56: Excess glucose up-regulates first trimester trophoblast secretion of pro-inflammatory cytokines and chemokines and reduces anti-inflammatory IL-10 secretion

AbstractCOPD is a prevalent lung disease with significant impacts on public health. Affected airways exhibit pulmonary neutrophilia and consequent secretion of pro-inflammatory cytokines and proteases, which result in lung emphysema. Probiotics act as nonspecific modulators of the innate immune system that improve several inflammatory responses. To investigate the effect of Lactobacillus rhamnosus (Lr) on cigarette smoke (CS)-induced COPD C57Bl/6 mice were treated with Lr during the week before COPD induction and three times/week until euthanasia. For in vitro assays, murine bronchial epithelial cells as well as human bronchial epithelial cells exposed to cigarette smoke extract during 24 hours were treated with Lr 1 hour before CSE addition. Lr treatment attenuated the inflammatory response both in the airways and lung parenchyma, reducing neutrophilic infiltration and the production of pro-inflammatory cytokines and chemokines. Also, Lr-treated mice presented with lower metalloproteases in lung tissue and lung remodeling. In parallel to the reduction in the expression of TLR2, TLR4, TLR9, STAT3, and NF-κB in lung tissue, Lr increased the levels of IL-10 as well as SOCS3 and TIMP1/2, indicating the induction of an anti-inflammatory environment. Similarly, murine bronchial epithelial cells as well as human bronchial epithelial cells (BEAS) exposed to CSE produced pro-inflammatory cytokines and chemokines, which were inhibited by Lr treatment in association with the production of anti-inflammatory molecules. Moreover, the presence of Lr also modulated the expression of COPD-associated transcription found into BALF of COPD mice group, i.e., Lr downregulated expression of NF-κB and STAT3, and inversely upregulated increased expression of SOCS3. Thus, our findings indicate that Lr modulates the balance between pro- and anti-inflammatory cytokines in human bronchial epithelial cells upon CS exposure and it can be a useful tool to improve the lung inflammatory response associated with COPD.

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Nobiletin exerts anti-diabetic and anti-inflammatory effects in an in vitro human model and in vivo murine model of gestational diabetes

Clinical Science ◽

10.1042/cs20191099 ◽

2020 ◽

Vol 134 (6) ◽

pp. 571-592 ◽

Cited By ~ 5

Author(s):

Caitlyn Nguyen-Ngo ◽

Carlos Salomon ◽

Stephanie Quak ◽

Andrew Lai ◽

Jane C Willcox ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Metabolism ◽

Gestational Diabetes ◽

Mrna Expression ◽

Inflammatory Cytokines ◽

Cytokines And Chemokines ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.

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SYSTEM INFLAMMATORY RESPONSE AT THE EXACERBATION OF CHRONIC SIMPLE BRONCHITIS CAUSED BY INFLUENZA VIRUS B IN WOMEN IN THE FIRST TRIMESTER OF PREGNANCY

Bulletin physiology and pathology of respiration ◽

10.12737/20123 ◽

2016 ◽

Vol 1 (60) ◽

pp. 67-69

Author(s):

Смирнова ◽

Tatyana Smirnova ◽

Резник ◽

Vadim Reznik ◽

Одиреев ◽

...

Keyword(s):

Influenza Virus ◽

Inflammatory Cytokines ◽

First Trimester ◽

Fourth Group ◽

The Third ◽

Early Stages ◽

Tnf Α ◽

Antibody Titers ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

The contents of anti-inflammatory and pro-inflammatory cytokines in 95 women in the first trimester of gestation were studied. The first (control) group included 25 women with physiologic course of pregnancy; the second group consisted of 25 patients with exacerbation of chronic simple bronchitis caused by influenza virus B (antibody titers were 1:16-1:64); the third group consisted of 24 pregnant women with exacerbation of chronic simple bronchitis under influenza virus В (antibody titers were 1:32-1:128); the fourth group consisted of 21 women with exacerbation of chronic simple bronchitis induced by influenza virus B (antibody titers were 1:64-1:256) at early stages of gestation. In the patients of the second group in comparison with the patients of the first group there was an increase of IL-4 till 19.7±2.17 pg/ml, of TNF-α till 33.4±3.09 pg/ml and of INF-γ till 30.9±2.64 pg/ml (in the control it was 12.9±1.16 pg/ml, р<0.01; 24.7±2.27 pg/ml, р<0.05 and 22.3±2.08 pg/ml, р<0.05, respectively). In the third group in comparison with the second group there was no growth of anti-inflammatory and pro-inflammatory cytokines. In the fourth group in comparison with the second group there was the biggest increase of IL-4 till 27.7±2.42 pg/ml (р<0.05), of TNF-α till 43.6±2.79 pg/ml (p<0.05) and of INF-γ till 40.7±2.96 pg/ml (p<0.05). This suggest the paramount importance of the growth of anti-virus antibodies titers in the pathogenesis of exacerbation of chronic simple bronchitis under influenza virus B in women at early stages of gestation.

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Development of an Advanced Multicellular Intestinal Model for Assessing Immunomodulatory Properties of Anti-Inflammatory Compounds

Frontiers in Pharmacology ◽

10.3389/fphar.2021.639716 ◽

2021 ◽

Vol 12 ◽

Author(s):

Diego Marescotti ◽

Giuseppe Lo Sasso ◽

Diego Guerrera ◽

Kasper Renggli ◽

Pedro A. Ruiz Castro ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Intestinal Inflammation ◽

Epithelial Layer ◽

Barrier Integrity ◽

Cytokines And Chemokines ◽

Inflammatory State ◽

Tobacco Alkaloids ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Intestinal inflammation is the collective term for immune system-mediated diseases of unknown, multifactorial etiology, with often complex interactions between genetic and environmental factors. To mechanistically investigate the effect of treatment with compounds possessing immunomodulating properties in the context of intestinal inflammation, we developed an immunocompetent in vitro triculture intestinal model consisting of a differentiated intestinal epithelial layer (Caco-2/HT29-MTX) and immunocompetent cells (differentiated THP-1). The triculture mimicked a healthy intestine with stable barrier integrity. Lipopolysaccharide treatment triggered a controlled and reversible inflammatory state, resulting in significant impairment of barrier integrity and release of pro-inflammatory cytokines and chemokines, which are known hallmarks of intestinal inflammation. Treatment with known anti-inflammatory reference compounds (TPCA-1 and budenoside) prevented the induction of an inflammatory state; the decreasing triculture responses to this treatment measured by cytokine release, transepithelial electric resistance (TEER), and epithelial layer permeability proved the suitability of the intestinal model for anti-inflammatory drug screening. Finally, selected tobacco alkaloids (nicotine and anatabine (R/S and S forms)) were tested in the in vitro triculture for their potential anti-inflammatory properties. Indeed, naturally occurring alkaloids, such as tobacco-derived alkaloids, have shown substantial anti-inflammatory effects in several in vitro and in vivo models of inflammation, gaining increasing interest. Similar to the anti-inflammatory reference compounds, one of the tobacco alkaloids under investigation partially prevented the decrease in the TEER and increase in permeability and reduced the release of pro-inflammatory cytokines and chemokines. Taken together, these data confirm that our in vitro model is suitable for screening potential anti-inflammatory compounds in the context of intestinal inflammation.

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A Pathophysiological Role for Selective Alteration of the Cytokine-Chemokine Network – Inflammatory Theory in Alzheimer’s Disease

European Neurological Review ◽

10.17925/enr.2009.04.01.22 ◽

2009 ◽

Vol 4 (1) ◽

pp. 22

Author(s):

Domenico Gambi ◽

Marcella Reale ◽

◽

Keyword(s):

Inflammatory Cytokines ◽

Neuronal Damage ◽

Amyloid Β ◽

Oxygen Species ◽

Disease Treatment ◽

Cytokines And Chemokines ◽

Pathophysiological Role ◽

Altered Metabolism ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

There is growing evidence that an altered metabolism of the amyloid β (Aβ) precursor protein (APP) with progressive deposition of its Aβ fragment is a crucial event in the pathogenesis of AD. Increasing evidence suggests that inflammation and alteration of the cytokine–chemokine network contributes to the pathophysiology of AD. Activated microglia produce multiple pro-inflammatory cytokines, chemokines and reactive oxygen species (ROS); additionally, Aβ itself can stimulate microglia, astrocytes and oligodendrocytes to secrete pro-inflammatory cytokines, chemokines and ROS, which can lead to neuronal damage. The concomitant release of pro-inflammatory cytokines, which influence neurodegenerative pathways, and anti-inflammatory cytokines may contribute to the chronicity of the disease. It is the balance of pro-inflammatory products and anti-inflammatory products that may be essential in the degenerative process. Influencing this balance may help in slowing the disease. Promising results for neurological disease treatment may be achieved by targeting cytokines and chemokines in the development of antagonists and synthesis inhibitors.

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A Pathophysiological Role for Selective Alteration of the Cytokine–Chemokine Network—Inflammatory Theory in Alzheimer’s Disease

US Neurology ◽

10.17925/usn.2009.05.01.15 ◽

2009 ◽

Vol 05 (01) ◽

pp. 15

Author(s):

Domenico Gambi ◽

Marcella Reale ◽

◽

Keyword(s):

Inflammatory Cytokines ◽

Neuronal Damage ◽

Amyloid Β ◽

Oxygen Species ◽

Disease Treatment ◽

Cytokines And Chemokines ◽

Pathophysiological Role ◽

Altered Metabolism ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

There is growing evidence that an altered metabolism of the amyloid β (Aβ) precursor protein (APP) with progressive deposition of its Aβ fragment is a crucial event in the pathogenesis of AD. Increasing evidence suggests that inflammation and alteration of the cytokine–chemokine network contributes to the pathophysiology of AD. Activated microglia produce multiple pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS); additionally, Aβ itself can stimulate microglia, astrocytes, and oligodendrocytes to secrete pro-inflammatory cytokines, chemokines, and ROS, which can lead to neuronal damage. The concomitant release of pro-inflammatory cytokines, which influence neurodegenerative pathways, and anti-inflammatory cytokines may contribute to the chronicity of the disease. It is the balance of proinflammatory products and anti-inflammatory products that may be essential in the degenerative process. Influencing this balance may help in slowing the disease. Promising results for neurological disease treatment may be achieved by targeting cytokines and chemokines in the development of antagonists and synthesis inhibitors.

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Downregulation of Cytokines and Chemokines By GB Virus C after Transfusion-Transmission in HIV+ Blood Recipients

Blood ◽

10.1182/blood.v124.21.4122.4122 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4122-4122

Author(s):

Marion Lanteri ◽

Farnaz Vahidnia ◽

Sylvia Tan ◽

Jack Stapleton ◽

Philip J. Norris ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Pathway Analysis ◽

Myeloid Cells ◽

Host Immune System ◽

Cytokines And Chemokines ◽

Cell Counts ◽

Significant Difference ◽

Anti Inflammatory ◽

The Impact ◽

Pro Inflammatory Cytokines

Abstract Background: An association between GBV-C and improved HIV-infection outcome has been reported in HIV+ individuals with active GBV-C co-infection. The host immunological response underlying GBV-C and HIV co-infection that results in better HIV survival is not well characterized. This longitudinal study provides insight into the immune mechanisms underlying the potential protective role of GBV-C in HIV infected patients. Methods: Concentrations of 64 cytokines and chemokines were measured in plasma samples from the Viral Activation Transfusion Study (VATS) cohort before and longitudinally after GBV-C acquisition in 30 HIV+/GBV-C+ cases and 30 HIV+/GBV-C- controls up to 15 months following first transfusion. Adjusted mixed modeling was used to analyze the impact of GBV-C infection on cytokine/chemokine concentrations over time, adjusting for time elapsed, HAART treatment status, HIV VL, and subject. Pathway Analysis (PA; Qiagen Ingenuity Pathway Analysis) was performed to help predict what effect the observed cytokine changes might have on the host immune system. Results: A significant decrease in HIV VL was observed in HIV+/GBV-C+ cases from a mean log10(HIV VL) = 4.33 at baseline down to 3.24 at 100 days post-GBV-C detection (p<0.01) and maintained at 3.39 at 300 days post-GBV-C detection (p=0.02). GBV-C+/HIV+ cases had higher CD4 T cell counts than controls after acquisition of GBV-C infection. At baseline, there was no significant difference between HIV+/GBV-C+ cases and HIV+/GBV-C- controls in cytokine/chemokine levels. Most of the modulated cytokines and chemokines were reduced post-GBV-C detection, including many pro-inflammatory cytokines, suggesting an overall anti-inflammatory effect of GBV-C after co-infection in HIV+ subjects (Figure 1). After adjustment for HIV VL and HAART status, GBV-C infection significantly associated with decreases in the levels of nine cytokines (p<0.05 and FDR≤0.2): one anti-inflammatory cytokines IL-10 , two pro-inflammatory cytokines IL-6 and IL-7, four chemo-attractants MIP-1α, 6Ckine, I-TAC and GCP-2, and the growth factor SCF (Figure 2). Pathway Analysis showed HIV+/GBV-C+ cases had an enrichment in genes associated with cell death and apoptosis pathways of various cells (phagocytes, leukocytes including T cells, myeloid cells, dendritic cells, granulocytes, APC, neutrophils, neuroglia) and in the development of phagocytes and function of APCs and a decrease in binding, migration, and movement of cells within 3 months post-GBV-C detection. Similarly, 300 days post-GBV-C detection, there was a further decrease in cellular activation (PBMCs, myeloid cells) and cellular trafficking with an increase in the proliferation of myeloid progenitor cells and leukocyte infection. Conclusion: GBV-C has a protective effect in part through a competition mechanism leading to decreased inflammation and improved HIV disease outcome in GBV-C+/HIV+ individuals. Further studies are necessary to establish whether this purportedly non-pathogenic virus causing immune down-regulation could have deleterious effects on the host at the cellular level, including depleting the cells which are HIV targets. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

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Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽

10.3390/biom11050653 ◽

2021 ◽

Vol 11 (5) ◽

pp. 653

Author(s):

Seth O. Asiedu ◽

Samuel K. Kwofie ◽

Emmanuel Broni ◽

Michael D. Wilson

Keyword(s):

Molecular Docking ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Binding Energies ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Computational Techniques ◽

Cytokine Storm ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00237-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Carolyn A. Harris ◽

Diego M. Morales ◽

Rooshan Arshad ◽

James P. McAllister ◽

David D. Limbrick

Keyword(s):

Cerebrospinal Fluid ◽

Inflammatory Cytokines ◽

Protein Concentration ◽

Shunt Revision ◽

Csf Shunt ◽

Shunt Failure ◽

Revision Operation ◽

Protein Levels ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Background Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. Methods Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. Results Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. Conclusion Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

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Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽

10.3390/vaccines9050436 ◽

2021 ◽

Vol 9 (5) ◽

pp. 436

Author(s):

Ali A. Rabaan ◽

Shamsah H. Al-Ahmed ◽

Javed Muhammad ◽

Amjad Khan ◽

Anupam A Sule ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Markers ◽

Therapeutic Drug ◽

Molecular Pathways ◽

Cytokine Storm ◽

Immunomodulatory Drugs ◽

Alveolar Cells ◽

Systemic Complications ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

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