Metabolomic analysis of the serum and urine of rats exposed to diazinon, dimethoate, and cypermethrin alone or in combination.

BACKGROUND: Multiple pesticides are often used in combination for plant protection and public health. Therefore, it is important to analyze the physiological changes induced by multiple pesticides exposure. The objective of this study was to investigate the combined toxicity of the widely-used organophosphorus and pyrethroid pesticides diazinon, dimethoate, and cypermethrin. METHODS: Male Wistar rats were administrated by gavage once daily with the three pesticides individual or in combination for consecutive 28 days. The metabolic components of serum and urine samples were detected by using 1H nuclear magnetic resonance (NMR)-based metabolomics method. Histopathological examination of liver and kidneys and serum biochemical determination were also carried out. RESULTS: The results showed that after the 28-day subacute exposure, serum glutamic transaminase and albumin were significantly increased and blood urea nitrogen was significantly decreased in the rats exposed to the mixture of the pesticides compared with the control rats, suggesting that the co-exposure impaired liver and kidney function. Metabolomics analysis indicated that the indicators 14 metabolites were statistically significant altered in the rats after the exposure of the pesticides. The increase in 3-hydroxybutyric acid in urine or decrease of lactate and N-acetyl-L-cysteine in serum could be a potentially sensitive biomarker of the subchronic combined effects of the three insecticides. The reduction level of 2-oxoglutarate and creatinine in urine may be indicative of dysfunction of liver and kidneys. CONCLUSION: In summary, the exposure of rats to pesticides diazinon, dimethoate, and cypermethrin could cause disorder of lipid and amino acid metabolism, induction of oxidative stress, and dysfunction of liver and kidneys, which contributes to the understanding of combined toxic effects of the pesticides revealed by using the metabolomics analysis of the urine and serum profiles.

Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives.

Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.

Application of Nanoparticles in the Diagnosis of Gastrointestinal Diseases: A Complete Future Perspective.

The diagnosis of gastrointestinal (GI) diseases currently relies primarily on invasive procedures like digestive endoscopy. However, these procedures can cause discomfort, respiratory issues, and bacterial infections in patients, both during and after the examination. In recent years, nanomedicine has emerged as a promising field, providing significant advancements in diagnostic techniques. Nanoprobes, in particular, offer distinct advantages, such as high specificity and sensitivity in detecting GI diseases. Integration of nanoprobes with advanced imaging techniques, such as nuclear magnetic resonance, optical fluorescence imaging, tomography, and optical correlation tomography, has significantly enhanced the detection capabilities for GI tumors and inflammatory bowel disease (IBD). This synergy enables early diagnosis and precise staging of GI disorders. Among the nanoparticles investigated for clinical applications, superparamagnetic iron oxide, quantum dots, single carbon nanotubes, and nanocages have emerged as extensively studied and utilized agents. This review aimed to provide insights into the potential applications of nanoparticles in modern imaging techniques, with a specific focus on their role in facilitating early and specific diagnosis of a range of GI disorders, including IBD and colorectal cancer (CRC). Additionally, we discussed the challenges associated with the implementation of nanotechnology-based GI diagnostics and explored future prospects for translation in this promising field.

Exploring the efficacy of herbal medicinal products as oral therapy for inflammatory bowel disease.

Inflammatory bowel disease (IBD) encompasses a collection of idiopathic diseases characterized by chronic inflammation in the gastrointestinal (GI) tract. Patients diagnosed with IBD often experience necessitate long-term pharmacological interventions. Among the multitude of administration routes available for treating IBD, oral administration has gained significant popularity owing to its convenience and widespread utilization. In recent years, there has been extensive evaluation of the efficacy of orally administered herbal medicinal products and their extracts as a means of treating IBD. Consequently, substantial evidence has emerged, supporting their effectiveness in IBD treatment. This review aimed to provide a comprehensive summary of recent studies evaluating the effects of herbal medicinal products in the treatment of IBD. We delved into the regulatory role of these products in modulating immunity and maintaining the integrity of the intestinal epithelial barrier. Additionally, we examined their impact on antioxidant activity, anti-inflammatory properties, and the modulation of intestinal flora. By exploring these aspects, we aimed to emphasize the significant advantages associated with the use of oral herbal medicinal products in the treatment of IBD. Of particular note, this review introduced the concept of herbal plant-derived exosome-like nanoparticles (PDENs) as the active ingredient in herbal medicinal products for the treatment of IBD. The inclusion of PDENs offers distinct advantages, including enhanced tissue penetration and improved physical and chemical stability. These unique attributes not only demonstrate the potential of PDENs but also pave the way for the modernization of herbal medicinal products in IBD treatment.

Edible exosome-like nanoparticles from portulaca oleracea L mitigate DSS-induced colitis via facilitating double-positive CD4+CD8+T cells expansion.

Plant-derived exosome-like nanoparticles (PDENs) have been paid great attention in the treatment of ulcerative colitis (UC). As a proof of concept, we isolated and identified Portulaca oleracea L-derived exosome-like nanoparticles (PELNs) from edible Portulaca oleracea L, which exhibited desirable nano-size (~ 160 nm) and a negative zeta potential value (-31.4 mV). Oral administration of PELNs effectively suppressed the expressions of pro-inflammatory cytokines (TNF-α, IL-6, IL-12, and IL-1ß) and myeloperoxidase (MPO), increased levels of the anti-inflammatory cytokine (IL-10), and alleviated acute colitis in dextran sulfate sodium (DSS)-induced C57 mice and IL-10-/- mice. Notably, PELNs exhibited excellent stability and safety within the gastrointestinal tract and displayed specific targeting to inflamed sites in the colons of mice. Mechanistically, oral administration of PELNs played a crucial role in maintaining the diversity and balance of gut microbiota. Furthermore, PELNs treatment enhanced Lactobacillus reuteri growth and elevated indole derivative levels, which might activate the aryl-hydrocarbon receptor (AhR) in conventional CD4+ T cells. This activation downregulated Zbtb7b expression, leading to the reprogramming of conventional CD4+ T cells into double-positive CD4+CD8+T cells (DP CD4+CD8+ T cells). In conclusion, our findings highlighted the potential of orally administered PELNs as a novel, natural, and colon-targeted agent, offering a promising therapeutic approach for managing UC. Schematic illustration of therapeutic effects of oral Portulaca oleracea L -derived natural exosome-like nanoparticles (PELNs) on UC. PELNs treatment enhanced Lactobacillus reuteri growth and elevated indole derivative levels, which activate the aryl-hydrocarbon receptor (AhR) in conventional CD4+ T cells leading to downregulate the expression of Zbtb7b, reprogram of conventional CD4+ T cells into double-positive CD4+CD8+T cells (DP CD4+CD8+ T cells), and decrease the levels of pro-inflammatory cytokines.

Plant-derived exosomal nanoparticles: potential therapeutic for inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic autoimmune disorder characterized by inflammation. However, currently available disease-modifying anti-IBD drugs exhibit limited efficacy in IBD therapy. Furthermore, existing therapeutic approaches provide only partial relief from IBD symptoms and are associated with certain side effects. In recent years, a novel category of nanoscale membrane vesicles, known as plant-derived exosome-like nanoparticles (PDENs), has been identified in edible plants. These PDENs are abundant in bioactive lipids, proteins, microRNAs, and other pharmacologically active compounds. Notably, PDENs possess immunomodulatory, antitumor, regenerative, and anti-inflammatory properties, making them particularly promising for the treatment of intestinal diseases. Moreover, PDENs can be engineered as targeted delivery systems for the efficient transport of chemical or nucleic acid drugs to the site of intestinal inflammation. In the present study, we provided an overview of PDENs, including their biogenesis, extraction, purification, and construction strategies, and elucidated their physiological functions and therapeutic effects on IBD. Additionally, we summarized the applications and potential of PDENs in IBD treatment while highlighting the future directions and challenges in the field of emerging nanotherapeutics for IBD therapy.

Stem cell-derived intestinal organoids: a novel modality for IBD.

The organoids represent one of the greatest revolutions in the biomedical field in the past decade. This three-dimensional (3D) micro-organ cultured in vitro has a structure highly similar to that of the tissue and organ. Using the regeneration ability of stem cells, a 3D organ-like structure called intestinal organoids is established, which can mimic the characteristics of real intestinal organs, including morphology, function, and personalized response to specific stimuli. Here, we discuss current stem cell-based organ-like 3D intestinal models, including understanding the molecular pathophysiology, high-throughput screening drugs, drug efficacy testing, toxicological evaluation, and organ-based regeneration of inflammatory bowel disease (IBD). We summarize the advances and limitations of the state-of-the-art reconstruction platforms for intestinal organoids. The challenges, advantages, and prospects of intestinal organs as an in vitro model system for precision medicine are also discussed. Key applications of stem cell-derived intestinal organoids. Intestinal organoids can be used to model infectious diseases, develop new treatments, drug screens, precision medicine, and regenerative medicine.

A 2D flexible cobalt-MOF: reversible solid-state structural transformation, two-step and gate-opening adsorption behaviours, and selective adsorption of C2H2 over CO2 and CH4.

A new 2D flexible cobalt(II) framework (Co-MOF) exhibits a reversible solid-state structural transformation upon guest molecule removal/uptake. After activation, Co-MOF-α with 1D porous channels transformed into Co-MOF-ß (0D voids) accompanied by a shift in metal and carboxylate coordination modes, the rotation of organic linkers and the contraction of interstitial spaces. Gas adsorption experiments reveal that Co-MOF-ß exhibits a two-step CO2 adsorption isotherm and close-to-open (type F-IV) isotherms for C2H2, C2H4 and C2H6 at 195 K. Moreover, it shows typical type I adsorption isotherms for the above gases and the selective uptake of C2H2 over CH4 and CO2 at room temperature.

Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.

Nanomaterials for mRNA-based therapeutics: Challenges and opportunities.

Messenger RNA (mRNA) holds great potential in developing immunotherapy, protein replacement, and genome editing. In general, mRNA does not have the risk of being incorporated into the host genome and does not need to enter the nucleus for transfection, and it can be expressed even in nondividing cells. Therefore, mRNA-based therapeutics provide a promising strategy for clinical treatment. However, the efficient and safe delivery of mRNA remains a crucial constraint for the clinical application of mRNA therapeutics. Although the stability and tolerability of mRNA can be enhanced by directly retouching the mRNA structure, there is still an urgent need to improve the delivery of mRNA. Recently, significant progress has been made in nanobiotechnology, providing tools for developing mRNA nanocarriers. Nano-drug delivery system is directly used for loading, protecting, and releasing mRNA in the biological microenvironment and can be used to stimulate the translation of mRNA to develop effective intervention strategies. In the present review, we summarized the concept of emerging nanomaterials for mRNA delivery and the latest progress in enhancing the function of mRNA, primarily focusing on the role of exosomes in mRNA delivery. Moreover, we outlined its clinical applications so far. Finally, the key obstacles of mRNA nanocarriers are emphasized, and promising strategies to overcome these obstacles are proposed. Collectively, nano-design materials exert functions for specific mRNA applications, provide new perception for next-generation nanomaterials, and thus revolution of mRNA technology.

Emerging role of bacterial outer membrane vesicle in gastrointestinal tract.

Bacteria form a highly complex ecosystem in the gastrointestinal (GI) tract. In recent years, mounting evidence has shown that bacteria can release nanoscale phospholipid bilayer particles that encapsulate nucleic acids, proteins, lipids, and other molecules. Extracellular vesicles (EVs) are secreted by microorganisms and can transport a variety of important factors, such as virulence factors, antibiotics, HGT, and defensive factors produced by host eukaryotic cells. In addition, these EVs are vital in facilitating communication between microbiota and the host. Therefore, bacterial EVs play a crucial role in maintaining the GI tract's health and proper functioning. In this review, we outlined the structure and composition of bacterial EVs. Additionally, we highlighted the critical role that bacterial EVs play in immune regulation and in maintaining the balance of the gut microbiota. To further elucidate progress in the field of intestinal research and to provide a reference for future EV studies, we also discussed the clinical and pharmacological potential of bacterial EVs, as well as the necessary efforts required to understand the mechanisms of interaction between bacterial EVs and gut pathogenesis.

Development of a model for Colletotrichum diseases with calibration for phylogenetic clades on different host plants.

Fungi in the genus Colletotrichum cause serious pre- and post-harvest losses to several agricultural crops worldwide. Through a systematic literature review, we retrieved the published information on Colletotrichum anthracnose diseases on different host plants and developed a mechanistic model incorporating the main stages of the pathogen's life cycle and the effect of weather. The model predicts anthracnose progress during the growing season on the aerial organs of different crops, and was parameterized for seven Colletotrichum clades (acutatum, dematium, destructivum, gloeosporioides, graminicola, and orbiculare) and the singleton species, C. coccodes. The model was evaluated for the anthracnose diseases caused by fungi belonging to five clades on six hosts by using data from 17 epidemics that occurred in Italy, the USA, Canada, and Japan. A comparison of observed versus predicted data showed a concordance correlation coefficient of 0.928 and an average distance between real data and the fitted line of 0.044. After further validation, the model could be used to support decision-making for crop protection.

Mesenchymal Stem Cell-derived Exosomes: Novel Therapeutic Approach for Inflammatory Bowel Diseases.

As double membrane-encapsulated nanovesicles (30-150 nm), exosomes (Exos) shuttle between different cells to mediate intercellular communication and transport active cargoes of paracrine factors. The anti-inflammatory and immunomodulatory activities of mesenchymal stem cell (MSC)-derived Exos (MSC-Exos) provide a rationale for novel cell-free therapies for inflammatory bowel disease (IBD). Growing evidence has shown that MSC-Exos can be a potential candidate for treating IBD. In the present review, we summarized the most critical advances in the properties of MSC-Exos, provided the research progress of MSC-Exos in treating IBD, and discussed the molecular mechanisms underlying these effects. Collectively, MSC-Exos had great potential for cell-free therapy in IBD. However, further studies are required to understand the full dimensions of the complex Exo system and how to optimize its effects.

[Experimental Study of Using Aloe Vera Gel to Treat Diabetic Chronic Cutaneous Ulcers in Bama Miniature Pigs].

Objective: To investigate the efficacy, safety, and mechanism of topical application of aloe vera gel (AVG) to treat diabetic chronic cutaneous ulcers in Bama miniature pigs. Methods: The Bama miniature pig model of diabetic chronic skin wounds was constructed and the model pigs were randomly assigned to AVG daily administration group (AVG QD), aloe vera gel every-other-day administration group (AVG QOD), and diabetic control group (DC). A non-diabetic chronic skin wounds model pig was set as the non-diabetic control group (NDC). Treatment efficacy was evaluated based on the amount of time needed for complete healing of the wounds, healing rates, granulation growth rates, and skin histopathological changes. Safety was evaluated according to whether adverse reactions were observed. In addition, the dynamic changes of the relative expression levels of miR21, miR29a, miR126, miR146a, miR155, and miR210 in wound granulation tissues were examined. Results: 1) Efficacy and safety: The amount of time needed for complete healing of the wounds was shorter in the NDC group than those of the three other groups, DC group, AVG QD group, and AVG QOD group (all P<0.05). The amount of time needed for complete healing of the wounds was shorter in the AVG QD group and AVG QOD group than that of DC group (all P<0.05). The amount of time needed for complete healing of the wounds was shorter in the AVG QOD group than that of AVG QD group (all P<0.05). No adverse reactions were detected in the whole process of AVG topical treatment. The granulation growth rate of NDC group was higher than those of DC group, AVG QD group, and AVG QOD group (all P<0.05). The wound healing rate of NDC group was higher than those of DC group, AVG QD group, and AVG QOD group (all P<0.05); the wound healing rate of AVG QOD group was higher than those of DC group and AVG QD group (all P<0.05). 2) Histopathology: The results of HE staining light microscopy showed that collagen fiber production increased, and that microvascular formation with slight inflammatory cell infiltration was observed in the dermal interstitium at the initial stage of wound healing after AVG treatment. One year of after complete healing, pathological examination results of wound healing skin showed that the epidermal keratinization was complete, that collagen was arranged neatly and orderly, and that many microvessels were found in the interstitium. The results of picric acid celestite scarlet staining showed that, after AVG treatment, type Ⅰ collagen mainly increased in the initial stage of wound healing, type Ⅲ collagen gradually increased when the wound healed completely, and the collagen was arranged neatly during the whole process. 3) The relative expression of microRNAs: The relative expression of miR21, miR126, and miR210 in NDC group, AVG QD group, and AVG QOD group were higher than that in DC group (all P<0.05). The relative expression of miR29a and miR155 in NDC group, AVG QD group, and AVG QOD group was lower than that in DC group (all P<0.05). The relative expression of miR146a in NDC group was higher than that in DC group ( P<0.05). Conclusion: AVG topical application can shorten the time needed for complete healing of diabetic chronic wounds in Bama minipigs. The wound healing speed of the alternate-day treatment group was faster than that of the daily treatment group. No adverse reactions were observed over the course of the treatment. The mechanism may be related to the up-regulation of the expressions of miR21, miR126, and miR210 and the down-regulation of miR29a and miR155 in wound granulation tissue.

Evaluation of the Clinical Efficacy of the Classic Prescription "Baihe Dihuang Decoction" Based on Meta-Analysis.

Purpose: To explore the clinical application of Baihe Dihuang Decoction. To provide certain data support and theoretical basis for the clinical application of Baihe Dihuang Decoction in the future. Methods: With "Baihe Rehmannia Tang" as the search term, the search was carried out on CNKI, VIP, Wanfang, PubMed and other databases. The statistical analysis of Baihe Dihuang decoction for treating diseases was obtained. Meta-analysis of the data was performed using RevMan 5.3 software to analyze the main therapeutic indicators of the disease. Results: According to the 83 valid literature that can be found, it is shown that 17 are used for the treatment of depression, 14 are used for the treatment of menopausal syndrome, 24 are used for the treatment of insomnia, and 28 are used for the treatment of other diseases. Conclusion: In the treatment of depression, menopausal syndrome, and insomnia combined with Baihe Dihuang Decoction can have a better therapeutic effect and diminish the incidence of adverse reactions. It provides a theoretical basis for the study and experimental study of its active components.

Extracellular Vesicles: The Next Generation Theranostic Nanomedicine for Inflammatory Bowel Disease.

The recent rapid development in the field of extracellular vesicles (EVs) based nanotechnology has provided unprecedented opportunities for nanomedicine platforms. As natural nanocarriers, EVs such as exosomes, exosome-like nanoparticles and outer membrane vesicles (OMVs), have unique structure/composition/morphology characteristics, and show excellent physical and chemical/biochemical properties, making them a new generation of theranostic nanomedicine. Here, we reviewed the characteristics of EVs from the perspective of their formation and biological function in inflammatory bowel disease (IBD). Moreover, EVs can crucially participate in the interaction and communication of intestinal epithelial cells (IECs)-immune cells-gut microbiota to regulate immune response, intestinal inflammation and intestinal homeostasis. Interestingly, based on current representative examples in the field of exosomes and exosome-like nanoparticles for IBD treatment, it is shown that plant, milk, and cells-derived exosomes and exosome-like nanoparticles can exert a therapeutic effect through their components, such as proteins, nucleic acid, and lipids. Moreover, several drug loading methods and target modification of exosomes are used to improve their therapeutic capability. We also discussed the application of exosomes and exosome-like nanoparticles in the treatment of IBD. In this review, we aim to better and more clearly clarify the underlying mechanisms of the EVs in the pathogenesis of IBD, and provide directions of exosomes and exosome-like nanoparticles mediated for IBD treatment.

Nanoparticles for oral delivery: targeted therapy for inflammatory bowel disease.

As a group of chronic and idiopathic gastrointestinal (GI) disorders, inflammatory bowel disease (IBD) is characterized by recurrent intestinal mucosal inflammation. Oral administration is critical for the treatment of IBD. Unfortunately, it is difficult to target the bowel located in the GI tract due to multiple physical barriers. The unique physicochemical properties of nanoparticle-based drug delivery systems (DDSs) and their enhanced permeability and retention effects in the inflamed bowel, render nanomedicines to be used to implement precise drug delivery at diseased sites in IBD therapy. In this review, we described the pathophysiological features of IBD, and designed strategies to exploit these features for intestinal targeting. In addition, we introduced the types of currently developed nano-targeted carriers, including synthetic nanoparticle-based and emerging naturally derived nanoparticles (e.g., extracellular vesicles and plant-derived nanoparticles). Moreover, recent developments in targeted oral nanoparticles for IBD therapy were also highlighted. Finally, we presented challenges associated with nanotechnology and potential directions for future IBD treatment.

Water vapour induced reversible switching between a 1-D coordination polymer and a 0-D aqua complex.

[Zn(3-tba)2], 1, a 1-D coordination polymer synthesised as 1 DMA, 1α, transformed to a nonporous form, 1ß, upon activation. 1ß underwent further transformation to the dimeric complex [Zn(3-tba)2(H2O)2], 2, above 40% RH. The reverse transformations, 2 to 1ß and 1ß to 1α, were accomplished by heating and exposure to DMA, respectively, and were single-crystal-to-single-crystal phase changes. Single crystal X-ray diffraction revealed that the second transformation resulted from Zn-carboxylate bond breakage and concomitant coordination of water molecules. Other solvent molecules did not induce a phase change.

Long-term low-dose exposure of permethrin induces liver and kidney damage in rats.

BACKGROUND: Permethrin is one of the pyrethroid insecticides, which is widely used in agriculture and public health. Although acute toxicity of the insecticide has been studied, the chronic toxicity upon the long-term exposure has not been clear yet. The purpose of the current study is to investigate the organ toxicities of permethrin following its long-term low-dose exposure. METHODS: Male Wistar rats were daily administrated orally with permethrin (75 mg/kg body weight/day, gavage) for 90 days, and then the samples of biofluids (blood and urine) and organs including liver and kidney were collected. The serum and urine samples were measured by biochemical assay and the tissues of kidney and liver were examined and analyzed by histopathological method. RESULTS: The results showed that no change was found in serum and urine biochemical parameters for the toxicity; however, significant changes including hyperchromatic nuclei swollen in the hepatic parenchymal cells and the swelling proximal tubules in the kidneys were observed in the tissue structures of liver and kidneys in the histopathological sections. CONCLUSION: These results indicate that low-dose long-term exposure of permethrin can cause chronic toxicity with slight liver and kidney damage.

Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC. METHODS: DNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model. RESULTS: Bioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4+T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4+CD8+T (DP CD4+CD8+T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model. CONCLUSIONS: Epigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4+T cells and repressed the differentiation of DP CD4+CD8+ T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.