Network Pharmacology, Molecular Docking and Experimental Exploring Molecular Mechanisms of Yinqiao Anti-Epidemic Formula in Regulating Mucosal Immune System of Respiratory Tract

[Objectives]To explore the molecular mechanisms of Yinqiao anti-epidemic formula(YQAEF)in regulating mucosal immune system of respiratory tract.[Methods]The active components of YQAEF were obtained from the TCMSP database,and RMIS targets were obtained from the GeneCards database.A"YQAEF components-RMIS targets-pathways"network was constructed by analyzing the above data to screen core targets for molecular docking verification.A mouse model of acute upper respiratory tract infection(AURI)was developed.Based on the experimental models,the key pathway target genes screened by network pharmacology were verified in vivo.[Results]The main active components of YQAEF involved in the regulation of the RMIS included quercetin,acetic acid,and raffinose.Key targets,such as angiotensin-converting enzyme(ACE),galactosidase alpha(GLA),matrix metalloproteinase 2(MMP2),Serpin Family E Member 1(SERPINE1),and myeloperoxidase(MPO)and important viral infection and endocrine resistance signaling pathways were included in the regulation of the RMIS with YQAEF.Molecular docking assays showed that the key targets had good binding activities with the components of YQAEF.Based on the results of network pharmacology,key target proteins in ACE,GLA,MMP2,SERPINE1,and MPO were selected for experimental verification.The results showed that ACE/ACE2 and MPO expressions were increased in the oral and throat mucosa of the AURI mice.Under YQAEF treatment,the expression levels of ACE/ACE2 and MPO were decreased.[Conclusions]This study revealed the mechanism of YQAEF in the regulation of RMIS,which is associated with multiple components,targets,and pathways.Further experiments confirmed that YQAEF interfered with MPO and ACE/ACE2 signaling pathways to regulate the RMIS in the oral and throat mucosa tissue of mice with AURI,and provide a new direction for exploring the potential antiviral mechanism of YQAEF.

Fecal calprotectin and endoscopic scores: The cornerstones in clinical practice for evaluating mucosal healing in inflammatory bowel disease

Managing inflammatory bowel disease(IBD)is becoming increasingly complex and personalized,considering the advent of new advanced therapies with distinct mechanisms of action.Achieving mucosal healing(MH)is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares,hospitalization,surgery,intestinal damage,and colorectal cancer.Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation,even if subclinical,to alter the natural course of IBD.Periodic monitoring of fecal calprotectin(FC)levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD,assessing MH,and detecting subclinical recurrence.Here,we comment on the article by Ishida et al Moreover,this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD.Furthermore,we intend to present some evidence on the role of these markers in future targets,such as histological and transmural healing.Additional prospective multicenter studies with a stricter MH criterion,standardized endoscopic and histopathological analyses,and virtual chromoscopy,potentially including artificial intelligence and other biomarkers,are desired.

Characteristics of early gastric tumors with different differentiation and predictors of long-term outcomes after endoscopic submucosal dissection

BACKGROUND Gastric cancer is a common malignant tumor of the digestive tract,and endosco-pic submucosal dissection(ESD)is the preferred treatment for early-stage gastric cancer.The analysis of the epidemiological characteristics of gastric mucosal tumors with different differentiation degrees and the influencing factors of long-term ESD efficacy may have certain significance for revealing the development of gastric cancer and ESD.AIM To analyze the features of gastric mucosal tumors at different differentiation levels,and to explore the prognostic factors of ESD.METHODS We retrospectively studied 301 lesions in 285 patients at The Second Affiliated Hospital of Xi'an Jiaotong University from 2014 to 2021,according to the latest Japanese guidelines(sixth edition),and divided them into low-grade intrae-pithelial neoplasia(LGIN),high-grade intraepithelial neoplasia(HGIN),and computed tomography at 3,6 and 12 months after ESD.We compared clinicopathologic characteristics,ESD efficacy,and complications with different degrees of differentiation,and analyzed the related factors associated with ESD.RESULTS HGIN and differentiated carcinoma patients were significantly older compared with LGIN patients(P<0.001)and accounted for more 0-IIc(P<0.001),atrophic gastritis was common(P<0.001),and irregular microvascular patterns(IMVPs)and demarcation lines(DLs)were more obvious(P<0.001).There was more infiltration in the undifferentiated carcinoma tissue(P<0.001),more abnormal folds and poorer mucosal peristalsis(P<0.001),and more obvious IMVPs,irregular microsurface patterns and DLs(P<0.05)than in the LGIN and HGIN tissues.The disease-free survival rates at 2,5,and 8 years after ESD were 95.0%,90.1%,and 86.9%,respectively.Undifferen-tiated lesions(HR 5.066),white moss(HR 7.187),incomplete resection(HR 3.658),and multiple primary cancers(HR 2.462)were significantly associated with poor prognosis.CONCLUSION Differentiations of gastric mucosal tumors have different epidemiological and endoscopic characteristics,which are closely related to the safety and efficacy of ESD.

Alkaline sphingomyelinase deficiency impairs intestinal mucosal barrier integrity and reduces antioxidant capacity in dextran sulfate sodium-induced colitis

BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon with an unknown etiology.Alkaline sphingomyelinase(alk-SMase)is specifically expressed by intestinal epithelial cells,and has been reported to play an anti-inflammatory role.However,the underlying mechanism is still unclear.AIM To explore the mechanism of alk-SMase anti-inflammatory effects on intestinal barrier function and oxidative stress in dextran sulfate sodium(DSS)-induced colitis.METHODS Mice were administered 3%DSS drinking water,and disease activity index was determined to evaluate the status of colitis.Intestinal permeability was evaluated by gavage administration of fluorescein isothiocyanate dextran,and bacterial translocation was evaluated by measuring serum lipopolysaccharide.Intestinal epithelial cell ultrastructure was observed by electron microscopy.Western blotting and quantitative real-time reverse transcription-polymerase chain reaction were used to detect the expression of intestinal barrier proteins and mRNA,respectively.Serum oxidant and antioxidant marker levels were analyzed using commercial kits to assess oxidative stress levels.RESULTS Compared to wild-type(WT)mice,inflammation and intestinal permeability in alk-SMase knockout(KO)mice were more severe beginning 4 d after DSS induction.The mRNA and protein levels of intestinal barrier proteins,including zonula occludens-1,occludin,claudin-3,claudin-5,claudin-8,mucin 2,and secretory immunoglobulin A,were significantly reduced on 4 d after DSS treatment.Ultrastructural observations revealed progressive damage to the tight junctions of intestinal epithelial cells.Furthermore,by day 4,mitochondria appeared swollen and degenerated.Additionally,compared to WT mice,serum malondialdehyde levels in KO mice were higher,and the antioxidant capacity was significantly lower.The expression of the transcription factor nuclear factor erythroid 2-related factor 2(Nrf2)in the colonic mucosal tissue of KO mice was significantly decreased after DSS treatment.mRNA levels of Nrf2-regulated downstream antioxidant enzymes were also decreased.Finally,colitis in KO mice could be effectively relieved by the injection of tertiary butylhydroquinone,which is an Nrf2 activator.CONCLUSION Alk-SMase regulates the stability of the intestinal mucosal barrier and enhances antioxidant activity through the Nrf2 signaling pathway.

Efficacy and safety of endoscopic submucosal dissection for early gastric cancer and precancerous lesions in elderly patients

BACKGROUND With advancements in the development of endoscopic technologies,the endo-scopic submucosal dissection(ESD)has been one of the gold-standard therapies for early gastric cancer.AIM To investigate the efficacy and safety ESD in the treatment of early gastric cancer and precancerous lesions in the elderly patients.METHODS Seventy-eight elderly patients with early gastric cancer and precancerous lesions admitted to the Third Affiliated Hospital of Qiqihar Medical University were se-lected and classified into two groups according to the different surgical therapies they received between January 2021 and June 2022.Among them,39 patients treated with ESD were included in an experimental group,and 39 patients treated with endoscopic mucosal resection(EMR)were included in a control group.We compared the basic intraoperative conditions,postoperative short-term recovery,long-term recovery effects and functional status of gastric mucosa between the two groups;the basic intraoperative conditions included lesion resection,intra-operative bleeding and operation time;the postoperative short-term recovery assessment indexes were length of hospital stay and incidence of surgical complic-ations;and the long-term recovery assessment indexes were the recurrence rate at 1 year postoperatively and the survival situation at 1 year and 3 years postoper-atively;and we compared the preoperative and predischarge serum pepsinogen I(PG I)and PG II levels and PG I/PG II ratio in the two groups before surgery and discharge.RESULTS The curative resection rate and the rate of en bloc resection were higher in the experimental group than in the control group.The intraoperative bleeding volume was higher in the experimental group than in the control group.The operation time was longer in the experimental group than that in the control group,and the rate for base residual focus was lower in the experimental group than that of the control group,and the differences were all statistically significant(all P<0.05).The length of hospital stay was longer in the experi-mental group than in the control group,and the incidence of surgical complications,1-year postoperative recu-rrence rate and 3-year postoperative survival rate were lower in the experimental group than in the control group,and the differences were statistically significant(all P<0.05).However,the difference in the 1-year postoperative survival rate was not statistically significant between the two groups(P>0.05).Before discharge,PG I and PG I/PG II ratio were elevated in both groups compared with the preoperative period,and the above indexes were higher in the experimental group than those in the control group,and the differences were statistically significant(both P<0.05).Moreover,before discharge,PG II level was lower in both groups compared with the preoperative period,and the level was lower in the experimental group than in the control group,and the differences were all statistically significant(all P<0.05).CONCLUSION Compared with EMR,ESD surgery is more thorough.It reduces the rate of base residual focus,recurrence rate,surgical complications,and promotes the recovery of gastric cells and glandular function.It is safe and suitable for clinical application.

Editorial article to:Animal experimental study on magnetic anchor technique-assisted endoscopic submucosal dissection of early gastric cancer

In this editorial we comment on the article published in the recent issue of the World Journal of Gastrointestinal Endoscopy 2023;15(11):634-680.Gastric cancer(GC)remains the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide.The overall prevalence of GC has declined,although that of proximal GC has increased over time.Thus,a significant proportion of GC cases and deaths can be avoided if preventive interventions are taken.Early GC(EGC)is defined as GC confined to the mucosa or submucosa.Endoscopic resection is considered the most appropriate treatment for precancerous gastrointestinal lesions improving patient quality of life,with reduced rates of complications,shorter hospitalization period,and lower costs when compared to surgical resection.Endoscopic mucosal resection(EMR)and endoscopic sub-mucosal dissection(ESD)are representative endoscopic treatments for EGC and precancerous gastric lesions.Standard EMR implies injection of a saline solution into the sub-mucosal space,followed by excision of the lesion using a snare.Complete resection rates vary depending on the size and severity of the lesion.When using conventional EMR methods for lesions less than 1 cm in size,the complete resection rate is approximately 60%,whereas for lesions larger than 2 cm,the complete resection rate is low(20%-30%).ESD can be used to remove tumors exceeding 2 cm in diameter and lesions associated with ulcers or submucosal fibrosis.Compared with EMR,ESD has higher en bloc resection rates(90.2%vs 51.7%),higher complete resection rates(82.1 vs 42.2%),and lower recurrence rates(0.65%vs 6.05%).Thus,innovative techniques have been introduced.

Giant Brunner's gland hyperplasia of the duodenum successfully resected en bloc by endoscopic mucosal resection: A case report

BACKGROUND Duodenal Brunner's gland hyperplasia(BGH)is a therapeutic target when complications such as bleeding or gastrointestinal obstruction occur or when malignancy cannot be ruled out.Herein,we present a case of large BGH treated with endoscopic mucosal resection(EMR).CASE SUMMARY An 83-year-old woman presented at our hospital with dizziness.Blood tests revealed severe anemia,esophagogastroduodenoscopy showed a 6.5 cm lesion protruding from the anterior wall of the duodenal bulb,and biopsy revealed the presence of glandular epithelium.Endoscopic ultrasonography(EUS)demonstr-ated relatively high echogenicity with a cystic component.The muscularis propria was slightly elevated at the base of the lesion.EMR was performed without complications.The formalin-fixed lesion size was 6 cm×3.5 cm×3 cm,showing nodular proliferation of non-dysplastic Brunner's glands compartmentalized by fibrous septa,confirming the diagnosis of BGH.Reports of EMR or hot snare polypectomy are rare for duodenal BGH>6 cm.In this case,the choice of EMR was made by obtaining information on the base of the lesion as well as on the internal characteristics through EUS.CONCLUSION Large duodenal lesions with good endoscopic maneuverability and no evident muscular layer involvement on EUS may be resectable via EMR.

Systemic interleukin-9 in inflammatory bowel disease: Association with mucosal healing in ulcerative colitis

AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease(CD) and 74 with ulcerative colitis(UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index(CDAI) and the Mayo Scoring System(MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex x MAP? technology. Highsensitive C-reactive protein concentrations(hs CRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTS Systemic IL9 was significantly lower in healthy individuals [9 pg/m L(95%CI: 8.2-10)] than in patients with inflammatory bowel disease(IBD): both inactive [14.3 pg/m L(11.9-19.9)] and active [27.6 pg/m L(24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/m L(23.4-32.2)] and in active UC [32.7 pg/m L(27-38.9)] compared to inactive diseases [15.9 pg/m L(10.8-23.4) in CD and 19.4 pg/m L(13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI(ρ = 0.32, P = 0.003) and MDAI(ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC(ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing(MH), IL9 had an accuracy superior to hs CRP and IL6 [97%(P < 0.0001), 67%(P = 0.071), and 55%(P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/m L(24.4-37.5) vs 21.88 pg/m L(18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations(ρ =-0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSION The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.

The mucosal immune system in the oral cavity——an orchestra of T cell diversity

The mucosal immune system defends against a vast array of pathogens, yet it exhibits limited responses to commensal microorganisms under healthy conditions. The oral-pharyngeal cavity, the gateway for both the gastrointestinal and respiratory tracts, is composed of complex anatomical structures and is constantly challenged by antigens from air and food. The mucosal immune system of the oral-pharyngeal cavity must prevent pathogen entry while maintaining immune homeostasis, which is achieved via a range of mechanisms that are similar or different to those utilized by the gastrointestinal immune system. In this review, we summarize the features of the mucosal immune system,focusing on T cell subsets and their functions. We also discuss our current understanding of the oral-pharyngeal mucosal immune system.

Lingual mucosal graft urethroplasty 12 years later: Systematic review and meta-analysis

Objective:To evaluate the functional results and complications of the lingual mucosal graft(LMG)urethroplasty and to sum up the current state of the art of this surgical technique.Methods:A systematic search of PubMed and Scopus electronic databases was performed,according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)statement.Studies involving male patients treated with LMG urethroplasty for urethral stricture were included.Complete protocol is available at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017080121.A meta-analysis comparing functional and long-term oral complication outcomes of LMG and buccal mucosal graft(BMG)was performed,calculating the odds ratio(OR)and 95%confidence interval(CI).Results:Twenty original articles were included in the qualitative analysis.Strictures of 1.5e16.5 cm have been treated with LMG urethroplasty,due to the improvement of harvesting technique and very low rate of long-term oral complications.Very good functional results have been reported by different authors for LMG urethroplasty,with lower rate of oral complications than BMG.The meta-analysis included six comparative studies involving 187 and 178 patients treated with LMG and BMG urethroplasty,respectively.An OR of 1.65(95%CI[0.95e2.87],I^2=0%)and 0.18(95%CI[0.03e1.26],I^2=68%)were found for LMG vs.BMG urethroplasty,in terms of success and oral complication rate,respectively.Conclusion:LMG urethroplasty can be reasonably considered a first choice technique for urethral stricture with very good results.Oral complications are temporary and minimally disabling,basically less than those for BMG,and depend mainly on the graft extent.

Surrogate markers of mucosal healing in inflammatory bowel disease:A systematic review

Mucosal healing(MH)has emerged as a key therapeutic target in inflammatory bowel disease(IBD),and achievement of this goal is documented by endoscopy with biopsy.However,colonoscopy is burdensome and invasive,and substitution with an accurate noninvasive biomarker is desirable.AIM To summarize published data regarding the performance of noninvasive biomarkers in assessing MH in IBD patients.METHODS We conducted a systematic review of studies that reported the performance of biomarkers in diagnosing MH in patients with IBD.The main outcome measure was to review the diagnostic accuracy of serum and fecal markers that showed promising utility in assessing MH.RESULTS We screened 1301 articles,retrieved 46 manuscripts and included 23 articles for full-text analysis.The majority of the included manuscripts referred to fecal markers(12/23),followed by circulatory markers(8/23);only 3/23 of the included manuscripts investigated combined markers(serum and/or fecal markers).Fecal calprotectin(FC)was the most investigated fecal marker for assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization.

A Peptide Containing T-Cell Epitopes of <i>Chlamydia trachomatis</i>Recombinant MOMP Induces Systemic and Mucosal Antibody Responses in Mice

We reported that intranasal immunization of mice with recombinant major outer membrane protein (MOMP) of Chlamydia trachomatis genetically fused with modified cholera toxin elicited mucosal and systemic antibody responses, but with inefficient protective mechanisms for complete protection of mice against a homologous C. trachomtis challenged infection. To begin to identify specific immunogenic MOMP regions to pursue as vaccine candidates, herein we selected small gene fragments of the MOMP gene containing T-cell epitopes (278-370 aa) and generated a rMOMP peptide (rMOMP-278). rMOMP and rMOMP-278 proteins were cloned, expressed, and their purities and specificities confirmed by SDS-PAGE and Western blot, respectively. We tested the immunogenicity of rMOMP-278 as compared to the parent rMOMP in mice. Mice were immunized intramuscularly with purified rMOMP proteins;total- and isotype- (IgA, IgG1, IgG2a, and IgG2b) specific antibodies in sera and vaginal washes were measured by ELISA. Immunized mice developed antigen-specific total antibodies in a kinetic fashion, with responses being higher to rMOMP than rMOMP- 278. However, antigen-specific isotype antibodies were detected in the order of IgG2b > IgG2a > IgG1 for rMOMP- 278, indicating more of a mixed Th1/Th2 response. Contrastingly, antibody responses to rMOMP was more of a predominant Th2 response in the order of IgG1 > IgG2b > IgG2a. Our data are evidence to suggest that rMOMP-278 is immunogenic by its ability to evoke systemic and mucosal immune responses with a Th1 bias in mice, and therefore may be an attractive peptide alternative to full MOMP as a vaccine candidate against C. trachomatis genital tract infection.

Treatment of high-grade dysplasia and intramucosal carcinoma using radiofrequency ablation or endoscopic mucosal resection + radiofrequency ablation: Meta-analysis and systematic review

BACKGROUND The progression of Barrett's esophagus(BE) to early esophageal carcinoma occurs sequentially; the metaplastic epithelium develops from a low-grade dysplasia to a high-grade dysplasia(HGD), resulting in early esophageal carcinoma and,eventually, invasive carcinoma. Endoscopic approaches including resection and ablation can be used in the treatment of this condition.AIM To compare the effectiveness of radiofrequency ablation(RFA) vs endoscopic mucosal resection(EMR) + RFA in the endoscopic treatment of HGD and intramucosal carcinoma.METHODS In accordance with PRISMA guidelines, this systematic review included studies comparing the two endoscopic techniques(EMR + RFA and RFA alone) in the treatment of HGD and intramucosal carcinoma in patients with BE. Our analysis included studies involving adult patients of any age with BE with HGD or intramucosal carcinoma. The studies compared RFA and EMR + RFA methods were included regardless of randomization status.RESULTS The seven studies included in this review represent a total of 1950 patients, with742 in the EMR + RFA group and 1208 in the RFA alone group. The use of EMR +RFA was significantly more effective in the treatment of HGD [RD 0.35(0.15,0.56)] than was the use of RFA alone. The evaluated complications(stenosis,bleeding, and thoracic pain) were not significantly different between the two groups.CONCLUSION Endoscopic resection in combination with RFA is a safe and effective method in the treatment of HGD and intramucosal carcinoma, with higher rates of remission and no significant differences in complication rates when compared to the use of RFA alone.

Mucosal healing and inflammatory bowel disease:Therapeutic implications and new targets

Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.

Unlocking quality in endoscopic mucosal resection

A review of the development of the key performance metrics of endoscopic mucosal resection(EMR),learning from the experience of the establishment of widespread colonoscopy quality measurements.Potential future performance markers for both colonoscopy and EMR are also evaluated to ensure continued high quality performance is maintained with a focus service framework and predictors of patient outcome.

Dietary supplementation of bilberry anthocyanin on growth performance,intestinal mucosal barrier and cecal microbes of chickens challenged with Salmonella Typhimurium

Background Anthocyanins(AC)showed positive effects on improving the intestinal health and alleviating intestinal pathogen infections,therefore,an experiment was conducted to explore the protective effects of supplemented AC on Salmonella-infected chickens.Methods A total of 240 hatchling chickens were randomly allocated to 4 treatments,each with 6 replicates.Birds were fed a basal diet supplemented with 0(CON,and ST),100(ACL)and 400(ACH)mg/kg of AC for d 60,and orally challenged with PBS(CON)or 10^(9) CFU/bird(ST,ACL,ACH)Salmonella Typhimurium at d 14 and 16.Results(1)Compared with birds in ST,AC supplementation increased the body weight(BW)at d 18 and the average daily gain(ADG)from d 1 to 18 of the Salmonella-infected chickens(P<0.05);(2)AC decreased the number of Salmonella cells in the liver and spleen,the contents of NO in plasma and inflammatory cytokines in ileal mucosa of Salmonella-infected chickens(P<0.05);(3)Salmonella infection decreased the ileal villi height,villi height to crypt depth(V/C),and the expression of zonulaoccludins-1(ZO-1),claudin-1,occludin,and mucin 2(MUC2)in ileal mucosa.AC supplementation relieved these adverse effects,and decreased ileal crypt depth(P<0.05);(4)In cecal microbiota of Salmonella-infected chickens,AC increased(P<0.05)the alpha-diversity(Chao1,Pd,Shannon and Sobs indexes)and the relative abundance of Firmicutes,and decreased(P<0.05)the relative abundance of Proteobacteria and Bacteroidota and the enrichment of drug antimicrobial resistance,infectious bacterial disease,and immune disease pathways.Conclusions Dietary AC protected chicken against Salmonella infection via inhibiting the Salmonella colonization in liver and spleen,suppressing secretion of inflammatory cytokines,up-regulating the expression of ileal barrier-related genes,and ameliorating the composition and function of cecal microbes.Under conditions here used,100 mg/kg bilberry anthocyanin was recommended.

Characteristics of glucose and lipid metabolism and the interaction between gut microbiota and colonic mucosal immunity in pigs during cold exposure

Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold and non-cold adaptation regarding glucose and lipid metabolism,gut microbiota and colonic mucosal immunological features in pigs are unknown.This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation.Moreover,the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs.Results Cold and non-cold-adapted models were established by Min and Yorkshire pigs.Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models(Yorkshire pigs),decreasing plasma glucose concentrations.In this case,cold exposure enhanced the ATGL and CPT-1αexpression to promote liver lipolysis and fatty acid oxidation.Meanwhile,the two probiotics(Collinsella and Bifidobacterium)depletion and the enrichment of two pathogens(Sutterella and Escherichia-Shigella)in colonic microbiota are not conducive to colonic mucosal immunity.However,glucagon-mediated hepatic glycogenolysis in cold-adapted pig models(Min pigs)maintained the stability of glucose homeostasis during cold exposure.It contributed to the gut microbiota(including the enrichment of the Rikenellaceae RC9 gut group,[Eubacterium]coprostanoligenes group and WCHB1-41)that favored cold-adapted metabolism.Conclusions The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa.During non-cold adaptation,cold-induced glucose overconsumption promotes thermogenesis through lipolysis,but interferes with the gut microbiome and colonic mucosal immunity.Furthermore,glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.

Molecular regulation mechanism of intestinal stem cells in mucosal injury and repair in ulcerative colitis

Ulcerative colitis(UC)is a chronic nonspecific inflammatory disease with complex causes.The main pathological changes were intestinal mucosal injury.Leucinerich repeat-containing G protein coupled receptor 5(LGR5)-labeled small intestine stem cells(ISCs)were located at the bottom of the small intestine recess and inlaid among Paneth cells.LGR5+small ISCs are active proliferative adult stem cells,and their self-renewal,proliferation and differentiation disorders are closely related to the occurrence of intestinal inflammatory diseases.The Notch signaling pathway and Wnt/β-catenin signaling pathway are important regulators of LGR5-positive ISCs and together maintain the function of LGR5-positive ISCs.More importantly,the surviving stem cells after intestinal mucosal injury accelerate division,restore the number of stem cells,multiply and differentiate into mature intestinal epithelial cells,and repair the damaged intestinal mucosa.Therefore,in-depth study of multiple pathways and transplantation of LGR5-positive ISCs may become a new target for the treatment of UC.

Xiaojianzhong decoction prevents gastric precancerous lesions in rats by inhibiting autophagy and glycolysis in gastric mucosal cells

BACKGROUND Gastric precancerous lesions(GPL)precede the development of gastric cancer(GC).They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation,bacterial infection,and injury.Abnormalities in autophagy and glycolysis affect GPL progression,and their effective regulation can aid in GPL treatment and GC prevention.Xiaojianzhong decoction(XJZ)is a classic compound for the treatment of digestive system diseases in ancient China which can inhibit the progression of GPL.However,its specific mechanism of action is still unclear.AIM To investigate the therapeutic effects of XJZ decoction on a rat GPL model and the mechanisms underlying its effects on autophagy and glycolysis regulation in GPLs.METHODS Wistar rats were randomly divided into six groups of five rats each and all groups except the control group were subjected to GPL model construction for 18 wk.The rats’body weight was monitored every 2 wk starting from the beginning of modeling.Gastric histopathology was examined using hematoxylin-eosin staining and Alcian blue-periodic acid-Schiff staining.Autophagy was observed using transmission electron microscopy.The expressions of autophagy,hypoxia,and glycolysis related proteins in gastric mucosa were detected using immunohistochemistry and immunofluorescence.The expressions of the following proteins in gastric tissues:B cell lymphoma/Leukemia-2 and adenovirus E1B19000 interacting protein 3(Bnip-3),microtubule associated protein 1 light chain 3(LC-3),moesin-like BCL2-interacting protein 1(Beclin-1),phosphatidylinositol 3-kimase(PI3K),protein kinase B(AKT),mammalian target of rapamycin(mTOR),p53,AMP-activated protein kinase(AMPK),and Unc-51 like kinase 1(ULK1)were detected using western blot.The relative expressions of autophagy,hypoxia,and glycolysis related mRNA in gastric tissues was detected using reverse transcription-polymerase chain reaction.RESULTS Treatment with XJZ increased the rats’body weight and improved GPL-related histopathological manifestations.It also decreased autophagosome and autolysosome formation in gastric tissues and reduced Bnip-3,Beclin-1,and LC-3II expressions,resulting in inhibition of autophagy.Moreover,XJZ down-regulated glycolysis-related monocarboxylate transporter(MCT1),MCT4,and CD147 expressions.XJZ prevented the increase of autophagy level by decreasing gastric mucosal hypoxia,activating the PI3K/AKT/mTOR pathway,inhibiting the p53/AMPK pathway activation and ULK1 Ser-317 and Ser-555 phosphorylation.In addition,XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression.CONCLUSION This study demonstrates that XJZ may inhibit autophagy and glycolysis in GPL gastric mucosal cells by improving gastric mucosal hypoxia and regulating PI3K/AKT/mTOR and p53/AMPK/ULK1 signaling pathways,providing a feasible strategy for the GPL treatment.

Multicenter evaluation of recurrence in endoscopic submucosal dissection and endoscopic mucosal resection in the colon:A Western perspective

BACKGROUND While colon endoscopic mucosal resection(EMR)is an effective technique,removal of larger polyps often requires piecemeal resection,which can increase recurrence rates.Endoscopic submucosal dissection(ESD)in the colon offers the ability for en bloc resection and is well-described in Asia,but there are limited studies comparing ESD vs EMR in the West.AIM To evaluate different techniques in endoscopic resection of large polyps in the colon and to identify factors for recurrence.METHODS The study is a retrospective comparison of ESD,EMR and knife-assisted endoscopic resection performed at Stanford University Medical Center and Veterans Affairs Palo Alto Health Care System between 2016 and 2020.Knife-assisted endoscopic resection was defined as use of electrosurgical knife to facilitate snare resection,such as for circumferential incision.Patients≥18 years of age undergoing colonoscopy with removal of polyp(s)≥20 mm were included.The primary outcome was recurrence on follow-up.RESULTS A total of 376 patients and 428 polyps were included.Mean polyp size was greatest in the ESD group(35.8 mm),followed by knife-assisted endoscopic resection(33.3 mm)and EMR(30.5 mm)(P<0.001).ESD achieved highest en bloc resection(90.4%)followed by knife-assisted endoscopic resection(31.1%)and EMR(20.2%)(P<0.001).A total of 287 polyps had follow-up(67.1%).On follow-up analysis,recurrence rate was lowest in knife-assisted endoscopic resection(0.0%)and ESD(1.3%)and highest in EMR(12.9%)(P=0.0017).En bloc polyp resection had significantly lower rate of recurrence(1.9%)compared to non-en bloc(12.0%,P=0.003).On multivariate analysis,ESD(in comparison to EMR)adjusted for polyp size was found to significantly reduce risk of recurrence[adjusted hazard ratio 0.06(95%CI:0.01-0.57,P=0.014)].CONCLUSION In our study,EMR had significantly higher recurrence compared to ESD and knife-assisted endoscopic resection.We found factors including resection by ESD,en bloc removal,and use of circumferential incision were associated with significantly decreased recurrence.While further studies are needed,we have demonstrated the efficacy of ESD in a Western population.