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Biochemistry and Biophysics Reports Sep 2016The non-essential amino acid L-glutamine (Gln) displays potent anti-inflammatory activity by deactivating p38 mitogen activating protein kinase and cytosolic...
The non-essential amino acid L-glutamine (Gln) displays potent anti-inflammatory activity by deactivating p38 mitogen activating protein kinase and cytosolic phospholipase A via induction of MAPK phosphatase-1 (MKP-1) in an extracellular signal-regulated kinase (ERK)-dependent way. In this study, the mechanism of Gln-mediated ERK-dependency in MKP-1 induction was investigated. Gln increased ERK phosphorylation and activity, and phosphorylations of Ras, c-Raf, and MEK, located in the upstream pathway of ERK, in response to lipopolysaccharide and . Gln-induced dose-dependent transient increases in intracellular calcium ([Ca]) in MHS macrophage cells. Ionomycin increased [Ca] and activation of Ras → ERK pathway, and MKP-1 induction, in the presence, but not in the absence, of LPS. The Gln-induced pathways involving Ca→ MKP-1 induction were abrogated by a calcium blocker. Besides Gln, other amino acids including L-phenylalanine and l-cysteine (Cys) also induced Ca response, activation of Ras → ERK, and MKP-1 induction, albeit to a lesser degree. Gln and Cys were comparable in suppression against 2, 4-dinitrofluorobenzene-induced contact dermatitis. Gln-mediated, but not Cys-mediated, suppression was abolished by MKP-1 small interfering RNA. These data indicate that Gln induces MKP-1 by activating Ca→ ERK pathway, which plays a key role in suppression of inflammatory reactions.
PubMed: 28955885
DOI: 10.1016/j.bbrep.2016.05.011 -
European Journal of Immunology Jan 2017Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not...
Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not completely understood. We investigated the potential of common experimental allergens to induce mast cell activation using murine bone marrow-derived cultured mast cells and rat peritoneal mast cells. Among these allergens, 1-chloro-2,4-dinitrobenzene and 1-fluoro-2,4-dinirobenzene (DNFB) were found to induce degranulation of rat peritoneal mast cells. DNFB-induced degranulation is accompanied by cytosolic Ca mobilization and is significantly inhibited by pertussis toxin, U73122 (a phospholipase C inhibitor), and BAPTA (a Ca chelator), raising the possibility that DNFB acts on the G protein-coupled receptors and activates G , which induces activation of phospholipase C, as well as known mast cell secretagogues, such as compound 48/80. DNFB could induce mast cell degranulation in the absence of serum proteins and IgE. Structure-activity relationship analyses revealed an inverse correlation between the degree of degranulation and the electron density of the C1 carbon of the DNFB derivatives. These findings raise a possibility that DNFB functions as a potent contact allergen through induction of cutaneous mast cell degranulation.
Topics: Allergens; Animals; Calcium; Cell Degranulation; Cytokines; Dinitrofluorobenzene; GTP-Binding Proteins; Male; Mast Cells; Mice; Molecular Structure; Protein Binding; Protein Multimerization; Rats; Signal Transduction; Type C Phospholipases
PubMed: 27748951
DOI: 10.1002/eji.201646536 -
Mediators of Inflammation 2016The leaves of Artemisia argyi Lev. et Vant. and A. princeps Pamp. are well known medicinal herbs used to treat patients in China, Japan, and Korea with skin problems...
The leaves of Artemisia argyi Lev. et Vant. and A. princeps Pamp. are well known medicinal herbs used to treat patients in China, Japan, and Korea with skin problems such as eczema and itching, as well as abdominal pain and dysmenorrhoea. We investigated the anti-inflammatory effects of Artemisia leaf extract (ALE) using CD mice and Raw 264.7 cells. The effects of ALE on histopathological changes and cytokine production in ear tissues were assessed in mice with CD induced by 1-fluoro-2,4-dinitrobenzene (DNFB). Moreover, the anti-inflammatory effects on production levels of prostaglandin E2 (PGE2) and nitric oxide (NO) and expression levels of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) were investigated in Raw 264.7 cells. Topical application of ALE effectively prevented ear swelling induced by repeated DNFB application. ALE prevented epidermal hyperplasia and infiltration of immune cells and lowered the production of interferon- (IFN-) gamma (γ), tumour necrosis factor- (TNF-) alpha (α), and interleukin- (IL-) 6 in inflamed tissues. In addition, ALE inhibited expression of COX-2 and iNOS and production of NO and PGE2 in Raw 264.7 cells. These results indicate that Artemisia leaf can be used as a therapeutic agent for inflammatory skin diseases and that its anti-inflammatory effects are closely related to the inhibition of inflammatory mediator release from macrophages and inflammatory cytokine production in inflamed tissues.
Topics: Animals; Anti-Inflammatory Agents; Artemisia; China; Cyclooxygenase 2; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Dinoprostone; Epidermis; Hyperplasia; Inflammation; Interferon-gamma; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Plant Extracts; Plant Leaves; RAW 264.7 Cells; Tumor Necrosis Factor-alpha
PubMed: 27647952
DOI: 10.1155/2016/8027537 -
PloS One 2015Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive...
Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP's role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP's role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis.
Topics: Animals; CDX2 Transcription Factor; Cell Count; Colitis; Dinitrofluorobenzene; Disease Susceptibility; Epithelial Cells; Goblet Cells; Homeodomain Proteins; Homeostasis; Intestines; Male; Mice, Inbred C57BL; Mice, Knockout; Protective Agents; Real-Time Polymerase Chain Reaction; Signal Transduction; Transcription Factors; Vasoactive Intestinal Peptide
PubMed: 25932952
DOI: 10.1371/journal.pone.0125225 -
Journal of Microscopy and Ultrastructure 2020Contact dermatitis (CD) is considered among the common inflammatory skin diseases worldwide. Duchesne has antioxidant, anti-inflammatory, and antidepressant activity...
BACKGROUND
Contact dermatitis (CD) is considered among the common inflammatory skin diseases worldwide. Duchesne has antioxidant, anti-inflammatory, and antidepressant activity beside many other beneficial effects.
OBJECTIVES
This study aimed to assess the effect of pumpkin fruit extract in treating CD in mice exposed to chronic stress and to explore the mechanism through which pumpkin can relief these changes.
MATERIALS AND METHODS
Thirty male albino rats were divided into three groups ( = 10); the control and two experimental groups that were exposure to chronic unpredictable mild stress for 4 weeks then painting with 1-fluoro-2,4-dinitrofluorobenzene (DNFB) for 3 consecutive days/week for 2 weeks to induce CD. Biochemical assessment of corticosterone level and antioxidants activity was performed. Skin of affected areas was excised, processed for histopathological examination.
RESULTS
DNFB-induced CD presented with dryness, hardness, and scaling. There was a significant reduction ( < 0.001) in the levels of superoxide dismutase, glutathione peroxidase and catalase activity in the skin of rats had CD. Histopathologically, the shin showed hyperplastic-thickened epidermis, focal elongation of the rete ridges, inflammatory cells infiltration in the superficial dermis, and increased collagen fibers. Local administration of pumpkin extract significantly increased the antioxidants activity in the skin and alleviated the CD-associated changes.
CONCLUSIONS
This study showed that the pumpkin fruit extract could have a potential in treating CD in stressed conditions mainly via its enhancement of skin antioxidant activity.
PubMed: 32766119
DOI: 10.4103/JMAU.JMAU_37_19 -
Allergy Jun 2021Fatty acid-binding protein 3 (FABP3) is a cytosolic carrier protein of polyunsaturated fatty acids (PUFAs) and regulates cellular metabolism. However, the physiological...
BACKGROUND
Fatty acid-binding protein 3 (FABP3) is a cytosolic carrier protein of polyunsaturated fatty acids (PUFAs) and regulates cellular metabolism. However, the physiological functions of FABP3 in immune cells and how FABP3 regulates inflammatory responses remain unclear.
METHODS
Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin wild-type and Fabp3 mice. Skin inflammation was assessed using FACS, histological, and qPCR analyses. The development of γ/δ T cells was evaluated by a co-culture system with OP9/Dll1 cells in the presence or absence of transgene of FABP3.
RESULTS
Fabp3-deficient mice exhibit a more severe phenotype of contact hypersensitivity (CHS) accompanied by infiltration of IL-17-producing Vγ4 γ/δ T cells that critically control skin inflammation. In Fabp3 mice, we found a larger proportion of Vγ4 γ/δ T cells in the skin, even though the percentage of total γ/δ T cells did not change at steady state. Similarly, juvenile Fabp3 mice also contained a higher amount of Vγ4 γ/δ T cells not only in the skin but in the thymus when compared with wild-type mice. Furthermore, thymic double-negative (DN) cells expressed FABP3, and FABP3 negatively regulates the development of Vγ4 γ/δ T cells in the thymus.
CONCLUSIONS
These findings suggest that FABP3 functions as a negative regulator of skin inflammation through limiting pathogenic Vγ4 γ/δ T-cell generation in the thymus.
Topics: Animals; Dermatitis, Contact; Disease Models, Animal; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes
PubMed: 33090507
DOI: 10.1111/all.14630 -
Allergology International : Official... Apr 2024Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin...
BACKGROUND
Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin inflammation. However, few studies have investigated the effect of topical application of AP-1 inhibitors in treating inflammatory skin disorders.
METHODS
Immunohistochemistry was conducted to detect phosphorylated AP-1/c-Jun expression of skin lesions in AD patients. In the in vivo study, 1 % T-5224 ointment was topically applied for 8 days to the ears of 2,4 dinitrofluorobenzene challenged AD-like dermatitis model mice. Baricitinib, a conventional therapeutic agent Janus kinase (JAK) inhibitor, was also topically applied. In the in vitro study, human epidermal keratinocytes were treated with T-5224 and stimulated with AD-related cytokines.
RESULTS
AP-1/c-Jun was phosphorylated at skin lesions in AD patients. In vivo, topical T-5224 application inhibited ear swelling (P < 0.001), restored filaggrin (Flg) expression (P < 0.01), and generally suppressed immune-related pathways. T-5224 significantly suppressed Il17a and l17f expression, whereas baricitinib did not. Baricitinib suppressed Il4, Il19, Il33 and Ifnb expression, whereas T-5224 did not. Il1a, Il1b, Il23a, Ifna, S100a8, and S100a9 expression was cooperatively downregulated following the combined use of T-5224 and baricitinib. In vitro, T-5224 restored the expression of FLG and loricrin (LOR) (P < 0.05) and suppressed IL33 expression (P < 0.05) without affecting cell viability and cytotoxicity.
CONCLUSIONS
Topical T-5224 ameliorates clinical manifestations of AD-like dermatitis in mice. The effect of this inhibitor is amplified via combined use with JAK inhibitors.
Topics: Animals; Humans; Mice; Azetidines; Benzophenones; Cytokines; Dermatitis, Atopic; Inflammation; Interleukin-33; Isoxazoles; Purines; Pyrazoles; Skin; Sulfonamides; Transcription Factor AP-1
PubMed: 38350816
DOI: 10.1016/j.alit.2023.12.006 -
Research Square Jul 2023Nanoparticle (NP) skin exposure is linked to the increased prevalence of allergic contact dermatitis. In prior studies using the mouse contact hypersensitivity (CHS)...
Nanoparticle (NP) skin exposure is linked to the increased prevalence of allergic contact dermatitis. In prior studies using the mouse contact hypersensitivity (CHS) model, we reported that silica 20 nm (Si20nm) suppressed the allergic response and TiO2 doped with manganese (mTiO2) exacerbated it. In this work, we conducted in vitro experiments using bone marrow-derived dendritic cells (BMDCs) to study the combinatorial effect of the potent 2, 4-dinitrofluorobenzene (DNFB) hapten sensitizer with Si20nm and mTiO2 NPs on BMDC cytotoxicity, cytokine secretion and phenotype using the B7 family ligands. Results show that DNFB and mTiO2 behave similarly and exhibit proinflammatory characteristics while Si20nm promotes a naive phenotype. We observe that the B7-H3 (CD276) ligand is only expressed on CD80+ (B7-1) BMDC. Results from adoptive transfer CHS studies, combined with BMDC phenotype analysis, point to the importance of PD-L2 expression in modulating the adaptive immune response. This work identifies metrics that can be used to predict the effects of NPs on contact allergy and to guide efforts to engineer cell-based therapies to induce antigen specific immune tolerance.
PubMed: 37503107
DOI: 10.21203/rs.3.rs-3069059/v1 -
PloS One 2017This study evaluated the intestinal anti-inflammatory effects of goat whey in a mouse model of colitis induced by 2,4-dinitrobenzenesulfonic acid that resembles human...
This study evaluated the intestinal anti-inflammatory effects of goat whey in a mouse model of colitis induced by 2,4-dinitrobenzenesulfonic acid that resembles human IBD. At a concentration of 4 g/kg/day, the goat whey improved the symptoms of intestinal inflammation, namely by decreasing the disease activity index, colonic weight/length, and leukocyte infiltration. Moreover, goat whey inhibited NF-κB p65 and p38 MAPK signaling pathways and consequently down-regulated the gene expression of various proinflammatory markers such as IL-1β, IL-6, IL-17, TNF-α, iNOS, MMP-9, ICAM-1. Also, goat whey increased the expression of proteins such as mucins, occludin proteins and cytokine signalling suppressors. The immunomodulatory properties of goat whey were also evaluated in vitro using the murine macrophage cell line Raw 264 and CMT-93 cells derived from mouse rectum carcinomas. The results revealed the ability of goat whey to inhibit the production of NO and reduce IL-6 production in LPS-stimulated cells. In conclusion, goat whey exhibited anti-inflammatory effects in the DNBS model of intestinal inflammation, and these observations were confirmed by its immunomodulatory properties in vitro. Together, our results indicate that goat whey could have applications for the treatment of IBD.
Topics: Animals; Anti-Inflammatory Agents; Colitis; Cytokines; Dinitrofluorobenzene; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Gene Expression Regulation; Goats; Inflammation Mediators; Intestinal Mucosa; Intestines; Male; Mice; RAW 264.7 Cells; Real-Time Polymerase Chain Reaction; Whey
PubMed: 28957373
DOI: 10.1371/journal.pone.0185382 -
PeerJ 2016Background. Resveratrol is a natural polyphenol that exhibits anti-inflammatory effects. The aim of this study was to investigate the effects of resveratrol treatment on...
Background. Resveratrol is a natural polyphenol that exhibits anti-inflammatory effects. The aim of this study was to investigate the effects of resveratrol treatment on epithelium-derived cytokines and epithelial apoptosis in a murine model of atopic dermatitis-like lesions. Material and Methods. Atopic dermatitis-like lesions were induced in BALB/c mice by repeated application of 2,4-dinitrofluorobenzene to shaved dorsal skin. Twenty-one BALB/c mice were divided into three groups: group I (control), group II (vehicle control), and group III (resveratrol). Systemic resveratrol (30 mg/kg/day) was administered repeatedly during the 6th week of the experiment. After the mice had been sacrificed, skin tissues were examined histologically for epithelial thickness. Epithelial apoptosis (caspase-3) and epithelium-derived cytokines [interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP)] were evaluated immunohistochemically. Results. Epithelial thickness and the numbers of IL-25, IL-33, TSLP and caspase-3-positive cells were significantly higher in group II compared to group I mice. There was significant improvement in epithelial thickness in group III compared with group II mice (p < 0.05). The numbers of IL-25, IL-33, and TSLP-positive cells in the epithelium were lower in group III than in group II mice (p < 0.05). The number of caspase-3-positive cells, as an indicator of apoptosis, in the epithelium was significantly lower in group III than in group II mice (p < 0.05). Conclusion. Treatment with resveratrol was effective at ameliorating histological changes and inflammation by acting on epithelium-derived cytokines and epithelial apoptosis.
PubMed: 27069818
DOI: 10.7717/peerj.1889