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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 -
Frontiers in Immunology 2023Major histocompatibility complex (MHC) class Ib molecules present antigens to subsets of T cells primarily involved in host defense against pathogenic microbes and...
Major histocompatibility complex (MHC) class Ib molecules present antigens to subsets of T cells primarily involved in host defense against pathogenic microbes and influence the development of immune-mediated diseases. The MHC class Ib molecule MHC-related protein 1 (MR1) functions as a platform to select MR1-restricted T cells, including mucosal-associated invariant T (MAIT) cells in the thymus, and presents ligands to them in the periphery. MAIT cells constitute an innate-like T-cell subset that recognizes microbial vitamin B metabolites and plays a defensive role against microbes. In this study, we investigated the function of MR1 in allergic contact dermatitis (ACD) by examining wild-type (WT) and MR1-deficient (MR1) mice in which ACD was induced with 2,4-dinitrofluorobenzene (DNFB). MR1 mice exhibited exaggerated ACD lesions compared with WT mice. More neutrophils were recruited in the lesions in MR1 mice than in WT mice. WT mice contained fewer MAIT cells in their skin lesions following elicitation with DNFB, and MR1 mice lacking MAIT cells exhibited a significant increase in IL-17-producing αβ and γδ T cells in the skin. Collectively, MR1 mice displayed exacerbated ACD from an early phase with an enhanced type 3 immune response, although the precise mechanism of this enhancement remains elusive.
Topics: Animals; Mice; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Histocompatibility Antigens Class I; Interleukin-17; Minor Histocompatibility Antigens
PubMed: 37409131
DOI: 10.3389/fimmu.2023.1215478 -
Indian Journal of Dermatology 2023This study aims to investigate the anti-inflammatory effects of cinnamaldehyde in atopic dermatitis (AD) in the mouse model.
BACKGROUND
This study aims to investigate the anti-inflammatory effects of cinnamaldehyde in atopic dermatitis (AD) in the mouse model.
MATERIALS AND METHODS
Twenty-four mice were divided into four groups: Group A (control), group B [AD with no treatment (AD + NoTre)], group C [AD with corticosteroids (AD + Cort)] and group D [AD with cinnamaldehyde (AD + Cin)]. 2,4-dinitrofluorobenzene was used to form the AD model. Topical corticosteroid was applied to group C, and oral cinnamaldehyde was administered to group D. Dorsal skin biopsies were evaluated immunohistochemically with interleukin (IL)-25, IL-33, thymic stromal lymphopoietin and caspase-3.
RESULTS
Epithelial thicknesses were significantly higher in group B-D mice compared to group A ( = 0.002, 0.009, 0.004, respectively). Significantly, higher staining with IL-25 was observed in group B (AD + NoTre) and group D (AD + Cin) than in group A (control) ( = 0.003, 0.002, respectively). However, no significant difference was observed between group D (AD + Cin) and group B (AD + NoTre). All three groups (B-D) had significantly higher staining in terms of diffuseness of IL-33 compared to group A (control) ( = 0.002, 0.002, 0.002, respectively). Caspase-3 staining was significantly lower in group D (AD + Cin) than in group B (AD + NoTre) ( = 0.003, 0.002, respectively). Moreover, caspase-3 staining intensity was significantly lower in group D (AD + Cin) than in group C (AD + Cort) ( = 0.002).
CONCLUSIONS
Our study demonstrated that IL-33, IL-25 and caspase-3 have a role in the pathogenesis of AD. Furthermore, cinnamaldehyde reduced caspase-3 activity more than topical corticosteroids and anti-inflammatory effects might be investigated in AD therapy with future studies.
PubMed: 37275806
DOI: 10.4103/ijd.ijd_576_22 -
Experimental and Therapeutic Medicine Jul 2023polysaccharides (MCPs) have been reported to exert beneficial roles, such as disease healing, in medicine and pharmacy. However, little is known about their effects on...
polysaccharides (MCPs) have been reported to exert beneficial roles, such as disease healing, in medicine and pharmacy. However, little is known about their effects on immunomodulation The present study aimed to explore the possible effects of polysaccharide (MCP) on the immunomodulatory activity of mice lymphocytes. To this aim, male BALB/c mice aged 6-8 weeks were assigned to the following six experimental groups: i) Normal (NG); ii) model (MG); iii) positive (PG); iv) MCP low-dose (MLG); v) MCP medium-dose (MMG); and vi) MCP high-dose (MHG). An immunosuppressive model was established by the intraperitoneal injection of cyclophosphamide in all groups apart from NG. The NG and MG mice were fed with distilled water, whereas the PG mice were administered with levamisole and the MLG, MMG and MHG mice were fed on low, medium and high (100, 200 and 300 mg/kg, respectively) doses of MCP for 21 consecutive days. Subsequently, the mice underwent surgical procedure and were analysed using a range of procedures, including measurement of the thymus index (TI) and spleen index (SI), assessment of the lymphocyte proliferation rate and cell phagocytosis of peritoneal macrophages, lymphocyte proliferation, secretion and mRNA expression of cytokines IFN-γ, IL-6 and IL-12. The mice divided into six groups as mentioned above and treated for 7 days, in the first 6 days, except NG group, mice in each group were desiccated in the abdominal cavity and sensitized by 1% dinitrofluorobenzene (DNFB). On day 6, mice were sensitized with 20 µl DNFB/acetone/olive oil solution behind the right ear and in front of the right ear. Compared with those in the NG mice (not injected with 80 mg/kg cyclophosphamide), the TIs and SIs of the PG, MLG, MMG and MHG mice were increased. In addition, the inhibitory rate of ear swelling and the phagocytic activity of peritoneal macrophages in the PG, MLG, MMG and MHG mice were increased compared with those of MG. Furthermore, the lymphocyte proliferation rate, the secretion and relative mRNA expression levels of cytokines IFN-γ, IL-6 and IL-12 were significantly increased in the PG, MMG and MHG mice compared with those in the NG mice. The results from the present study suggest that treatment with MCP led to an upregulation of the organ indices of immunosuppressed mice, reduced their delayed allergic reaction indicated by the differential cytokine levels, improved the phagocytic activity of peritoneal macrophages, enhanced the proliferation rate of lymphocytes, increased the secretion and expression of IFN-γ, IL-6 and IL-12. Therefore, MCP may improve the immune function of the immunosuppressed mice.
PubMed: 37273762
DOI: 10.3892/etm.2023.12006 -
IL-22RA2 Is a SMAD7 Target Mediating the Alleviation of Dermatitis and Psoriatic Phenotypes in Mice.The Journal of Investigative Dermatology Nov 2023Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study...
Long-term management of inflammatory skin diseases is challenging because of side effects from repeated use of systemic treatments or topical corticosteroids. This study sought to identify the mechanisms and developmental therapeutics for these diseases using genetic models and pharmacological approaches. We found that mice overexpressing SMAD7 in keratinocytes but not mice overexpressing the N-terminal domain of SMAD7 (i.e., N-SMAD7) were resistant to imiquimod-induced T helper 1/17- and T helper 2-type inflammation. We generated a Tat-PYC-SMAD7 (truncated SMAD7 protein encompassing C-terminal SMAD7 and PY motif fused with cell-penetrating Tat peptide). Topically applied Tat-PYC-SMAD7 to inflamed skin entered cells upon contact and attenuated imiquimod-, 2,4-dinitrofluorobenzene-, and tape-stripping-induced inflammation. RNA-sequencing analyses of mouse skin exposed to these insults showed that in addition to inhibiting TGFβ/NF-κB, SMAD7 blunted IL-22/signal transducer and activator of transcription 3 activation and associated pathogenesis, which is due to SMAD7 transcriptionally upregulating IL-22 antagonist IL-22RA2. Mechanistically, SMAD7 facilitated nuclear translocation and DNA binding of C/EBPβ to IL22RA2 promoter for IL22RA2 transactivation. Consistent with the observations in mice mentioned earlier, transcript levels of IL22RA2 were increased in human atopic dermatitis and psoriasis lesions with clinical remission. Our study identified the anti-inflammation functional domain of SMAD7 and suggests the mechanism and feasibility for developing SMAD7-based biologics as a topical therapy for skin inflammatory disorders.
Topics: Mice; Humans; Animals; Imiquimod; Smad7 Protein; Skin; Psoriasis; Dermatitis; Keratinocytes; Inflammation; Phenotype; Disease Models, Animal; Mice, Inbred BALB C; Receptors, Interleukin
PubMed: 37211203
DOI: 10.1016/j.jid.2023.04.029 -
Oncotarget May 2023The creatine shuttle translocates the energy generated by oxidative phosphorylation to the cytoplasm via mitochondrial creatine kinase (MTCK) and creatine kinase B (CKB)...
The creatine shuttle translocates the energy generated by oxidative phosphorylation to the cytoplasm via mitochondrial creatine kinase (MTCK) and creatine kinase B (CKB) in the cytoplasm. It is not apparent how the creatine shuttle is related to cancer. Here, we analyzed the expression and function of CKB and MTCK in colorectal cancer (CRC) and investigated the role of the creatine shuttle in CRC. Compared with normal mucosa, 184 CRC tissues had higher levels of CKB and MTCK, and these levels were associated with histological grade, tumor invasion, and distant metastasis. CK inhibitor dinitrofluorobenzene (DNFB) on CRC cell lines HT29 and CT26 inhibited cell proliferation and stemness to less than 2/3 and 1/20 of their control levels, respectively. In this treatment, the production of reactive oxygen species increased, mitochondrial respiration decreased, and mitochondrial volume and membrane potential decreased. In a syngeneic BALB/c mouse model using CT26 cells pretreated with DNFB, peritoneal metastasis was suppressed to 70%. Phosphorylation of EGFR, AKT, and ERK1/2 was inhibited in DNFB-treated tumors. High ATP concentrations prevented EGFR phosphorylation in HT29 cells following DNFB treatment, CKB or MTCK knockdown, and cyclocreatine administration. Despite not being immunoprecipitated, CKB and EGFR were brought closer together by EGF stimulation. These findings imply that blocking the creatine shuttle decreases the energy supply, suppresses oxidative phosphorylation, and blocks ATP delivery to phosphorylation signals, preventing signal transduction. These findings highlight the critical role of the creatine shuttle in cancer cells and suggest a potential new cancer treatment target.
Topics: Mice; Animals; Creatine; Creatine Kinase; Dinitrofluorobenzene; Creatine Kinase, Mitochondrial Form; Oxidative Phosphorylation; Adenosine Triphosphate; Colorectal Neoplasms; ErbB Receptors
PubMed: 37204253
DOI: 10.18632/oncotarget.28436 -
Lipids in Health and Disease May 2023Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex...
BACKGROUND
Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis.
METHODS
Colitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS.
RESULTS
GF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation.
CONCLUSIONS
These results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.
Topics: Mice; Animals; Dinitrobenzenes; Colitis; Inflammation; Lipids
PubMed: 37189092
DOI: 10.1186/s12944-023-01823-1 -
Biological & Pharmaceutical Bulletin Jul 2023Allergic contact dermatitis (ACD) is a common skin disorder caused by contact with allergens. The optimal treatment for ACD is to avoid contact with allergens. However,...
Allergic contact dermatitis (ACD) is a common skin disorder caused by contact with allergens. The optimal treatment for ACD is to avoid contact with allergens. However, in some cases, avoiding exposure is not possible when the allergens are unknown. Therefore, establishing treatment methods other than allergen avoidance is important. We previously reported that the continuous administration of methionine, an essential amino acid, in a mouse model of atopic dermatitis alleviated its symptoms. In the present study, we investigated the effect of methionine on a mouse model of ACD caused by 1-fluoro-2,4-dinitrobenzene (DNFB). Differences in the effect of methionine were observed in DNFB-induced ACD model mice based on the mouse strain used. This difference was attributed to the suppression of hepatic dimethylglycine (DMG) production, which is associated with the suppression of hepatic betaine-homocysteine methyltransferase (Bhmt) expression by ACD. Although we did not reveal the mechanism underlying DMG suppression, our study suggests the presence of interactions between the liver and skin in dermatitis, such as the regulation of hepatic metabolic enzyme expression in dermatitis and the alleviation of dermatitis symptoms by the hepatic metabolism status of DMG.
Topics: Mice; Animals; Methionine; Dinitrofluorobenzene; Dermatitis, Allergic Contact; Allergens; Racemethionine
PubMed: 37183024
DOI: 10.1248/bpb.b23-00098 -
Molecules (Basel, Switzerland) Apr 2023Resveratrol (RSV), a naturally occurring metabolite, is widely used in skincare products, but its hydrophobicity impairs its own incorporation into cosmetic...
Resveratrol (RSV), a naturally occurring metabolite, is widely used in skincare products, but its hydrophobicity impairs its own incorporation into cosmetic formulations. RSV-GS is a synthetic hydrophilic sulfated glycosylated derivative inspired by marine natural products that present a lower cytotoxicity than RSV while exhibiting similar levels of bioactivity. Herein, we predict the skin sensitization potential of this new compound using an in vitro approach based on the OECD 442E guideline. Furthermore, the anti-allergic potential of RSV-GS was also disclosed. The monocyte THP-1 cell line was stimulated with RSV and RSV-GS in the presence or absence of the extreme skin allergen 1-fluoro-2,4-dinitrobenzene (DNFB). The results demonstrated that RSV-GS alone (500 µM) evoked a relative fluorescence index (RFI) lower than the thresholds established by the OECD guideline for CD54 (200%) and CD86 (150%), indicating the absence of a skin sensitization potential. Interestingly, in the presence of the skin allergen DNFB, RSV-GS exhibited the ability to rescue the DNFB-induced maturation of THP-1 cells, with RFI values lower than those for RSV, suggesting the potential of RSV-GS to mitigate skin sensitization evoked by allergens and, consequently, allergic contact dermatitis. These results open new avenues for the use of RSV-GS as a safe and anti-allergic active cosmetic ingredient.
Topics: Resveratrol; Anti-Allergic Agents; Sulfates; Dinitrofluorobenzene; Allergens
PubMed: 37049922
DOI: 10.3390/molecules28073158 -
Molecules (Basel, Switzerland) Feb 2023Biothiols, including glutathione (GSH), homocysteine (Hcy) and cysteine (Cys), play crucial roles in various physiological processes. Though an array of fluorescent...
Biothiols, including glutathione (GSH), homocysteine (Hcy) and cysteine (Cys), play crucial roles in various physiological processes. Though an array of fluorescent probes have been designed to visualize biothiols in living organisms, few one-for-all imaging agents for sensing biothiols with fluorescence and photoacoustic imaging capabilities have been reported, since instructions for synchronously enabling and balancing every optical imaging efficacy are deficient. Herein, a new near-infrared thioxanthene-hemicyanine dye (Cy-DNBS) has been constructed for fluorescence and photoacoustic imaging of biothiols in vitro and in vivo. Upon treatment with biothiols, the absorption peak of Cy-DNBS shifted from 592 nm to 726 nm, resulting in a strong NIR absorption as well as a subsequent turn-on PA signal. Meanwhile, the fluorescence intensity increased instantaneously at 762 nm. Then, Cy-DNBS was successfully utilized for imaging endogenous and exogenous biothiols in HepG2 cells and mice. In particular, Cy-DNBS was employed for tracking biothiols upregulation in the liver of mice triggered by S-adenosyl methionine by means of fluorescent and photoacoustic imaging methods. We expect that Cy-DNBS serves as an appealing candidate for deciphering biothiols-related physiological and pathological processes.
Topics: Animals; Mice; Cysteine; Fluorescent Dyes; Spectrometry, Fluorescence; Optical Imaging; Liver; Neoplasms; Glutathione; Homocysteine
PubMed: 36903474
DOI: 10.3390/molecules28052229