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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 -
Journal of Gastroenterology and... Aug 2023Bifidobacterium breve was the first bacteria isolated in the feces of healthy infants and is a dominant species in the guts of breast-fed infants. Some strains of B....
BACKGROUND AND AIM
Bifidobacterium breve was the first bacteria isolated in the feces of healthy infants and is a dominant species in the guts of breast-fed infants. Some strains of B. breve have been shown to be effective at relieving intestinal inflammation, but the modes of action have yet to be elucidated. In this study, we investigated the mechanisms of action of B. breve CBT BR3 isolated from South Korean infant feces in relieving colitis in vitro and in vivo.
METHODS
Colitis was induced in mice with dextran sodium sulfate (DSS) and dinitrobenzene sulfonic acid (DNBS). Quantitative reverse-transcription polymerase chain reaction, in vitro FITC-dextran flux permeability assay, and aryl hydrocarbon receptor (AhR) luciferase assay are performed using Caco-2 cells and HT29-Lucia™ AhR cells.
RESULTS
B. breve CBT BR3 was orally administered. B. breve CBT BR3 improved colitis symptoms in both DSS- and DNBS-induced colitis models. B. breve CBT BR3 increased the number of goblet cells per crypt. B. breve increased the mRNA expressions of Notch, Spdef, Muc5, and Il22. The mRNA expressions of Occludin, which encodes a membrane tight-junction protein, and Foxo3, which encodes a protein related to butyrate metabolism, were also increased in the DSS- and DNBS-induced colitis models. B. breve CBT BR3 protected inflammation-induced epithelial cell permeability and improved goblet cell function by inducing aryl hydrocarbon receptor in vitro.
CONCLUSIONS
These results indicate that B. breve CBT BR3 is effective at relieving intestinal inflammation by augmenting goblet cell regeneration.
Topics: Humans; Animals; Mice; Goblet Cells; Bifidobacterium breve; Receptors, Aryl Hydrocarbon; Caco-2 Cells; Colitis; Inflammation; RNA, Messenger; Regeneration; Dextran Sulfate; Intestinal Mucosa; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37157108
DOI: 10.1111/jgh.16209 -
Journal of Ethnopharmacology Sep 2023Probiotic fermentation is a mild and safe biological method to boost the performance of herbs. Portulaca oleracea L. (PO), with folklore records of purgative,...
ETHNOPHARMACOLOGICAL RELEVANCE
Probiotic fermentation is a mild and safe biological method to boost the performance of herbs. Portulaca oleracea L. (PO), with folklore records of purgative, anti-dermatological and anti-epidemic effects, has been demonstrated to possess anti-inflammatory, immunomodulatory, and antioxidant properties. However, the potential of PO for the treatment of atopic dermatitis (AD) has not been sufficiently explored.
AIM OF STUDY
This study aimed to evaluate the therapeutic benefits of PO and fermented Portulaca oleracea L. (FPO) and explore their intrinsic mechanisms.
METHODS
By utilizing 2,4-dinitrofluorobenzene-induced AD mice as a model, the histopathology of the lesions was observed using H&E and toluidine blue staining methods; the levels of immunoglobulin E (Ig E), histamine (HIS), and thymic stromal lymphopoietin (TSLP) in serum were measured using ELISA, whereas, the expression of inflammatory cytokines in skin lesion was measured using ELISA and immunohistochemistry experiments. The expression of tumor necrosis factor-α (TNF-α), IKKα, NF-κB mRNA was measured using qPCR; and the expression of TNF-α、p-IKKα, p-IκBα, p-NF-κB was measured using western blotting.
RESULTS
Both 20 mg/mL PO and FPO alleviated mast cell infiltration and lesion pathology, reduced serum levels of Ig E, HIS and TSLP, down-regulated the expression of AD-related inflammatory cytokines, such as, TNF-α, interferon-γ, and interleukin-4, and increased filaggrin expression. Furthermore, they inhibited the expression of TNF-α, IKKα, and NF-κB genes and TNF-α, p-IKKα, p-NF-κB and p-IκBα proteins associated with the NF-κB signaling pathway.
CONCLUSIONS
PO and FPO has a positive therapeutic potential on AD, indicating that it may be employed as alternative therapies for AD.
Topics: Mice; Animals; Dermatitis, Atopic; NF-kappa B; Dinitrofluorobenzene; NF-KappaB Inhibitor alpha; Tumor Necrosis Factor-alpha; I-kappa B Kinase; Portulaca; Cytokines; Signal Transduction; Thymic Stromal Lymphopoietin; Immunoglobulin E
PubMed: 37156447
DOI: 10.1016/j.jep.2023.116613 -
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 -
Spectrochimica Acta. Part A, Molecular... Aug 2023Here, a corrole-based dual-responsive fluorescent probe DPC-DNBS was rationally designed and synthesized for the separate detection of hydrazine (NH) and hydrogen...
Here, a corrole-based dual-responsive fluorescent probe DPC-DNBS was rationally designed and synthesized for the separate detection of hydrazine (NH) and hydrogen sulfide (HS) with high selectivity and sensitivity. The probe DPC-DNBS is intrinsically none fluorescent due to PET effect, however, addition of increasing amount of NH or HS to DPC-DNBS turned on an excellent NIR fluorescence centered at 652 nm and thereby provided a colorimetric signaling behavior. The sensing mechanism was verified by HRMS, H NMR and the DFT calculations. Common metal ions and anions do not interfere with the interactions of DPC-DNBS with NH or HS. Furthermore, the presence of NH does not affect the detection of HS; however, the presence of HS interferes with the detection of NH. Hence, quantitative detection of NH must occur in an HS-free environment. The probe DPC-DNBS displayed some fascinating merits in separate detection of these two analytes, including large Stokes shift (233 nm), fast response (15 min for NH, 30 s for HS), low detection limit (90 nM for NH, 38 nM for HS), wide pH range (6-12) and outstanding biological compatibility. Significantly, DPC-DNBS was utilized to detect hydrazine in real water, soil and food samples. And its favorable performances for separate detection NH and HS were successfully demonstrated in HeLa cells and zebrafish, indicating its value of practical application in biology.
Topics: Humans; Animals; Fluorescent Dyes; HeLa Cells; Hydrogen Sulfide; Zebrafish; Hydrazines; Spectrometry, Fluorescence
PubMed: 37019005
DOI: 10.1016/j.saa.2023.122678 -
Journal of the Science of Food and... Aug 2023Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by pruritus and eczema lesions and psychiatric comorbidities. The gut-brain-skin axis plays...
BACKGROUND
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by pruritus and eczema lesions and psychiatric comorbidities. The gut-brain-skin axis plays a pivotal role during AD development, which might suggest a novel therapeutic strategy for AD. The present study aims to uncover the protective effects and underlying mechanisms of fructo-oligofructose (FOS), a type of prebiotic, on AD-like skin manifestations and comorbid anxiety and depression in AD mice.
RESULTS
Female Kunming mice were treated topically with 2,4-dinitrofluorobenzene (DNFB) to induce AD-like symptoms and FOS was administered daily for 14 days. The results showed that FOS could alleviate AD-like skin lesions markedly as evidenced by dramatic decreases in severity score, scratching bouts, the levels of immunoglobulin E (IgE) and T helper 1(Th1)/Th2-related cytokines, and the infiltration of inflammatory cells and mast cells to the dermal tissues. The comorbid anxiety and depressive-like behaviors, estimated by the forced swimming test (FST), the tail-suspension test (TST), the open-field test (OFT), and the zero maze test (ZMT) in AD mice, were significantly attenuated by FOS. Fructo-oligofructose significantly upregulated brain neurotransmitters levels of 5-hydroxytryptamine (5-HT) and dopamine (DA). Furthermore, FOS treatment increased the relative abundance of gut microbiota, such as Prevotella and Lactobacillus and the concentrations of short-chain fatty acids (SCFAs), especially acetate and iso-butyrate in the feces of AD mice. The correlation analysis indicated that the reshaped gut microbiome composition and enhanced SCFAs formation are associated with skin inflammation and behavioral alteration.
CONCLUSION
Collectively, these data identify FOS as a promising microbiota-targeted treatment for AD-like skin inflammation and comorbid anxiety and depressive-like behaviors. © 2023 Society of Chemical Industry.
Topics: Mice; Female; Animals; Dermatitis, Atopic; Dinitrofluorobenzene; Skin; Cytokines; Inflammation
PubMed: 36987580
DOI: 10.1002/jsfa.12582 -
Molecular Nutrition & Food Research May 2023Epidemiological data suggest that altered gut microbiota contributes to the development of atopic dermatitis (AD). The effect of an olive-derived antioxidant dietary...
SCOPE
Epidemiological data suggest that altered gut microbiota contributes to the development of atopic dermatitis (AD). The effect of an olive-derived antioxidant dietary fiber (OADF) in relieving AD symptoms in a murine model of 2,4-dinitrofluorobenzene (DNFB)-induced AD is examined and the effect of OADF in modulating host gut microbiota is explored.
METHODS AND RESULTS
Mice are fed with either standard diet or standard diet + OADF for 3 weeks prior to induction of AD and maintained on the same diet throughout the DNFB application period. Dietary OADF causes significant improvement of AD-like symptoms with reduced serum levels of immunoglobulin (Ig)E, interleukin (IL)-1β, IL-6, C-X-C motif ligand (CXCL)1, and increased serum levels of IL-10. OADF supplementation restore gut microbiota composition that are altered in AD mice. Specifically, OADF increases the proportion of intestinal bacteria (Ruminococcaceae UCG014, GCA900066575, UBA1819) associated with enhanced butyrate production, along with inhibiting Clostridiales vadin BB60 which are more prevalent in AD mice.
CONCLUSION
OADF modulates gut microbiota composition, improves cytokine profile and butyrate production influencing AD-associated immune response. Results highlight the importance of the gut-skin axis for the AD dietary therapeutic agents.
Topics: Animals; Mice; Dermatitis, Atopic; Antioxidants; Olea; Gastrointestinal Microbiome; Dinitrofluorobenzene; Inflammation; Dietary Fiber; Butyrates; Immunoglobulin E
PubMed: 36929605
DOI: 10.1002/mnfr.202200127