scholarly journals Role of Angiopoietin/Tie2 in Critical Illness: Promising Biomarker, Disease Mediator, and Therapeutic Target?

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Alexander Lukasz ◽  
Philipp Kümpers ◽  
Sascha David
Keyword(s):  
Critical Illness ◽  
Inflammatory Responses ◽  
Endothelial Activation ◽  
Multiple Organ ◽  
Endothelial Barrier Function ◽  
Major Step ◽  
Immune Paralysis ◽  
Broad Term ◽  
Critical Ill Patients

Critical illness is a descriptive, broad term for a serious clinical condition that can result from enormously heterogeneous etiologies. A common end feature these patients regularly suffer from is the so-called multiple organ dysfunction syndrome (MODS), often a consequence of organ hypoperfusion and ischemia, coagulopathies, overwhelming inflammatory responses, immune paralysis and mitochondrial dysfunction. Mechanistically, endothelial injury and particularly microvascular leakage is a major step in the pathophysiology of MODS and contributes to its mortality. The angiopoietin (Angpt)/Tie2 system consists of the endothelial tyrosine kinase Tie2 and its 4 circulating ligands (Angpt1-4). The balance between the agonistic ligand “Angpt-1" and the antagonistic one “Angpt-2" regulates baseline endothelial barrier function and its response to injury and is therefore considered a gatekeeper of endothelial activation. This paper provides a systematic overview of the Angpt/Tie2 system with respect to (1) its role as a global biomarker of endothelial activation in critical ill patients, (2) its contribution to MODS pathophysiology as a disease mediator, and last but not least (3) putative therapeutic applications to modify the activation state of Tie2 in mice and men.

scholarly journals CNS-Spleen Axis – a Close Interplay in Mediating Inflammatory Responses in Burn Patients and a Key to Novel Burn Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Noorisah Khan ◽  
Supreet Kaur ◽  
Carly M. Knuth ◽  
Marc G. Jeschke
Keyword(s):  
Inflammatory Responses ◽  
Immune Dysfunction ◽  
Multiple Organ ◽  
Burn Patients ◽  
Severe Burn ◽  
Therapeutic Techniques ◽  
Immune Balance ◽  
The Central Nervous System ◽  
Immune Imbalance

Severe burn-induced inflammation and subsequent hypermetabolic response can lead to profound infection and sepsis, resulting in multiple organ failure and high mortality risk in patients. This represents an extremely challenging issue for clinicians as sepsis is the leading cause of mortality in burn patients. Since hyperinflammation and immune dysfunction are a result of an immune imbalance, restoring these conditions seem to have promising benefits for burn patients. A key network that modulates the immune balance is the central nervous system (CNS)-spleen axis, which coordinates multiple signaling pathways, including sympathetic and parasympathetic pathways. Modulating inflammation is a key strategy that researchers use to understand neuroimmunomodulation in other hyperinflammatory disease models and modulating the CNS-spleen axis has led to improved clinical outcomes in patients. As the immune balance is paramount for recovery in burn-induced sepsis and patients with hyperinflammatory conditions, it appears that severe burn injuries substantially alter this CNS-spleen axis. Therefore, it is essential to address and discuss the potential therapeutic techniques that target the CNS-spleen axis that aim to restore homeostasis in burn patients. To understand this in detail, we have conducted a systematic review to explore the role of the CNS-spleen axis and its impact on immunomodulation concerning the burn-induced hypermetabolic response and associated sepsis complications. Furthermore, this thorough review explores the role of the spleen, CNS-spleen axis in the ebb and flow phases following a severe burn, how this axis induces metabolic factors and immune dysfunction, and therapeutic techniques and chemical interventions that restore the immune balance via neuroimmunomodulation.

scholarly journals Mucosal Immunity and the Intestinal Microbiome in the Development of Critical Illness

2011 ◽  
Vol 2011 ◽  
pp. 1-12
Author(s):  
Krisztina Madách ◽  
Katalin Kristóf ◽  
Eszter Tulassay ◽  
Zsolt Iványi ◽  
Anna Erdei ◽  
...  
Keyword(s):  
Critical Illness ◽  
Mucosal Immunity ◽  
Multiple Organ ◽  
Intestinal Microbiome ◽  
Multiple Organ Dysfunction ◽  
First Line ◽  
External Intervention ◽  
Host Tissues

The intestinal community, including the commensal microbial flora as well as the host tissues, represents a functional whole in vivo. Under physiological circumstances, this symbiosis brings great benefit for the host; however, critical illness induces profound disturbances in the intestinal ecosystem affecting both procaryotic and eucaryotic members. Today, 25 years after the gut was first described as a motor of multiple organ dysfunction syndrome, the role of the injured splanchnic compartment in the pathomechanism and development of critical illness is still in the first line of research. Multiple mechanisms have been identified by which the stressed gut may affect host homeostasis, and how external intervention might help to rebalance physiology. This paper provides a brief overview of the present of this field.

The Immunomodulatory Role of G2013 (α-L-Guluronic Acid) on the Expression of TLR2 and TLR4 in HT29 cell line

2019 ◽  
Vol 16 (1) ◽  
pp. 91-95 ◽  
Author(s):  
Hamid Farhang ◽  
Laleh Sharifi ◽  
Mohammad Mehdi Soltan Dallal ◽  
Mona Moshiri ◽  
Zahra Norouzbabaie ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Rna Extraction ◽  
Cell Plate ◽  
Inhibitory Effect ◽  
Control Group ◽  
Ht29 Cells ◽  
Guluronic Acid ◽  
Tlr4 Mrna

Background: The non-steroidal anti-inflammatory drugs (NSAIDs) play crucial role in the controlling of inflammatory diseases. Due to the vast side effects of NSAIDs, its use is limited. G2013 or &amp;#945;-L-Guluronic Acid is a new NSAID with immunomodulatory features. Objectives: Considering the leading role of TLRs in inflammatory responses, in this study, we aimed to evaluate G2013 cytotoxicity and its effect on the expression of TLR2 and TLR4 molecules. Methods: HEK293-TLR2 and HEK293-TLR4 cells were cultured and seeded on 96-well cell plate, and MTT assay was performed for detecting the viability of the cells after treatment with different concentrations of G2013. HT29 cells were grown and treated with low and high doses of G2013. After total RNA extraction and cDNA synthesis, quantitative real-time PCR were performed to assess the TLR2 and TLR4 mRNA synthesis. Results: We found that concentrations of ≤125 &amp;#181;g/ml of G2013 had no apparent cytotoxicity effect on the HEK293-TLR2 and -TLR4 cells. Our results indicated that after G2013 treatment (5 &amp;#181;g/ml) in HT29 cells, TLR2 and TLR4 mRNA expression decreased significantly compared with the untreated control group (p=0.02 and p=0.001 respectively). Conclusion: The results of this study revealed that G2013 can down regulate the TLR2 and TLR4 gene expression and exerts its inhibitory effect. Our findings are parallel to our previous finding which showed G2013 ability to down regulate the signaling pathway of TLRs. However, further studies are needed to identify the molecular mechanism of G2013.<p&gt;

scholarly journals Manipulation of Quercetin and Melatonin in the Down-Regulation of HIF-1α, HSP-70 and VEGF Pathways in Rat’s Kidneys Induced by Hypoxic Stress

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582094979
Author(s):  
Aliah R. Alshanwani ◽  
Sameerah Shaheen ◽  
Laila M. Faddah ◽  
Ahlam M. Alhusaini ◽  
Hanaa M. Ali ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Histopathological Examination ◽  
Hemoglobin Concentration ◽  
Vascular Endothelial ◽  
Hsp 70 ◽  
Reactive Protein ◽  
Defensive Role ◽  
Factor Α ◽  
Endothelial Growth Factor

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment.

scholarly journals Modulation of Macrophages M1/M2 Polarization Using Carbohydrate-Functionalized Polymeric Nanoparticles

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 88
Author(s):  
Raquel G. D. Andrade ◽  
Bruno Reis ◽  
Benjamin Costas ◽  
Sofia A. Costa Lima ◽  
Salette Reis
Keyword(s):  
Inflammatory Responses ◽  
Polymeric Nanoparticles ◽  
Interaction Mechanism ◽  
Mannose Receptor ◽  
The Body ◽  
Receptor Expression ◽  
Production Methods ◽  
Polymeric Nanocarriers ◽  
Efficient Delivery

Exploiting surface endocytosis receptors using carbohydrate-conjugated nanocarriers brings outstanding approaches to an efficient delivery towards a specific target. Macrophages are cells of innate immunity found throughout the body. Plasticity of macrophages is evidenced by alterations in phenotypic polarization in response to stimuli, and is associated with changes in effector molecules, receptor expression, and cytokine profile. M1-polarized macrophages are involved in pro-inflammatory responses while M2 macrophages are capable of anti-inflammatory response and tissue repair. Modulation of macrophages’ activation state is an effective approach for several disease therapies, mediated by carbohydrate-coated nanocarriers. In this review, polymeric nanocarriers targeting macrophages are described in terms of production methods and conjugation strategies, highlighting the role of mannose receptor in the polarization of macrophages, and targeting approaches for infectious diseases, cancer immunotherapy, and prevention. Translation of this nanomedicine approach still requires further elucidation of the interaction mechanism between nanocarriers and macrophages towards clinical applications.

scholarly journals Adaptive metabolic and inflammatory responses identified using accelerated aging metrics are linked to adverse outcomes in severe SARS-CoV-2 infection

2021 ◽  
Author(s):  
Alejandro Márquez-Salinas ◽  
Carlos A Fermín-Martínez ◽  
Neftalí Eduardo Antonio-Villa ◽  
Arsenio Vargas-Vázquez ◽  
Enrique C. Guerra ◽  
...  
Keyword(s):  
Critical Illness ◽  
Proportional Hazards ◽  
Inflammatory Responses ◽  
Age Groups ◽  
Accelerated Aging ◽  
Cox Proportional Hazards ◽  
Adverse Outcomes ◽  
Adaptive Responses ◽  
Predictive Capacity ◽  
Risk Of Death

Abstract Background Chronological age (CA) is a predictor of adverse COVID-19 outcomes; however, CA alone does not capture individual responses to SARS-CoV-2 infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components. Methods In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (ICU admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components. Results We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel&gt;0 had higher risk of death and critical illness compared to those with lower values (log-rank p&lt;0.001). Using unsupervised clustering we identified four adaptive responses to SARS-CoV-2 infection: 1) Inflammaging associated with CA, 2) metabolic dysfunction associated with cardio-metabolic comorbidities, 3) unfavorable hematological response, and 4) response associated with favorable outcomes. Conclusions Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.

scholarly journals Role of MDA5 in regulating CXCL10 expression induced by TLR3 signaling in human rheumatoid fibroblast-like synoviocytes

2021 ◽  
Author(s):  
Tatsuro Saruga ◽  
Tadaatsu Imaizumi ◽  
Shogo Kawaguchi ◽  
Kazuhiko Seya ◽  
Tomoh Matsumiya ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Poly I:C ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Inflammatory Reactions ◽  
Polyinosinic:Polycytidylic Acid ◽  
Tlr3 Signaling ◽  
Fibroblast Like Synoviocytes

AbstractC-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

The Role of Histones and Heparin in Sepsis: A Review

2021 ◽  
pp. 088506662199232
Author(s):  
Xiaojuan Zhang ◽  
Xin Li
Keyword(s):  
Septic Shock ◽  
Multiple Organ ◽  
Clinical Settings ◽  
The Past ◽  
Life Saving ◽  
Extracellular Histones ◽  
Sepsis And Septic Shock ◽  
Development And Management ◽  
Made In

Septic shock with multiple organ failure is a devastating situation in clinical settings. Through the past decades, much progress has been made in the management of sepsis and its underlying pathogenesis, but a highly effective therapeutic has not been developed. Recently, macromolecules such as histones have been targeted in the treatment of sepsis. Histones primarily function as chromosomal organizers to pack DNA and regulate its transcription through epigenetic mechanisms. However, a growing body of research has shown that histone family members can also exert cellular toxicity once they relocate from the nucleus into the extracellular space. Heparin, a commonly used anti-coagulant, has been shown to possess life-saving capabilities for septic patients, but the potential interplay between heparin and extracellular histones has not been investigated. In this review, we summarize the pathogenic roles of extracellular histones and the therapeutic roles of heparin in the development and management of sepsis and septic shock.

scholarly journals Crosstalk between Gut and Brain in Alzheimer’s Disease: The Role of Gut Microbiota Modulation Strategies

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 690
Author(s):  
Umair Shabbir ◽  
Muhammad Sajid Arshad ◽  
Aysha Sameen ◽  
Deog-Hwan Oh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Dietary Habits ◽  
Inflammatory Responses ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Gut Dysbiosis ◽  
Dynamic Population

The gut microbiota (GM) represents a diverse and dynamic population of microorganisms and about 100 trillion symbiotic microbial cells that dwell in the gastrointestinal tract. Studies suggest that the GM can influence the health of the host, and several factors can modify the GM composition, such as diet, drug intake, lifestyle, and geographical locations. Gut dysbiosis can affect brain immune homeostasis through the microbiota–gut–brain axis and can play a key role in the pathogenesis of neurodegenerative diseases, including dementia and Alzheimer’s disease (AD). The relationship between gut dysbiosis and AD is still elusive, but emerging evidence suggests that it can enhance the secretion of lipopolysaccharides and amyloids that may disturb intestinal permeability and the blood–brain barrier. In addition, it can promote the hallmarks of AD, such as oxidative stress, neuroinflammation, amyloid-beta formation, insulin resistance, and ultimately the causation of neural death. Poor dietary habits and aging, along with inflammatory responses due to dysbiosis, may contribute to the pathogenesis of AD. Thus, GM modulation through diet, probiotics, or fecal microbiota transplantation could represent potential therapeutics in AD. In this review, we discuss the role of GM dysbiosis in AD and potential therapeutic strategies to modulate GM in AD.

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