ABSTRACT
IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.
Subject(s)
Inflammatory Bowel Diseases , Interleukin-12 , Interleukin-23 , Janus Kinase Inhibitors , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Janus Kinase Inhibitors/therapeutic use , Interleukin-23/antagonists & inhibitors , Interleukin-23/metabolism , Interleukin-23/immunology , Interleukin-12/antagonists & inhibitors , Interleukin-12/metabolism , Interleukin-12/immunology , Animals , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: To confirm the efficacy and safety of Ganyushu Granule (GYSG) in treating premenstrual syndrome (PMS) in patients with Gan (Liver) depression and qi stagnation syndrome (GDQSS) and determine its effective dosage. METHODS: From June 2018 to March 2021, a total of 240 PMS women with GDQSS were included and randomly divided into 3 groups in a 1:1:1 ratio using central block randomization: high-dose GYSG group (n=78, GYSG 2 packs/time), low-dose GYSG group (n=82, GYSG and its simulant 1 pack/time), and placebo group (n=80, GYSG simulant 2 packs/time). Treatment with GYSG or placebo was given thrice daily and for up to 3 menstrual cycles. Primary outcomes were PMS diary (PMSD) score and premenstrual tension syndrome self-rating scale (PMTS). Secondary outcomes were Chinese medicine (CM) syndrome efficacy. PMSD, PMTS, and efficacy of CM were evaluated with menstrual cycles during the treatment period. Outcome indicators were analyzed after each menstrual cycle. All analyses were performed using an intention-to-treat method, and clinical safety was assessed. RESULTS: Of the 216 patients included in the effectiveness analysis, 70, 75, and 71 patients were in the high-, low-dose GYSG, and placebo groups, respectively. From the 2nd treatment cycle, the change in PMSD scores in the high- and low-dose groups was lower than that in the placebo group (P<0.05). PMTS scores in the high-dose GYSG group after the 1st treatment cycle was lower than that in the placebo group (P<0.05), while after the 3rd treatment cycle, that in the low-dose group was lower than that in the placebo group (P<0.05). After the 2nd treatment cycle, the high-dose GYSG group had the best CM syndrome efficacy (P<0.05). No serious adverse reactions were reported. CONCLUSIONS: GYSG was safe and well-tolerated at both doses for treating PMS patients with GDQSS. High-dose GYSG might be the optimal dose for a phase III trial. (Registration No. ChiCTR1800016595).
Subject(s)
Drugs, Chinese Herbal , Premenstrual Syndrome , Qi , Humans , Premenstrual Syndrome/drug therapy , Female , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/adverse effects , Drugs, Chinese Herbal/administration & dosage , Double-Blind Method , Adult , Treatment Outcome , Young Adult , Depression/drug therapy , Liver/drug effects , Medicine, Chinese Traditional/methodsABSTRACT
Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.
ABSTRACT
BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms. METHODS: Single-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR+ memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of SIGIRR in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-α production in CD4 T cells. RESULTS: SIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPß/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis. CONCLUSION: Taken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.
Subject(s)
Arthritis, Rheumatoid , Tumor Necrosis Factor-alpha , Humans , Mice , Animals , CD4-Positive T-Lymphocytes/metabolism , Receptors, Interleukin-1/genetics , Receptors, Interleukin-1/metabolism , Signal Transduction/physiology , Arthritis, Rheumatoid/geneticsABSTRACT
This study aimed to use the internal design of 3D food printing (3DFP) technology to obtain freeze-dried pumpkin with controllable crispness and higher shape fidelity. Two internal structural variables, namely filling pattern (honeycomb, rectilinear, grid, and triangular) and filling rate (25, 50, 75, and 100%), were studied to assess the impact on the shape fidelity and crispness characteristic of the product. As the filling rate decreased, the printing accuracy of the samples increased. Regardless of the filling patterns, the 75% filled samples exhibited the greatest deformation. The crispness of the samples was closely related to the filling pattern and filling rate. In the case of the high filling rate, the internal structure of the samples was dense. It was less likely to be broken under the action of force and the crispness was reduced. In addition, the internal structure of the sample influenced its physical properties, and the crispness customization of the product can be achieved by designing the porosity. Morphological differences between printed and cast samples suggested that 3DFP was beneficial for the processing and preparation of highly viscoelastic materials. The crispness of cast sample was obviously less than that of the 100% filled printed samples. The results opened an interesting perspective to create crisp foods with high shape fidelity that meet specific texture requirements and provide new sensory perceptions.
Subject(s)
Cucurbita , Snacks , Food Technology/methods , Freeze Drying , Printing, Three-DimensionalABSTRACT
Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL-38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12-dimethylbenzanthracene/12-O-tetradecanoyl phorbol-13-acetate-induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte-specific deletion of IL-38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL-38 is dispensable for epidermal mutagenesis, but IL-38 keratinocyte-specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL-38 activates the c-Jun N-terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer-related inflammatory cytokines and proliferation and migration of tumor cells in an IL-1 receptor-related protein 2 (IL-1Rrp2)-dependent manner. Our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2/JNK and suggest IL-38/IL-1Rrp2 as a preventive and potential therapeutic target in skin cancer.
Subject(s)
Carcinoma, Squamous Cell , Interleukin-1/metabolism , Receptors, Interleukin-1/metabolism , Skin Neoplasms , Animals , Carcinogenesis/genetics , Carcinogenesis/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cytokines , Hyperplasia/pathology , Interleukins/genetics , Mice , Skin/metabolism , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
Parallel to traditional Th1/Th2/Th17/Treg lineages, granulocyte-macrophage colony-stimulating factor-producing T helper (Th-GM) cells have been identified as a distinct subset of T helper cells (GM-CSF+ IFN-γ- IL-17A- IL-22- effector CD4+ T cells) in human and mice. Contact hypersensitivity (CHS) is considered an excellent animal model for allergic contact dermatitis (ACD) in human, manifesting an intact T cell-mediated immune response. To provide a standardized and comprehensive assay to analyze the Th-GM cell subset in the T cell-dependent immune response in vivo, a murine CHS model was induced by sensitization/challenge with a reactive, low-molecular-weight, organic hapten, 2,4-dinitrofluorobenzene (DNFB). The Th-GM subset in effector CD4+ T cells generated upon immunization with the hapten was analyzed by flow cytometry. We found that Th-GM was mainly expanded in lesions and draining lymph nodes in the DNFB-induced CHS mouse model. This method can be applied to further study the biology of Th-GM cells and pharmacological research of therapeutic strategies centered on GM-CSF in various conditions, such as ACD.
Subject(s)
Dermatitis, Contact , Granulocyte-Macrophage Colony-Stimulating Factor , Animals , Haptens , Mice , T-Lymphocytes, Regulatory , Th17 CellsABSTRACT
Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.
Subject(s)
Carcinogenesis/immunology , Colitis/immunology , Colorectal Neoplasms/immunology , Interleukin-1/immunology , Neoplasm Proteins/immunology , Receptors, Interleukin-1/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Carcinogenesis/genetics , Colitis/genetics , Colitis/pathology , Colorectal Neoplasms/genetics , Interleukin-1/genetics , Mice , Mice, Transgenic , Neoplasm Proteins/genetics , Receptors, Interleukin-1/geneticsABSTRACT
AIMS: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. METHODS AND RESULTS: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. CONCLUSION: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.
Subject(s)
Calcium-Binding Proteins , Cell Adhesion Molecules , Extracellular Traps , Macrophages , Myocardial Infarction , Ventricular Remodeling , Animals , Biomarkers/blood , Calcium-Binding Proteins/blood , Calcium-Binding Proteins/deficiency , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/deficiency , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Extracellular Traps/genetics , Extracellular Traps/metabolism , Humans , Macrophages/metabolism , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/blood , Myocardial Infarction/metabolism , Myocardium/metabolism , Ventricular Remodeling/genetics , Ventricular Remodeling/physiology , c-Mer Tyrosine Kinase/metabolismABSTRACT
Defects have been found to enhance the electrocatalytic performance of NiFe-LDH for oxygen evolution reaction (OER). Nevertheless, their specific configuration and the role played in regulating the surface reconstruction of electrocatalysts remain ambiguous. Herein, cationic vacancy defects are generated via aprotic-solvent-solvation-induced leaking of metal cations from NiFe-LDH nanosheets. DFT calculation and in situ Raman spectroscopic observation both reveal that the as-generated cationic vacancy defects tend to exist as VM (M=Ni/Fe); under increasing applied voltage, they tend to assume the configuration VMOH , and eventually transform into VMOH-H which is the most active yet most difficult to form thermodynamically. Meanwhile, with increasing voltage the surface crystalline Ni(OH)x in the NiFe-LDH is gradually converted into disordered status; under sufficiently high voltage when oxygen bubbles start to evolve, local NiOOH species become appearing, which is the residual product from the formation of vacancy VMOH-H . Thus, we demonstrate that the cationic defects evolve along with increasing applied voltage (VM â VMOH â VMOH-H ), and reveal the essential motif for the surface restructuration process of NiFe-LDH (crystalline Ni(OH)x â disordered Ni(OH)x â NiOOH). Our work provides insight into defect-induced surface restructuration behaviors of NiFe-LDH as a typical precatalyst for efficient OER electrocatalysis.
ABSTRACT
Psoriasis is a common chronic inflammatory skin disease mediated by innate and adaptive immune systems, characterized by abnormal proliferation and differentiation of epidermal keratinocytes and infiltration of inflammatory cells. Skin-specific keratinocytes are key participants in innate immunity, responding to immune cells and environmental stimulation, thereby serving an important role in the immunopathogenesis of psoriasis. Here, we present a method for inducing psoriasiform keratinocytes inflammation at transcription level with HaCaT cell line using five proinflammatory cytokines combination (M5 combination), including IL-17A, IL-22, IL-1α, TNF-α, and oncostatin M. Results demonstrate that M5 combination induced HaCaT cells showed increased levels of antimicrobial peptides (BD2, S100A7, S100A8, and S100A9), chemokines, and cytokines (CXCL1, CXCL2, CXCL8, CCL20, IL-1ß, IL-6 and, IL-18). The mRNA levels of keratinocytes differentiation markers (Keratin1, Keratin10, Filaggrin, and Loricrin) were down regulated, which was consistent with the transcriptome data derived from psoriasis-like keratinocytes. The method described here, therefore, establishes an in vitro psoriasiform cutaneous inflammation at transcription level and contributes to the research for molecular pathogenesis of psoriasis.
Subject(s)
Cytokines/metabolism , HaCaT Cells/metabolism , Psoriasis/genetics , Transcription Factors/metabolism , Filaggrin Proteins , HumansABSTRACT
The precise mechanism through which macroautophagy/autophagy affects psoriasis is poorly understood. Here, we found that keratinocyte (KC) autophagy, which was positively correlated with psoriatic severity in patients and mouse models and could be inhibited by mitogen-activated protein kinase (MAPK) family inactivation. The impairment of autophagic flux alleviated psoriasisform inflammation. We also found that an autophagy-based unconventional secretory pathway (autosecretion) dependent on ATG5 (autophagy related 5) and GORASP2 (golgi reassembly stacking protein 2) promoted psoriasiform KC inflammation. Moreover, the alarmin HMGB1 (high mobility group box 1) was more effective than other autosecretory proteins in regulating psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs eliminated the differences in psoriasiform inflammation between Krt14+/+-Atg5f/f KCs and Krt14Cre/+-atg5f/f KCs, and conversely, recombinant HMGB1 almost completely restored psoriasiform inflammation in Krt14Cre/+-atg5f/f KCs in vivo. These results suggest that HMGB1-associated autosecretion plays a pivotal role in cutaneous inï¬ammation. Finally, we demonstrated that Krt14Cre/+-hmgb1f/f mice displayed attenuated psoriatic inï¬ammation due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, this study uncovered a novel autophagy mechanism in psoriasis pathogenesis, and the findings imply the clinical significance of investigating and treating psoriasis.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AGER: advanced glycosylation end-product specific receptor; Anti-HMGB1: anti-HMGB1 neutralizing antibody; Anti-IL18: anti-IL18 neutralizing antibody; Anti-IL1B: anti-IL1B neutralizing antibody; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CASP1: caspase 1; CCL: C-C motif chemokine ligand; CsA: cyclosporine A; ctrl shRNA: lentivirus harboring shRNA against control; CXCL: C-X-C motif chemokine ligand; DCs: dendritic cells; DMEM: dulbecco's modified Eagle's medium; ELISA: enzyme-linked immunosorbent assay; EM: electron microscopy; FBS: fetal bovine serum; GORASP2 shRNA: lentivirus harboring shRNA against GORASP2; GORASP2/GRASP55: golgi reassembly stacking protein 2; GR1: a composite epitope between LY6 (lymphocyte antigen 6 complex) locus C1 and LY6 locus G6D antigens; H&E: hematoxylin and eosin; HMGB1: high mobility group box 1; HMGB1 shRNA: lentivirus harboring shRNA against HMGB1; IFNG/IFN-γ: interferon gamma; IL17A: interleukin 17A; IL18: interleukin 18; IL1A/IL-1α: interleukin 1 alpha; IL1B/IL-1ß: interleukin 1 beta; IL22/IL-22: interleukin 22; IL23A: interleukin 23 subunit alpha; IL23R: interleukin 23 receptor; IMQ: imiquimod; ITGAM/CD11B: integrin subunit alpha M; ITGAX/CD11C: integrin subunit alpha X; IVL: involucrin; KC: keratinocyte; KD: knockdown; KO: knockout; Krt14+/+-Atg5f/f mice: mice bearing an Atg5 flox allele, in which exon 3 of the Atg5 gene is flanked by two loxP sites; Krt14+/+-Hmgb1f/f: mice bearing an Hmgb1 flox allele, in which exon 2 to 4 of the Hmgb1 gene is flanked by two loxP sites; Krt14Cre/+-atg5f/f mice: keratinocyte-specific atg5 knockout mice generated by mating Atg5-floxed mice with mice expressing Cre recombinase under the control of the promoter of Krt4; Krt14Cre/+-hmgb1f/f mice: keratinocyte-specific hmgb1 knockout mice generated by mating Hmgb1-floxed mice with mice expressing Cre recombinase under the control of the promoter of Krt14; Krt14-Vegfa mice: mice expressing 164-amino acid Vegfa splice variant recombinase under the control of promoter of Krt14; LAMP1: lysosomal associated membrane protein 1; LDH: lactate dehydrogenase; LORICRIN: loricrin cornified envelope precursor protein; M5: TNF, IL1A, IL17A, IL22 and OSM in combination; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MKI67: marker of proliferation Ki-67; MTT: thiazolyl blue tetrazolium bromide; NFKB/NF-κB: nuclear factor kappa B; NHEKs: primary normal human epidermal keratinocytes; NS: not significant; OSM: oncostatin M; PASI: psoriasis area and severity index; PtdIns3K: class III phosphatidylinositol 3-kinase; qRT-PCR: quantitative RT-PCR; RELA/p65: RELA proto-oncogene, NF-kB subunit; rHMGB1: recombinant HMGB1; rIL18: recombinant interleukin 18; rIL1B: recombinant interleukin 1 beta; S100A: S100 calcium binding protein A; SQSTM1/p62: sequestosome 1; T17: IL17A-producing T; TCR: T-cell receptor; tcrd KO mice: tcrd (T cell receptor delta chain) knockout mice, which show deficient receptor expression in all adult lymphoid and epithelial organs; TLR: toll-like receptor; TNF/TNF-α: tumor necrosis factor; WOR: wortmannin; WT: wild-type; γδT17 cells: IL17A-producing γδ T cells.
Subject(s)
Autophagy/physiology , HMGB1 Protein/metabolism , Inflammation/metabolism , Keratinocytes/metabolism , Animals , Autophagy-Related Protein 5/metabolism , Interleukin-1beta/metabolism , Mice, Transgenic , NF-kappa B/metabolism , Proto-Oncogene MasABSTRACT
BACKGROUND: Appendicitis complicated with appendiceal perforation is common among children. The delay in diagnosis of appendicitis is due to children's varied presentations and their difficulty in communicating symptoms. We aimed to identify clinical factors that aid in predicting acute appendicitis (AA) and perforated appendicitis (PA) among children. METHODS: This retrospective study involved 215 children aged 12 years and below with the initial diagnosis of AA and PA. Clinical factors studied were demographics, presenting symptoms, body temperature on admission (BTOA), white cell count (WCC), absolute neutrophil count (ANC), platelet count and urinalysis. Simple and multiple logistic regressions were used to determine the odds ratio of the statistically significant clinical factors. Results: The mean age of the included children was 7.98 ± 2.37 years. The odds of AA increased by 2.177 times when the age was ≥ 8 years (P = 0.022), 2.380 times when duration of symptoms ≥ 2 days (P = 0.011), 2.447 times with right iliac fossa (RIF) pain (P = 0.007), 2.268 times when BTOA ≥ 38 °C (P = 0.020) and 2.382 times when neutrophil percentage was ≥ 76% (P = 0.045). It decreased by 0.409 times with non-RIF pain (P = 0.007). The odds of PA was increased by 4.672 times when duration of symptoms ≥ 2 days (P = 0.005), 3.611 times when BTOA ≥ 38 °C (P = 0.015) and 3.678 times when neutrophil percentage ≥ 76% (P = 0.016). There was no significant correlation between WCC and ANC with AA and PA. CONCLUSION: Older children with longer duration of symptoms, RIF pain and higher BTOA are more likely to have appendicitis. The risk of appendiceal perforation increases with longer duration of symptoms and higher BTOA.
ABSTRACT
Psoriasis is a chronic inflammatory skin disease. Keratinocytes (KCs), as skinspecific cells, serve an important role in the immunopathogenesis of psoriasis. In the present study, transcriptome data derived from psoriasislike KCs were used together with the reported transcriptome data from the skin/epidermis of patient with psoriasis, excluding known psoriasisassociated genes that have been well described in the previous studies according to GeneCards database, to screen for novel psoriasisassociated genes. According to the human expressed sequence tag of UniGene dataset, six genes that are located near psoriasisassociated loci were highly expressed in skin. Among these six genes, four genes (epiregulin, NIPA like domain containing 4, serpin family B member 7 and WAP fourdisulfide core domain 12) were highly expressed in normal mouse epidermis (mainly KCs) and mouse psoriatic epidermis cells, but not in psoriatic dermis cells, which further emphasized the specificity of these genes. Furthermore, in systemic inflammatory response syndrome (SIRS), SERPINB7 showed no difference in expression in immuneactivated tissues from SIRS and control mice. It was also found that the mRNA expression levels of SERPINB in lesional skin of patients with psoriasis were significantly higher than in nonlesional psoriatic skin from the same patients. SERPINB7 may be a valuable candidate for further studies. In the present study, a method for identifying novel key pathogenic skinspecific molecules is presented, which may be used for investigating and treating psoriasis.
Subject(s)
Psoriasis/genetics , Serpins/genetics , Systemic Inflammatory Response Syndrome/genetics , Transcriptome/genetics , Animals , Epidermis/metabolism , Epidermis/pathology , Epiregulin/genetics , Gene Expression Regulation , Humans , Keratinocytes/metabolism , Keratinocytes/pathology , Mice , Psoriasis/pathology , RNA, Messenger/genetics , Skin/metabolism , Skin/pathology , Systemic Inflammatory Response Syndrome/pathologyABSTRACT
BACKGROUND: Elderly patients have an increased risk of a stress response during extubation after general anesthesia. In this study, we aimed to investigate whether transcutaneous electrical acupoint stimulation (TEAS) might decrease the stress response and improve the quality of recovery in elderly patients after elective supratentorial craniotomy. MATERIALS AND METHODS: In this prospective randomized controlled study, patients were randomly assigned to either a TEAS group (n=37) or a control group (n=38). The primary outcomes were the hemodynamic parameters and plasma concentrations of epinephrine, norepinephrine, and cortisol. The secondary outcome included the consumption of remifentanil and propofol, time to extubation and reorientation, extubation quality score, postoperative quality of recovery, and postoperative complications. RESULTS: Compared with the control group, hemodynamic parameters and plasma concentrations of epinephrine, norepinephrine, and cortisol during extubation were decreased in the TEAS group. TEAS reduced the consumption of remifentanil (P<0.01), as well as incidence of postoperative complications. The extubation quality score was lower (P<0.01) and the quality of recovery score was higher (P<0.01) in the TEAS group than in the control group. However, the time to extubation and reorientation, and the consumption of propofol were not significantly different between the 2 groups. CONCLUSIONS: TEAS may decrease the stress response during extubation, improve quality of postoperative recovery, and decrease incidence of postoperative complications in elderly patients undergoing elective supratentorial craniotomy.
Subject(s)
Acupuncture Points , Airway Extubation/adverse effects , Anesthesia, General/adverse effects , Craniotomy/adverse effects , Stress, Physiological , Transcutaneous Electric Nerve Stimulation/methods , Aged , Anesthesia Recovery Period , Epinephrine/blood , Female , Hemodynamics , Humans , Hydrocortisone/blood , Male , Middle Aged , Norepinephrine/blood , Postoperative Complications/epidemiology , Prospective Studies , Supratentorial Neoplasms/surgeryABSTRACT
Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis.
Subject(s)
Acitretin/therapeutic use , Dermatologic Agents/therapeutic use , Keratolytic Agents/therapeutic use , Liver Cirrhosis/chemically induced , Methotrexate/therapeutic use , Psoriasis/drug therapy , Acitretin/administration & dosage , Acitretin/adverse effects , Animals , Cells, Cultured , Dermatologic Agents/administration & dosage , Dermatologic Agents/adverse effects , Drug Therapy, Combination , Humans , Keratolytic Agents/administration & dosage , Keratolytic Agents/adverse effects , Liver/drug effects , Liver/pathology , Liver Cirrhosis/pathology , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Mice , Psoriasis/pathology , Skin/drug effects , Skin/pathologyABSTRACT
Eutrophication and acidification have been the most concerned environmental problems in coastal ecosystem. However, their combined effect on coastal ecosystem function was unknown. Both diatom (Conticribra weissflogii) and dinoflagellate (Prorocentrum donghaiense) are used as coastal algal model. Seven parameters were determined for physiological function assessment, including cell density, chlorophyll a (Chl a), protein, malonaldehyde (MDA), superoxide dismutase, carbonic anhydrase (CA), and nitrate reductase (NR). The influence of nitrate (N) and phosphate (P) on MDA and CA in C. weissflogii was significant, and that on Chl a and protein in P. donghaiense were also significant. However, the influence of acidification on physiological functions was not significant. The effect of acidification could be intensified by coastal eutrophication. More importantly, the coexist influence of acidification and eutrophication on CA, NR and protein in C. weissflogii and MDA in P. donghaiense was significant. Both NR activity and Chl a content in P. donghaiense were positively correlated to N and P concentration when pH were 7.9 and 7.8, respectively. With simultaneous worsening of acidification and eutrophication, the cell growth of P. Donghaiense was accelerated more obviously than C. weissflogii, i.e., dinoflagellate was more adaptable than diatom, thus algal species distribution and abundance could be changed.
Subject(s)
Diatoms/growth & development , Dinoflagellida/growth & development , Eutrophication/physiology , Carbonic Anhydrases/metabolism , Chlorophyll/metabolism , Chlorophyll A , Diatoms/drug effects , Diatoms/metabolism , Dinoflagellida/drug effects , Dinoflagellida/metabolism , Ecosystem , Hydrogen-Ion Concentration , Malondialdehyde/metabolism , Nitrates/chemistry , Phosphates/chemistry , Superoxide Dismutase/metabolism , Water Pollutants, Chemical/toxicityABSTRACT
Objective To evaluate the effect of transcutaneous acupoint electrical stimulation (TEAS) on propofol usage in closed-loop anesthesia delivery system and pediatric hemodynamics. Methods Sixty children patients undergoing selective tonsillectomy and adenoidectomy surgeries were randomly allocated to the TEAS group (T) and the control group (C) , 30 in each group. Anesthesia maintenance in both groups was performed by propofol closed-loop anesthesia infusion system after induction of anesthesia. Patients in group T were treated with continuous TEAS (2/100 Hz sparsedense wave, 8 - 12 mA) at unilateral Hegu (L14) and Shenmen till the end of surgery. No TEAS was performed to patients in group C. Mean arterial pressure (MAP) and heart rate (HR) were recorded before anesthesia (TO), immediately after intubation ( T1) , 5 min after intubation (T2) , 10 min after intubation (T3) , 15 min after intubation (T4) , the time for intubation (T5) , respectively. The total dose of propofol, times for propofol dose adjustment, average target concentration, cases of patients with extra Fentanyl were recorded during anesthesia maintenance. Bispectral index (BIS) was recorded. Pediatric Anesthesia Emergence Delirium (PAED) scale and Modified Children's Hospital of Eastern Ontario Pain Scale (MCHEOPS) were assessed at T5, 5 min after extubation (T6) , 10 min after extubation (T7) , 15 min after extubation (T8), 30 min after extubation (T9) , respectively. Epinephrine (NE) was measured at TO, T1, T5, and T9, concentrations of IL-1 and IL-6 were measured at TO, T5, 24 h after surgery ( T10) , 48 h after surgery (T11), respectively. Results Compared with group C, MAP at T4 and T5 and HR at T1-T5 all de- creased, PAED scale and MCHEOPS decreased at T5-T9, NE concentrations were significantly reduced at T5 and T9, concentrations of IL-1 and IL-6 decreased at T5, T10, T1 1 in group T (P <0. 05, P <0. 01). Compared with group C, the total dose of propofol, times for propofol dose adjustment, average target concentration were reduced in group T during surgery (P <0. 05, P <0. 01). Twenty cases (67%) used propofol in group C and 9 cases (30% ) used propofol in group T during surgery, with statistical difference (P <0. 01). Changes of BIS was not statistically different between the two groups (P >0. 05). Conclusion TEAS could inhibit stress response and inflammatory response of children patients, stabilize their hemo- dynamics during surgery, thereby reducing propofol dose in closed-loop anesthesia delivery system.
Subject(s)
Acupuncture Points , Anesthetics, Intravenous , Cardiac Surgical Procedures , Propofol , Transcutaneous Electric Nerve Stimulation , Anesthetics, Intravenous/administration & dosage , Child , Electric Stimulation , Endocrine System Diseases , Humans , Propofol/administration & dosageABSTRACT
Interleukin-30 (IL-30), or IL-27p28, is the α subunit of IL-27 constructed by Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28 binding via noncovalent bonds. IL-30 can be independently secreted and function independently of IL-27. Recent studies demonstrated IL-30 could concurrently antagonize T helper 1 (Th1) and Th17 responses and might have therapeutic implications for controlling autoimmune diseases. However, no reports have stated an efficient method to generate a relatively large quantity of IL-30. In this study, an Escherichia coli expression system for the rapid expression of the mouse IL-30 is developed. For the first time, IL-30 was expressed in a form of soluble fusion protein and purified using a method of simple affinity chromatography. In order to avoid the impact of minor codons on expressing eukaryotic protein in E. coli and to improve the expression quantity, the nucleotide sequence of IL-30 was optimized. The optimized gene sequence was then subcloned into the pET-44a(+) vector, which allowed expression of IL-30 with a fusion tag, NusA. The vector was transformed into E. coli and the expressed fusion protein, NusA-IL-30, was purified by Ni chromatography. Then the fusion tag was removed by cleavage with thrombin. The purity of purified IL-30 was identified using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) as well as high-performance liquid chromatography (HPLC) and the purity was up to about 92%. The yield of IL-30 was 8.95 mg from 1 L of bacterial culture. Western blot confirmed the identity of the purified protein. The recombinant IL-30 showed its biological activity by inhibiting Th17 differentiating from naive CD4(+) T cells. Therefore, this method of express and purifying IL-30 provides novel procedures to facilitate structural and functions studies of IL-30.
Subject(s)
Escherichia coli/genetics , Interleukins/genetics , Amino Acid Sequence , Animals , Blotting, Western , Cell Differentiation/drug effects , Electrophoresis, Polyacrylamide Gel , Genetic Vectors , Immunity, Innate , Interleukins/chemistry , Interleukins/isolation & purification , Interleukins/pharmacology , Mice , Mice, Inbred C57BL , Protein Conformation , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/isolation & purification , Recombinant Fusion Proteins/pharmacology , Sequence Homology, Amino Acid , Solubility , Th17 Cells/cytology , Th17 Cells/drug effectsABSTRACT
BACKGROUND: Psoriasis is an autoimmune disease that is caused by a shift in the Th1/Th2 balance toward Th1-dominant immunity. It has been established as an effective treatment to counteract psoriasis by subcutaneous injection of recombinant interleukin (IL)-4, and IL-4 gene therapy by topical transdermal penetration has shown its antipsoriatic effect in mice. Retinoic acid (RA) and dimethylsulfoxide can increase the efficiency of gene transfection in the topical transdermal delivery system. OBJECTIVE: We investigated whether RA could improve anti-psoriasis efficiency using IL-4 expression plasmid pORF-mIL-4 (pIL-4) via transdermal delivery system in K14-vascular endothelial growth (K14-VEGF) factor transgenic mice. METHODS: After pretreatment with RA, plasmid pIL-4 in 10% dimethylsulfoxide was applied to the ear skin by topical transdermal penetration. Hematoxylin- eosin staining and immunohistochemistry were performed with ear samples to evaluate anti-psoriasis efficiency in mice. RESULTS: The psoriasis pathological features were relieved and psoriasis-associated factors were significantly reduced. CONCLUSION: Our results reveal that topical application of pIL-4 in dimethylsulfoxide by transdermal delivery with RA pretreatment can improve psoriasis significantly.