚组(Ⅲ组,n=30);观察麻醉前30 min,手术开始后1、2h,手术结束后1、24和48 h六个时点患者血清肿瘤坏死因子-α(TNF-α)、白细胞介素-8(IL-8)和白细胞介素-10(IL-10)水平的变化.结果 三组患者术后血清TNF-α、IL-8和IL-10水平与麻醉前值比较均升高(P＜0.01),一般在术后24 h达峰值.比较血清TNF-α、IL-8和IL-10浓度变化,Ⅰ组和Ⅱ组之间差异无统计学意义,Ⅲ组抑制这三种细胞因子释放的能力明显强于Ⅰ组和Ⅱ组(P＜0.05).结论 应用七氟醚或异丙酚进行麻醉维持在官颈癌手术中,两者控制炎性应激反应的作用类似;七氟醚联合异丙酚进行麻醉维持可更有效地降低术后炎性应激反应.     

Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 2

We previously reported a novel pyrrole derivative 1 which possesses a tetrahydropyridine group at the β-position with a proinflammatory cytokine TNFα production inhibitor. Herein, we report the synthesis and biological activity of N- and α-position substituted tetrahydropyridine derivatives. In this series, we found that compound 3o showed good inhibitory activity in vitro (inhibition of lipopolysaccharide (LPS)-induced TNFα production in human whole blood, IC₅₀ = 0.44 μM) and compound 3i demonstrated potent inhibitory activity in vivo (inhibition of LPS-induced TNFα production in mice, ID₅₀ = 1.42 mg/kg).     

Acute effects of testosterone on serum PGE2 levels in male dogs

Serum prostaglandin levels are influenced by testosterone. To test the hypothesis that the effect of testosterone is mediated through the prostate gland, testosterone was given acutely to intact and to prostatectomized male dogs. Intact dogs responded to testosterone with an abrupt, transient rise in plasma PGE2 levels; prostatectomized dogs did not respond. We conclude that testosterone has an acute effect on the prostate gland which results in release of PGE2 into the blood stream.