Effect of rhubarb on inflammatory cytokines and complements in patients with systemic inflammation reaction syndrome and its significance

Background Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that targets the kidney to promote urinary phosphate excretion. In patients with chronic kidney disease (CKD), serum concentrations of phosphate (Pi) and FGF23 gradually increase as renal function declines and associate with various pathologies, including systemic inflammation and anemia. Our previous studies revealed FGF23 contributes to inflammation by directly targeting hepatocytes via FGF receptor 4 (FGFR4) and inducing phospholipase Cγ (PLCγ) signaling and the expression of inflammatory cytokines. Experimental studies have shown Pi can accelerate CKD-associated pathologies, but direct effects of Pi on the liver are not well described. Here we compare the effects of Pi versus FGF23 on hepatocytes and determine their respective contributions to inflammation and anemia in the context of CKD. Methods We subject mice with global deletion of FGFR4 and wild-type littermates to increasing dietary Pi load (0.7%, 2.0%, or 3.0%) or an adenine-rich diet (used as a CKD model) in order to examine systemic inflammation and alterations in iron metabolism in the setting of normal and impaired renal function. In addition, we study primary mouse hepatocytes treated with FGF23 and increasing Pi concentrations and examine the activation of downstream signaling events and expression levels of specific target genes. Furthermore, we determine if co-treatment with inhibitors of Pi uptake and downstream signal mediators block the observed effects. Results A 3% Pi diet as well as an adenine-rich diet promote inflammation and iron dysregulation in mice. These effects are exacerbated in FGFR4 knockout mice. In cultured hepatocytes, expression of inflammatory cytokines, hepcidin and FGF23 are induced by Pi in a dose-dependent manner. Furthermore, Pi activates NFkB signaling and the inhibition of Pi uptake and of NFkB protects from Pi-induced effects. Conclusion We postulate that in CKD, gradual elevations in serum Pi promote inflammation and anemia by targeting the liver to induce gene programs which regulate the inflammatory response and iron metabolism. Our study indicates these Pi effects may be independent of FGF23. Pharmacological approaches targeting hyperphosphatemia or hepatic Pi actions might alleviate various CKD-associated pathologies. Disclosures No relevant conflicts of interest to declare.

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Are age-related biomarkers of dementia risk accelerated by low educational attainment?

Proceedings of IMPRS ◽

10.18060/25846 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Katherine A. Schaefer ◽

Frederick W. Unverzagt ◽

Huiping Xu ◽

Daniel O. Clark

Keyword(s):

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Neurofilament Light ◽

Early Onset Dementia ◽

Natural Logarithm ◽

Age Related ◽

Dementia Risk ◽

Low Education ◽

Anti Inflammatory ◽

Young Old

Background: Low education significantly elevates dementia risk but it is not clear whether this is through chronic systemic inflammation, early-onset dementia pathology, or other factors. This project compares biomarkers of inflammation and dementia pathology in a young-old and older cohort. Due to significantly lower education in the young-old cohort, we hypothesized evidence of similar or higher biomarker levels in the young-old cohort compared to the older cohort. Methods: Blood samples were used to measure pro-inflammatory cytokines (C-reactive protein (CRP), tumor necrosis factor (TNF interleukin (IL)-6, and IL-1 anti-inflammatory cytokines (IL-10 and IL-1RA), and the brain biomarkers phosphorylated tau (p-tau) and neurofilament light (NfL). Inflammatory markers were measured at the Considine Lab at the Indiana University School of Medicine using ELISA assays while p-tau and NfL were measured with Simoa assays at the Quanterix lab in Massachusetts. We used the natural logarithm of all biomarker variables to address skewed data. Linear regression was used to investigate race- and gender-adjusted differences in the biomarkers. Results: The young-old cohort (N=42) has a mean age of 62.4, 69.1% are female, and 78.6% are non-Hispanic black (NHB), while the older cohort (N=60) has a mean age of 80.3, 60% are female, and 20% are NHB. Median education in the young-old cohort is 12 vs 16 in the older cohort. Adjusted models showed higher mean CRP (p=0.004) and lower mean IL-10 (p<0.001) in the young-old cohort. TNF- (p <0.001), IL-6 (p=0.021), and IL-1(p=0.017), P-tau (p=0.003), and NfL (p<0.001) were all higher in the older cohort. Conclusion: We found partial support of our hypothesis in that the younger, low education cohort had higher mean CRP and lower mean IL-10 (anti-inflammatory). However, brain biomarkers were higher in the older cohort. More research will be needed to determine if and how low education elevates ADRD risk through systemic inflammation.

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Abstract 205: Ouabain Activates the NF-κB Pathway in Macrophages via Na/K-ATPase/TLR4 Complex Leading to Pro-Inflammatory Cytokine Production

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.205 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Yiliang Chen ◽

Roy L Silverstein

Keyword(s):

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Culture Media ◽

Mrna Level ◽

Mrna Levels ◽

Inflammatory Cytokine Production ◽

Protein Levels ◽

Pro Inflammatory Cytokines

Cardiotonic steroids such as ouabain, digoxin, and marinobufagenin are known ligands for the plasma membrane receptor Na/K-ATPase (NKA). These ligands are able to stimulate interaction of the NKA with other membrane and cytosolic proteins leading to cellular events such as activation of kinase cascades and gene transcription. Endogenous cardiotonic steroids have been detected in human circulation and interestingly their levels were elevated in human patients with hypertension, congestive heart failure and diabetes, all of which were associated with chronic systemic inflammation. However, the role of cardiotonic steroids in systemic inflammation and immunity has not been well studied. We previously discovered that ouabain stimulated macrophages to produce pro-inflammatory cytokines, many of which are known targets of the transcription factor, NF-κB. Therefore, we hypothesized that ouabain activates NF-κB pathway leading to pro-inflammatory cytokine production in macrophages. Using Western blot and densitometry analysis, we showed that physiological concentrations of ouabain promoted IκBα degradation (as low as 5 nM ouabain decreased IκBα level by 66.8%±7.4%, n=4). This was accompanied by NF-κB translocation from cytoplasm to the nuclei as shown by immunocytochemistry (% of nuclei NF-κB signals increased from 30.5%±2.3% in control to 62.2%±2.6% in ouabain-treated macrophages, n>25). Moreover, via quantitative RT-PCR (n=3), we found that ouabain increased mRNA levels of pro-inflammatory cytokines such as MCP-1 (3.2±1.1 fold), TNF-α (59.7±35.6 fold), and CXCL-10 (2.8±1.6 fold), all of which are known NF-κB targets. Consistent with the increase in mRNA level, we found that MCP-1 protein levels were elevated in both cell lysates (1.8±0.3 fold) and culture media (1.4±0.1 fold; n=4). Addition of an NF-κB inhibitor blocked MCP-1 production induced by ouabain (n=4). Mechanistically, ouabain stimulated interaction between NKA and TLR4 as shown by Co-Immunoprecipitation (n=3). Blockade of TLR4 signaling using a specific peptide inhibitor, CLI-095, abolished the ouabain effect on NF-κB activation (n=3). We conclude that ouabain activates NF-κB through NKA/TLR4 complex leading to pro-inflammatory cytokine production by macrophages.

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TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation

Clinical Science ◽

10.1042/cs20120176 ◽

2012 ◽

Vol 123 (9) ◽

pp. 547-555 ◽

Cited By ~ 38

Author(s):

Stella Bernardi ◽

Giorgio Zauli ◽

Christos Tikellis ◽

Riccardo Candido ◽

Bruno Fabris ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Tolerance Test ◽

Metabolic Abnormalities ◽

High Fat ◽

Adipose Tissue Gene Expression ◽

Tissue Gene Expression ◽

Pro Inflammatory Cytokines

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).

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A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

Thrombosis and Haemostasis ◽

10.1160/th16-10-0799 ◽

2017 ◽

Vol 117 (09) ◽

pp. 1798-1807 ◽

Cited By ~ 12

Author(s):

Dorien Kiers ◽

Wouter A. van der Heijden ◽

Lisa van Ede ◽

Jelle Gerretsen ◽

Quirijn de Mast ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Platelet Reactivity ◽

Medical Center ◽

Randomised Trial ◽

P2y12 Inhibitors ◽

Supplementary Material ◽

P2y12 Antagonist ◽

Plasma Adenosine

SummaryThe use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y12 inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y12 antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y12 inhibition impaired platelet reactivity, there was no correlation with cytokine responses.Note: This work was performed at the Radboud University Medical Center, Nijmegen, The Netherlands.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Adjuvant treatment with crude rhubarb for patients with systemic inflammation reaction syndrome/sepsis: A meta-analysis of randomized controlled trials

Journal of Critical Care ◽

10.1016/j.jcrc.2014.11.008 ◽

2015 ◽

Vol 30 (2) ◽

pp. 282-289 ◽

Cited By ~ 9

Author(s):

Liyuan Zhang ◽

Jing Chen ◽

Dapeng Jiang ◽

Peng Zhang

Keyword(s):

Randomized Controlled Trials ◽

Systemic Inflammation ◽

Adjuvant Treatment ◽

Meta Analysis ◽

Controlled Trials ◽

Randomized Controlled ◽

Inflammation Reaction

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Endothelial cell apicobasal polarity coordinates distinct responses to luminally versus abluminally delivered TNF-α in a microvascular mimetic

Integrative Biology ◽

10.1093/intbio/zyaa022 ◽

2020 ◽

Vol 12 (11) ◽

pp. 275-289

Author(s):

Alec T Salminen ◽

Jeffrey Tithof ◽

Yara Izhiman ◽

Elysia A Masters ◽

Molly C McCloskey ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Polymorphonuclear Neutrophil ◽

Apical Surface ◽

Necrosis Factor Alpha ◽

Apicobasal Polarity ◽

Tnf Α ◽

Luminal Side ◽

Cytokine Tumor Necrosis Factor ◽

Key Barrier

Abstract Endothelial cells (ECs) are an active component of the immune system and interact directly with inflammatory cytokines. While ECs are known to be polarized cells, the potential role of apicobasal polarity in response to inflammatory mediators has been scarcely studied. Acute inflammation is vital in maintaining healthy tissue in response to infection; however, chronic inflammation can lead to the production of systemic inflammatory cytokines and deregulated leukocyte trafficking, even in the absence of a local infection. Elevated levels of cytokines in circulation underlie the pathogenesis of sepsis, the leading cause of intensive care death. Because ECs constitute a key barrier between circulation (luminal interface) and tissue (abluminal interface), we hypothesize that ECs respond differentially to inflammatory challenge originating in the tissue versus circulation as in local and systemic inflammation, respectively. To begin this investigation, we stimulated ECs abluminally and luminally with the inflammatory cytokine tumor necrosis factor alpha (TNF-α) to mimic a key feature of local and systemic inflammation, respectively, in a microvascular mimetic (μSiM-MVM). Polarized IL-8 secretion and polymorphonuclear neutrophil (PMN) transmigration were quantified to characterize the EC response to luminal versus abluminal TNF-α. We observed that ECs uniformly secrete IL-8 in response to abluminal TNF-α and is followed by PMN transmigration. The response to abluminal treatment was coupled with the formation of ICAM-1-rich membrane ruffles on the apical surface of ECs. In contrast, luminally stimulated ECs secreted five times more IL-8 into the luminal compartment than the abluminal compartment and sequestered PMNs on the apical EC surface. Our results identify clear differences in the response of ECs to TNF-α originating from the abluminal versus luminal side of a monolayer for the first time and may provide novel insight into future inflammatory disease intervention strategies.

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Baroreceptor denervation reduces inflammatory status and worsens cardiovascular collapse during systemic inflammation

10.1101/748608 ◽

2019 ◽

Author(s):

Mateus R. Amorim ◽

Júnia L. de Deus ◽

Camila A. Pereira ◽

Luiz E. V. da Silva ◽

Gabriela S. Borges ◽

...

Keyword(s):

Blood Pressure ◽

Blood Vessels ◽

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Vascular Function ◽

Vascular Dysfunction ◽

Cardiovascular Collapse ◽

Inflammatory Status ◽

Resistance Vessels ◽

Autonomic Cardiovascular Control

ABSTRACTBeyond the regulation of cardiovascular function, baroreceptor afferents play polymodal roles. We hypothesized that baroreceptor denervation affects lipopolysaccharide (LPS)-induced systemic inflammation (SI) and hemodynamic collapse in conscious rats, and that these parameters are interconnected. We combine: a) hemodynamic and thermoregulatory recordings after LPS administration at a septic-like dose b) analysis of the cardiovascular complexity, c) evaluation of vascular function in mesenteric resistance vessels, and d) measurements of inflammatory cytokines (plasma and spleen). LPS-induced drop in blood pressure was higher in sino-aortic denervated (SAD) rats. LPS-induced hemodynamic collapse was associated with SAD-dependent autonomic disbalance. LPS-induced vascular dysfunction was not affected by SAD. Surprisingly, SAD blunted LPS-induced surges of plasma and spleen cytokines. These data indicate that sino-aortic afferents are key to alleviate LPS-induced cardiovascular collapse, affecting the autonomic cardiovascular control, without affecting resistance blood vessels. Moreover, baroreflex modulation of the LPS-induced SI and hemodynamic collapse seem not to be interconnected.

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COVID-19 Pathology on Various Organs and Regenerative Medicine and Stem Cell-Based Interventions

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.675310 ◽

2021 ◽

Vol 9 ◽

Author(s):

Babak Arjmand ◽

Sepideh Alavi-Moghadam ◽

Peyvand Parhizkar Roudsari ◽

Mostafa Rezaei-Tavirani ◽

Fakher Rahim ◽

...

Keyword(s):

Stem Cell ◽

Severe Acute Respiratory Syndrome ◽

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Multiple Organ ◽

Cytokine Storm ◽

Functional Impairments ◽

Therapeutic Approaches ◽

Novel Coronavirus ◽

Pro Inflammatory Cytokines

Severe acute respiratory syndrome-coronavirus 2, a novel betacoronavirus, has caused the global outbreak of a contagious infection named coronavirus disease-2019. Severely ill subjects have shown higher levels of pro-inflammatory cytokines. Cytokine storm is the term that can be used for a systemic inflammation leading to the production of inflammatory cytokines and activation of immune cells. In coronavirus disease-2019 infection, a cytokine storm contributes to the mortality rate of the disease and can lead to multiple-organ dysfunction syndrome through auto-destructive responses of systemic inflammation. Direct effects of the severe acute respiratory syndrome associated with infection as well as hyperinflammatory reactions are in association with disease complications. Besides acute respiratory distress syndrome, functional impairments of the cardiovascular system, central nervous system, kidneys, liver, and several others can be mentioned as the possible consequences. In addition to the current therapeutic approaches for coronavirus disease-2019, which are mostly supportive, stem cell-based therapies have shown the capacity for controlling the inflammation and attenuating the cytokine storm. Therefore, after a brief review of novel coronavirus characteristics, this review aims to explain the effects of coronavirus disease-2019 cytokine storm on different organs of the human body. The roles of stem cell-based therapies on attenuating cytokine release syndrome are also stated.

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