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1.
New insights into molecular pathways in colorectal cancer: Adiponectin, interleukin-6 and opioid signaling.
Świerczyński, M, Szymaszkiewicz, A, Fichna, J, Zielińska, M
Biochimica et biophysica acta. Reviews on cancer. 2021;(1):188460
Abstract
Colorectal cancer (CRC) is one of the most common cause of death among neoplasms around the world. The environmental factors, like diet and obesity, are crucial in CRC pathogenesis by creating cancer-favorable microenvironment and hormonal changes. Adiponectin, the adipose tissue-specific hormone, is generally considered to negatively correlate with CRC development. The interleukin 6 (IL-6) is one of the most important pro-inflammatory cytokine connected with CRC, which is strongly inflammation-associated. The opioids are variable group substantially correlated with cancers - the endogenous opioids affect immune system and cell cycle including proliferation and cell death whereas exogenous opioids are leading clinically used analgesics in terminal cancer patients. In this review we discuss the involvement of adiponectin, IL-6 and opioids in CRC pathogenesis, their link with obesity, possible cross-talk and potential novel therapeutic approach in CRC treatment.
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Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells.
Püschel, F, Favaro, F, Redondo-Pedraza, J, Lucendo, E, Iurlaro, R, Marchetti, S, Majem, B, Eldering, E, Nadal, E, Ricci, JE, et al
Proceedings of the National Academy of Sciences of the United States of America. 2020;(18):9932-9941
Abstract
Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
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Role of inositol to improve surfactant functions and reduce IL-6 levels: A potential adjuvant strategy for SARS-CoV-2 pneumonia?
Laganà, AS, Unfer, V, Garzon, S, Bizzarri, M
Medical hypotheses. 2020;:110262
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Abstract
To date, the spread of SARS-CoV-2 infection is increasing worldwide and represents a primary healthcare emergency. Although the infection can be asymptomatic, several cases develop severe pneumonia and acute respiratory distress syndrome (ARDS) characterized by high levels of pro-inflammatory cytokines, primarily interleukin (IL)-6. Based on available data, the severity of ARDS and serum levels of IL-6 are key determinants for the prognosis. In this scenario, available in vitro and in vivo data suggested that myo-inositol is able to increase the synthesis and function of the surfactant phosphatidylinositol, acting on the phosphoinositide 3-kinase (PI3K)-regulated signaling, with amelioration of both immune system and oxygenation at the bronchoalveolar level. In addition, myo-inositol has been found able to decrease the levels of IL-6 in several experimental settings, due to an effect on the inositol-requiring enzyme 1 (IRE1)-X-box-binding protein 1 (XBP1) and on the signal transducer and activator of transcription 3 (STAT3) pathways. In this scenario, treatment with myo-inositol may be able to reduce IL-6 dependent inflammatory response and improve oxygenation in patients with severe ARDS by SARS-CoV-2. In addition, the action of myo-inositol on IRE1 endonuclease activity may also inhibit the replication of SARS-CoV-2, as was reported for the respiratory syncytial virus. Since the available data are extremely limited, if this potential therapeutic approach will be considered valid in the clinical practice, the necessary future investigations should aim to identify the best dose, administration route (oral, intravenous and/or aerosol nebulization), and cluster(s) of patients which may get beneficial effects from this treatment.
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, LCK, Wilson, SJ, et al
The Journal of allergy and clinical immunology. 2019;(2):577-590
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Abstract
BACKGROUND Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. CONCLUSIONS Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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The study of vitamin D administration effect on CRP and Interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
Miroliaee, AE, Salamzadeh, J, Shokouhi, S, Sahraei, Z
Journal of critical care. 2018;:300-305
Abstract
PURPOSE In regard with the effect of immune-stimulants in the treatment of infectious diseases, the effect of vitamin D administration on the outcome of patients with Ventilator-Associated Pneumonia (VAP) with a high rate of mortality, was studied. MATERIAL AND METHOD In this trial, 46 adult patients suffering from VAP and vitamin D deficiency were enrolled. The first group of patients received single intramuscular injection of vitamin D (300000Unit), while the other group were given the placebo. RESULTS Administration of vitamin D significantly enhanced its levels (P<0.0001) in the treated patients (12.28±8.26) in comparison with placebo group (1.15±1.50). Serum Interleukin-6 levels were significantly reduced in the treated group compared to placebo (P=0.01). Although C-Reactive protein (CRP) levels showed an improving trend in the vitamin D group, no significant difference between groups (P=0.12) was found. Interestingly, the mortality rate of patients that treated with vitamin D (5/24) was significantly lower (p=0.04) than that of the placebo group (11/22). CONCLUSION Our results indicate that vitamin D administration can significantly reduce the IL-6 as prognostic marker in VAP patients, and must be considered as adjunct option in the treatment of VAP patients.
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Nutritional interventions and the IL-6 response to exercise.
Hennigar, SR, McClung, JP, Pasiakos, SM
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017;(9):3719-3728
Abstract
IL-6 is a pleiotropic cytokine with a wide range of biologic effects. In response to prolonged exercise, IL-6 is synthesized by contracting skeletal muscle and released into circulation. Circulating IL-6 is thought to maintain energy status during exercise by acting as an energy sensor for contracting muscle and stimulating glucose production. If tissue damage occurs, immune cells infiltrate and secrete cytokines, including IL-6, to repair skeletal muscle damage. With adequate rest and nutrition, the IL-6 response to exercise is attenuated as skeletal muscle adapts to training. However, sustained elevations in IL-6 due to repeated bouts of unaccustomed activities or prolonged exercise with limited rest may result in untoward physiologic effects, such as accelerated muscle proteolysis and diminished nutrient absorption, and may impair normal adaptive responses to training. Recent intervention studies have explored the role of mixed meals or carbohydrate, protein, ω-3 fatty acid, or antioxidant supplementation in mitigating exercise-induced increases in IL-6. Emerging evidence suggests that sufficient energy intake before exercise is an important factor in attenuating exercise-induced IL-6 by maintaining muscle glycogen. We detail various nutritional interventions that may affect the IL-6 response to exercise in healthy human adults and provide recommendations for future research exploring the role of IL-6 in the adaptive response to exercise.-Hennigar, S. R., McClung, J. P., Pasiakos, S. M. Nutritional interventions and the IL-6 response to exercise.
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ERAS Protocol Reduces IL-6 Secretion in Colorectal Laparoscopic Surgery: Results From a Randomized Clinical Trial.
Mari, G, Crippa, J, Costanzi, A, Mazzola, M, Rossi, M, Maggioni, D
Surgical laparoscopy, endoscopy & percutaneous techniques. 2016;(6):444-448
Abstract
BACKGROUND Enhanced Recovery After Surgery (ERAS) program applied to colorectal laparoscopic surgery is well known to reduce hospitalization improving short-terms outcomes. Its goal is to minimize the surgical stress response in order to maintain the physiological homeostasis altered by surgery. However, there is little knowledge about the involved dynamics in the reduction of the surgical stress that these programs allow. The primary aim of this study was to compare the level of immune and nutritional serum investigators across surgery in patients undergoing elective colorectal laparoscopic surgery within an ERAS protocol or according to a standard care program. MATERIALS AND METHODS One hundred forty patients undergoing major colorectal laparoscopic surgery were enrolled and randomized in 2 groups (70 per arm).Cortisol, C-reactive protein (CRP), white blood cell count, prolactin, interleukin (IL)-6 levels were collected preoperatively, 1, 3, and 5 days after surgery. Transferrin, prealbumin, albumin, and triglyceride level were collected preoperatively, 1 and 5 days after surgery. Short-term outcomes were also prospectively assessed. RESULTS IL-6 levels were lower in the ERAS group on 1, 3, and 5 days postoperatively (P<0.05). IL-6 levels in the enhanced group, differently from control group, returned to preoperative level 3 days after surgery. CRP level was lower in the enhanced group on day 1, 3, and 5 (P<0.05). There was no difference in cortisol and prolactin levels between groups. Prealbumin serum level was higher on day 5 (P<0.05) compared to standard group. CONCLUSIONS ERAS protocol applied to colorectal laparoscopic surgery affects surgical stress response, decreasing IL-6 and CRP levels postoperatively and improving prealbumin postoperative synthesis.
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Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: A randomized controlled trial.
Kuebler, U, Arpagaus, A, Meister, RE, von Känel, R, Huber, S, Ehlert, U, Wirtz, PH
Brain, behavior, and immunity. 2016;:200-208
Abstract
Flavanol-rich dark chocolate consumption relates to lower risk of cardiovascular mortality, but underlying mechanisms are elusive. We investigated the effect of acute dark chocolate consumption on inflammatory measures before and after stress. Healthy men, aged 20-50years, were randomly assigned to a single intake of either 50g of flavanol-rich dark chocolate (n=31) or 50g of optically identical flavanol-free placebo-chocolate (n=34). Two hours after chocolate intake, both groups underwent the 15-min Trier Social Stress Test. We measured DNA-binding-activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, as well as plasma and whole blood mRNA levels of the pro-inflammatory cytokines IL-1β and IL-6, and the anti-inflammatory cytokine IL-10, prior to chocolate intake as well as before and several times after stress. We also repeatedly measured the flavanol epicatechin and the stress hormones epinephrine and cortisol in plasma and saliva, respectively. Compared to the placebo-chocolate-group, the dark-chocolate-group revealed a marginal increase in IL-10 mRNA prior to stress (p=0.065), and a significantly blunted stress reactivity of NF-κB-BA, IL-1β mRNA, and IL-6 mRNA (p's⩽0.036) with higher epicatechin levels relating to lower pro-inflammatory stress reactivity (p's⩽0.033). Stress hormone changes to stress were controlled. None of the other measures showed a significant chocolate effect (p's⩾0.19). Our findings indicate that acute flavanol-rich dark chocolate exerts anti-inflammatory effects both by increasing mRNA expression of the anti-inflammatory cytokine IL-10 and by attenuating the intracellular pro-inflammatory stress response. This mechanism may add to beneficial effects of dark chocolate on cardiovascular health.
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Surgical Stress Reduction in Elderly Patients Undergoing Elective Colorectal Laparoscopic Surgery within an ERAS Protocol.
Mari, G, Costanzi, A, Crippa, J, Falbo, R, Miranda, A, Rossi, M, Berardi, V, Maggioni, D, ,
Chirurgia (Bucharest, Romania : 1990). 2016;(6):476-480
Abstract
ERAS program applied to colorectal laparoscopic surgery is well known to reduce hospitalization improving short terms outcomes and minimizing the Surgical Stress Response. However its effectiveness in elderly population is yet to be demonstrated. The primary aim of this study is to compare the level of immune and nutritional serum indexes across surgery in patients aged over 70 years old undergoing elective colorectal laparoscopic surgery within an ERAS protocol or according to a Standard program. 83 patients undergoing colorectal laparoscopic surgery were enrolled and randomized in two groups (ERAS Group 40, Standard Group 43) within a larger randomized trial on a general population. Surgical stress parameters were collected preoperatively, 1, 3 and 5 days after surgery. Nutritional parameters were collected preoperatively, 1 and 5 days after surgery. Short Term Outcomes were also prospectively assessed. IL-6 levels were lower in the EG on 1, 3, and 5 days post-operatively (p 0.05). IL-6 levels in the Enhanced group returned to pre operative level 3 days after surgery. C-reactive protein level was lower in the Enhanced group on day 1, 3, and 5 (p 0.05). There was no difference in Cortisol and Prolactin levels between groups. Prealbumin serum level was higher on day 5 (p 0.05) compared to standard group. Postoperative outcomes in terms of normal bowel function and length of hospital stay were significantly improved in the ERAS group. Colorectal laparoscopic surgery within an ERAS prototcol in elderly patients affects Surgical Stress Response, decreasing IL-6 and CRP levels postoperatively and improving Prealbumin post operative synthesis.
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Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.
Staiano, RI, Loffredo, S, Borriello, F, Iannotti, FA, Piscitelli, F, Orlando, P, Secondo, A, Granata, F, Lepore, MT, Fiorelli, A, et al
Journal of leukocyte biology. 2016;(4):531-40
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Abstract
Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.