scholarly journals Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice

2021 ◽  
Vol 22 (13) ◽  
pp. 6872
Author(s):  
Shilpashree Mallesh ◽  
Reiner Schneider ◽  
Bianca Schneiker ◽  
Mariola Lysson ◽  
Patrik Efferz ◽  
...  
Keyword(s):  
Nervous System ◽  
Immune Modulation ◽  
Postoperative Ileus ◽  
Ex Vivo ◽  
Late Phase ◽  
Surgical Trauma ◽  
Inflammatory Genes ◽  
Anti Inflammatory ◽  
Muscularis Externa

Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.

scholarly journals CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus

Gut ◽  
2017 ◽  
Vol 66 (12) ◽  
pp. 2098-2109 ◽  
Author(s):  
Giovanna Farro ◽  
Michelle Stakenborg ◽  
Pedro J Gomez-Pinilla ◽  
Evelien Labeeuw ◽  
Gera Goverse ◽  
...  
Keyword(s):  
Postoperative Ileus ◽  
Critical Role ◽  
Early Time ◽  
Point Of View ◽  
Surgical Trauma ◽  
Monocyte Migration ◽  
Gi Transit ◽  
Stimulating Factor ◽  
Muscularis Externa

ObjectivePostoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinalmuscularis externa(ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility.DesignIM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2,Ccr2−/−mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation.ResultsAt early time points, IM-induced GI transit delay and inflammation were equal in WT andCcr2−/−mice. However, GI transit recovery after IM was significantly delayed inCcr2−/−mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit inCcr2−/−mice.ConclusionOur study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions.

scholarly journals Role and Therapeutic Potential of Melatonin in the Central Nervous System and Cancers

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1567
Author(s):  
Sangiliyandi Gurunathan ◽  
Min-Hee Kang ◽  
Jin-Hoi Kim
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Circadian Rhythms ◽  
Pineal Gland ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Dark Phase ◽  
Anti Inflammatory ◽  
The Impact

Melatonin (MLT) is a powerful chronobiotic hormone that controls a multitude of circadian rhythms at several levels and, in recent times, has garnered considerable attention both from academia and industry. In several studies, MLT has been discussed as a potent neuroprotectant, anti-apoptotic, anti-inflammatory, and antioxidative agent with no serious undesired side effects. These characteristics raise hopes that it could be used in humans for central nervous system (CNS)-related disorders. MLT is mainly secreted in the mammalian pineal gland during the dark phase, and it is associated with circadian rhythms. However, the production of MLT is not only restricted to the pineal gland; it also occurs in the retina, Harderian glands, gut, ovary, testes, bone marrow, and lens. Although most studies are limited to investigating the role of MLT in the CNS and related disorders, we explored a considerable amount of the existing literature. The objectives of this comprehensive review were to evaluate the impact of MLT on the CNS from the published literature, specifically to address the biological functions and potential mechanism of action of MLT in the CNS. We document the effectiveness of MLT in various animal models of brain injury and its curative effects in humans. Furthermore, this review discusses the synthesis, biology, function, and role of MLT in brain damage, and as a neuroprotective, antioxidative, anti-inflammatory, and anticancer agent through a collection of experimental evidence. Finally, it focuses on the effect of MLT on several neurological diseases, particularly CNS-related injuries.

Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor

1992 ◽  
Vol 70 (6) ◽  
pp. 799-807 ◽  
Author(s):  
C. Brideau ◽  
C. Chan ◽  
S. Charleson ◽  
D. Denis ◽  
J. F. Evans ◽  
...  
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Potent Inhibitor ◽  
Ex Vivo ◽  
Late Phase ◽  
Squirrel Monkeys ◽  
Propanoic Acid ◽  
Orally Active

MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid, previously L-686,708) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human and elicited rat polymorphonuclear leukocytes (PMNLs) (IC50 values 3.1 and 6.1 nM, respectively) and in human, squirrel monkey, and rat whole blood (IC50 values 510, 69, and 9 nM, respectively). MK-0591 had no effect on rat 5-lipoxygenase. MK-0591 has a high affinity for 5-lipoxygenase activating protein (FLAP) as evidenced by an IC50 value of 1.6 nM in a FLAP binding assay and inhibition of the photoaffinity labelling of FLAP by two different photoaffinity ligands. Inhibition of activation of 5-lipoxygenase was shown through inhibition of the translocation of the enzyme from the cytosol to the membrane in human PMNLs. MK-0591 was a potent inhibitor of LT biosynthesis in vivo, first, following ex vivo challenge of blood obtained from treated rats and squirrel monkeys, second, in a rat pleurisy model, and, third, as monitored by inhibition of the urinary excretion of LTE4 in antigen-challenged allergic sheep. Inhibition of antigen-induced bronchoconstriction by MK-0591 was observed in inbred rats pretreated with methysergide, Ascaris-challenged squirrel monkeys, and Ascaris-challenged sheep (early and late phase response). These results indicate that MK-0591 is a potent inhibitor of LT biosynthesis both in vitro and in vivo indicating that the compound will be suitable for assessing the role of leukotrienes in pathological situations.Key words: leukotriene, 5-lipoxygenase, leukotriene inhibitor, bronchoconstriction, inflammation, 5-lipoxygenase activating protein.

scholarly journals Role of the Cholinergic Anti-Inflammatory Reflex in Central Nervous System Diseases

2021 ◽  
Vol 22 (24) ◽  
pp. 13427
Author(s):  
Ivan Emmanuel Ramos-Martínez ◽  
María Carmen Rodríguez ◽  
Marco Cerbón ◽  
Juan Carlos Ramos-Martínez ◽  
Edgar Gustavo Ramos-Martínez
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Strategies ◽  
Chemical Stimulation ◽  
Nervous System Diseases ◽  
Central Nervous System Diseases ◽  
Pathological Conditions ◽  
Bidirectional Communication ◽  
Anti Inflammatory

In several central nervous system diseases, it has been reported that inflammation may be related to the etiologic process, therefore, therapeutic strategies are being implemented to control inflammation. As the nervous system and the immune system maintain close bidirectional communication in physiological and pathological conditions, the modulation of inflammation through the cholinergic anti-inflammatory reflex has been proposed. In this review, we summarized the evidence supporting chemical stimulation with cholinergic agonists and vagus nerve stimulation as therapeutic strategies in the treatment of various central nervous system pathologies, and their effect on inflammation.

Proinflammatory and Anti-inflammatory Genes in Stroke Pathogenesis

2020 ◽  
Vol 26 (34) ◽  
pp. 4220-4233
Author(s):  
Mengmeng Jiang ◽  
Penglin Yin ◽  
Xiaodan Bai ◽  
Liji Yang ◽  
Junping Zhang ◽  
...  
Keyword(s):  
Inflammatory Process ◽  
Ischemic Brain ◽  
Inflammatory Genes ◽  
Proinflammatory Mediators ◽  
Inflammatory Mechanism ◽  
Ischemic Brain Tissue ◽  
Anti Inflammatory ◽  
The Brain

The brain's response to ischemic injury is an acute and long-term inflammatory process. This process involves activation of resident cells (mainly microglia, hematogenous macrophages), production of proinflammatory mediators and infiltration of various proinflammatory cells (mainly neutrophils and lymphocytes). These cells play an essential role in ischemic brain tissue by releasing either proinflammatory or anti-inflammatory mediators at different time points. However, the exact pathogenesis of proinflammatory or anti-inflammatory genes in this process has not yet been elucidated. This review aims to investigate the inflammatory process of stroke, especially the role of proinflammatory and anti-inflammatory genes in the pathogenesis of stroke. We also summarize the current clinical trials of drugs that target the inflammatory mechanism for intervention.

scholarly journals Tryptophol acetate and tyrosol acetate, metabolites secreted by a probiotic yeast, halt cytokine storm

2021 ◽  
Author(s):  
orit malka ◽  
ravit malishev ◽  
marina bersudsky ◽  
manikand rajendran ◽  
mathumathi krishnamohan ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Ex Vivo ◽  
Fermented Foods ◽  
Cytokine Storm ◽  
Immune Functions ◽  
Therapeutic Benefits ◽  
Probiotic Yeast ◽  
Anti Inflammatory

Probiotic fermented foods are perceived as contributing to human health and capable of protecting against inflammation, however solid mechanistic evidence for the presumptive therapeutic benefits is lacking. Here we report that tryptophol acetate and tyrosol acetate, small molecule metabolites secreted by the probiotic milk-fermented yeast Kluyveromyces marxianus exhibit remarkable anti-inflammatory properties. Comprehensive in vivo, ex vivo and in vitro experiments, employing LPS-induced 'cytokine storm' models, reveal dramatic effects of the two molecules, added in tandem, on mice morbidity, laboratory parameters and mortality. In parallel, significant attenuation of pro-inflammatory cytokines including IL-6, IL-1α, IL-1β and TNF-κB, and reduction of reactive oxygen species were recorded. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress cytokine generation, but rather brought their concentrations back to baseline levels, further maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, attenuating NF-kB level. In addition, the two molecules had a significant impact on mice microbiome, increasing the abundance of the genus Bactericides, known to exhibit anti-inflammatory properties. Overall, this work illuminates pronounced and broad-based immune modulation properties of probiotic yeast-secreted metabolites, uncovering their mechanism of action and underscoring potential new therapeutic avenues for severe inflammation.

Abstract 580: Regulation of Inflammatory Gene Expression by Angiotensin II-induced KLF4 in Vascular Smooth Muscle Cells

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Wen Jin ◽  
Marpadga A Reddy ◽  
Zhuo Chen ◽  
Sadhan Das ◽  
Linda Lanting ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Transcription Factors ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Phenotypic Switching ◽  
Ang Ii ◽  
Inflammatory Genes ◽  
Anti Inflammatory

Angiotensin II (Ang II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a critical role in the pathogenesis of Cardiovascular Diseases (CVDs). However, the role of Ang II-induced transcription factors in the diverse effects of Ang II remains unclear. We profiled Ang II induced gene expression by microarray analysis of RNA isolated from Ang II-treated and control VSMC. Our results identified numerous differentially regulated genes including several key transcription factors in Ang II-stimulated VSMC compared with controls. Ingenuity Pathway Analysis indicated that Ang II-regulated genes are involved in VSMC dysfunction highly relevant to CVDs. We validated the expression of several genes by RT-qPCR and further characterized the functions of the most differentially regulated gene, KLF4, known to regulate growth factor induced VSMC phenotypic switching. We demonstrated that Ang II induced the expression of KLF4 in cultured VSMC in vitro , in mice aortas cultured ex vivo , and in aortas isolated from Ang II-infused mice in vivo . Ang II-induced KLF4 expression was inhibited by Losartan, demonstrating regulation via the AT1 receptor. Transfection experiments using WT and mutant KLF4 promoter constructs revealed the key role of cis -elements with consensus binding sites for p53, SP1 and YY1 in Ang II-induced KLF4 promoter activation. Next, we performed gene expression profiling by Affymetrix gene arrays after siRNA mediated KLF4 knockdown in VSMC. The differentially expressed genes were subsequently analyzed by DAVID to obtain enriched biological processes and potential pathways relevant to cardiovascular functions. Results showed that KLF4 knockdown upregulated the expression of several genes related to cell proliferation and hypertrophy. Interestingly, KLF4 knockdown also enhanced the expression of multiple pro-inflammatory genes including IL-6 and downregulated several anti-inflammatory genes including Thrombomodulin, suggesting an anti-inflammatory role for KLF4 in VSMC. Together, these results suggest that KLF4 may act as a novel molecular brake to modulate Ang II actions that, when disrupted, can further augment Ang II mediated VSMC dysfunction associated with vascular diseases.

scholarly journals Effects of Oxidative Stress on Mesenchymal Stem Cell Biology

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Ryan A. Denu ◽  
Peiman Hematti
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Biology ◽  
Immune Modulation ◽  
Ex Vivo ◽  
Multipotent Stem Cells ◽  
Clinical Potential ◽  
Stromal Stem Cells

Mesenchymal stromal/stem cells (MSCs) are multipotent stem cells present in most fetal and adult tissues.Ex vivoculture-expanded MSCs are being investigated for tissue repair and immune modulation, but their full clinical potential is far from realization. Here we review the role of oxidative stress in MSC biology, as their longevity and functions are affected by oxidative stress. In general, increased reactive oxygen species (ROS) inhibit MSC proliferation, increase senescence, enhance adipogenic but reduce osteogenic differentiation, and inhibit MSC immunomodulation. Furthermore, aging, senescence, and oxidative stress reduce theirex vivoexpansion, which is critical for their clinical applications. Modulation of sirtuin expression and activity may represent a method to reduce oxidative stress in MSCs. These findings have important implications in the clinical utility of MSCs for degenerative and immunological based conditions. Further study of oxidative stress in MSCs is imperative in order to enhance MSCex vivoexpansion andin vivoengraftment, function, and longevity.

Su1994 Cholinergic Anti-Inflammatory Pathway in Postoperative Ileus: Role of the Spleen and Intestinal Innervation

2012 ◽  
Vol 142 (5) ◽  
pp. S-555
Author(s):  
Lea Costes ◽  
Jan van der Vliet ◽  
Martijn Nolte ◽  
Sjoerd H. van Bree ◽  
Guy E. Boeckxstaens ◽  
...  
Keyword(s):  
Postoperative Ileus ◽  
Inflammatory Pathway ◽  
Anti Inflammatory

scholarly journals A Herbal Composition ofScutellaria baicalensisandEleutherococcus senticosusShows Potent Anti-Inflammatory Effects in an Ex Vivo Human Mucosal Tissue Model

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Nan Zhang ◽  
Koen Van Crombruggen ◽  
Gabriele Holtappels ◽  
Claus Bachert
Keyword(s):  
Vitamin C ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Treatment Options ◽  
Beat Frequency ◽  
Late Phase ◽  
Significant Inhibition ◽  
Mucosal Tissue ◽  
Anti Inflammatory

Background. Patients seek an effective alternative to pharmacotherapy including herbal treatment options for allergic rhinitis and rhinosinusitis.Material and Methods. Nasal mucosal tissue was obtained from 12 patients, fragmented, preincubated with tissue culture medium,S. baicalensisand/orE. senticosusand/or vitamin C (each compound 0.2 μg/mL and 2 μg/mL) for 1 hour at 37°C/5% CO2, and stimulated with anti-IgE for 30 minutes and 6 hours to imitate the allergic early and late phases. Furthermore, Staphylococcus aureus superantigen B (SEB) stimulation for 6 hours was used to imitate T-cell activation.Results. The combination ofS. baicalensisandE. senticosushad a more potent suppressive effect on the release of PGD2, histamine, and IL-5 thanS. baicalensisalone. The combination also resulted in a significant inhibition of SEB-induced cytokines comparable or superior to an established topical corticosteroid, fluticasone propionate. Vitamin C increased ciliary beat frequency, but had no anti-inflammatory effects.Discussion. The combination ofS. baicalensisandE. senticosusmay be able to significantly block allergic early-and late-phase mediators and substantially suppress the release of proinflammatory, and Th1-, Th2-, and Th17—derived cytokines.

Sign in / Sign up

Export Citation Format

Share Document