TPPU treatment of burned mice dampens inflammation and generation of bioactive DHET which impairs neutrophil function

AbstractOxylipins modulate the behavior of immune cells in inflammation. Soluble epoxide hydrolase (sEH) converts anti-inflammatory epoxyeicosatrienoic acid (EET) to dihydroxyeicosatrienoic acid (DHET). An sEH-inhibitor, TPPU, has been demonstrated to ameliorate lipopolysaccharide (LPS)- and sepsis-induced inflammation via EETs. The immunomodulatory role of DHET is not well characterized. We hypothesized that TPPU dampens inflammation and that sEH-derived DHET alters neutrophil functionality in burn induced inflammation. Outbred mice were treated with vehicle, TPPU or 14,15-DHET and immediately subjected to either sham or dorsal scald 28% total body surface area burn injury. After 6 and 24 h, interleukin 6 (IL-6) serum levels and neutrophil activation were analyzed. For in vitro analyses, bone marrow derived neutrophil functionality and mRNA expression were examined. In vivo, 14,15-DHET and IL-6 serum concentrations were decreased after burn injury with TPPU administration. In vitro, 14,15-DHET impaired neutrophil chemotaxis, acidification, CXCR1/CXCR2 expression and reactive oxygen species (ROS) production, the latter independent from p38MAPK and PI3K signaling. We conclude that TPPU administration decreases DHET post-burn. Furthermore, DHET downregulates key neutrophil immune functions and mRNA expression. Altogether, these data reveal that TPPU not only increases anti-inflammatory and inflammation resolving EET levels, but also prevents potential impairment of neutrophils by DHET in trauma.

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Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway

Molecules ◽

10.3390/molecules26092529 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2529

Author(s):

Haeyeop Kim ◽

Woo Seok Yang ◽

Khin Myo Htwe ◽

Mi-Nam Lee ◽

Young-Dong Kim ◽

...

Keyword(s):

Ethanol Extract ◽

Serum Levels ◽

Hepatoprotective Activity ◽

Tnf Α ◽

Anti Inflammatory ◽

Related Proteins ◽

Pro Inflammatory Cytokines ◽

Inflammatory Effect

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

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In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽

10.3390/biomedicines9060615 ◽

2021 ◽

Vol 9 (6) ◽

pp. 615

Author(s):

Shang-En Huang ◽

Erna Sulistyowati ◽

Yu-Ying Chao ◽

Bin-Nan Wu ◽

Zen-Kong Dai ◽

...

Keyword(s):

Articular Cartilage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Serum Levels ◽

Gene Expressions ◽

Tnf Α ◽

Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

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Dual Role of Interleukin-10 in Murine NZB/W F1 Lupus

International Journal of Molecular Sciences ◽

10.3390/ijms22031347 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1347

Author(s):

Anaïs Amend ◽

Natalie Wickli ◽

Anna-Lena Schäfer ◽

Dalina T. L. Sprenger ◽

Rudolf A. Manz ◽

...

Keyword(s):

B Cell ◽

Disease Model ◽

Interleukin 10 ◽

Immune Functions ◽

Murine Lupus ◽

Anti Inflammatory ◽

In Vivo Effects

As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.

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The Potential Anti-Inflammatory Effects of Brucea javanica (L.) Merr.

International Journal of Pharmaceutical Sciences and Medicine ◽

10.47760/ijpsm.2021.v06i09.001 ◽

2021 ◽

Vol 6 (9) ◽

pp. 1-7

Author(s):

Sisi Mustika ◽

Sri Oktavia ◽

Ifora Ifora

Keyword(s):

Mrna Expression ◽

Initial Response ◽

In Vivo Studies ◽

Brucea Javanica ◽

Ppar Γ ◽

Pharmacological Studies ◽

Ifn Γ ◽

Anti Inflammatory

Inflammation is the initial response to acute and chronic tissue damage, which is characterized by redness, swelling, heat, and pain. Natural products derived from plants have specific pharmacological activity and minimal side effects. Brucea javanica is a plant that has an anti-inflammatory effect, this plant contains alkaloid and flavonoid compounds. Flavonoids have the ability to block cyclooxygenase and lipoxygenase while alkaloids as an anti-inflammatory are thought to work by inhibiting prostaglandin H2 PGH2 which is an inflammatory mediator. From the data obtained, there is no complete literature that reviews its use as an anti-inflammatory. The search databases used are as follows: Pubmed, ScienceDirect, and Google Scholar to study the anti-inflammatory activity of Brucea javanica. All recent research articles were published between 2010 to 2021. Based on eligibility, 4 studies were included in this study, consisting of 2 In vivo studies and 2 In vitro and In vivo studies. A series of pharmacological studies have reported that Brucea javanica can block the Nf-kB signaling pathway and decrease the production of inflammatory mediators. It has been reported to be able to inhibit the production of NO, PGE2, TNF-, IL-1β, IL-18IL-23, COX-2, NF-κB, IFN-γ, IL-6, the levels of MPO (Myeloperoxidase), reducing the edema and induce the production of the anti-inflammatory cytokine (IL-4, IL-10 and TGF-β). Brucea javanica also markedly activates Nrf2 expression suppressing the inflammatory response-mediated NLRP3 and NF-κB activation. In addition, the elevated mRNA expression of MMP-1, MMP-3 and RAGE was remarkably inhibited by Brucea javanica, while the mRNA expression of PPAR-γ was significantly enhanced. In vitro and in vivo studies strongly indicate that Brucea javanica has the potential as an anti-inflammatory.

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Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System

Mediators of Inflammation ◽

10.1155/2019/2750528 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Xiao-Jing Ji ◽

Ji-Wei Hao ◽

Guang-Lei Li ◽

Ning Dong ◽

Xin-Qi Wang ◽

...

Keyword(s):

Nervous System ◽

T Cell ◽

Sympathetic Nervous System ◽

Cell Function ◽

Burn Injury ◽

Total Body Surface Area ◽

T Cell Function ◽

Sympathetic Nervous

Background. Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic nervous system in burn injury. Methods. Male Balb/c mice were subjected to sham or thermal injury of 15% total body surface area. Exendin-4 on T cell function in vitro was examined in cultured splenocytes in the presence of β-adrenoceptor antagonist propranolol (1 nmol/L) or GLP-1R antagonist exendin (9-39) (1 μmol/L), whereas its in vivo effect was determined by i.p. injection of exendin-4 (2.4 nmol/kg) in mice. To further elucidate the sympathetic mechanism, propranolol (30 mg/kg) or vehicle was applied 30 min prior to injury. Results. Although the exacerbated burn-induced mortality by exendin-4 was worsened by propranolol pretreatment, the inhibition of T cell proliferation by exendin-4 in vitro could be restored by propranolol instead of exendin (9-39). However, a Th2 switch by exendin-4 in vitro could only be reversed by exendin (9-39). Likewise, the inhibition of splenic T cell function and NFAT activity by exendin-4 in vivo was restored by propranolol. By contrast, the increased splenic NF-κB translocation by exendin-4 in vivo was potentiated by propranolol in sham mice but suppressed in burn mice. Accordingly, propranolol abrogated the heightened inflammatory response in the lung and the accelerated organ injuries by exendin-4 in burn mice. On the contrary, a Th2 switch and higher serum levels of inflammatory mediators by exendin-4 were potentiated by propranolol in burn mice. Lastly, exendin-4 raised serum stress hormones which could be remarkably augmented by propranolol. Conclusions. Exendin-4 suppresses T cell function and promotes organ inflammation through the activation of the sympathetic nervous system, while elicits Th2 switch via GLP-1R in burn injury.

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

10.1101/2021.12.16.472991 ◽

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.

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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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HPLC/MSn Profiling and Healing Activity of a Muco-Adhesive Formula of Salvadora persica against Acetic Acid-Induced Oral Ulcer in Rats

Nutrients ◽

10.3390/nu14010028 ◽

2021 ◽

Vol 14 (1) ◽

pp. 28

Author(s):

Nahla Ayoub ◽

Nadia Badr ◽

Saeed S. Al-Ghamdi ◽

Safaa Alsanosi ◽

Abdullah R. Alzahrani ◽

...

Keyword(s):

Acetic Acid ◽

Mrna Expression ◽

Ethyl Acetate Fraction ◽

Type I ◽

Salvadora Persica ◽

Sulphur Compounds ◽

Wide Range ◽

Anti Inflammatory

Salvadora persica L. (S. persica, Siwak) is an ethnic plant that is widely used for improving oral hygiene. This study aimed to provide a phytochemical profiling of S. persica ethyl acetate fraction (SPEAF) and to evaluate the healing activity of a muco-adhesive formula of the fraction against acetic acid-induced oral ulcers in rats. HPLC-ESI-QTOF-MS-MS analysis of SPEAF resulted in the tentative identification of 56 metabolites containing fatty acids (23%), urea derivatives (10.5%) and sulphur compounds (10%), in addition to several amides, polyphenols and organic acids (6.5%, 5% and 2%, respectively). For the first time, 19 compounds were identified from S. persica. In vitro and in vivo experiments indicated that the extract is non-toxic. SPEAF exhibited superior healing activities compared to both the negative and positive control groups on days 7 and 14 of tongue ulcer induction. This was confirmed by histopathological examinations of haematoxylin and eosin-stained (H&E) and Masson’s trichrome-stained tongue sections. Moreover, SPEAF showed potent anti-inflammatory activities, as evidenced by the inhibited expression of interleukin-6 (IL-6) and tumour necrosis alpha (TNF-α). Moreover, SPEAF exhibited potent antioxidant activity, as it prevented malondialdehyde (MDA) accumulation, reduced glutathione (GSH) depletion and superoxide dismutase (SOD) exhaustion. SPEAF significantly enhanced hydroxyproline tongue content and upregulated collagen type I alpha 1 (Col1A1) mRNA expression. SPEAF also improved angiogenesis, as shown by the increased mRNA expression of the angiopoietin-1 (Ang-1). In conclusion, S. persica has a wide range of secondary metabolites and ameliorates acetic acid-induced tongue ulcers in rats. This can be attributed, at least partly, to its anti-inflammatory, antioxidant, procollagen and angiogenic activities. These findings provide support and validity for the use of S. persica as a traditional and conventional treatment for oral disorders.

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Toxicity and Anti-inflammatory Activities of an Extract of the Eleutherine bulbosa Rhizome on Collagen Antibody-induced Arthritis in a Mouse Model

Natural Product Communications ◽

10.1177/1934578x1801300725 ◽

2018 ◽

Vol 13 (7) ◽

pp. 1934578X1801300

Author(s):

Pham Thi Bich Hanh ◽

Do Thi Thao ◽

Nguyen Thi Nga ◽

Ngo Thi Phuong ◽

Le Ngoc Hung ◽

...

Keyword(s):

Mouse Model ◽

Ethanol Extract ◽

Serum Levels ◽

Negative Control ◽

High Dose ◽

Necrosis Factor Alpha ◽

Beneficial Effects ◽

Anti Inflammatory

As a continuation of our interest in the anti-inflammatory activities of Vietnamese plants, we searched for novel anti-inflammatory agents in Eleutherine bulbosa and evaluated the anti-inflammatory effects of an ethanol extract of the rhizome of E. bulbosa (EBE) on lipopolysaccharide-stimulated RAW 264.7 macrophages in vitro and in a collagen antibody-induced arthritic (CAIA) mouse model in vivo. Treatment of the CAIA mice with EBE decreased the incidence of arthritis, especially at a dose of 1000 mg/kg body weight. A significant ( P<0.05) decrease in the arthritis score was seen after high-dose EBE treatment between days 10 and 14 in comparison with the negative control. The serum levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-10 in the mice were measured using commercial ELISA kits. The results suggest that an ethanol extract of the E. bulbosa rhizome has beneficial effects on inflammatory cytokine regulation in an experimental CAIA model.

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Effects of burn injury on myocardial signaling and cytokine secretion: possible role of PKC

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00555.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. R887-R896 ◽

Cited By ~ 11

Author(s):

Jing Tan ◽

David L. Maass ◽

D. Jean White ◽

Jureta W. Horton

Keyword(s):

Burn Injury ◽

Total Body Surface Area ◽

Cytokine Secretion ◽

Sprague Dawley ◽

Inhibitory Peptide ◽

Adult Rat ◽

Pkc Isoforms ◽

Major Burn

This study examined the effects of major burn injury on the cellular distribution of several PKC isoforms in adult rat hearts and examined the hypothesis that PKC plays a regulatory role in cardiomyocyte cytokine secretion. Burn trauma was given over 40% total body surface area in Sprague-Dawley rats. An in vitro model of burn injury included addition of burn serum, 10% by volume, to primary cardiomyocyte cultures (collagen perfusion). In vivo burn injury produced redistribution of PKCδ, PKCε, and PKCα from the cytosol (soluble) to the membrane (particulate) component of the myocardium. This activation of the PKC isoforms was evident 2 h after burn injury and progressively increased over 24 h postburn. Addition of burn serum to isolated myocytes produced similar PKC isoform redistribution from the soluble to the particulate compartment, promoted myocyte Ca2+ and Na+ loading, and promoted robust myocyte secretion of inflammatory cytokines similar to that reported after in vivo burn injury. Pretreating cardiomyocytes with either calphostin or PKCε inhibitory peptide, a potent inhibitor of PKCε, prevented burn serum-related redistribution of the PKCε isoform and prevented burn serum-related cardiomyocyte secretion of TNF-α, IL-1β, IL-6, and IL-10. These data suggest that the PKCε isoform plays a pivotal role in myocardial inflammatory response to injury, altering cardiac function by modulating cardiomyocyte inflammatory cytokine response to injury.

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