Proteins are potent biomarkers to detect colon cancer progression

Colon cancer is the most common type of cancer and major cause of death worldwide. The detection of colon cancer is difficult in early stages. However, the secretory proteins have been used as ideal biomarker for the detection of colon cancer progress in cancer patients. Serum/tissue protein expression could help general practitioners to identify colon cancer at earlier stages. By this way, we use the biomarkers to evaluate the anticancer drugs and their response to therapy in cancer models. Recently, the biomarker discovery is important in cancer biology and disease management. Also, many measurable specific molecular components have been studied in colon cancer therapeutics. The biomolecules are mainly DNA, RNA, metabolites, enzymes, mRNA, aptamers and proteins. Thus, in this review we demonstrate the important protein biomarker in colon cancer development and molecular identification of protein biomarker discovery.     

Peripheral TNFalpha, but not peripheral IL-1, requires endogenous IL-1 or TNFalpha induction in the brain for the febrile response

It is known that peripherally administered IL-1 and TNFα induce fever through mechanisms involving prostaglandin (PG)E₂. In this report, we compared the signaling cascade induced in the brain by TNFα and IL-1. Peripheral administration of TNFα-induced enhanced fever in IL-1 Receptor antagonist KO mice, suggesting that IL-1 is involved in the TNFα mediated fever. IL-1α, but not TNFα, induced fever in IL-1α/β/TNFα KO mice, although central administration of TNFα-induced fever. Only IL-1α, but not TNFα, induced IL-6 in the IL-1α/β/TNFα KO mouse brain, while both cytokines induced cyclooxygenase (Cox)-2. Icv administration of PGE₂ induced only transient fever in contrast to the TNFα- or IL-1α-induced fever that lasted longer. Taken together, either IL-1 or TNFα induction in the brain is required for the response induced by TNFα but not by IL-1α, and that both Cox-2 and IL-6 induction are required for prolonged febrile response against these cytokines.     

细菌成孔毒素研究进展

成孔毒素是多种致病性细菌分泌的一种重要毒力因子,通过在真核细胞膜上形成孔道结构,引起细胞裂解。基于毒素产生孔径的大小和与细胞作用方式的不同,可将其分为大成孔毒素、小成孔毒素和RTX毒素。成孔毒素主要通过改变细胞膜的通透性发挥毒性效应,导致细胞死亡,然而失去细胞通透性屏障的早期后果通常是细胞因子的释放,细胞内蛋白激酶的激活,有时会诱导细胞凋亡。     

舒芬太尼复合地佐辛镇痛对中老年胸科手术后胰岛素抵抗及促炎细胞因子的影响

目的:研究舒芬太尼复合地佐辛镇痛对中老年胸科手术后胰岛素抵抗及促炎细胞因子的影响。方法:选取2012年12月到2014年12月我院收治的中老年胸科手术患者80例,按照随机数字表法将患者分为研究组和对照组,每组40例。研究组给予舒芬太尼复合地佐辛镇痛,对照组给予舒芬太尼镇痛,比较两组术后2 h和24 h视觉模拟评分(VAS)和镇静程度评分(Ramsay),比较手术前、术后2 h和24 h两组胰岛素含量、胰岛素敏感性以及肿瘤坏死因子-a(TNF-a)、白介素-6(IL-6)情况。结果:术后2 h和24 h研究组VAS评分均显著低于对照组,Ramsay评分显著高于对照组,两组比较差异具有统计学意义(P0.05);两组术后2 h和24 h胰岛素含量、胰岛素敏感性比较差异具有统计学意义(P0.05);手术前两组TNF-a、IL-6水平比较均无统计学意义(P0.05),术后2 h和24 h研究组TNF-a、IL-6显著低于对照组,两组比较差异具有统计学意义(P0.05)。结论:舒芬太尼复合地佐辛应用于中老年胸科手术具有较好的术后镇痛效果,且具有抑制胰岛素抵抗和促炎细胞因子的作用。     

Size and time-dependent induction of proinflammatory cytokines expression in brains of mice treated with gold nanoparticles

Gold nanoparticles (GNPs) are among the ideal nano-sized materials for medical applications such as imaging and drug delivery. Considering the significance of recent reports on acute phase induction of inflammatory mediators by GNPs, we studied the effect of GNPs on proinflammatory cytokines gene expression in mouse brain. Group 1 served as control whereas groups 2–4 were given only one intraperitoneal dose of 5, 20 and 50?nm GNPs, respectively and sacrificed after 24?h. The animals in groups 5–7 also received the same treatment but sacrificed after 7?days. Groups 8–10 received two injections of GNPs (5, 20 and 50?nm, respectively), first at the beginning of study and second on day 6, and sacrificed on day 7. Total RNA was extracted from the cerebral tissue and analyzed for the gene expressions of IL-1β, IL-6 and TNF-α. A single injection of 5?nm diameter GNPs significantly increased the mRNA expression of IL-1β and IL-6 in mouse brain on day 7, which was not augmented by the second dose of the same GNPs. Larger size GNPs (20?nm and 50?nm) did not cause any significant change in the expression of proinflammatory cytokines in mouse brain. In conclusion, systemic administration of small sized GNPs (5?nm) induced a proinflammatory cascade in mouse brain indicating a crucial role of GNPs size on immune response. It is important to use the right sized GNPs in order to avoid an acute phase inflammatory response that could be cytotoxic or interfere with the bioavailability of nanomaterials.     

The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro

To investigate the modulation of lung local immune responses of hesperidin (HES) on the acute lung inflammation induced by LPS in vivo. Mice were challenged with intratracheal lipopolysaccharide (100 μg) 30 min before with treatment hesperidin (200 mg/kg oral administration) or vehicle. After 4 and 24 h, bronchoalveolar lavage fluid was obtained to measure proinflammatory (TNF-α, IL-1β, IL-6), anti-inflammatory (IL-10, IL-4, IL-12) cytokines, chemokines (KC, MCP-1 and MIP-2), total cell counts, nitric oxide production, and proteins. Lung histology was performed in inflated-fixed lungs. Hesperidin downregulate the LPS-induced expression of TNF-α, IL-1β, IL-6, KC, MIP-2, MCP-1, and IL-12. It also enhanced the production of IL-4, IL-10. Total leukocyte counts; nitric oxide production, iNOS expression, and proteins were significantly decreased by hesperidin. In vitro, HES suppressed the expression of IL-8 on A549 cells and THP-1 cells, the expression of TNF-α, IL-1β, and IL-6 on THP-1 cells, the expression of ICAM-1 and VCAM-1 on A549 cells which effect cell adhesion function. The suppression of those molecules is controlled by NF-κB and AP-1, which are activated by IκB and MAPK pathways. HES inhibits those pathways, thereby suppressing the expression of IL-8, TNFα, IL-1β, IL-6, IL-12, ICAM-1 and VCAM-1. This study indicates that HES had a markedly immunomodulatory effect in a clinically relevant model of ARDS. Nevertheless, further investigations are required to determine the potential clinical usefulness of HES in the adjunctive therapy of ARDS.     

3-(Naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride attenuates NLRP3 inflammasome-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglial cells

The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome is a multiprotein complex with a role in innate immune responses. NLRP3 inflammasome dysfunction is a common feature of chronic inflammatory diseases. Microglia activation is also associated with neuroinflammatory pathologies. We previously reported that 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) reduced hypoxia-induced toxicity by modulating inflammation. However, no studies have elucidated the precise mechanisms for the anti-inflammatory action of KHG26792, in particular via inflammasome mediation. This study investigated the effects of KHG26792 on the inflammasome-mediated signaling pathway in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. KHG26792 significantly attenuated several inflammatory responses including tumor necrosis factor-α, interleukin-1β, interleukin-6, reactive oxygen species, and mitochondrial potential in these cells. KHG26792 also suppressed LPS-induced increase NLRP3, activated caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) levels. Furthermore, KHG26792 successfully blocked LPS-activated adenosine triphosphate (ATP) level, likely through the purinergic receptor P2X ligand-gated ion channel 7 (P2X7) receptor. Our results suggest that the anti-inflammatory functions of KHG26792 may be, at least in part, due to regulation of the P2X7R/NLRP3-mediated signaling pathway during microglial activation.     

Granulocyte colony-stimulating factor negatively regulates Toll-like receptor agonist-induced cytokine production in human neutrophils

We studied the effect of G-CSF on TLR agonist-induced cytokine production in human neutrophils. Human neutrophils produced IL-8 and TNF-α in response to stimulation with TLR agonists such as LPS and N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine. This response was dependent on activation of ERK, p38, and PI3K, but not JNK. TLR agonist-induced cytokine production in neutrophils was inhibited by G-CSF, whereas it was enhanced by GM-CSF, and GM-CSF-mediated enhancement was attenuated by G-CSF. G-CSF and GM-CSF did not affect TLR agonist-induced phosphorylation of ERK, p38, JNK, Akt, and IκBα. STAT3 activation was much greater in G-CSF-stimulated neutrophils than that in GM-CSF-stimulated cells. G-CSF-mediated STAT3 phosphorylation and inhibition of TLR agonist-induced cytokine production were prevented by pretreatment of cells with AG-490 (JAK2 inhibitor). These findings suggest that G-CSF and GM-CSF exert the opposite effects on TLR agonist-induced cytokine production, and G-CSF negatively regulates TLR agonist-induced cytokine production in neutrophils via activation of STAT3.     

Intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc(Min/+) mouse

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. While the link between inflammation and colon cancer is well established, the temporal sequence of the inflammatory response in relation to tumorigenesis has not been characterized. We examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc^Min/+ mouse. Apc^Min/+ mice and wildtype mice were sacrificed at one of 4 time-points: 8, 12, 16, and 20 weeks of age. Intestinal tissue was analyzed for polyp burden (sections 1, 4 and 5) and mRNA expression and protein concentration of MCP-1, IL-1β, IL-6 and TNF-α (sections 2 and 3). The results show that polyp burden was increased at 12, 16 and 20 weeks compared to 8 weeks (P < 0.05). Gene expression (mRNA) of MCP-1, IL-1β, IL-6 and TNF-α was increased in sections 2 and 3 starting at week 12 (P < 0.05), with further increases in MCP-1, IL-1β and IL-6 at 16 weeks (P < 0.05). Protein concentration for these cytokines followed a similar pattern in section 3. Similarly, circulating MCP-1 was increased at 12 weeks (P < 0.05) and then again at 20 weeks (P < 0.05). In general, overall polyp number and abundance of large polyps were significantly correlated with the inflammatory cytokine response providing further support for a relationship between polyp progression and these markers. These data confirm the association between intestinal cytokines and tumorigenesis in the Apc^Min/+ mouse and provide new information on the timing and magnitude of this response in relation to polyp development. These findings may lead to the development of inflammatory mediators as important biomarkers for colon cancer progression. Further, these data may be relevant in the design of future investigations of therapeutic interventions to effectively target inflammatory processes in rodent models.     

Proinflammatory cytokine gene expression in endometrial cytobrush samples harvested from cows with and without subclinical endometritis

Thirty postpartum cows (28 to 41 days in milk) without signs of clinical endometritis were categorized as inflammation-negative (N = 18) or subclinical endometritis-positive (N = 12) based on endometrial cytobrush cytology (> 18% polymorphonuclear cells; PMNs). Slides for cytology were prepared before the same cytobrush was transferred to a tube containing 1 mL Trizol reagent. Total RNA was extracted from each cytobrush sample and analysis of il6, il8, tnfα, and βactin gene expression was performed using quantitative real-time polymerase chain reaction. Cytobrush sampling provided sufficient material to prepare cytosmears and extract high quality endometrial mRNA (mean = 0.96 μg RNA per sample). Cytokine expression varied between experimental groups with a 20-fold higher tnfα (P = 0.001), a 30-fold higher il6 (P = 0.01), and a greater than 50-fold higher il8 mRNA expression level (P = 0.0001) in subclinical endometritis-positive versus disease-negative cows. Regression analysis of gene expression levels (cycle threshold) versus PMN frequency showed that the frequency of PMNs in the cytosmear decreased by 3.3% (P = 0.000 01), 2.3% (P = 0.015), and 2.4% (P = 0.05) for each additional cycle threshold required to detect il8, il6, and tnfα gene expression, respectively. Expression of the individual cytokines was positively associated: il8 and il6 (P = 0.0001); il8 and tnfα (P = 0.000 01); and il6 and tnfα (P = 0.0002). In conclusion, the endometrial cytobrush technique was successfully used to obtain material for both cytology and RNA extraction, and il8 gene expression may be useful to predict endometrial inflammation.     

复合应激型ED大鼠模型促炎细胞因子IL-6、TNF-α和TGF-β1水平的研究

目的:探讨环境雌激素样饲料联合冷刺激诱导的ED大鼠血清与阴茎组织中促炎因子IL-6、TNF-α和TGF-β1的变化及其对ED大鼠阴茎组织纤维化的影响.方法:取100只SD雄性大鼠,20只为正常组(N),其余120只为建模组,以环境雌激素样饲料联合冷刺激予以复合干预,24周后通过APO阴茎勃起实验和交配实验筛选ED大鼠,...     

Serum fetuin--a concentrations are inversely related to cytokine concentrations in patients with chronic renal failure

Background/Aims: A close relationship exists between inflammation and vascular calcification. Although fetuin-A is known to be an inhibitor of calcification, studies correlating levels of this glycoprotein to markers of inflammation are limited. To understand these relationships, we investigated the relationship between serum fetuin-A and proinflammatory cytokine levels in patients with chronic renal failure (CRF). Methods: Thirty-two patients on haemodialysis (HD), 32 conservatively managed chronic kidney disease (CKD) patients and a control group of 25 subjects with normal renal function were enrolled in this study. Serum fetuin-A, IL-1β, IL-6 and TNF-α levels were measured by ELISA. Correlations between serum fetuin-A and IL-1β, IL-6 and TNF-α concentrations were investigated by the Spearman correlation test. Results: In 64 CRF patients (on HD and with CKD), serum fetuin-A was significantly and inversely related to IL-1β (P < 0.001), IL-6 (P = 0.025) and TNF-α levels (P = 0.007), respectively. The serum fetuin-A levels of the control subjects were not significantly correlated to levels of the inflammatory markers IL-1β, IL-6 and TNF-α (P = 0.551, 0.985 and 0.984, respectively). Conclusion: The negative correlation between serum fetuin-A and cytokine concentrations in CRF patients supports the hypothesis of inflammation-dependent down-regulation of fetuin-A expression.     

Glucocorticoids regulate natural killer cell function epigenetically

Although glucocorticoids are well known for their capacity to suppress the immune response, glucocorticoids can also promote immune responsiveness. It was the purpose of this investigation to evaluate the molecular basis for this apparent dichotomous immunologic effect. Glucocorticoid treatment of natural killer cells (NK) was shown to reduce NK cell cytolytic activity by reduction of histone promoter acetylation for perforin and granzyme B, which corresponded with reduced mRNA and protein for each. In contrast, glucocorticoid treatment increased histone acetylation at regulatory regions for interferon gamma and IL-6, as well as chromatin accessibility for each. This increase in histone acetylation was associated with increased proinflammatory cytokine mRNA and protein production upon cellular stimulation. These immunologic effects were evident at the level of the individual cell and demonstrate glucocorticoids to epigenetically reduce NK cell cytolytic activity while at the same time to prime NK cells for proinflammatory cytokine production.     

Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men

Total sleep deprivation in humans is associated with increased daytime sleepiness, decreased performance, elevations in inflammatory cytokines, and hormonal/metabolic disturbances.To assess the effects of 40 h of total sleep deprivation (TSD) under constant and well controlled conditions, on plasma levels of TNF-α and its receptor (TNFR1), interleukin-6 (IL-6), cortisol and C-reactive protein (CRP), sleepiness and performance, 12 healthy men (29 ± 3 years) participated in a 5-days sleep deprivation experiment (two control nights followed by a night of sleep loss and one recovery night). Between 0800 and 2300 (i.e. between 25 and 40 h of sleep deprivation), a serial of blood sampling, multiple sleep latency, subjective levels of sleepiness and reaction time tests were completed before (day 2: D2) and after (day 4: D4) one night of sleep loss. We showed that an acute sleep deprivation (i.e. after 34 and 37 h of sleep deprivation) induced a significant increase in TNF-α (P < 0.01), but there were no significant changes in TNFR1, IL-6, cortisol and CRP. In conclusion, our study in which constant and controlled experimental conditions were realized with healthy subjects and in absence of psychological or physical stressors, an acute total sleep deprivation (from 34 h) was sufficient to induce secretion of pro-inflammatory cytokine such as TNF-α, a marker more described in chronic sleep restriction or deprivation and as mediators of excessive sleepiness in humans in pathological conditions.     

Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species

Upon activation by phytohemagglutine (PHA), T-lymphocytes (T-cells) express receptors for growth factors, insulin, IGF-1 and IL2 and become insulin sensitive. Diabetic ketoacidosis (DKA) is associated with in vivo emergence of these growth factor receptors without incubation with PHA. As DKA consists of multiple metabolic alterations, in addition to hyperglycemia, we investigated the in vitro effect of different concentrations of glucose (5, 15, and 30 mM) in isolated CD4 of human T-cells at various time intervals (0, 24, 48, and 72 h). Hyperglycemia, but not euglycemia, resulted in de novo emergence of growth factor receptors in a dose- and time-dependent fashion. The activation was also associated with incremental changes in GLUT 4, IRS-1, proinflammatory cytokines, and oxidative stress components. We propose that activation of T-cells with development of insulin receptors in hyperglycemic conditions may serve as a mechanism for control of glucose entry into these cells, thus, protecting them against glucose toxicity.     

Alpha-lipoic acid protects against cisplatin-induced ototoxicity via the regulation of MAPKs and proinflammatory cytokines

Cisplatin is an effective antineoplastic drug that is widely used to treat various cancers; however, it causes side effects such as ototoxicity via the induction of apoptosis of hair cells in the cochlea. Alpha-lipoic acid (ALA) has been reported to exert a protective effect against both antibiotic-induced and cisplatin-induced hearing loss. Therefore, this study was conducted to (1) elucidate the mechanism of the protective effects of ALA against cisplatin-induced ototoxicity using in vitro and ex vivo culture systems of HEI-OC1 auditory cells and rat cochlear explants and (2) to gain additional insight into the apoptotic mechanism of cisplatin-induced ototoxicity. ALA pretreatment significantly reduced apoptotic cell death of the inner and outer hair cells in cisplatin-treated organ of Corti explants and attenuated ototoxicity via marked inhibition of the increase in the expression of IL-1β and IL-6, the phosphorylation of ERK and p38, the degradation of IκBα, the increase in intracellular levels of ROS, and the activation of caspase-3 in cisplatin-treated HEI-OC1 cells. This study represents the first histological evaluation of the organ of Corti following treatment with ALA, and these results indicate that the protective effects of ALA against cisplatin-induced ototoxicity are mediated via the regulation of MAPKs and proinflammatory cytokines.     

Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase

Ceramide produced by hydrolysis of plasma membrane sphingomyelin (SM) in different cells including brain cells in response to proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta)] plays an important role in coordinating cellular responses to stress, growth suppression, and apoptosis. The present study underlines the importance of IL-10 and IL-13, cytokines with potent antiinflammatory properties, in inhibiting the proinflammatory cytokine (TNF-alpha and IL-1beta)-mediated degradation of SM to ceramide in rat primary astrocytes. Treatment of rat primary astrocytes with TNF-alpha or IL-1beta led to rapid degradation of SM to ceramide, whereas IL-10 and IL-13 by themselves were unable to induce the degradation of SM to ceramide. Interestingly, both IL-10 and IL-13 prevented proinflammatory cytokine-induced degradation of SM to ceramide. Both IL-10 and IL-13 caused rapid activation of phosphatidylinositol (PI) 3-kinase, and inhibition of that kinase activity by wortmannin and LY294002 potently blocked the inhibitory effect of IL-10 and IL-13 on proinflammatory cytokine-mediated induction of ceramide production. This study suggests that the inhibition of proinflammatory cytokine-mediated degradation of SM to ceramide by IL-10 and IL-13 is mediated through the activation of PI 3-kinase. As ceramide induces apoptosis and IL-10 and IL-13 inhibit the induction of ceramide production, we examined the effect of IL-10 and IL-13 on proinflammatory cytokine-mediated apoptosis. Inhibition of TNF-alpha-induced apoptosis by IL-10 and IL-13 suggests that the antiapoptotic nature of IL-10 and IL-13 is probably due to the inhibition of ceramide production.     

The potential biochemical markers of Kashin–Beck disease: a meta-analysis

Objective: The objective of this study is to explore the cytokines in serum, synovial fluid as potential biomarkers of Kashin–Beck disease (KBD) and to further understand the role of these cytokines in the pathogenesis of KBD.

Methods: A systematic electronic database search was performed from inception up to 15 March 2015. Meta-analysis was performed for cytokines more than one repetition in studies with available data. The effect size was summarized as standardized mean difference (SMD) with 95% confidence intervals (CIs) by a random effect model.

Results: A total of 18 articles were included. The pooled standardized mean differences showed the serum levels of tumor necrosis factor alpha (2.72, 95% CI: 1.8 5–3.59), interleukin-1 beta (1.21, 95% CI: 0.6 1–1.80), and nitric oxide (2.60, 95% CI: 1.5 2–3.68) were significantly higher in adult KBD patients compared with that in healthy controls.

Conclusions: There was explicit evidence showing that the tumor necrosis factor alpha, interleukin-1 beta and nitric oxide were closely related to the presence of KBD, and these cytokines played a vital role in the pathogenesis of KBD.