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OBJECTIVE@#To investigate the effects of composite Sophora colon-soluble Capsule (CSCC) on gut microbiota-mediated short-chain fatty acids (SCFAs) production and downstream group 3 innate lymphoid cells (ILC3s) of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model.@*METHODS@#The main components of CSCC were analyzed by hybrid ultra-high-performance liquid chromatography ion mobility spectromety quadrupole time-of-flight mass spectrometry (UHPLC-IM-QTOF/MS). Twenty-four male BALB/c mice were randomly divided into 4 groups (n=6) by using a computer algorithm-generated random digital, including control, DSS model, mesalazine, and CSCC groups. A DSS-induced colitis mice model was established to determine the effects of CSCC by recording colonic weight, colonic length, index of colonic weight, and histological colonic score. The variations in ILC3s were assessed by immunofluorescence and flow cytometry. The results of gut microbiota and SCFAs were acquired by 16s rDNA and gas chromatography-mass spectrometry (GC-MS) analysis. The expression levels of NCR+ ILC3-, CCR6+ Nkp46- (Lti) ILC3-, and ILCreg-specific markers were detected by enzyme-linked immunosorbent assay, and real-time quantitative polymerase chain reaction and Western blot, respectively.@*RESULTS@#The main components of CSCC were matrine, ammothamnine, Sophora flavescens neoalcohol J, and Sophora oxytol U. After 7 days of treatment, CSCC significantly alleviated colitis by promoting the reproduction of intestinal probiotics manifested as upregulation of the abundance of Bacteroidetes species and specifically the Bacteroidales_S24-7 genus (P<0.05). Among the SCFAs, the content of butyric acid increased the most after CSCC treatment. Meanwhile, compared with the model group, Lti ILC3s and its biomarkers were significantly downregulated and NCR+ ILC3s were significantly elevated in the CSCC group (P<0.01). Further experiments revealed that ILC3s were differentiated from Lti ILC3s to NCR+ ILC3s, resulting in interleukin-22 production which regulates gut epithelial barrier function.@*CONCLUSION@#CSCC may exert a therapeutic effect on UC by improving the gut microbiota, promoting metabolite butyric acid production, and managing the ratio between NCR+ ILC3s and Lti ILC3s.
Subject(s)
Male , Animals , Mice , Colitis, Ulcerative/pathology , Immunity, Innate , Butyric Acid/therapeutic use , Sophora , Gastrointestinal Microbiome , Lymphocytes , Colon , Colitis/pathology , Disease Models, Animal , Mice, Inbred C57BLABSTRACT
Objective : To investigate the effect of mechanistic target of rapamycin complex 1 (mTORC1) on group 3 innate lymphoid cells (ILC3) function. Methods ¡¤ Intestinal lamina propria leukocytes (LPL) of C57BL/6 wild type mice were stimulated by rapamycin, the specific inhibitor of mTORC1 signaling pathway, in vitro, and then quantity and function of ILC3 were detected by flow cytometry. Next, purified ILC3 from mice intestinal LPL were sorted by flow cytometry. After the activation of ILC3 with IL-23, mRNA expression levels of Rorc (the gene encoding retinoic acid receptor related orphan receptor, i.e. RORγt), Il22 and Rptor (the gene encoding key component protein of mTORC1, i.e. Raptor) were detected by real-time qPCR. For further study, a genetically engineered mouse model specifically knocked out Raptor in ILC3 was constructed. Effects of mTORC1 loss on the quantity and function of ILC3 as well as gut structure were detected by flow cytometry, real-time qPCR and hematoxylin-eosin staining. Results ¡¤ The total ILC3 number had no change, but the secretion of IL-22 by ILC3 reduced after stim-ulation with rapamycin. Il22, Rorc and Rptor mRNA expression levels were upregulated simultaneously in ILC3 after activation with IL-23. In addition, there was no significant difference in the numbers and proportions of total ILC3 and ILC3 subsets as well as gut structure in Rap-tor-deficient mice, but the cytokine IL-22 secretion level of ILC3 significantly decreased in these mice. Conclusion ¡¤ Loss of mTORC1 func-tion inhibits ILC3 from secreting IL-22 but has no effect on the intestinal structure and intestinal ILC3 development, which reveals the positive regulation of mTORC1 signaling on intestinal ILC3 function.
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Intestinal?barrier?act?as?the?crucial?defender?against?pathogen?invasion,?and?is?indispensable?in?maintaining?tissue?homeostasis?both?locally?and?systemically.?Severe?disease?can?lead?to?impaired?intestinal?barrier.?In?addition?to?cause?a?variety?of?gastrointestinal?diseases,?intestinal?barrier?damage?can?also?worsen?the?disease?progression?in?critically?ill?patients.?Innate?lymphoid?cells?(ILCs)?is?a?group?of?newly?defined?innate?immune?cells?which?have?some?characteristics?as?adaptive?immune?cells.?Group?3?innate?lymphoid?cells?(ILC3),?which?mainly?reside?at?gut?associate?mucosal?tissue,?have?been?reported?to?play?a?critical?role?in?maintaining?intestinal?barrier?function.?After?a?brief?introduction?about?its?origination?and?classification,?we?will?focus?on?function?of?ILC3?physiologically?and?pathologically,?and?provide?a?new?theoretical?basis?for?maintaining?intestinal?barrier?function?under?pathological?conditions?in??this?review.
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Medulloblastoma (MB)is the most prevalent pediatric brain tumor. Group3 MB is the most malignant subgroup,quiet a part of which are MYC-amplified. Blocking the upstream gene sites of MYC is mainly achieved through the blockade of miR-494,DDX3,NOTCH1 pathway;BETi or ATR/ Chk1 double-inhi-bition realizes the inhibition of duplication or transcription of MYC;as to the blockade of downstream genes of MYC,researchers mainly focus on LDHA,SETD8 and EZH2. All of these researches which target on MYC-amplified associated anti-tumor treatment mechanism present the theoretical basis for anti-MYC-associated medulloblastoma clinically.
ABSTRACT
Medulloblastoma (MB) is the most prevalent pediatric brain tumor. Group3 MB is the most malignant subgroup, quiet a part of which are MYC-amplified. Blocking the upstream gene sites of MYC is mainly achieved through the blockade of miR-494, DDX3, NOTCH1 pathway; BETi or ATR/Chk1 double-inhibition realizes the inhibition of duplication or transcription of MYC; as to the blockade of downstream genes of MYC, researchers mainly focus on LDHA, SETD8 and EZH2. All of these researches which target on MYC-amplified associated anti-tumor treatment mechanism present the theoretical basis for anti-MYC-associated medulloblastoma clinically.
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Innate lymphoid cells (ILCs) are key players during an immune response at the mucosal surfaces, such as lung, skin, and gastrointestinal tract. Giardia lamblia is an extracellular protozoan pathogen that inhabits the human small intestine. In this study, ILCs prepared from the lamina propria of mouse small intestine were incubated with G. lamblia trophozoites. Transcriptional changes in G. lamblia-exposed ILCs resulted in identification of activation of several immune pathways. Secretion of interleukin (IL)-17A, IL-17F, IL-1β, and interferon-γ was increased, whereas levels of IL-13, IL-5, and IL-22, was maintained or reduced upon exposure to G. lamblia. Goup 3 ILC (ILC3) was found to be dominant amongst the ILCs, and increased significantly upon co-cultivation with G. lamblia trophozoites. Oral inoculation of G. lamblia trophozoites into mice resulted in their presence in the small intestine, of which, the highest number of parasites was detected at the 5 days-post infection. Increased ILC3 was observed amongst the ILC population at the 5 days-post infection. These findings indicate that ILC3 from the lamina propria secretes IL-17 in response to G. lamblia, leading to the intestinal pathology observed in giardiasis.
Subject(s)
Animals , Humans , Mice , Gastrointestinal Tract , Giardia lamblia , Giardia , Giardiasis , Interleukin-13 , Interleukin-17 , Interleukin-5 , Interleukins , Intestine, Small , Lung , Lymphocytes , Mucous Membrane , Parasites , Pathology , Skin , TrophozoitesABSTRACT
OBJECTIVE To study the association between polymorphism of DNA repair gene XRCC3Thr 241 Met and the risks of developing laryngeal carcinoma. METHODS Sixty patients with laryngeal carcinoma and 120 cancer-free controls were genotyped for the polymorphism by Multiplex SNaPshot.The odds ratios (ORs) and 95% confidence intervals (Cls) were calculated using unconditional logistic regression model.RESULTS The XRCC3 241 Met allele increased the risks of developing laryngeal carcinoma.Comparing with subjects having the XRCC3241 Thr/Thr genotype,the subjects at least having one XRCC3 241 Met allele had OR of 4.27 (95%CI 1.49-12.18). CONCLUSION XRCC3 Thr 241 Met plays an important role in the development of laryngeal carcinoma.
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Objective To predict and identify the linear B-cell epitopes in the major group 3 allergen derived from Derma-tophagoides farina(Der f 3). Methods The linear B-cell epitopes of Der f 3 allergen were analyzed based on the physicochemi-cal properties of amino acids including antigenicity,surface accessibility,flexibility,hydrophilicity,beta-turn by online bioinfor-matics softwares. The eight predicted peptides of linear B-cell epitopes were artificially synthesized and incubated with three aller-gic serum pools(4 serum samples in each),which were consisted of total 12 serum samples from the allergic individuals,and the strong positive epitopes were selected. Results Eight B-cell epitopes from Der f 3 were predicted successfully. Five of eight B-cell epitopes were identified with strong IgE-binding abilities followed by specific IgE assay. The amino acid sequences of them were following:33KAKAGDCP40, 86HASGGEKIQVAEIYQHENYDSMTID110, 118LKTPMTLDQTNAKPVPLPPQGSDVKVG144, 156QEGSYSLP163 and 199DVANGGVDSCQGDSGGPVVD218. Conclusions Five linear B-cell epitopes of Der f 3 allergen have been identified successfully. This result might provide a basis of the diagnosis and treatment for asthma.
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Objective To predict and identify T cell epitopes of major group 3 allergen derived from Dermatophagoides fari-na(Der f 3). Methods The T cell epitopes of Der f 3 were analyzed through the sequence analysis by using the bioinformatics online tools. The five predicted peptides of T-cell epitopes were artificially synthesized. The spleen lymphocytes were co-cultured with the five T cell epitopes by using the modified MTT method and the levels of IL-2,IFN-γ,IL-4 and IL-5 in the supernatant of the cultures were detected by ELISA. Results Five T cell epitopes of Der f 3 were predicted and three of which could pro-mote the proliferation of the mouse spleen lymphocytes. The secretions of IL-2 and IFN-γwere significantly induced and the se-cretions of IL-4 and IL-5 were significantly decreased by three of five prediction epitopes of Der f 3:37GDCPYQISLQSSSHFC-GG54,98IYQHENYDSMTIDNDVALIKLKTPMT123 and 164SELQRVDIDVVSREQCDQLYS184. Conclusion Three T cell epitopes of Der f 3 have been initially identified,which lays the foundation of the diagnosis and treatment of asthma.
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Medulloblastoma is the most frequent malignant brain tumor in children. Current therapeutic stratification for medulloblastoma is based on age, metastases, extent of resection, and histological variants. Recent molecular pathologic studies have suggested that medulloblastoma is not a single disease but consists of multiple distinct molecular subgroups. The consensus conference concludes four main subgroups, termed as WNT, SHH, Group 3 and Group 4. The subgroups differ in demographics, clinical presentation, transcriptional profile, genetic abnormality, and clinical outcome. The identification of molecular subgroup will lead to the optimal treatment and more targeted therapy for these patients. The molecular classification of medulloblastoma will continue to diversify as larger cohorts and be applicable to the prospective clinical trials. This review outlines the differences between the medulloblastoma subgroups.
Subject(s)
Child , Humans , Brain Neoplasms , Cohort Studies , Consensus , Demography , Medulloblastoma , Neoplasm MetastasisABSTRACT
Medulloblastoma is the most frequent malignant brain tumor in children. Current therapeutic stratification for medulloblastoma is based on age, metastases, extent of resection, and histological variants. Recent molecular pathologic studies have suggested that medulloblastoma is not a single disease but consists of multiple distinct molecular subgroups. The consensus conference concludes four main subgroups, termed as WNT, SHH, Group 3 and Group 4. The subgroups differ in demographics, clinical presentation, transcriptional profile, genetic abnormality, and clinical outcome. The identification of molecular subgroup will lead to the optimal treatment and more targeted therapy for these patients. The molecular classification of medulloblastoma will continue to diversify as larger cohorts and be applicable to the prospective clinical trials. This review outlines the differences between the medulloblastoma subgroups.
Subject(s)
Child , Humans , Brain Neoplasms , Cohort Studies , Consensus , Demography , Medulloblastoma , Neoplasm MetastasisABSTRACT
Objective To study the relationship between the single nucleotide polymorphisms (SNP)of X-ray repair cross-complementing group-3(XRCC3),human 8-hydroxyguanine glycosylase-1 (HOGG1)gene of repair DNA and the radiosensitivity in esophageal squamous cell carcinoma(ESCC).Methotis Genome DNA was exracted from whole blood cells of ESCC patients.XRCC3 and HOGG1 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method.The relationship was analyzed between SNP of XRCC3 Thr242 Met,HOGG1 Ser326 Cys and the response to radiotherapy in ESCC.Results Totally 199 ESCC patients were treated with radical radiotherapy.The response rate w88 81.4%.The response rate in patients with the XRCC3 Thr/Met genotype was significant higher than that in patients with Thr/Thr genotype(91.5%vs 77.1%,X2=5.67,P=0.017),with the same in HOGGlSet/Ser,Ser/Cys and Cys/Cys genotype(74.1%,84.2%,83.9%,X2=2.64,P=0.268).The esophageal radioactivity injury rate in patients with the XRCC3 Thr/Met genotype was also significant higher than that in patients with Thr/Thr genotype(35.6%vs 20.0%,X2=5.44,P= 0.020),with the same in HOGG1 Ser/Ser,Ser/Cys and Cys/Cys genotype(24.1%,24.6%,25.8%,X2=0.03,P=0.984).In Iogistic multivariate analysis,the SNP of XRCC3 was the independent influencing factor closely correlating with the mdiosensitivity of esophageal cancer(X2=16.12,4.43,P=0.009.0.035).No significant difierence was observed between the SNP in HOGG1 Ser326 Cys and the response rate of radiotherapy or the rate of esophageal radioactivity injury(X2=3.74,0.58,P=0.053,0.445).Conclusions SNP of XRCC3 Thr/Met is associated with the radiosensitivity in ESCC patients,which suggests that the XRCC3 Thr/Met SNP may be a predictor for ESCC patients who likely to response to radiotherapy.
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The purpose of this study was to set the guidelines for selection of patients to do early surgery in ruptured intracranial aneurysm. We assessed 706 patients with single rupture and without large hematoma, who underwent aneurysm surgery from 1985 to 1995. The male and female ratio was 1:1.5. Among the 706 patients, early surgery was performed in 214 cases. The results of early surgery were good in 193 cases(90.2%), fair in 13 cases(6.0%), poor in 1 case(0.5%) and dead in 7 cases(3.3%). The rate of dead outcome in the early surgery group was higher compared to other timing groups. The Fisher group 1, 2 and 3 reveale good outcome in early surgery group;92.6%, 96.3%, 88.8% respectively. The incidence of delayed ischemic deficits(DID) of early surgery group was same as other groups. However, in Fisher group 3, the incidence of DID was significantly low, 32.5%, in early surgery group. It is suggested that the criteria of selection of early surgery in patients with ruptured intracranial aneurysm would include as follows:1) patients with good clinical grade, 2) poor grade patients with marked irritability, acute hydrocephalus, and poorly controlled hypertension, 3) none-complex aneurysm requiring less brain retraction, dissection and brief temporary clipping, 4) age under 60 or over 60 with good physical status, and 5) Fisher group 3 requiring cisternal larvage and anticipated triple-H therapy.