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Biological & Pharmaceutical Bulletin 2018Interleukin (IL)-19 is a member of the IL-10 family of interleukins and is an immuno-modulatory cytokine produced by the main macrophages. The gastrointestinal tissues...
Interleukin (IL)-19 is a member of the IL-10 family of interleukins and is an immuno-modulatory cytokine produced by the main macrophages. The gastrointestinal tissues of IL-19 knockout mice show exacerbated experimental colitis mediated by the innate immune system and T cells. There is an increasing focus on the interaction and relationship of IL-19 with the function of T cells. Contact hypersensitivity (CHS) is T cell-mediated cutaneous inflammation. Therefore, we asked whether IL-19 causes CHS. We investigated the immunological role of IL-19 in CHS induced by 1-fluoro-2,4-dinitrofluorobenzene as a hapten. IL-19 was highly expressed in skin exposed to the hapten, and ear swelling was increased in IL-19 knockout mice. The exacerbation of the CHS response in IL-19 knockout mice correlated with increased levels of IL-17 and IL-6, but no alterations were noted in the production of interferon (IFN)γ and IL-4 in the T cells of the lymph nodes. In addition to the effect on T cell response, IL-19 knockout mice increased production of inflammatory cytokines. These results show that IL-19 suppressed hapten-dependent skin inflammation in the elicitation phase of CHS.
Topics: Animals; Cells, Cultured; Dermatitis, Contact; Dinitrofluorobenzene; Ear; Gene Expression Regulation; Haptens; Immunity, Innate; Immunohistochemistry; Interleukin-10; Interleukin-17; Interleukin-6; Interleukins; Lymph Nodes; Mice, Inbred BALB C; Mice, Knockout; RNA, Messenger; Skin; Spleen; T-Lymphocytes; Th1 Cells
PubMed: 29386478
DOI: 10.1248/bpb.b17-00594 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2022A multifunctional photodynamic molecular beacon (PMB) has been designed and synthesized which contains an epidermal growth factor receptor (EGFR)-targeting cyclic...
A multifunctional photodynamic molecular beacon (PMB) has been designed and synthesized which contains an epidermal growth factor receptor (EGFR)-targeting cyclic peptide and a trimeric phthalocyanine skeleton in which the three zinc(II) phthalocyanine units are each substituted with a glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS) quencher and are linked via two cathepsin B-cleavable GFLG peptide chains. This tailor-made conjugate is fully quenched in the native form due to the photoinduced electron transfer effect of the DNBS moieties and the self-quenching of the phthalocyanine units. It can target the EGFR overexpressed in cancer cells, and after receptor-mediated endocytosis, it can be activated selectively by the co-existence of intracellular GSH and cathepsin B, both of which are also overproduced in cancer cells, in terms of fluorescence emission and singlet oxygen generation. The cell-selective behavior of this PMB has been demonstrated using a range of cancer cells with different expression levels of EGFR, while the stimuli-responsive properties have been studied both in vitro and in various aqueous media. The overall results show that this advanced PMB, which exhibits several levels of control of the tumor specificity, is a promising photosensitizer for precise antitumoral photodynamic therapy.
Topics: Cathepsin B; Cell Line, Tumor; Dinitrofluorobenzene; ErbB Receptors; Glutathione; Humans; Indoles; Neoplasms; Peptides; Peptides, Cyclic; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen
PubMed: 35852020
DOI: 10.1002/chem.202201652 -
International Journal of Molecular... Dec 2022Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a...
Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a photoinduced electron transfer (PET) effect between BODIPY and the 2,4-dinitrobenzenesulfonate (DNBS) group, and an ROS-responsive thioketal linker connecting BODIPY and the chemotherapeutic agent camptothecin (CPT). Interestingly, CPT displayed low toxicity because the active site of CPT was modified by the BODIPY-based macrocycle. Additionally, BTC was encapsulated with the amphiphilic polymer DSPE-mPEG to improve drug solubility and tumor selectivity. The resulting nano-prodrug passively targeted tumor cells through enhanced permeability and retention (EPR) effects, and then the photosensitizing ability of the BODIPY dye was restored by removing the DNBS group with the high concentration of GSH in tumor cells. Light-triggered ROS from activated BODIPY can not only induce apoptosis or necrosis of tumor cells but also sever the thioketal linker to release CPT, achieving the combination treatment of selective photodynamic therapy and chemotherapy. The antitumor activity of the prodrug has been demonstrated in mouse mammary carcinoma 4T1 and human breast cancer MCF-7 cell lines and 4T1 tumor-bearing mice.
Topics: Humans; Mice; Animals; Female; Prodrugs; Breast Neoplasms; Reactive Oxygen Species; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Cell Line, Tumor
PubMed: 36555298
DOI: 10.3390/ijms232415656 -
Chinese Journal of Integrative Medicine Aug 2022To investigate the anti-inflammatory potential of Ampelopsis japonica on contact dermatitis (CD).
OBJECTIVE
To investigate the anti-inflammatory potential of Ampelopsis japonica on contact dermatitis (CD).
METHODS
A total of 38 Balb/c mice were divided into 5 groups by using a random number table: normal mice (n=6), CD model mice (n=8), CD mice treated with 3 or 30 mg/kg of the ethanol extract of A. japonica (EEAJ, n=8) and 7.5 mg/kg dexamethasone treated CD mice (DEX, n=8). CD was induced using topical application of 1-fluoro-2,4-dinitrofluorobenzene in mice. EEAJ and DEX were topically applied to the shaved skin of each mouse for 6 days, and the effects of EEAJ and DEX on skin lesions and color, histopathological abnormalities such as epidermal hyperplasia and immune cell infiltration, and tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) production were investigated. The effects on changes in body weights and spleen/body weight ratio were also investigated.
RESULTS
EEAJ at 30 mg/kg significantly prevented scaling, erythema and enlargement of skin weight compared to using carbon dioxide. EEAJ also prevented epithelial hyperplasia and immune cell infiltrations induced by repeated application of DNFB (P<0.01). In addition, EEAJ significantly lowered levels of TNF-α, IL-6 and MCP-1 (P<0.05 or P<0.01). The anti-inflammatory effects of EEAJ were similar to those of DEX.
CONCLUSION
A. japonica may be a new therapeutic agent with the potential to reduce or replace corticosteroids and its mechanisms are closely related to regulation of TNF-α production.
Topics: Ampelopsis; Animals; Anti-Inflammatory Agents; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Hyperplasia; Interleukin-6; Mice; Mice, Inbred BALB C; Plant Extracts; Tumor Necrosis Factor-alpha
PubMed: 35907172
DOI: 10.1007/s11655-022-3517-0 -
Environmental Microbiology Sep 2022Traditional farm environments induce protection from allergic diseases. In this study, farm environmental factors were classified into three categories, environmental...
Traditional farm environments induce protection from allergic diseases. In this study, farm environmental factors were classified into three categories, environmental microbes, soil, and organic matter. To explore the impact of soil and environmental microorganisms on gut microbiota and immune function, mice were fed sterilized soil and inhaling microbes, soil microbes, or non-sterilized soil. Metagenomic sequencing results showed the intake of sterile soil, that is, inhaling a small amount of soil microbes in the air increased gut microbial diversity and the abundance of type III secretion system (T3SS) genes, and decreased serum immune IgE levels induced by 2-4-dinitrofluorobenzene (DNFB). The intake of soil microbes increased the abundance of genes involved in the metabolism of short-chain fatty acids and amino acid biosynthesis. Meanwhile, the intake of soil increased gut microbial diversity, the abundance of T3SS genes and related infectious elements, and genes associated with the metabolism of short-chain fatty acids and amino acid biosynthesis, and decreased serum IgE levels. Therefore, soil may be useful as a potential 'prebiotic' promoting the reproduction and growth of some intestinal microorganisms that harbour bacterial secretion system genes, especially those of T3SS, whose abundance was positively and significantly correlated with innate immune function of mice.
Topics: Amino Acids; Animals; Dinitrofluorobenzene; Fatty Acids, Volatile; Gastrointestinal Microbiome; Immunoglobulin E; Mice; Soil; Type III Secretion Systems
PubMed: 35315566
DOI: 10.1111/1462-2920.15979 -
Brain and Behavior Jun 2018The interactive aggravation of pruritus and depression is well-known, but an appropriate experimental model that could mimic this behavioral phenomenon is still lacking....
BACKGROUND
The interactive aggravation of pruritus and depression is well-known, but an appropriate experimental model that could mimic this behavioral phenomenon is still lacking. Thus, a systematic animal behavioral investigation was carried out in this study. This will promote the research and treatment of pruritus and depression.
METHODS
The 2,4-dinitrofluorobenzene (DNFB)-induced chronic itch model was established to measure the depression index by forced swimming test (FST), tail suspension test (TST), and splash test (ST). The chronic unpredicted mild stress (CUMS)-induced depression model was established to measure spontaneous itch and acute histamine or chloroquine-induced itch behaviors. A depression and itch combining model was also established to measure the scratching and depression behaviors. The motor function of DNFB mice was analyzed by the rotarod test.
RESULTS
The scratching number, the immobility time in the FST and TST, and the grooming number in the ST test were all significantly increased in the chronic itch model. Mice receiving CUMS treatment showed significantly increased spontaneous scratching number, immobility time in the FST and TST tests, and grooming number in the ST. The combined model showed increased immobility time in FST and TST tests and increased grooming number in ST comparing to the depression model, and showed increased scratching number comparing to the chronic itch model. After histamine (His) or chloroquine (CQ) injection, the scratching numbers of CUMS mice were all significantly increased compared to those of His- and CQ-control, respectively. Anti-depression drug ketamine could significantly inhibit the depression-like behaviors of CUMS mice, and simultaneously stopped the promoting effect on His-induced acute itch.
CONCLUSIONS
This study established an appropriate cross aggravation experimental mode and demonstrated that there is cross aggravation between pruritus and depression. The illumination of related mechanisms underlying this cross aggravation effect will provide theoretical basis for the prevention and treatment of depression and pruritus.
Topics: Animals; Antidepressive Agents; Behavior, Animal; Chloroquine; Depression; Depressive Disorder; Disease Models, Animal; Histamine; Histamine Agonists; Ketamine; Male; Mice; Pruritus; Treatment Outcome
PubMed: 30106230
DOI: 10.1002/brb3.964 -
Polymers Feb 2020Electrospinning and post-spun conformations of hydrophobic poly(-amino acid)s are described in this study. The poly(-amino acid)s, poly(Gly), poly(L-Ala), poly(L-Val),...
Electrospinning and post-spun conformations of hydrophobic poly(-amino acid)s are described in this study. The poly(-amino acid)s, poly(Gly), poly(L-Ala), poly(L-Val), and poly(L-Leu) were synthesized via corresponding -carboxy--amino acid anhydrides. The average molecular weight and degree of polymerization of these polymers were determined by -terminus labeling using 2,4-dinitrofluorobenzene and by viscometry in the case of poly(Gly). These poly(-amino acid)s were electrospun from trifluoroacetic acid or trifluoroacetic acid/dichloromethane solutions. The FT-IR spectroscopy and wide-angle X-ray diffraction indicated that the electrospun poly(L-Ala) and poly(L-Leu) fibers predominantly adopts -helical structure, whereas poly(L-Val) and poly(Gly) fibers exhibited mainly -strand and random coil structures, respectively.
PubMed: 32033154
DOI: 10.3390/polym12020327 -
Stem Cell Research & Therapy Dec 2021Pruritus is a recurring, long-lasting skin disease with few effective treatments. Many patients have unsatisfactory responses to currently available antipruritic...
BACKGROUND
Pruritus is a recurring, long-lasting skin disease with few effective treatments. Many patients have unsatisfactory responses to currently available antipruritic treatments, and effective therapeutics are urgently needed to relieve symptoms. A previous study reported that mesenchymal stem cell (MSC)-mediated immune regulation could be used to treat skin inflammatory diseases. Multilineage-differentiating stress-enduring (Muse) cells are a new type of pluripotent stem cell that may also have the potential to treat inflammatory skin diseases.
METHODS
Muse cells were isolated from human bone marrow-derived MSCs (BMSCs) via the 8-h longterm trypsin incubation (LTT) method. Repeated use of 2,4-dinitrofluorobenzene (DNFB) induced atopic dermatitis (AD) in a mouse model. Immunofluorescence, behavior recording, and image analysis were used to evaluate the therapeutic effect of subcutaneous Muse cell injection. Real-time quantitative polymerase chain reaction (qPCR) was used to measure the expression of inflammatory factors. In vitro, wound healing and cell proliferation experiments were used to examine the effect of Muse cell supernatant on keratinocytes.
RESULTS
Our results showed that subcutaneous injection of Muse cells after AD model induction significantly alleviated scratching behavior in mice. The evaluation of dermatitis and photos of damaged skin on the back of the neck revealed that Muse cells reduced dermatitis, playing an active role in healing the damaged skin. The activation of spinal glial cells and scratching behavior were also reduced by Muse cell injection. In addition, we also showed that the expression levels of the inflammatory factors interleukin (IL)-6, IL-17α, and IL-33 in both the spinal cord and skin were suppressed by Muse cells. Furthermore, Muse cells not only exerted anti-inflammatory effects on lipopolysaccharide (LPS)-induced human HaCat cells but also promoted wound healing and keratinocyte proliferation.
CONCLUSIONS
In vivo, Muse cells could alleviate scratching symptoms, reduce epidermal inflammation, and promote wound healing. In vitro, Muse cells could also promote the migration and proliferation of keratinocytes. In summary, Muse cells may become a new therapeutic agent for the treatment of AD.
Topics: Animals; Dermatitis, Atopic; Humans; Keratinocytes; Mesenchymal Stem Cells; Mice; Pluripotent Stem Cells; Skin
PubMed: 34930455
DOI: 10.1186/s13287-021-02671-5 -
Biochemistry Feb 2019Site-selective lysine post-translational modifications such as acetylation, methylation, hydroxylation, and isopeptide formation mediate the precise control of important...
Site-selective lysine post-translational modifications such as acetylation, methylation, hydroxylation, and isopeptide formation mediate the precise control of important signaling events in cells with unmistakable accuracy. This unparalleled site selectivity (modification of a single lysine in a particular protein in the proteome) is still a challenge for non-enzymatic protein reactions; the difficulty lies in the differentiation of the lysine ε-amino group from other reactive groups and in the precise pinpointing of one particular lysine ε-amino group out of many other lysine ε-amino groups and the N-terminal amine of the protein that have similar chemical reactivity. Here, we have explored proximal lysine conjugation reactions through peptide-guided fluorodinitrobenzene, isothiocyanate, and phenyl ester reactions and have validated the site-specific targeting of the ε-amino group of one single lysine in natural proteins that contain multiple lysine residues. This precise site selectivity is a result of the proximity-induced reactivity guided by a specific protein-peptide interaction: the binding interaction preorganizes an amine-reactive group in the peptide and one of the lysine side chain ε-amino groups of the protein into close proximity, thereby confining the reactivity to a selected area of the target protein. The binding-guide lysine reactions were first examined on an SH3 domain and then tested on several ubiquitin-like proteins such as SUMO, Atg8 protein family, plant ATG8, and mammalian LC3 proteins that contain at least seven lysine residues on the surface. Exquisite site selectivity was confirmed in all of the proteins tested. A set of amine reactions were tested for their feasibility in the site-selective lysine reaction. Selected amine-reactive groups were optimized, and the reaction sites on the LC3 protein were confirmed by mass spectrometry.
Topics: Autophagy-Related Protein 8 Family; Binding Sites; CSK Tyrosine-Protein Kinase; Dinitrofluorobenzene; HeLa Cells; Humans; Lysine; Microtubule-Associated Proteins; Peptides; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; SUMO-1 Protein; src Homology Domains; src-Family Kinases
PubMed: 30624906
DOI: 10.1021/acs.biochem.8b01223 -
Neuroscience Mar 2020Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in...
Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. In this study, we found that TLR2 was expressed in mouse dorsal root ganglia (DRG) and trigeminal ganglia (TG) neurons. Itch and pain behaviors, including histamine-dependent and histamine-independent acute itching, acetone/diethyl ether/water and 2,4-dinitrofluorobenzene-induced chronic itching and inflammatory pain, were largely attenuated in TLR2 knockout (KO) mice. The TLR2 agonist Pam3CSK4, which targets TLR2/1 heterodimers, evoked pain and itch behavior, whereas lipoteichoic acid (LTA) and zymosan, which recognize TLR2/6 heterodimers, produced only pain response. The TLR2 agonist-induced nociceptive and pruritic behaviors were largely diminished in transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) KO mice. Finally, Pam3Csk4 and zymosan increased the [Ca2] in DRG neurons from wild-type mice. However, the enhancement of [Ca2] was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.
Topics: Animals; Ganglia, Spinal; Mice; Pain; Pruritus; TRPA1 Cation Channel; TRPV Cation Channels; Toll-Like Receptor 2; Transient Receptor Potential Channels
PubMed: 31954829
DOI: 10.1016/j.neuroscience.2020.01.010