Lipocalin-2 and intestinal diseases

Dysfunction of the intestinal barrier is a prevalent phenomenon observed across a spectrum of diseases,encompassing conditions such as mesenteric artery dissection,inflammatory bowel disease,cirrhosis,and sepsis.In these pathological states,the integrity of the intestinal barrier,which normally serves to regulate the selective passage of substances between the gut lumen and the bloodstream,becomes compromised.This compromised barrier function can lead to a range of adverse consequences,including increased permeability to harmful substances,the translocation of bacteria and their products into systemic circulation,and heightened inflammatory responses within the gut and beyond.Understanding the mechanisms underlying intestinal barrier dysfunction in these diverse disease contexts is crucial for the development of targeted therapeutic interventions aimed at restoring barrier integrity and ameliorating disease progression.Lipocalin-2(LCN2)expression is significantly upregulated during episodes of intestinal inflammation,making it a pivotal indicator for gauging the extent of such inflammatory processes.Notably,however,LCN2 derived from distinct cellular sources,whether intestinal epithelial cells or immune cells,exhibits notably divergent functional characteristics.Furthermore,the multifaceted nature of LCN2 is underscored by its varying roles across different diseases,sometimes even demonstrating contradictory effects.

Intestinal microecology: A crucial strategy for targeted therapy of liver diseases

Intestinal microecology is an important part of human internal environment and is an extremely complex ecosystem consisting of gut microbiota, intestinal mucosa and intestinal immune system [1]. Gut is highly specialized for the digestion and absorption of different nutrients. The gut microbiota is the largest and most complex, which not only affects the local function of the intestine, but also plays an important role in the maturation and maintenance of the whole immune system.

Helminths as an alternative therapy for intestinal diseases

Animal models and clinical studies have shown that helminth infections exert immunomodulatory activity,altering intestinal permeability and providing a potential beneficial action on autoimmune and inflammatory disorders in human beings,such as inflammatory bowel disease(IBD) and celiac disease. This is consistent with the theory that intestinal microbiota is responsible for shaping human immunological responses. With the arrival of the immunobiologic era and the use of antibodies,we propose a distinctive pathway for treating patients with IBD and celiac disease. We have some evidence about the safety and tolerability of helminth use,but evidence about their impact on disease activity is lacking. Using worms to treat diseases could be a possible way to lower treatment costs,since the era of immunobiologic agents is responsible for a significant rise in expenses. Some questions remain to be investigated regarding the use of helminths in intestinal disease,such as the importance of the specific species of helminths used,appropriate dosing regimens,optimal timing of treatment,the role of host genetics,diet,environment,and the elucidation of the exact mechanisms of action. One promising approach is the use of helminth-derived anti-inflammatory molecules as drugs. Yet there are still many challenges with this method,especially with regard to safety. Studies on intestinal permeability point to Strongyloides stercoralis as a useful nematode for these purposes.

The gut-eye axis:from brain neurodegenerative diseases to age-related macular degeneration

Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are consequently lacking.The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host.The intestinal microbiome undergoes dynamic changes owing to age,diet,genetics,and other factors.Such dysregulation of the intestinal flora can disrupt the microecological balance,resulting in immunological and metabolic dysfunction in the host,and affecting the development of many diseases.In recent decades,significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract,including the brain.Indeed,several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.Similarly,the role of the“gut-eye axis”has been confirmed to play a role in the pathogenesis of many ocular disorders.Moreover,age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies.As such,the intestinal flora may play an important role in age-related macular degeneration.Given the above context,the present review aims to clarify the gut-brain and gut-eye connections,assess the effect of intestinal flora and metabolites on age-related macular degeneration,and identify potential diagnostic markers and therapeutic strategies.Currently,direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited,while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration.Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions,while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway:a potential therapeutic approach for neurodegenerative diseases

The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

Predicting short-term major postoperative complications in intestinal resection for Crohn’s disease:A machine learning-based study

BACKGROUND Due to the complexity and numerous comorbidities associated with Crohn’s disease(CD),the incidence of postoperative complications is high,significantly impacting the recovery and prognosis of patients.Consequently,additional stu-dies are required to precisely predict short-term major complications following intestinal resection(IR),aiding surgical decision-making and optimizing patient care.AIM To construct novel models based on machine learning(ML)to predict short-term major postoperative complications in patients with CD following IR.METHODS A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022.The study participants were randomly allocated to either a training cohort or a validation cohort.The logistic regression and random forest(RF)were applied to construct models in the training cohort,with model discrimination evaluated using the area under the curves(AUC).The validation cohort assessed the performance of the constructed models.RESULTS Out of the 259 patients encompassed in the study,5.0%encountered major postoperative complications(Clavien-Dindo≥III)within 30 d following IR for CD.The AUC for the logistic model was 0.916,significantly lower than the AUC of 0.965 for the RF model.The logistic model incorporated a preoperative CD activity index(CDAI)of≥220,a diminished preoperative serum albumin level,conversion to laparotomy surgery,and an extended operation time.A nomogram for the logistic model was plotted.Except for the surgical approach,the other three variables ranked among the top four important variables in the novel ML model.CONCLUSION Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complic-ations in patients with CD,with the RF model showing more superiority.A preoperative CDAI of≥220,a di-minished preoperative serum albumin level,and an extended operation time might be the most crucial variables.The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

Small heat shock protein B8:from cell functions to its involvement in diseases and potential therapeutic applications

Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and migration.HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective autophagy.In line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation.In cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation.Moreover,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar hemorrhage.Of note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases.This is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis.This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its modulation.Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.

Current perspectives and the future of disease-modifying therapies in type 1 diabetes

Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.

Differential diagnosis of Crohn’s disease and intestinal tuberculosis based on ATR-FTIR spectroscopy combined with machine learning

BACKGROUND Crohn’s disease(CD)is often misdiagnosed as intestinal tuberculosis(ITB).However,the treatment and prognosis of these two diseases are dramatically different.Therefore,it is important to develop a method to identify CD and ITB with high accuracy,specificity,and speed.AIM To develop a method to identify CD and ITB with high accuracy,specificity,and speed.METHODS A total of 72 paraffin wax-embedded tissue sections were pathologically and clinically diagnosed as CD or ITB.Paraffin wax-embedded tissue sections were attached to a metal coating and measured using attenuated total reflectance fourier transform infrared spectroscopy at mid-infrared wavelengths combined with XGBoost for differential diagnosis.RESULTS The results showed that the paraffin wax-embedded specimens of CD and ITB were significantly different in their spectral signals at 1074 cm^(-1) and 1234 cm^(-1) bands,and the differential diagnosis model based on spectral characteristics combined with machine learning showed accuracy,specificity,and sensitivity of 91.84%,92.59%,and 90.90%,respectively,for the differential diagnosis of CD and ITB.CONCLUSION Information on the mid-infrared region can reveal the different histological components of CD and ITB at the molecular level,and spectral analysis combined with machine learning to establish a diagnostic model is expected to become a new method for the differential diagnosis of CD and ITB.

Computed tomography-based radiomics combined with machine learning allows differentiation between primary intestinal lymphoma and Crohn's disease

BACKGROUND Due to similar clinical manifestations and imaging signs,differential diagnosis of primary intestinal lymphoma(PIL)and Crohn's disease(CD)is a challenge in clinical practice.AIM To investigate the ability of radiomics combined with machine learning methods to differentiate PIL from CD.METHODS We collected contrast-enhanced computed tomography(CECT)and clinical data from 120 patients form center 1.A total of 944 features were extracted singlephase images of CECT scans.Using the last absolute shrinkage and selection operator model,the best predictive radiographic features and clinical indications were screened.Data from 54 patients were collected at center 2 as an external validation set to verify the robustness of the model.The area under the receiver operating characteristic curve,accuracy,sensitivity and specificity were used for evaluation.RESULTS A total of five machine learning models were built to distinguish PIL from CD.Based on the results from the test group,most models performed well with a large area under the curve(AUC)(>0.850)and high accuracy(>0.900).The combined clinical and radiomics model(AUC=1.000,accuracy=1.000)was the best model among all models.CONCLUSION Based on machine learning,a model combining clinical data with radiologic features was constructed that can effectively differentiate PIL from CD.

Advances in the research of intestinal fungi in Crohn's disease

This article reviews of the original research published by Wu et al in the World Journal of Gastroenterology,delving into the pivotal role of the gut microbiota in the pathogenesis of Crohn's disease(CD).Insights were gained from fecal microbiota transplantation(FMT)in mouse models,revealing the intricate interplay between the gut microbiota,mesenteric adipose tissue(MAT),and creeping fat.The study uncovered the characteristics of inflammation and fibrosis in the MAT and intestinal tissues of patients with CD;moreover,through the FMT mouse model,it observed the impact of samples from healthy patients and those with CD on symptoms.The pathogenesis of CD is complex,and its etiology remains unclear;however,it is widely believed that gut microbiota dysbiosis plays a significant role.Recently,with the development and application of next-generation sequen-cing technology,research on the role of fungi in the pathogenesis and chronicity of CD has deepened.This editorial serves as a supplement to the research by Wu et al who discussed advances related to the study of fungi in CD.

Interleukin-mediated therapies in liver diseases and comorbidity effects

Cytokines like interleukins(ILs)play important roles in inflammation and innate immune.Yang and Zhang carried out an interesting study related to ILs and hepatic diseases.They described the role of ILs in the pathogenesis and resolution of hepatic disorders.The authors summarized alcohol-related liver disease and virus-induced hepatitis,as far as clinical studies a fortiori carried out on ILmediated treatments pertaining to these dysfunctions.This editorial contributes to the review by Yang and Zhang titled,"Interleukins in liver disease treatment",and focuses on therapies mediated by ILs in comorbid liver diseases.The documentary search was conducted on recent pertinent literature,primarily using the Google Scholar and PubMed databases.

Intestinal Behçet's disease: A review of clinical diagnosis and treatment

Behçet's disease(BD)is a chronic inflammatory disorder prone to frequent re-currences,with a high predilection for intestinal involvement.However,the ef-ficacy and long-term effects of surgical treatment for intestinal BD are unknown.In the current issue of World J Gastrointest Surg,Park et al conducted a retrospec-tive analysis of 31 patients with intestinal BD who received surgical treatment.They found that elevated C-reactive protein levels and emergency surgery were poor prognostic factors for postoperative recurrence,emphasizing the adverse impact of severe inflammation on the prognosis of patients with intestinal BD.This work has clinical significance for evaluating the postoperative condition of intestinal BD.The editorial attempts to summarize the clinical diagnosis and treatment of intestinal BD,focusing on the impact of adverse factors on surgical outcomes.We hope this review will facilitate more precise postoperative management of patients with intestinal BD by clinicians.

Overview of emerging therapies for demyelinating diseases

This paper provides an overview of autoimmune disorders of the central nervous system,specifically those caused by demyelination.We explore new research regarding potential therapeutic interventions,particularly those aimed at inducing remyelination.Remyelination is a detailed process,involving many cell types–oligodendrocyte precursor cells(OPCs),astrocytes,and microglia–and both the innate and adaptive immune systems.Our discussion of this process includes the differentiation potential of neural stem cells,the function of adult OPCs,and the impact of molecular mediators on myelin repair.Emerging therapies are also explored,with mechanisms of action including the induction of OPC differentiation,the transplantation of mesenchymal stem cells,and the use of molecular mediators.Further,we discuss current medical advancements in relation to many myelin-related disorders,including multiple sclerosis,optic neuritis,neuromyelitis optica spectrum disorder,myelin oligodendrocyte glycoprotein antibodyassociated disease,transverse myelitis,and acute disseminated encephalomyelitis.Beyond these emerging systemic therapies,we also introduce the dimethyl fumarate/silk fibroin nerve conduit and its potential role in the treatment of peripheral nerve injuries.Despite these aforementioned scientific advancements,this paper maintains the need for ongoing research to deepen our understanding of demyelinating diseases and advance therapeutic strategies that enhance affected patients’quality of life.

Influencing factors and preventive measures of infectious complications after intestinal resection for Crohn’s disease

The incidence of Crohn’s disease(CD)has increased in recent years,with most patients requiring intestinal resection.Complications after intestinal resection for CD can lead to poor prognosis and recurrence,among which infectious complic-ations are the most common.This study aimed to investigate the common risk factors,including medications,preoperative nutritional status,surgery-related factors,microorganisms,lesion location and type,and so forth,causing infectious complications after intestinal resection for CD,and to propose corresponding preventive measures.The findings provided guidance for identifying suscept-ibility factors and the early intervention and prevention of infectious complic-ations after intestinal resection for CD in clinical practice.

Machine learning as a tool predicting short-term postoperative complications in Crohn’s disease patients undergoing intestinal resection: What frontiers?

The recent study,“Predicting short-term major postoperative complications in intestinal resection for Crohn’s disease:A machine learning-based study”invest-igated the predictive efficacy of a machine learning model for major postoperative complications within 30 days of surgery in Crohn’s disease(CD)patients.Em-ploying a random forest analysis and Shapley Additive Explanations,the study prioritizes factors such as preoperative nutritional status,operative time,and CD activity index.Despite the retrospective design’s limitations,the model’s robu-stness,with area under the curve values surpassing 0.8,highlights its clinical potential.The findings align with literature supporting preoperative nutritional therapy in inflammatory bowel diseases,emphasizing the importance of compre-hensive assessment and optimization.While a significant advancement,further research is crucial for refining preoperative strategies in CD patients.

Dajianzhong decoction:a review of its phytochemistry and therapeutic potential for gastrointestinal disease

Dajianzhong decoction(DJZD)is one of the traditional herbal prescriptions originated from Synopsis of Golden Chamber,which clinically used for the treatment of various gastrointestinal(GI)disease.This paper was aimed to provide a systematic review on the phytochemistry of DJZD and its therapeutic potential for GI disease and the mechanism.Finally,the possible development and perspectives for future research on this prescription were also discussed.To date,over 60 compounds have been identified form DJZD,including unsaturated fatty acid,saponins,and polyphenols,with hydroxy-sanshool and ginsenoside compounds as the predominant ones.DJZD possessed widely pharmacological activities on the GI disease from the Eastern Han Dynasty to the present,such as intestinal obstruction,colitis,and irritable bowel syndrome.Especially for the intestinal obstruction,it had demonstrated the efficacy of DJZD treatment for relief of postoperative ileus in patients undergoing surgery for GI cancer.The detailed mechanism was mainly related with NF-ᴋB signaling pathway.However,further research elucidating the protective effects of DJZD on GI disease,exploring new clinical effects,as well as establishing criteria for quality control for DJZD should be studied.

Transabdominal intestinal ultrasound and its parameters used in the assessment of pediatric inflammatory bowel disease

This article extends on the use of transabdominal intestinal ultrasound in diagnosing pediatric inflammatory bowel disease.Some of the more essential features used in assessing bowel inflammation,such as hyperemia and wall thickness on ultrasound,are expanded upon from the publication on imaging and endoscopic tools in pediatric inflammatory bowel disease.

Different roles of capsule endoscopy and double-balloon enteroscopy in obscure small intestinal diseases

AIM: To compare the roles of capsule endoscopy(CE)and double-balloon enteroscopy(DBE) in the diagnosis of obscure small bowel diseases.METHODS: From June 2009 to December 2014, 88 patients were included in this study; the patients had undergone gastroscopy, colonoscopy, radiological small intestinal barium meal, abdominal computed tomography or magnetic resonance imaging scan and mesenteric angiography, but their diagnoses were still unclear. The patients with gastrointestinal obstructions,fistulas, strictures, or cardiac pacemakers, as well as pregnant women, and individuals who could not accept the capsule-retention or capsule-removal surgery were excluded. Patients with heart, lung and other vital organ failure diseases were also excluded. Everyone involved in this study had undergone CE and DBE. The results were divided into:(1) the definite diagnosis(the diagnosis was confirmed at least by one of the biopsy,surgery, pathology or the drug treatment effects with follow-up for at least 3 mo);(2) the possible diagnosis(a possible diagnosis was suggested by CE or DBE,but not confirmed by the biopsy, surgery or follow-up drug treatment effects); and(3) the unclear diagnosis(no exact causes were provided by CE and DBE for the disease). The detection rate and the diagnostic yield of the two methods were compared. The differencein the etiologies between CE and DBE was estimated,and the different possible etiologies caused by the age groups were also investigated.RESULTS: CE exhibited a better trend than DBE for diagnosing scattered small ulcers(P = 0.242, Fisher's test), and small vascular malformations(χ 2 = 1.810,P = 0.179, Pearson χ 2 test), but with no significant differences, possible due to few cases. However,DBE was better than CE for larger tumors(P =0.018, Fisher's test) and for diverticular lesions with bleeding ulcers(P = 0.005, Fisher's test). All three hemangioma cases diagnosed by DBE in this study(including sponge hemangioma, venous hemangioma,and hemangioma with hamartoma lesions) were all confirmed by biopsy. Two parasite cases were found by CE, but were negative by DBE. This study revealed no obvious differences in the detection rates(DR) of CE(60.0%, 53/88) and DBE(59.1%, 52/88). However,the etiological diagnostic yield(DY) difference was apparent. The CE diagnostic yield was 42.0%(37/88),and the DBE diagnostic yield was 51.1%(45/88).Furthermore, there were differences among the age groups(χ 2 = 22.146, P = 0.008, Kruskal Wallis Test). Small intestinal cancer(5/6 cases), vascular malformations(22/29 cases), and active bleeding(3/4cases) appeared more commonly in the patients over50 years old, but diverticula with bleeding ulcers were usually found in the 15-25-year group(4/7cases). The over-25-year group accounted for the stromal tumors(10/12 cases).CONCLUSION: CE and DBE each have their own advantages and disadvantages. The appropriate choice depends on the patient's age, tolerance, and clinical manifestations. Sometimes CE followed by DBE is necessary.

Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases

BACKGROUND： The well-known functions of bile acids（BAs） are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases.DATA SOURCES： Detailed and comprehensive search of PubM ed and Scopus databases was carried out for original and review articles.RESULTS： Disturbances in BA homeostasis contribute to the development of several hepatobiliary and intestinal disorders, such as non-alcoholic fatty liver disease, liver cirrhosis, cholesterol gallstone disease, intestinal diseases and both hepatocellular and colorectal carcinoma.CONCLUSION： Further efforts made in order to advance the understanding of sophisticated BA signaling network may be promising in developing novel therapeutic strategies related not only to hepatobiliary and gastrointestinal but also systemic diseases.