scholarly journals Salicylates Ameliorate Intestinal Inflammation by Activating Macrophage AMPK

2020 ◽  
Author(s):  
Suhrid Banskota ◽  
Huaqing Wang ◽  
Yun Han Kwon ◽  
Jaya Gautam ◽  
Pallavi Gurung ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Sodium Sulfate ◽  
Intestinal Inflammation ◽  
Nuclear Translocation ◽  
Dextran Sodium Sulfate ◽  
Enzyme Linked Immunosorbent Assay ◽  
Aminosalicylic Acid ◽  
Inflammatory Conditions ◽  
Inflammatory Bowel

Abstract Background Inflammatory bowel diseases are the most common chronic intestinal inflammatory conditions, and their incidence has shown a dramatic increase in recent decades. Limited efficacy and questionable safety profiles with existing therapies suggest the need for better targeting of therapeutic strategies. Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular metabolism and has been implicated in intestinal inflammation. Macrophages execute an important role in the generation of intestinal inflammation. Impaired AMPK in macrophages has been shown to be associated with higher production of proinflammatory cytokines; however, the role of macrophage AMPK in intestinal inflammation and the mechanism by which it regulates inflammation remain to be determined. In this study, we investigated the role of AMPK with a specific focus on macrophages in the pathogenesis of intestinal inflammation. Methods A dextran sodium sulfate-induced colitis model was used to assess the disease activity index, histological scores, macroscopic scores, and myeloperoxidase level. Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β were measured by enzyme-linked immunosorbent assay. Transient transfection of AMPKβ1 and LC3-II siRNA in RAW 264.7 cells was performed to elucidate the regulation of autophagy by AMPK. The expression of p-AMPK, AMPK, and autophagy markers (eg, LC3-II, p62, Beclin-1, and Atg-12) was analyzed by Western blot. Results Genetic deletion of AMPKβ1 in macrophages upregulated the production of proinflammatory cytokines, aggravated the severity of dextran sodium sulfate-induced colitis in mice, which was associated with an increased nuclear translocation of nuclear factor-κB, and impaired autophagy both in vitro and in vivo. Notably, the commonly used anti-inflammatory 5-aminosalicylic acid (ie, mesalazine) and sodium salicylate ameliorated dextran sodium sulfate-induced colitis through the activation of macrophage AMPK targeting the β1 subunit. Conclusions Together, these data suggest that the development of therapeutic agents targeting AMPKβ1 may be effective in the treatment of intestinal inflammatory conditions including inflammatory bowel disease.

scholarly journals Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Ashok Kumar Pandurangan ◽  
Salmiah Ismail ◽  
Zeinab Saadatdoust ◽  
Norhaizan Mohd. Esa
Keyword(s):  
Body Weight ◽  
Proinflammatory Cytokines ◽  
Sodium Sulfate ◽  
Nuclear Translocation ◽  
Dextran Sodium Sulfate ◽  
Nuclear Accumulation ◽  
Mrna Levels ◽  
Inhibitory Protein ◽  
Reduced Body ◽  
Enzymic Antioxidants

The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such astumor necrosis factor- (TNF-)α, interleukin- (IL-) 1β, IL-6, andIL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P<0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3Y705pathways.

scholarly journals Going Beyond Bacteria: Uncovering the Role of Archaeome and Mycobiome in Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Yashar Houshyar ◽  
Luca Massimino ◽  
Luigi Antonio Lamparelli ◽  
Silvio Danese ◽  
Federica Ungaro
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
The Body ◽  
Inflammatory Conditions ◽  
Relapsing Remitting ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Inflammatory Bowel Disease (IBD) is a multifaceted class of relapsing-remitting chronic inflammatory conditions where microbiota dysbiosis plays a key role during its onset and progression. The human microbiota is a rich community of bacteria, viruses, fungi, protists, and archaea, and is an integral part of the body influencing its overall homeostasis. Emerging evidence highlights dysbiosis of the archaeome and mycobiome to influence the overall intestinal microbiota composition in health and disease, including IBD, although they remain some of the least understood components of the gut microbiota. Nonetheless, their ability to directly impact the other commensals, or the host, reasonably makes them important contributors to either the maintenance of the mucosal tissue physiology or to chronic intestinal inflammation development. Therefore, the full understanding of the archaeome and mycobiome dysbiosis during IBD pathogenesis may pave the way to the discovery of novel mechanisms, finally providing innovative therapeutic targets that can soon implement the currently available treatments for IBD patients.

scholarly journals Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles

2018 ◽  
Vol 115 (33) ◽  
pp. 8418-8423 ◽  
Author(s):  
Hisako Kayama ◽  
Masako Kohyama ◽  
Daisuke Okuzaki ◽  
Daisuke Motooka ◽  
Soumik Barman ◽  
...  
Keyword(s):  
Sodium Sulfate ◽  
Intestinal Inflammation ◽  
Local Environment ◽  
Dextran Sodium Sulfate ◽  
Dependent Manner ◽  
Tnf Α ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Mucosal Bleeding ◽  
Inducible Genes

The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX3CR1high Mϕs. Intestinal CX3CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX3CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the noninflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.

Cottonseed Oil Protects Against Intestinal Inflammation in Dextran Sodium Sulfate-Induced Inflammatory Bowel Disease

2019 ◽  
Vol 22 (7) ◽  
pp. 672-679 ◽  
Author(s):  
Jin-Sil Park ◽  
JeongWon Choi ◽  
Sun-Hee Hwang ◽  
Jae-Kyung Kim ◽  
Eun-Kyung Kim ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Sodium Sulfate ◽  
Intestinal Inflammation ◽  
Cottonseed Oil ◽  
Dextran Sodium Sulfate ◽  
Inflammatory Bowel

scholarly journals Selecting Lactic Acid Bacteria for Their Safety and Functionality by Use of a Mouse Colitis Model

2006 ◽  
Vol 72 (9) ◽  
pp. 5799-5805 ◽  
Author(s):  
Catherine Daniel ◽  
Sabine Poiret ◽  
Denise Goudercourt ◽  
Veronique Dennin ◽  
Gregory Leyer ◽  
...  
Keyword(s):  
Oral Administration ◽  
Intestinal Inflammation ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Conditions ◽  
Therapeutic Benefits ◽  
Inflammatory Bowel ◽  
High Doses ◽  
Colitis Model

ABSTRACT Studies showed that specific probiotics might provide therapeutic benefits in inflammatory bowel disease. However, a rigorous screening of new probiotics is needed to study possible adverse interactions with the host, particularly when intended for administration to individuals with certain health risks. In this context, the objective of this study was to investigate the role of three lactobacilli (LAB) on intestinal inflammation and bacterial translocation using variations of the mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis. We first compared the in vitro ability of LAB to survive gastrointestinal tract (GIT) conditions and their ability to persist in the GIT of mice following daily oral administration. As a control, we included a nonprobiotic Lactobacillus paracasei strain, previously isolated from an endocarditis patient. Feeding high doses of LAB strains to healthy and to TNBS-treated mice did not induce any detrimental effect or abnormal translocation of the bacteria. Oral administration of Lactobacillus salivarius Ls-33 had a significant preventive effect on colitis in mice, while Lactobacillus plantarum Lp-115 and Lactobacillus acidophilus NCFM did not. None of the three selected LAB strains translocated to extraintestinal organs of TNBS-treated mice. In contrast, L. paracasei exacerbated colitis under severe inflammatory conditions and translocated to extraintestinal organs. This study showed that evaluations of the safety and functionality of new probiotics are recommended. We conclude that not all lactobacilli have similar effects on intestinal inflammation and that selected probiotics such as L. salivarius Ls-33 may be considered in the prevention or treatment of intestinal inflammation.

scholarly journals Influence of the microenvironment on the modulation of the host response by the typhoid toxin

2020 ◽  
Author(s):  
Océane C.B. Martin ◽  
Deborah Butter ◽  
Eleni Paparouna ◽  
Sofia D.P. Theodorou ◽  
Maria M. Haykal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Intestinal Inflammation ◽  
Inflammatory Conditions ◽  
Damage Response ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Typhoid Toxin

SummaryBacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram negative bacteria, enriched in the microbiota of Inflammatory Bowel Disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We have addressed the role of the typhoid toxin in the modulation of the host-microbial interaction in health and disease.Infection with a genotoxigenic Salmonella protected mice from intestinal inflammation. The toxin-induced DNA damage caused senescence in vivo, which was uncoupled from the inflammatory response, and associated with the maintenance of an anti-inflammatory environment. This effect was lost when infection occurred in mice suffering from inflammatory conditions that mimic Ulcerative Colitis, a form of IBD.These data highlight a complex context-dependent crosstalk between bacterial genotoxins-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

scholarly journals The Role of Phosphoinositide 3-Kinase Signaling in Intestinal Inflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Catherine M. Cahill ◽  
Jack T. Rogers ◽  
W. Allan Walker
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Kinase Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Inflammatory Conditions ◽  
Adaptive Immune Cells ◽  
Inflammatory Bowel ◽  
Phosphatidylinositol 3

The phosphatidylinositol 3-kinase signaling pathway plays a central role in regulating the host inflammatory response. The net effect can either be pro- or anti-inflammatory depending on the system and cellular context studied. This paper focuses on phosphatidylinositol 3-kinase signaling in innate and adaptive immune cells of the intestinal mucosa. The role of phosphatidylinositol 3-kinase signaling in mouse models of inflammatory bowel disease is also discussed. With the development of new isoform specific inhibitors, we are beginning to understand the specific role of this complex pathway, in particular the role of the γ isoform in intestinal inflammation. Continued research on this complex pathway will enhance our understanding of its role and provide rationale for the design of new approaches to intervention in chronic inflammatory conditions such as inflammatory bowel disease.

scholarly journals Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2645
Author(s):  
Dinh Nam Tran ◽  
Seon Myeong Go ◽  
Seon-Mi Park ◽  
Eui-Man Jung ◽  
Eui-Bae Jeung
Keyword(s):  
Immune Response ◽  
Cellular Proliferation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Innate Immune ◽  
Inflammatory Conditions ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathway

2006 ◽  
Vol 95 (05) ◽  
pp. 829-835 ◽  
Author(s):  
Sang-Hyun Kwak ◽  
Xue-Qing Wang ◽  
Qianbin He ◽  
Wen-Feng Fang ◽  
Sanchayita Mitra ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Proinflammatory Cytokines ◽  
Nuclear Translocation ◽  
Plasminogen Activator Inhibitor ◽  
Neutrophil Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inflammatory Conditions ◽  
Jnk Activation ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen activator (uPA). Although the roles of uPA and PAI-1 in plasmin generation and the degradation of fibrin are well known, recent evidence also suggests that they can participate in acute inflammatory conditions that involve neutrophil activation. In the present experiments, we found that the addition of PAI-1 to LPS-stimulated neutrophils resulted in enhanced nuclear translocation of NF-κB and increased production of the proinflammatory cytokines IL-1β,Tnf-α,and Mip-2.uPA and the kringle domain (KD) of uPA potentiated cytokine expression and NF-κB activation by neutrophils cultured with LPS, and had additive effects when combined with PAI-1. The c-Jun N-terminal kinase (JNK) was activated after exposure of resting neutrophils to PAI-1 or the uPA KD. Enhanced JNK activation, but not that of other kinases induced by LPS, was present in neutrophils cocultured with PAI-1 or uPA KD. Inhibition of JNK activation prevented the potentiation of expression of proinflammatory cytokines induced by PAI-1 or uPA KD in LPS stimulated neutrophils. These results demonstrate that PAI-1 and uPA KD enhance LPSinduced neutrophil responses through their effects on JNK mediated pathways.

Obesity and inflammatory bowel disease

2021 ◽  
Vol 75 (1) ◽  
pp. 20-28
Author(s):  
Vladimír Teplan ◽  
Milan Lukáš
Keyword(s):  
Inflammatory Bowel Disease ◽  
Adipose Tissue ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Perioperative Complications ◽  
Overweight And Obesity ◽  
Special Role ◽  
Low Concentrations ◽  
Inflammatory Bowel

The incidence and prevalence of overweight and obesity has dramatically increased in the last decades and is generally considered to be global pandemics. The incidence of inflammatory bowel disease (IBD) is rising parallel with overweight and obesity. Contrary to a conventional believe, about 15–40% patients with IBD are obese, which can contribute to the development and course of IBD, especially in Crohn’s disease. Although the findings of some cohort studies are still conflicting, recent results indicate a special role of visceral adipose tissue and particularly mesenteric adipose tissue known as creeping fat, leading to intestinal inflammation. The involvement of altered adipocyte function and deregulated production of adipokines such as leptin and adiponectin has been suggested in the pathogenesis of IBD. The emerging role of Western diet and microbiota can also open new possibilities in IBD management. The effect of obesity on the IBD-related therapy remains to be studied. The finding that obesity results in suboptimal response to the therapy, potentially promoting rapid clearance of biologic agents and thus leading to their low concentrations, has a great importance. Obesity also makes IBD colorectal surgery technically challenging and might increase a risk of perioperative complications.

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