Mouse Model Of Ulcerative Colitis Research Articles

7-hydroxycoumarin ameliorates ulcerative colitis in mice by inhibiting the MAPK pathway and alleviating gut microbiota dysbiosis.

This research aimed to delineate the pharmacological mechanisms of 7-Hydroxycoumarin (7-HC) on ulcerative colitis (UC) employing network pharmacology and experimental validation. To investigate the therapeutic effects of 7-HC on UC, a UC mouse model was established through the unrestricted intake of 3.0% dextran sulfate sodium (DSS) in their drinking water. Subsequently, we predicted the core targets and signaling pathways of 7-HC for the treatment of UC using the network pharmacology approach. Finally, the insights gained from network pharmacology were further validated by molecular docking, molecular dynamics simulation as well as in vivo experiments. Administering 7-HC orally to mice with UC led to a marked improvement in colitis indicators. Furthermore, 7-HC significantly lowered the levels of inflammatory cytokines (TNF-α, IL-1β) in the colon and modulated oxidative stress markers (MPO, SOD). Subsequent studies identified 2 core targets (AKT1 and EGFR) in the colon of UC mice that were inhibited by 7-HC. Network pharmacology and experimental validation showed that 7-HC can reduce the expression of MAPK pathway markers P38, JNK, ERK, and their phosphorylation; 7-HC can also ameliorate UC by regulating the gut microbiome. 7-HC demonstrates considerable efficacy in alleviating UC in mice, primarily through substantial diminution of tissue inflammation and oxidative stress. This is the first time that 7-HC has been found to treat UC by inhibiting the MAPK pathway and modulating the gut microbiota, providing a fresh perspective on the pharmacological mechanisms through which 7-HC operates in the management of UC.

Exploring the mechanism of Suxin Hugan Fang in treating ulcerative colitis based on network pharmacology

As a traditional Chinese medicine formula used in clinical practice for an extended period, Suxin-Hugan-Fang (SXHGF) exhibits excellent anti-inflammatory properties. However, the efficacy of SXHGF in treating ulcerative colitis (UC) and its mechanism of action are still unclear. In this study, the therapeutic effects of SXHGF on UC were evaluated using network pharmacology and experimental validation, while also investigating its mechanism of action. By administering DSS to C57BL/6 mice to construct a mouse model of ulcerative colitis, the therapeutic effect of SXHGF on ulcerative colitis was evaluated based on weight loss percentage, disease activity index, colon length changes, and pathological conditions as indicators. The main chemical components of SXHGF were determined by LC-MS-QTOF method. The potential targets and mechanisms of action of SXHGF in the treatment of UC were inferred using bioinformatics methods, and further validated through ELISA, IHC, and Western blotting assays. The experimental results demonstrate that SXHGF can suppress oxidative stress and oxidative damage in the colon tissue of UC mice, and alleviate DSS-induced ulcerative colitis by inhibiting the JAK2/STAT3 and NFκB pathways.

Clinical, pharmacology and in vivo studies of QingDai (indigo naturalis) promotes mucosal healing and symptom improvement in ulcerative colitis by regulating the AHR-Th17/Treg pathway.

Qingdai (QD), derived from various plant sources, is commonly used in traditional Chinese medicine for ulcerative colitis (UC) treatment. However, the clinical efficacy and mechanisms of orally administered QD remain unclear. This study aims to evaluate QD's efficacy in UC treatment and uncover its active components and mechanisms. A randomized controlled trial compared QD to Adisa, followed by UPLC-Q-TOF/MS and network pharmacology analyses to identify QD's core components and targets. In vivo experiments on a UC mouse model explored QD's impact on the AHR-Th17/Treg pathway using PCR, WB, ELISA, and flow cytometry. Results showed QD's efficacy in UC treatment, with mucosal healing and remission comparable to Adisa. UPLC-Q-TOF/MS identified 16 core components in mouse colon tissue, with network pharmacology revealing 67 targets, potentially involving the IL-17 signaling pathway and Th17 cell differentiation. QD and its components up-regulated AHR, CYP1A1, and Foxp3, while down-regulating RORγt. Additionally, QD modulated pro-inflammatory (IL-6, IL-17A) and anti-inflammatory (IL-10, TGF-β1) factors, and Treg/Th17 cell ratios in LPMC. Oral QD administration effectively promoted mucosal healing and improved UC symptoms, potentially through AHR-Th17/Treg pathway regulation.

Anti-inflammatory activity of Ziziphus jujuba hydroalcoholic extract in acetic acid-induced ulcerative colitis model.

Ulcerative colitis (UC) is a common gastrointestinal (GI) disorder characterized by chronic inflammation. Current treatments primarily focus on symptom management, but they have inherent limitations. Global attention is increasingly directed towards exploring herbal remedies as complementary approaches. This study aims to investigate the effects of the hydroalcoholic extract of jujuba on an experimental model of ulcerative colitis. In this study, 15 male BALB/c mice were divided into three experimental groups. The first group served as the untreated UC model, acting as the positive control (PC). The second group received treatment with the hydroalcoholic extract of Ziziphus jujuba, while the third group was treated with mesalamine. UC was induced by injecting 100 μL of 4 % acetic acid (AA) intra-rectally several times. Treatment commenced after the onset of symptoms such as diarrhea and bloody stools. The mice were eventually euthanized ethically, and their spleen and intestinal tissues were collected for analysis. Evaluations included the Disease Activity Index (DAI), myeloperoxidase activity (MPO), nitric oxide (NO) levels, cytokine levels (IL-1β, IL-6, TNF-α), and gene expression (iNOS, COX-2, and cytokines). The hydroalcoholic extract of the jujuba plant significantly reduced MPO, NO, the DAI, and the production and expression of inflammatory cytokines, as well as the genes iNOS and COX-2, in the group receiving this extract compared to the positive control group (p<0.05). The study demonstrates that the hydroalcoholic extract of Ziziphus jujuba significantly reduces inflammation markers such as TNF-α, NO, MPO, IL-1β, and IL-6 in a mouse model of ulcerative colitis. Additionally, itdownregulates the expression of pro-inflammatory genes, including iNOS and COX-2. These findings suggest that Z.jujuba extract has potential as an effective anti-inflammatory treatment for managing ulcerative colitis symptoms.

Luteolin ameliorates ulcerative colitis in mice via reducing the depletion of NCR+ILC3 through Notch signaling pathway

The disorder of group 3 innate lymphoid cells (ILC3) subgroup, such as the predominance of NCR-ILC3 but the depletion of NCR+ILC3, is unfavorable to damaged intestinal barrier repair, which leads to the prolongations and obstinacy of ulcerative colitis (UC). Our previous studies had shown that luteolin promoted NCR−ILC3 differentitating into NCR+ILC3 to improving the depletion of NCR+ILC3 in UC mice, while the mechanism is unclear. This article aimed to explore the underlying mechanism of luteolin enhancing the proportion NCR+ILC3. UC mice model was established with 2% DSS and Notch signaling was blocked, then luteolin was used to intervene. The results showed that the effect of luteolin on ameliorating disease symptoms in UC mice, including inhibiting the weight loss, reducing the pathological damage of colon mucosa, etc., was diminished with blocking Notch signaling pathway. In addition, luteolin increased the proportion of NCR+ILC3, NCR+MNK3 and IL-22+ILC3, decreased intestinal permeability, promoted mucin secretion, and promoted ZO-1 and Occludin expression, the above effect of luteolin was neutralized by Notch inhibitor LY-411575. Luteolin activated the abnormally blocked Notch signaling pathway in UC mice. And molecular docking predicted the affinity of luteolin for RBPJ to be −7.5 kcal·mol−1 in mouse, respectively; the affinity of luteolin for Notch1 and RBPJ was respectively scored to be −6.4 kcal·mol−1 and −7.7 kcal·mol−1 homo sapiens. These results proved that luteolin is positive for enhancing the proportion of NCR+ILC3 via Notch signaling, and it provides a basis for targeting NCR+ILC3 for restoring intestinal barrier function to alleviating ulcerative colitis.

Acceptable daily intake of aspartame aggravates enteritis pathology and systemic inflammation in colitis mouse model.

In this study, a dextran sodium sulfate-induced ulcerative colitis model in C57BL/6 mice was used to explore the effect of acceptable daily intake (ADI) of aspartame on inflammation in colonic tissues. The effects of aspartame on the inflammatory state of the colon in mice were comprehensively evaluated by comparing the body weight, colon length/colon length index, splenic index, disease activity index (DAI) score, histological activity index (HAI) score, the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, claudin-3, and occludin, the infiltration characteristics of macrophage and neutrophil and the composition of the gut microbiota in the control group, aspartame group, ulcerative colitis model group, and aspartame + ulcerative colitis group. We demonstrated that, in a mouse model of dextran sulfate-induced ulcerative colitis, ADI of aspartame caused a significant decrease in body weight, colon length/colon length index, DAI scores, and expression levels of the proteins claudin-3 and occludin. Moreover, ADI of aspartame caused an increase in the splenic index, HAI scores, the levels of proinflammatory factors TNF-α, IL-1β, and IL-6 both in intestinal tissue and serum and infiltration of macrophages and neutrophils in colon tissues. These results showed that ADI of aspartame promoted intestinal pathology and systemic inflammation in a mouse model of colitis.

Anti-inflammatory effects of para-quinone methide derivatives on ulcerative colitis.

A series of para-quinone methide derivatives were evaluated their anti-inflammatory activity. Through the screening of the lipopolysaccharide (LPS)-induced inflammatory cell model in Raw264.7 cells, it was found that the inhibitory activity of meta-substituted derivatives on NO production was superior to that of ortho- and para-substituted derivatives. Among them, in the inflammatory cell model, the meta-trifluoromethyl substituted para-quinone methide derivative 1i had the best activity in inhibiting LPS-induced excess generation of NO. And 1i could effectively inhibit the increase of ROS in inflammatory cells, the expression of iNOS related to the production of NO, and the expressions of inflammation related initiating protein TLR4, pro-inflammatory cytokines IL-6 and TNF-α, inflammasome NLRP3 and Caspase1. In the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model, the active derivative 1i could inhibit DSS-induced colon shortening, and reverse DSS-induced pathological changes in colon tissue, such as inflammatory infiltration, structural destruction and crypt disappearance. 1i could effectively inhibit oxidative stress, inflammation and apoptosis in UC mice. Moreover, through the determination of serum biochemical indicators, tissue pathologies and tissue organ indexes, 1i could effectively reverse the damage to mouse liver and kidney caused by DSS, playing a protective role in liver and kidney of mice. In summary, 1i was an effective anti-inflammatory reagent and could be developed as a potential drug for anti-UC.

Protective effect of a cocktail of lactic acid bacteria on DSS-induced ulcerative colitis via activating the TGR5/PKA pathway

Ulcerative colitis (UC), a persistent intestinal disorder, is now considered a global disease. The present study was designed to investigate the alleviative effects of a cocktail of lactic acid bacteria (CLAB; Lactobacillus rhamnosus MP108, L. paracasei CCFM2711, Bifidobacterium animalis BB-115, and B. longum BLI-02) on UC and its mechanisms through a UC mouse model triggered by dextran sulfate sodium (DSS). The results indicated that CLAB improved colitis symptoms, intestinal pathologic damage, and intestinal barrier in mice. Moreover, CLAB attenuated colonic inflammatory responses in mice by remodeling the homeostasis between pro-inflammatory and anti-inflammatory cytokines. In addition, CLAB improved the structure of the gut microbiota and augmented the proportion of secondary bile acid-producing bacteria. Untargeted metabolomics analysis revealed that CLAB altered the metabolic profile of colonic contents and, importantly, increased the content of lithocholic acid (LCA). Further, CLAB activated the TGR5/PKA pathway via significantly upregulating the protein expression of TGR5, PKA, and p-CREB. Thus, CLAB alleviated UC, probably by increasing secondary bile acid-producing bacteria, resulting in increased levels of LCA, which in turn activated the TGR5/PKA pathway, thereby reducing the inflammatory response. The present study will offer a theoretical foundation for developing probiotic products to mitigate UC.

Layer by layer self-assembled hyaluronic acid nanoarmor for the treatment of ulcerative colitis

Natural compound-based treatments provide innovative ways for ulcerative colitis therapy. However, poor targeting and rapid degradation curtail its application, which needs to be addressed. Inspired by biomacromolecule-based materials, we have developed an orally administrated nanoparticle (GBP@HA NPs) using bovine serum albumin as a carrier for polyphenol delivery. The system synergizes galactosylated bovine serum albumin with two polyphenols, epigallocatechin gallate and tannic acid, which is then encased in “nanoarmor” of ε-Polylysine and hyaluronic acid to boost its stability and targeting. Remarkably, the nanoarmor demonstrated profound therapeutic effects in both acute and chronic mouse models of ulcerative colitis, mitigating disease symptoms via multiple mechanisms, regulating inflammation related factors and exerting a modulatory impact on gut microbiota. Further mechanistic investigations indicate that GBP@HA NPs may act through several pathways, including modulation of Keap1-Nrf2 and NF-κB signaling, as well as Caspase-1-dependent pyroptosis. Consequently, this novel armored nanotherapy promotes the way for enhanced polyphenol utilization in ulcerative colitis treatment research.

Agmatine attenuates the severity of immunometabolic disorders by suppressing macrophage polarization: an in vivo study using an ulcerative colitis mouse model

Agmatine, an endogenous polyamine generated by the gut microbiota, positively affects host lifespan by regulating mononuclear cell or macrophage function. Although the regulatory pathways governing monocyte/macrophage differentiation have been well studied, the influence of the microbiome and its metabolites on monocyte/macrophage function have not been fully elucidated. To address this, we aimed to investigate the mechanisms whereby agmatine inhibits immunometabolic disorders using the colon of ulcerative colitis (UC) model mice. Agmatine (10 mM) attenuated pathological damage to colonic tissue and significantly improved the survival rate of UC model mice. In particular, treatment of UC model mice with 0.4, 2, and 10 mM agmatine resulted in mortality rates of 70 %, 20 %, 10 %, and 0 %, respectively. In a macrophage-depletion model, agmatine regulated the inflammatory microenvironment by affecting macrophages: it reduced the proportion of M1 macrophages and increased that of M2 macrophages in UC model mice. In cultured macrophages, agmatine inhibited lipopolysaccharide-induced inflammatory cytokine and NO secretion, as detected by enzyme-linked immunosorbent assay and the Griess assay, respectively. Agmatine partially reduced inflammatory factor production by inhibiting histone deacetylase, as detected by fluorometric assay. These findings provide evidence that agmatine efficiently suppresses macrophage polarization in UC mice, highlighting its potential as an anti-inflammatory agent against UC.

Non-targeted metabolomics and pseudo-targeted lipidomics combined with gut microbes reveal the protective effects of Causonis japonica (Thunb.) Raf. in ulcerative colitis mice.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent inflammatory tissue damage to the intestinal mucosa and forming intestinal epithelial ulcers. It is one of the most intractable diseases in the world. To date, the mechanism is unclear. Causonis japonica (Thunb.) Raf. (Wu Lianmei in Chinese; WLM), a traditional Chinese medicine, which has a long history as an anti-inflammatory, but its effect on UC was unconfirmed yet. Therefore, we established a dextran sodium sulfate (DSS)-induced UC mice model and evaluated the therapeutic effect of WLM extract. The results indicated that WLM inhibits DSS-induced inflammatory response in colitis in vivo, decrease DSS-induced clinical manifestations, reverses colon length shortening, and reduces tissue damage. The results of ELISA kits suggested that WLM could reverse the levels of DSS-induced inflammatory factors. To explore the mechanism of WLM in treating DSS-induced UC, 1H NMR and UHPLC-Q/Orbitrap MS were used to perform non-targeted metabolomics analysis; 21 differential metabolites in colon tissues were closely related to UC. Meanwhile, the pseudo-targeted lipidomics based on UHPLC-Q/Trap MS was used to analyze lipid metabolism disorders, and 60 differential lipid compounds were screened. These differential compounds were mainly involved in glycerophospholipid, arachidonic acid, glycerolipid, citric acid, tyrosine, and ether lipid metabolisms. The analysis of gut microbial showed that WLM may improve the symptoms of UC mice by reducing the abundance of Helicobacter and Streptococcus and increasing the abundance of Limosilactobacillus and Akkermansia. Moreover, the real-time qPCR results showed that WLM extract could decrease the mRNA levels of inflammatory factors and may be associated with protecting the integrity of intestinal mucosal barrier by destroying in vivo metabolic pathways, especially by regulating energy and lipid metabolisms and reducing inflammatory reactions. It provides a beneficial reference for studying WLM to elucidate the therapeutic mechanism of UC.

Multifunctional MnGA Nanozymes for the Treatment of Ulcerative Colitis by Reducing Intestinal Inflammation and Regulating the Intestinal Flora.

In ulcerative colitis (UC), the formation of an inflammatory environment is due to the combined effects of excess production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), overproduction of proinflammatory cytokines, and disruption of immune system function. There are many kinds of traditional drugs for the clinical treatment of UC, but long-term drug use can cause toxic side effects and drug resistance and can also reduce patient compliance and other drawbacks. Hence, in light of the clinical challenges associated with UC, including the limitations of existing treatments, intense adverse reactions and the development of resistance to medications, no novel therapeutic agents that offer effective relief and maintain a high level of biosafety are urgently needed. Although many anti-inflammatory nanomedicines have been developed by researchers, the development of efficient and nontoxic nanomedicines is still a major challenge in clinical medicine. Using the natural product gallic acid and the metal compound manganese chloride, a highly effective and nontoxic multifunctional nanoenzyme was developed for the treatment of UC. Nanozymes can effectively eliminate ROS and RNS to reduce the inflammation of intestinal epithelial cells caused by oxidation, facilitate the restoration of the intestinal epithelial barrier through the upregulation of tight junction protein expression, and balance the intestinal microbiota to maintain the stability of the intestinal environment. Using a rodent model designed to mimic UC, we monitored body weight, colon length, the spleen index, and the degree of tissue damage and demonstrated that manganese gallate (MnGA) nanoparticles can reduce intestinal inflammation by clearing ROS and active nitrogen. Intestinal flora sequencing revealed that MnGA nanoparticles could regulate the intestinal flora, promote the growth of beneficial bacteria and decrease the levels of detrimental bacteria within the intestinal tract in a mouse model of UC. Thus, MnGA nanoparticles can maintain the balance of the intestinal flora. This study demonstrated that MnGA nanoparticles are excellent antioxidant and effective anti-inflammatory agents, have good biosafety, and can effectively treat UC.

Effect of dalargin on the content of goblet cells and mucins in the colonic mucosa in experimental ulcerative colitis

Aim. To investigate the protective effect of dalargin on the content of goblet cells and mucins in the colonic mucosa in a mouse model of ulcerative colitis.Materials and methods. Ulcerative colitis was simulated in Balb/C mice by replacing drinking water with 5% sodium dextran sulfate in boiled water for 5 days. Dalargin was administered subcutaneously in a volume of 0.1 ml at a dose of 100 μg / kg of body weight once a day for 7 days from the beginning of ulcerative colitis simulation. Sulfasalazine as a reference-listed drug was administered intragastrically at a dose of 200 mg / kg once a day for 7 days. The mice were sacrificed on day 5, 7, and 28. The sections of the distal colon were prepared and stained with hematoxylin and eosin, alcian blue (pH = 1.0) according to Mowry or by PAS reaction. In the sections, the number of goblet cells and acid and neutral mucins was determined.Results. In the mouse model of ulcerative colitis, the number of goblet cells (mainly at the bottom of the crypts), acid and neutral mucins decreased. Dalargin administration increased the number of goblet cells and the content of acid and neutral mucins in the colonic mucosa more effectively than sulfasalazine.Conclusion. Dalargin has a protective effect in ulcerative colitis.

Pharmacodynamic and pharmacokinetic study of Shaoyao Gancao decoction for repairing intestinal barrier damage in ulcerative colitis

ObjectiveTo study the therapeutic effect and mechanism of Shaoyao Gancao Decoction (SGD) on ulcerative colitis (UC) mice based on the perspective of intestinal barrier, and this study provides a new consultation for the clinical application of SGD. MethodsThe chemical composition of SGD was characterized by HPLC. The UC mouse model was constructed by 3 % dextran sodium sulfate (DSS), which were randomly divided into the model group (DSS), the positive drug group (5-ASA), the Shaoyao group (SYD), Gancao group (GCD), and the Shaoyao Gancao Decoction group (SGD) at low, medium, and high dosages, respectively. The effects of each drug treatment group on UC were evaluated by the rate of body weight loss, disease activity index (DAI), colon length, spleen index, histopathological evaluations, and the levels of serum inflammatory factors (IL-1β, IL-6, IL-10, IL-21, and TNF-α). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining, ELISA was used to detect the content of LPS in serum, and Western blot was used to detect the changes in the expression of tight junction proteins ZO-1, occludin, and the pathway proteins TLR4 and NF-κBp65 in the colonic tissues, to explore the protective effect of SGD on the intestinal barrier of UC mice. The vivo absorption process of the main active ingredients in the SG, SY and GC groups was determined by LC-MS. ResultsThe contents of albiflorin, paeoniflorin, liquiritin apioside, liquiritin and glycyrrhetinic acid were 6.1227 mg/g, 20.8993 mg/g, 4.0054 mg/g, 3.6140 mg/g and 8.2515 mg/g, respectively. Compared with DSS group, SGD reduced weight loss(P<0.01) and DAI scores(P<0.05), prevented colon shortening(P<0.01), and ameliorated histopathological damage of the colon in UC mice(P<0.01). SGD also protected the intestinal barrier to alleviate UC by significantly reducing serum LPS and inflammatory factor levels, altering the number of goblet cells, promoting tight junction proteins (ZO-1 and occludin) and decreasing the expression of TLR4 and NF-κB in colonic tissues. Pharmacokinetic results showed that there was no significant difference in Cmax, AUC0-t (μg/L.h) and Tmax of albiflorin and paeoniflorin between the SY and SG groups, the Tmax was within 1 h; the AUC0-t (μg/L.h) of liquiritin and glycyrrhizic acid were about 1.6 and 1.9 times higher in the SG group compared to the GC group, respectively. The Cmax, Tmax and AUC0-t (μg/L.h) of glycyrrhizinic acid were significantly reduced to 0.73, 0.68 and 0.68 times of that of the GC group. ConclusionSGD may have a therapeutic effect on DSS-induced UC mice by repairing the damaged intestinal barrier through the TLR4/NF-κB pathway. The combination of Shaoyao and Gancao increased the absorption of liquiritin and glycyrrhizic acid in vivo. The combination of Shaoyao and Gancao could promote the absorption of Gancao, and that the pairing of the two herbs could have a synergistic effect.

Compound sophorae decoction mitigates DSS-induced ulcerative colitis by activating autophagy through PI3K-AKT pathway: A integrative research combining network pharmacology and in vivo animal model validation

Ethnopharmacological relevanceCompound sophora decoction (CSD), a widely used Chinese herbal formula, has been shown to effectively alleviate symptoms ulcerative colitis (UC), including of bloody diarrhea, tenesmus, abdominal pain, and fever. Despite its clinical use, the precise pharmacological mechanisms of CSD remain enigmatic.Aim of the study: This study aims to investigate the potential efficacy and underlying mechanisms of CSD in the treatment of UC by employing an integrative pharmacology-based approach, molecular docking analysis and experimental validation. Materials and methodsIn this study, an integrative pharmacology-based approach was employed to predict the primary pathway through which CSD treats UC. The mechanism of CSD was further validated using a DSS-induced UC mouse model. Disease severity was assessed by monitoring stool property, body weight, colon length, and colon histopathology. Colonic pathological changes were examined using hematoxylin and eosin (HE) staining. The concentration of cytokines was measured via ELISA, while key molecules in the PI3K-AKT pathway and autophagy-related markers were evaluated using Western blotting. Autophagy in intestinal epithelial cells was observed using electron microscopy. ResultsThe results demonstrated that CSD alleviated DSS-induced UC by inhibiting the activation of PI3K-AKT pathway, reducing the release of inflammatory cytokines, down-regulating oxidative mediators, and enhancing autophagy. Moreover, the protective effects of CSD were diminished by bpV, a PTEN inhibitor, further supporting the involvement of the PI3K-AKT pathway. ConclusionsThe underlying mechanism of CSD’s therapeutic effect on UC may involve significant attenuation of DSS-induced intestinal inflammation by promoting autophagy through the inhibition of PI3K-AKT pathway activation.

Targeted no-releasing L-arginine-induced hesperetin self-assembled nanoparticles for ulcerative colitis intervention

Overproduction of reactive oxygen species (ROS) plays a crucial role in initiating and advancing ulcerative colitis (UC), and the persistent cycle between ROS and inflammation accelerates disease development. Therefore, developing strategies that can effectively scavenge ROS and provide targeted intervention are crucial for the management of UC. In this study, we synthesized natural carrier-free nanoparticles (HST-Arg NPs) using the Mannich reaction and π-π stacking for the intervention of UC. HST-Arg NPs are an oral formulation that exhibit good antioxidant capabilities and gastrointestinal stability. Benefiting from the negatively charged characteristics, HST-Arg NPs can specifically accumulate in positively charged inflamed regions of the colon. Furthermore, in the oxidative microenvironment of colonic inflammation, HST-Arg NPs respond to ROS by releasing nitric oxide (NO). In mice model of UC induced by dextran sulfate sodium (DSS), HST-Arg NPs significantly mitigated colonic injury by modulating oxidative stress, lowering pro-inflammatory cytokines, and repairing intestinal barrier integrity. In summary, this convenient and targeted oral nanoparticle can effectively scavenge ROS at the site of inflammation and achieve gas intervention, offering robust theoretical support for the development of subsequent oral formulations in related inflammatory interventions. Statement of significanceNanotechnology has been extensively explored in the biomedical field, but the application of natural carrier-free nanotechnology in this area remains relatively rare. In this study, we developed a natural nanoparticle system based on hesperetin (HST), L-arginine (L-Arg), and vanillin (VA) to scavenge ROS and alleviate inflammation. In the context of ulcerative colitis (UC), the synthesized nanoparticles exhibited excellent intervention effects, effectively protecting the colon from damage. Consequently, these nanoparticles provide a promising and precise nutritional intervention strategy by addressing both oxidative stress and inflammatory pathways simultaneously, demonstrating significant potential for application.

Drug screening identifies pyrrolidinedithiocarbamate ammonium ameliorating DSS-induced mouse ulcerative colitis via suppressing Th17 differentiation

T helper 17 (Th17) cells play crucial roles in various autoimmune diseases, including ulcerative colitis (UC), which is characterized by widespread inflammation in the mucosa of the colon and rectum. To identify small-molecule compounds capable of inhibiting CD4+T-cell differentiation into Th17 cells, we established a screening system. Through drug screening, we found that pyrrolidinedithiocarbamate ammonium (PDTC) effectively inhibits Th17 differentiation. In a dextran sulfate sodium (DSS)-induced UC mouse model, administration of PDTC significantly ameliorated colitis. PDTC treatment decreased the production of proinflammatory mediators and inhibited the proportion of Th17 cells in colitis-afflicted mice by suppressing NF-κB activation. These findings showed that PDTC can alleviate colitis by inhibiting NF-κB activation. The therapeutic effects of PDTC observed in a mouse model of UC provided a rationale for its application in clinical settings.

Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen.

NLRP3, a crucial member of the NLRP family, plays a pivotal role in immune regulation and inflammatory modulation. Here, we report a potent and specific NLRP3 inhibitor Z48 obtained though docking-based virtual screening and structure-activity relationship studies with an IC50 of 0.26 μM in THP-1 cells and 0.21 μM in mouse bone marrow-derived macrophages. Mechanistic studies indicated that Z48 could bind directly to the NLRP3 protein (KD = 1.05 μM), effectively blocking the assembly and activation of the NLRP3 inflammasome, consequently manifesting anti-inflammatory properties. Crucially, with acceptable mouse pharmacokinetic profiles, Z48 demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, while displaying no significant therapeutic impact on NLRP3KO mice. In conclusion, this study provided a promising NLRP3 inflammasome inhibitor with novel molecular scaffold, poised for further development as a therapeutic candidate in the treatment of inflammatory bowel disease.

Magnolol-loaded polydopamine-chitosan coated pH-responsive nanoparticles for alleviation of ulcerative colitis

This study designed and developed a novel three-layer electrostatic, slow-releasing nanoparticle drug delivery system for the treatment of ulcerative colitis. The nanoparticles were composed of layers of zein-based polydopamine, chitosan and cellulose acetate phthalate to form a polyelectrolyte multilayer core−shell nanoparticle structure. The anti-inflammatory natural product magnolol was chosen to be the model drug for the study. The nanoparticles (260.50 ± 23.90 nm) were prepared with layer-by-layer coating and then assessed in vitro and in vivo using a mouse model of ulcerative colitis. The in vitro data confirmed the slow-releasing and pH-dependent characteristics of particles. Quantitative analysis of the in vivo distribution of Mag in mice showed significantly higher concentrations in colonic tissue than in the upper gastrointestinal tract (854.6 ng/g vs 291.5–351.1 ng/g, respectively). Histological and pro-inflammatory cytokine analysis indicated that the nanoparticles had a significant anti-inflammatory effect and were protective against DSS-induced structural damage of the colonic mucosal structure. These results confirm that this nano-delivery system could increase the levels of Mag reaching the colon, resulting in greater efficacy than free Mag in treating UC in this mouse model.

Ginsenoside Rh2 suppresses ferroptosis in ulcerative colitis by targeting specific protein 1 by upregulating microRNA-125a-5p

BackgroundWorldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC.MethodsA DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance.ResultsDSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05).ConclusionsRh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.Graphical