Ulcerative colitis (UC), a chronic inflammatory bowel disease, is driven by dysregulated immune responses and persistent intestinal inflammation. Pyroptosis, a caspase/gasdermin-mediated inflammatory cell death that exacerbates mucosal damage through excessive cytokine release and epithelial barrier disruption. Although pyroptosis is considered to be a key mechanism in the pathogenesis of UC, the systematic assessment of the role of natural products in targeting the pyroptosis pathway remains a critical research gap. The purpose of this review is to investigate the regulatory effects of natural products on pyroptosis in UC and elucidate the mechanisms of action and potential therapeutic effects. Key findings highlight polyphenols (e.g., resveratrol), flavonoids (e.g., Quercetin), and terpenoids as promising agents that inhibit NLRP3 inflammasome activation, suppress gasdermin D cleavage, and restore barrier integrity, thereby reducing pro-inflammatory cytokine release in preclinical UC models. Current evidence shows enhanced efficacy and safety when these compounds are combined with standard therapies, but clinical translation requires overcoming three key barriers: limited human trial data, uncharacterized polypharmacology, and suboptimal pharmacokinetics needing formulation refinement. Future research should prioritize standardized animal-to-human translational models, mechanistic studies on synergistic pathways, and rigorous clinical validation to harness the full potential of natural products in pyroptosis-targeted UC therapies.

Colitis, a chronic intestinal disorder that causes inflammation of the colonic mucosa, has been linked with structural brain abnormalities. To combat intestinal inflammation, researchers have investigated how nutritional supplementation, such as butyric acid, may ameliorate untoward effects. By encapsulating and using conjugates of butyrate, such as butyrate glycerides (i.e., tributyrin), slower release to the lower portions of the gastrointestinal tract can be achieved. Additionally, butyrate supplementation has been linked with supporting brain function and regulating integrity.

In the present study, a total of 24 intact male pigs were artificially reared and randomly assigned to 1 of 3 treatment conditions: (1) a control milk replacer (CON), (2) control plus oral dextran sodium sulfate (DSS) to induce colitis, or (3) control supplemented with 9.0 mM of gamma-cyclodextrin encapsulated tributyrin (TBCD) plus oral DSS (TBCD+DSS). Pigs were orally administered DSS treatments daily from postnatal day (PND) 14-18. Continuous video recording began on PND 3 and ceased on PND 27 or 28, with videos processed and analyzed for home-cage tracking behavior. On PND 26 or 27, pigs underwent neuroimaging procedures to assess overall brain anatomy (MPRAGE), microstructure (DTI), and myelin (MWF).

Home-cage spatial preference was not altered prior to DSS dosing or during the overall study period. However, TBCD+DSS pigs spent less (p < 0.05) time within quadrant 4 when compared with CON pigs. Across almost all 29 brain regions assessed, absolute volumes were observed to be smaller in the TBCD+DSS group compared with CON and DSS groups. However, once individual volumes were assessed relative to the whole brain, most treatment effects dissipated other than for gray matter volume (p = 0.041). Diffusivity was found to be altered in several regions across treatment groups, thereby indicating differences in fiber organization. In areas like the hippocampus and thalamus, when fractional anisotropy (FA) values were highest for a given treatment, in the other diffusion metrics (mean, radial, axial diffusivity) values were lowest for that same treatment, indicating more organized cellular structure. Several other diffusion trends and differences were observed across various regions. Lastly, myelin water fraction (MWF) values were lowest in DSS-treated groups compared with CON (p < 0.05) for the whole brain and left/right cortices.

Overall, fiber organization and myelination were observed to be altered by experimentally induced colitis and contrary to expectations, tributyrin supplementation did not ameliorate these effects. Future work is warranted to investigate other protective nutritional mechanisms for colitis.

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract with limited treatment options. This study investigates the preventive effects of fermented Kamut wheat enzyme (FKW) diet on the progression of dextran sulfate sodium (DSS)-induced colitis in mice, with a focus on gut microbiota modulation and inflammatory cytokine regulation. Female C57BL/6J mice were divided into groups and fed a diet consisting of either a FKW diet (containing 39.80% FKW) or a control diet under 1.25% and 2.50% DSS conditions. The FKW diet was formulated based on the AIN-93G standard rodent formula, with the FKW diet providing comparable amounts of total proteins, crude lipids, and dietary fibers as the control diet. The FKW diet effectively mitigated the progression of colitis, as evidenced by improvements in key indicators such as dietary intake, body weight, colon length, stool consistency, and bleeding, particularly in the 1.25% DSS group. Histopathological analysis revealed preservation of colonic architecture and reduced mucosal damage in the FKW group. The diet also resulted in a significant reduction in pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and IFN-γ) and myeloperoxidase (MPO) levels, coupled with an increase in anti-inflammatory IL-10. Gut microbiota analysis showed increased abundance of beneficial bacteria such as Muribaculaceae, Lachnospiraceae NK4A136 and Bacteroides acidifaciens and decreased pathogenic bacteria like Escherichia/Shigella and Bilophila. These findings underscore the potential of FKW as a preventive dietary intervention for mitigating the progression of colitis, emphasizing the role of gut microbiota in supporting intestinal health. These results highlight FKW's potential to reduce the risk of colitis development, providing a foundation for future research into its preventive applications.

Flavonoid is a category of bioactive polyphenolic compounds that are extensively distributed in plants with specific pharmacological properties, such as anti-inflammatory and anti-oxidant. Importantly, natural flavonoids have shown the protected function on the dextran sulfate sodium (DSS)-induced colitis in animals and lipopolysaccharides (LPS)-induced inflammatory response in macrophages. The purpose of this systematic review is to explore the efficacy of natural flavonoids in animal models of IBD (inflammatory bowel disease) and potential mechanisms in macrophages by meta-analysis and network pharmacology in preclinical studies. Relevant foundation studies were searched from January 2010 to November 2023 in databases like PubMed, Elsevier ScienceDirect, and Web of Science. Then, OriginPro software was used to extract values from images, and the analysis was performed using Review Manager 5.3. The retrieved data was analyzed according to the fixed-effects model and random-effects model. Subsequently, heterogeneity was evaluated using the I2 statistics. Lastly, network pharmacology was applied to confirm mechanisms of natural flavonoids on IBD. According to the results of meta-analysis, we found the natural flavonoids exhibited powerful therapeutic effects against IBD, which not only reversed colonic shortness (WMD = 1.33, 95% CI (1.07, 1.59), P < 0.00001), but also reduced histological score (SMD =  - 2.66, 95% CI (- 3.77, - 1.95), P < 0.00001) between natural flavonoid treatment groups compared with the experimental IBD model. Furthermore, treatment with natural flavonoids decreased the levels of tumor necrosis factor-α (TNF-α) in macrophages. Mechanistically, our summarized data substantiate that natural flavonoids alleviate LPS-induced M1 macrophage polarization, anti-oxidant, anti-inflammatory, maintain intestinal barrier, and inhibit the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in macrophages. Moreover, the results of network pharmacology also support this. This systematic review demonstrated the efficiency of natural flavonoids in treating IBD in preclinical research by meta-analysis and network pharmacology, which offered supporting evidence for clinical trial implementation. However, some limitations remain present, such as technique quality shortage, missed reports on account of negative results, failure to count sample size, and the risk of bias.

Alteration of the gut microbiota and its metabolites plays a key role in the development of inflammatory bowel disease (IBD). Here, we investigated the mechanism of saponins, a byproduct from quinoa (SQ) processing, in regulating IBD. SQ ameliorated gut microbiota dysbiosis revealed by 16S rRNA sequencing and improved colonic antioxidant activities and barrier integrity in dextran sulfate sodium (DSS)-treated mice. Broad-spectrum antibiotics further proved that the gut-protective effects of SQ were mediated by gut microbiota. Next, fecal microbiota transplantation (FMT) of SQ-induced gut microbiota/metabolites to inoculate DSS-treated mice alleviated colitis significantly. Untargeted metabolomics and lipidomics revealed that ursodeoxycholic acid (UDCA) was enriched as a microbial metabolite after SQ supplementation. UDCA was then found to attenuate DSS-induced colitis in vivo by targeting the TLR4/NF-κB pathway, which was also verified in a Caco-2 cell model treated with a TLR4 agonist/antagonist. Overall, our findings established that gut microbiota-UDCA-TLR4/NF-κB signaling plays a key role in mediating the protective effects of SQ.

The involvement of mitochondrial and programmed cell death (mtPCD)-related genes in the pathogenesis of pre-eclampsia (PE) remains inadequately characterized.

This study explores the role of mtPCD genes in PE through bioinformatics and experimental approaches. Differentially expressed mtPCD genes were identified as potential biomarkers from the GSE10588 and GSE98224 datasets and subsequently validated. Hub genes were determined using support vector machine, least absolute shrinkage and selection operator, and Boruta based on consistent expression profiles. Their performance was assessed through nomogram and artificial neural network models. Biomarkers were subjected to localization, functional annotation, regulatory network analysis, and drug prediction. Clinical validation was conducted via real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and Western blot.

Four genes [solute carrier family 25 member 5 (SLC25A5), acyl-CoA synthetase family member 2 (ACSF2), mitochondrial fission factor (MFF), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)] were identified as biomarkers distinguishing PE from normal controls. Functional analysis indicated their involvement in various biological pathways. Immune analysis revealed associations between biomarkers and immune cell activity. A regulatory network was informed by biomarker expression and database predictions, in which KCNQ1OT1 modulates ACSF2 expression via hsa-miR-200b-3p. Drug predictions, including clodronic acid, were also proposed. Immunofluorescence, RT-qPCR, and Western blot confirmed reduced expression of SLC25A5, MFF, and PMAIP1 in PE, whereas ACSF2 was significantly upregulated.

These four mtPCD-related biomarkers may play a pivotal role in PE pathogenesis, offering new perspectives on the disease's diagnostic and mechanistic pathways.

Inflammatory, immune, and neurodegenerative diseases constitute a category of persistent and debilitating conditions affecting millions worldwide, with intertwined pathophysiological pathways. Recent research has spotlighted naturally occurring compounds like naringenin for potential therapeutic applications across multiple ailments.

This review offers an encompassing exploration of naringenin's anti-inflammatory, immune-protective, and neuroprotective mechanisms, elucidating its pharmacological targets, signal transduction pathways, safety profile, and insights from clinical investigations.

Data for this review were amassed through the scrutiny of various published studies via search engines such as PubMed and Google Scholar. Content from reputable publishers including Bentham Science, Taylor and Francis, Nature, PLOS ONE, among others, was referenced.

Naringenin exhibits substantial anti-inflammatory effects by restraining the NF-κB signaling pathway. It activates Nrf2, renowned for its anti-inflammatory properties, inducing the release of hemeoxynase-1 by macrophages. Furthermore, naringenin treatment downregulates the expression of Th1 cytokines and inflammatory mediators. It also impedes xanthine oxidase, counteracts reactive oxygen species (ROS), scavenges superoxide radicals, mitigates the accessibility of oxygen-induced K+ erythrocytes, and reduces lipid peroxidation. Naringenin's antioxidant prowess holds promise for addressing neurological conditions.

Extensive research has been undertaken to establish the anti-inflammatory, immunomodulatory, and neuroprotective attributes of naringenin across various medical domains, lending credence to its pharmacological utility. The principal obstacle to naringenin's adoption as a therapeutic agent remains the dearth of in vivo data. Efforts should focus on rendering naringenin delivery patient-friendly, economically viable, and technologically advanced.

Numerous studies have demonstrated a correlation between asthma and irritable bowel syndrome (IBS). The Chinese herbal compound Shaoyao Gancao Tang (SYGCT) has been found to have therapeutic effects on both asthma and IBS, but the underlying mechanisms are not yet fully understood. This study aims to explore the key components, key targets, and potential mechanisms of SYGCT in treating asthma with IBS by using network pharmacology, molecular docking techniques and molecular dynamics simulation.

The major chemical components and potential target genes of SYGCT were screened by bioinformatics. The key targets of Asthma-IBS comorbidity were identified based on network modules. The intersection of the drug targets and disease targets was identified as the potential targets of SYGCT in treating asthma-IBS. Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to identify the biological processes and signaling pathways involved in these potential targets. A protein-protein interaction network was constructed to identify hub targets, while a drug-compound-target topological network was built to screen key compounds. Molecular docking was used to verify the affinity between the hub targets and key compounds. Molecular dynamics analysis was utilized to assess the binding stability of these interactions.

Network pharmacology analysis revealed that the therapeutic effect of SYGCT on asthma-IBS involved multiple biological processes and signaling pathways. It may exert therapeutic effects primarily through signaling pathways such as IL-17, TNF, and Th17 cell differentiation. The possible targets of SYGCT in the treatment of asthma-IBS could be IL6, TNF, JUN, PTGS2, STAT3, IL1B, CASP3, NFKBIA, IL10, and PPARG. Molecular docking verification showed that the predicted targets had good binding affinity with the compounds, among which PTGS2, CASP3, and PPARG had higher binding energy. Molecular dynamics simulation revealed that PTGS2, CASP3, and PPARG proteins had good stability and high binding strength with the compounds 2-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenol and shinpterocarpin.

SYGCT plays a therapeutic role in asthma and IBS through multiple targets and pathways, providing a theoretical basis for explaining the mechanism and clinical application of SYGCT in treating different diseases with the same treatment in asthma and IBS.

NOD-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) implicated in the innate immune sensing of pathogens and damage signals. NLRs act as sensors in multi-protein complexes called inflammasomes. Inflammasome activity is necessary for the maintenance of intestinal homeostasis, although their aberrant activation contributes to the pathogenesis of several gastrointestinal diseases. In this review, we summarize the main features of the predominant types of inflammasomes involved in gastrointestinal immune responses and their implications in intestinal disease, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), celiac disease, and Colorectal Cancer (CRC). In addition, we report therapeutic discoveries that target the inflammasome pathway, highlighting promising novel therapeutic strategies in the treatment of intestinal diseases. Collectively, our understanding of the mechanisms of intestinal inflammasome activation and their interactions with other immune pathways appear to be not fully elucidated. Moreover, the clinical relevance of the efficacy of inflammasome inhibitors has not been evaluated. Despite these limitations, a greater understanding of the effectiveness, specificity, and reliability of pharmacological and natural inhibitors that target inflammasome components could be an opportunity to develop new therapeutic options for the treatment of intestinal disease.

Pyroptosis plays an important role in maintenance of intestinal homeostasis, the abnormal activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome can promote the event and development of ulcerative colitis (UC). Its protective effects such as inhibiting pyroptosis in various inflammation-related diseases have been demonstrated, but whether resveratrol (RES) can also alleviate the progression of the disease by inhibiting pyroptosis in UC and the mechanism have rarely been studied. In this study, lipopolysaccharide (LPS) combined with adenosine triphosphate (ATP) was used to induce HT29 human colon cancer cells to construct an intestinal epithelial cell pyroptosis and inflammation model in vitro to investigate the anti-inflammatory effect of RES, reveal the regulatory mechanism of RES on pyroptosis, and provide a new theoretical basis for the treatment of UC. In vitro experiences, HT29 cells were dividing into control group, LPS/ATP group, RES low-dose group, RES high-dose group, NF-κB inhibitor pyrrolidine dithiocarbamate group (PDTC group), and LPS/ATP+PDTC group. The mRNA expressions of pyroptosis-related indicators such as NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), Caspase-1(CASP1), IL-18, IL-1β, and inflammatory factors such as TNF-α and IL-6 were detected by qRT-PCR. The protein expressions of pyroptosis-related indicators NLRP3, ASC, CASP1, IL-18, IL-1β, NF-κB-p65 in the nucleus, and IκBα and p-IκBα in the cytoplasm were detected by Western blot. Immunofluorescence saw the distribution and expression of NLRP3, ASC and NF-κB-p65 protein in each group. The morphology and degree of pyroptosis in each group were observed by transmission electron microscope. The results showed that compared with the control group, the pyroptosis-related proteins including NLRP3, ASC, CASP1, IL-18, IL-1β, and inflammatory factors including TNF-α and IL-6 in the LPS/ATP group were increased, and LPS/ATP activated the activity of NF-κB signaling pathway. Compared with the LPS/ATP group, RES downregulated the expression of pyroptosis-related proteins and inflammatory factors in HT29 cells, and inhibited the activation of the NF-κB signaling pathway in HT29 cells pyroptosis. RES down-regulates the pyroptosis of HT29 cells induced by LPS/ATP and the expression of pyroptosis-related indicators NLRP3, ASC, CASP1, IL-18, IL-1β and inflammatory factors TNF-α and IL-6 in the inflammatory response and inhibits the occurrence of pyroptosis. The mechanism is related to the inhibition of NF-κB pathway activity.

Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the digestive tract, whose exact cause remains unknown, and its prevalence is on the rise. This study investigated the effects of a walnut-derived peptide LPLLR (LP-5) on intestinal inflammation and metabolism in IBD mice. Metabolomics revealed that LP-5 regulated the levels of metabolites, such as thalsimidine, fumagillin, and geniposide, and LP-5 could regulate several signaling pathways, such as protein digestion and absorption, aminoacyl-tRNA biosynthesis, and ABC transporters. Additionally, LP-5 alleviated dextran sulfate sodium (DSS)-induced colitis by modulating autophagy and inflammasome pathways. Western blotting demonstrated that LP-5 reduced the expressions of NLRP3, Caspase-1, ASC and IL-1β, and increased the expressions of Beclin-1 and LC3-II/LC3-I, corresponding to activation of the AMPK/mTOR/ULK1 pathway. These findings suggested that LP-5 activated autophagy in vivo to suppress inflammation and modulate metabolic substances, highlighting potential implications for gut health and the development of functional foods containing LP-5.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease (CD), without specific antifibrotic drugs, which usually relies on surgical intervention. The transcription factor XBP1, a key component of endoplasmic reticulum (ER) stress, is required for degranulation of mast cells and linked to PAR2 activation and fibrosis. Many studies have confirmed that naringin (NAR) can inhibit ER stress and reduce organ fibrosis. We hypothesized that ER stress activated the PAR2-induced epithelial-mesenchymal transition process by stimulating mast cell degranulation to release tryptase and led to intestinal fibrosis in CD patients; NAR might play an antifibrotic role by inhibiting ER stress-induced PAR2 activation. We report that the expression levels of XBP1, mast cell tryptase, and PAR2 are upregulated in fibrotic strictures of CD patients. Molecular docking simulates the interaction of NAR and spliced XBP1. ER stress stimulates degranulation of mast cells to secrete tryptase, activates PAR2-induced epithelial-mesenchymal transition process, and promotes intestinal fibrosis in vitro and vivo experiments, which is inhibited by NAR. Moreover, F2rl1 (the coding gene of PAR2) deletion in intestinal epithelial cells decreases the antifibrotic effect of NAR. Hence, the ER stress-mast cell tryptase-PAR2 axis can promote intestinal fibrosis, and NAR administration can alleviate intestinal fibrosis by inhibiting ER stress-induced PAR2 activation.

The degradation of the cartilage endplate (CEP) plays a critical role in the initiation and progression of intervertebral disc degeneration (IVDD), a disease closely associated with inflammation and oxidative stress. Naringin (NGN), a flavonoid compound derived from citrus fruits, has been shown to exhibit significant anti-inflammatory and antioxidant properties. This suggests a promising avenue for NGN's application in IVDD therapy. This study aims to elucidate the therapeutic effects and underlying mechanisms of NGN on CEP degeneration, contributing to the formulation of evidence-based treatment strategies for IVDD.

In vivo, we developed an intervertebral disc degeneration (IVDD) model in mice by excising the bilateral facet joints and surrounding ligaments, and evaluated the effects of naringin using HE staining and Micro-CT analysis. In vitro, endplate chondrocytes were isolated and subjected to TBHP to replicate the IVDD pathological condition. The protective effects of NGN on these cells were confirmed through immunofluorescence, Western Blot, and flow cytometry.

In vivo, NGN effectively mitigated IVDD progression and CEP calcification in mice. In vitro, NGN enhanced mitophagy and suppressed NLRP3 inflammasome activation through the SIRT3/FOXO3a/Parkin pathway. Furthermore, NGN safeguarded chondrocytes against apoptosis and calcification triggered by oxidative stress, in addition to mitigating the degradation of the extracellular matrix. However, silencing SIRT3 negated NGN's protective influence on chondrocytes.

Our study demonstrated that NGN effectively shields chondrocytes from apoptosis and NLRP3 inflammasome activation by facilitating SIRT3-mediated mitophagy. These insights could pave the way for innovative approaches in the prevention and management of IVDD.

An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.

Qin-Yu-Qing-Chang decoction (QYQC), an herbal formula from China, is extensively employed to manage ulcerative colitis (UC) and exhibits potential benefits for colonic function. Nevertheless, the fundamental molecular mechanisms of QYQC remain largely uncharted.

The primary constituents of QYQC were determined utilizing UHPLC-MS/MS analysis and the effectiveness of QYQC was assessed in a mouse model of colitis induced by dextran sulfate sodium. Evaluations of colon inflammatory responses and mucosal barrier function were thoroughly assessed. RNA sequencing, molecular docking, colonic energy metabolism, and 16S rRNA sequencing analysis were applied to uncover the complex mechanisms of QYQC in treating UC. Detect the signal transduction of the peroxisome proliferator-activated receptor-γ (PPAR-γ) both in the nucleus and cytoplasm. Furthermore, a PPAR-γ antagonist was strategically utilized to confirm the functional targets that QYQC exerts.

Utilizing UHPLC-MS/MS, the principal constituents of the nine traditional Chinese medicinal herbs comprising QYQC were systematically identified. QYQC treatment substantially ameliorated colitis in mice, as evidenced by the improvement in symptoms and the reduction in colonic pathological injuries. Besides, QYQC treatment mitigated the inflammatory response and improved mucosal barrier function. Furthermore, QYQC enhanced the mitochondria citrate cycle (TCA cycle) by triggering PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus. This prevented the unconstrained expansion of facultative anaerobes, particularly pathogenic Escherichia coli (E. coli, family Enterobacteriaceae) and thus improved colitis. Results of molecular docking indicated that the representative chemical components of QYQC including Baicalin, Paeoniflorin, Mollugin, and Imperatorin bound well with PPAR-γ. The impact of QYQC on colitis was diminished in the presence of a PPAR-γ antagonist.

In summary, QYQC ameliorates UC by activating PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus, which enhances the energy metabolism of intestinal epithelial cells and thereby preventing the uncontrolled proliferation of facultative anaerobes.

Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD.

This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment.

This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed.

This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges.

This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD.

Background: Endometritis seriously affects maternal reproductive health and fertility. Natural compounds have the characteristics of high efficiency and low residue in disease treatment. We aimed to discover and reveal the pharmacological effects of naringin, which is widely present in food and plants, on endometritis. Methods: Based on network pharmacology, the potential targets and pathways of naringin's actions on endometritis were predicted. Animal in vivo experiments were conducted to examine the inflammatory response of lipopolysaccharides (LPSs) in uterine tissue and the therapeutic effect of naringin. An in vitro primary bovine endometrial epithelial cell inflammation and drug treatment model was constructed. The production of reactive oxygen species (ROS) was measured using DCFH-DA, and the effect of naringin on LPS-induced endometritis was evaluated using HE staining, real-time quantitative PCR, Western blot, and immunofluorescence staining methods. Results: Naringin alleviated LPS-induced inflammatory injury and oxidative stress in the endometrium of mice and bovine endometrial epithelial cells (bEECs). Furthermore, in vitro studies were carried out to reveal the potential anti-inflammatory mechanisms of naringin based on network pharmacology. We found that naringin significantly inhibited LPS-stimulated endoplasmic reticulum stress (ERS)-related gene and protein expression, thus reducing the unfolded protein response (UPR). Furthermore, treatment of naringin attenuated the autophagic flux induced by ERS. In a further study, we observed that PI3K/AKT pathway inhibitors or ERS inducers partially reverse naringin's inhibition of autophagy and cell apoptosis. Conclusion: It is demonstrated that naringin suppresses autophagy by directly inhibiting the ERS-PI3K/AKT axis and exerting anti-inflammatory and antioxidant effects in endometritis. These findings provide novel insights into the pathogenesis of endometritis, highlighting potential therapeutic targets of traditional herbs and compounds.

Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease, and UC diagnosis rates continue to rise throughout the globe. The research and development of new drugs for the treatment of UC are urgent, and natural compounds are an important source. However, there is a lack of systematic summarization of natural compounds and their mechanisms for the treatment of UC.

We reviewed the literature in the databases below from their inception until July 2023: Web of Science, PubMed, China National Knowledge Infrastructure, and Wanfang Data, to obtain information on the relationship between natural compounds and UC.

The results showed that 279 natural compounds treat UC through four main mechanisms, including regulating gut microbiota and metabolites (Mechanism I), protecting the intestinal mucosal barrier (Mechanism II), regulating intestinal mucosal immune response (Mechanism III), as well as regulating other mechanisms (Mechanism Ⅳ) such as cellular autophagy modulation and ferroptosis inhibition. Of these, Mechanism III is regulated by all natural compounds. The 279 natural compounds, including 62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others, can effectively ameliorate UC. Of these, terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC. It is noteworthy to highlight that a total of 54 natural compounds exhibit their therapeutic effects by modulating Mechanisms I, II, and III.

This review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC. Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future.

Gastric intestinal metaplasia (IM) is a precancerous lesion that is associated with an elevated risk of gastric carcinogenesis. Weiwei Decoction (WWD) is a promising traditional Chinese herbal formula widely employed in clinical for treating IM. Previous studies suggested the potential involvement of the olfactomedin 4 (OLFM4)/nucleotide-binding oligomerization domain 1 (NOD1)/caudal-type homeobox gene 2 (CDX2) signaling pathway in IM regulation.

To verify the regulation of the OLFM4/NOD1/CDX2 pathway in IM, specifically investigating WWD's effectiveness on IM through this pathway.

Immunohistochemistry for OLFM4, NOD1, and CDX2 was conducted on tissue microarray. GES-1 cells treated with chenodeoxycholic acid were utilized as IM cell models. OLFM4 short hairpin RNA (shRNA), NOD1 shRNA, and OLFM4 pcDNA were transfected to clarify the pathway regulatory relationships. Protein interactions were validated by co-immunoprecipitation. To explore WWD's pharmacological actions, IM rat models were induced using N-methyl-N'-nitro-N-nitrosoguanidine followed by WWD gavage. Gastric cells were treated with WWD-medicated serum. Cytokines and chemokines content were assessed by enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction.

The OLFM4/NOD1/CDX2 axis was a characteristic of IM. OLFM4 exhibited direct binding and subsequent down-regulation of NOD1, thereby sustaining the activation of CDX2 and promoting the progression of IM. WWD improved gastric mucosal histological lesions while suppressing intestinal markers KLF transcription factor 4, villin 1, and MUCIN 2 expression in IM rats. Regarding pharmacological actions, WWD suppressed OLFM4 and restored NOD1 expression, consequently reducing CDX2 at the mRNA and protein levels in IM rats. Parallel regulatory mechanisms were observed at the protein level in IM cells treated with WWD-medicated serum. Furthermore, WWD-medicated serum treatment strengthened OLFM4 and NOD1 interaction. In case of anti-inflammatory, WWD restrained interleukin (IL)-6, interferon-gamma, IL-17, macrophage chemoattractant protein-1, macrophage inflammatory protein 1 alpha content in IM rat serum. WWD-medicated serum inhibited tumor necrosis factor alpha, IL-6, IL-8 transcriptions in IM cells.

The OLFM4/NOD1/CDX2 pathway is involved in the regulation of IM. WWD exerts its therapeutic efficacy on IM through the pathway, additionally attenuating the inflammatory response.

Autoimmune hepatitis (AIH), primarily mediated by T cells, is characterized by liver inflammation. Despite the advancements in understanding its pathogenesis, effective therapeutic options are limited. Naringin, a flavonoid abundant in citrus fruits, is recognized for its anti-inflammatory properties and ability to protect against various inflammatory diseases, including drug-induced liver injury. However, the exact effects of naringin on AIH and the mechanisms involved remain poorly understood.

We aim to determine the role of naringin in AIH, exploring its targets and actions in this disease.

Network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the HUB targets connecting naringin, T cell-mediated autoimmune disorders, and AIH. Cellular thermal shift assays were used to determine the binding abilities of naringin with the HUB targets. An in vivo experiment confirmed the impact of naringin treatment on AIH development and underlying mechanisms.

Naringin demonstrated therapeutic effects on ConA-induced AIH. There were 455 shared targets between naringin, T cell-mediated autoimmune diseases, and AIH. Ten HUB genes (AKT1, ALB, IL-6, IL-1β, CTNNB1, TNF, TP53, MAPK3, VEGFA, and JUN) were identified through the PPI network. Gene ontology analysis revealed involvement in gene expression regulation, lipopolysaccharide-mediated signaling, and I-kappa kinase/NFκB signaling. Pathway analysis suggested TNF, Th1/Th2 cell differentiation, and Toll-like receptor pathways, with favorable naringin-HUB gene binding. Molecular docking confirmed albumin (ALB), IL-1β, IL-6, and TNF as primary targets for naringin. Molecular dynamics simulations showed stable binding in ALB-naringin, TNF-naringin, and IL-1β-naringin complexes. Naringin's hepatoprotective effect on AIH was supported by increased serum ALB and decreased hepatic inflammatory cytokines including IL-1β, IL-6, and TNF-α.

Our data underscore the potential of naringin as a preventive or therapeutical agent in T cell-mediated autoimmune diseases including AIH.

Callicarpa nudiflora Hook (C. nudiflora) is an anti-inflammatory, antimicrobial, antioxidant, and hemostatic ethnomedicine. To date, little has been reported regarding the activity of C. nudiflora against ulcerative colitis (UC). In this study, we investigated the effect of a flavonoid extract of C. nudiflora on Dextran Sulfate Sodium (DSS)-induced ulcerative colitis in mice. Mice in the treatment group (CNLF+DSS group) and drug-only (CNLF group) groups were administered 400 mg/kg of flavonoid extract of C. nudiflora leaf (CNLF), and drinking water containing 2.5 % DSS was given to the model and treatment groups. The symptoms of colitis were detected, relevant indicators were verified, intestinal barrier function was assessed, and the contents of the cecum were analyzed for intestinal microorganisms. The results showed that CNLF significantly alleviated the clinical symptoms and histological morphology of colitis in mice, inhibited the increase in pro-inflammatory factors (TNF-α, IL-6, IL-1β, and IFN-γ), and increased the level of IL-10. The expression of NF-κB and MAPK inflammatory signal pathway-related proteins (p-p65, p-p38, p-ERK, p-JNK) was regulated. The expression of tight junction proteins (ZO-1, OCLDN, and CLDN1) was increased, while the content of D-LA, DAO, and LPS was decreased. In addition, 16S rRNA sequencing showed that CNLF restored the gut microbial composition, and increased the relative abundance of Prevotellaceae, Intestinimonas butyriciproducens, and Barnesiella_intestinihominis. In conclusion, CNLF alleviated colitis by suppressing inflammation levels, improving intestinal barrier integrity, and modulating the intestinal microbiota, and therefore has promising future applications in the treatment of UC.

Dextran Sulfate Sodium (DSS) induces ulcerative colitis (UC), a type of inflammatory bowel disease (IBD) that leads to inflammation, swelling, and ulcers in the large intestine. The aim of this experimental study is to examine how sinomenine, a plant-derived alkaloid, can prevent or reduce the damage caused by DSS in the colon and rectum of rats.

Induction of ulcerative colitis (UC) in rats was achieved by orally administering a 2% Dextran Sulfate Sodium (DSS) solution, while the rats concurrently received oral administrations of sinomenine and sulfasalazine. The food, water intake was estimated. The body weight, disease activity index (DAI), colon length and spleen index estimated. Antioxidant, cytokines, inflammatory parameters and mRNA expression were estimated. The composition of gut microbiota was analyzed at both the phylum and genus levels in the fecal samples obtained from all groups of rats.

Sinomenine treatment enhanced the body weight, colon length and reduced the DAI, spleen index. Sinomenine treatment remarkably suppressed the level of NO, MPO, ICAM-1, and VCAM-1 along with alteration of antioxidant parameters such as SOD, CAT, GPx, GR and MDA. Sinomenine treatment also decreased the cytokines like TNF-α, IL-1, IL-1β, IL-6, IL-10, IL-17, IL-18 in the serum and colon tissue; inflammatory parameters viz., PAF, COX-2, PGE2, iNOS, NF-κB; matrix metalloproteinases level such as MMP-1 and MMP-2. Sinomenine significantly (P < 0.001) enhanced the level of HO-1 and Nrf2. Sinomenine altered the mRNA expression of RIP1, RIP3, DRP3, NLRP3, IL-1β, caspase-1 and IL-18. Sinomenine remarkably altered the relative abundance of gut microbiota like firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia, and Actinobacteria.

The results clearly indicate that sinomenine demonstrated a protective effect against DSS-induced inflammation, potentially through the modulation of inflammatory pathways and gut microbiota.

Chichoric acid (CA) is a major active ingredient found in chicory and Echinacea. As a derivative of caffeic acid, it has various pharmacological effects.

Due to the unclear etiology and disease mechanisms, effective treatment methods for ulcerative colitis (UC) are currently lacking. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and dextran sulfate sodium (DSS)-induced mouse UC models.

Folate-chicory acid liposome was prepared using the double emulsion ultrasonic method with the aim of targeting folate receptors specifically expressed on macrophages. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and DSS -induced mouse UC models. Furthermore, the effects of the liposomes on macrophage polarization and their underlying mechanisms in UC were explored.

The average particle size of folate-chicory acid liposome was 120.4 ± 0.46 nm, with an encapsulation efficiency of 77.32 ± 3.19 %. The folate-chicory acid liposome could alleviate macrophage apoptosis induced by LPS, decrease the expression of inflammatory factors in macrophages, enhance the expression of anti-inflammatory factors, inhibit macrophage polarization towards the M1 phenotype, and mitigate cellular inflammation in vetro. In vivo test, folate-chicory acid liposome could attenuate clinical symptoms, increased colon length, reduced DAI scores, CMDI scores, and alleviated the severity of colonic histopathological damage in UC mice. Furthermore, it inhibited the polarization of macrophages towards the M1 phenotype in the colon and downregulated the TLR4/NF-κB signaling pathway, thereby ameliorating UC in mice.

Folate-chicory acid liposome exhibited a uniform particle size distribution and high encapsulation efficiency. It effectively treated UC mice by inhibiting the polarization of macrophages towards the M1 phenotype in the colon and downregulating the TLR4/NF-κB signaling pathway.

It is generally accepted that low vitamin D (VD) levels are associated with a high prevalence factor for Inflammatory bowel disease (IBD). IBD patients have observed higher levels of lipopolysaccharide (LPS), ALT, and AST than healthy people. Gut-derived LPS causes inflammatory injury in the liver and kidney. The VD-metabolizing mechanism is involved in the liver and kidney, which means IBD might impact VD metabolism. However, whether IBD affects VD metabolism has not been studied. In vitro LPS resulted in decreased CYP2R1 in liver cells as well as decreased CYP27B1 and increased CYP24A1 in kidney cells, revealing that LPS changed the activities of several hydroxylases. Mice with acute colitis had an increased LPS in serum and liver with mild hepatic injuries, while mice with chronic colitis had a significant elevation of LPS in serum, liver, and kidney with hepatorenal injuries. Thus, the liver hydroxylase for VD metabolism would be the first to be affected in IBD. Consequently, serum 25-hydroxyvitamin D declined dramatically with a significant elevation of 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D. Unchanged serum levels of 1,25-dihydroxyvitamin D might be the result of other factors in vivo. In acute colitis, a small dosage (4 IU/day) of cholecalciferol could protect the colon, decrease the serum level of LPS, and finally increase serum 25-hydroxyvitamin D. However, this improvement of cholecalciferol was fading in chronic colitis. These results suggested that VD supplementations for preventing and curing IBD in the clinic should consider hepatorenal hydroxylases and be employed as soon as possible for a better outcome.

Non-steroid anti-inflammatory drugs (NSAIDs) are a class of prescription drugs with antipyretic, analgesic, anti-inflammatory, and antiplatelet effects. However, long-term use of NSAIDs will disrupt the intestinal mucosal barrier, causing erosion, ulcers, bleeding, and even perforation. Pure total flavonoids from Citrus (PTFC) is extracted from the dried peel of Citrus, showing a protective effect on intestinal mucosal barrier with unclear mechanisms.

In the present study, we used diclofenac (7.5 mg kg-1, i.g.) to induce a rat model of NSAIDs-related intestinal lesions. PTFC (50, 75, 100 mg·kg-1 d-1, i.g.) was administered 9 days before the initial diclofenac administration, followed by co-administration on the last 5 days. Exosomes were identified by western blotting and transmission electron microscopy (TEM), and then co-cultured with IEC-6 cells. The expression of long non-coding RNA (lncRNA) H19, autophagy-related 5 (Atg5), ZO-1, Occludin, and Claudin-1 were detected by quantitative real-time PCR (qRT-PCR). The expression of light chain 3 (LC3)-I, LC3-II, ZO-1, Occludin and Claudin-1 proteins was tested by western blotting. The localization of both exosomes and autophagosomes was examined by immunofluorescent technique.

The treatment of PTFC attenuated intestinal mucosal mechanical barrier function disturbance in diclofenac-induced NSAIDs rats. IEC-6 cells co-cultured with NSAIDs rats-derived exosomes possessed the lowest levels of protective autophagy, and severe intestinal barrier injuries. Cells co-cultured with the exosomes extracted from rats administrated PTFC exhibited an improvement of autophagy and intestinal mucosal mechanical barrier function. The prevention effect was proportional to the concentration of PTFC administered.

PTFC ameliorated NSAIDs-induced intestinal mucosal injury by down-regulating exosomal lncRNA H19 and promoting autophagy.

Ulcerative colitis (UC) is characterized by continuous mucosal ulceration of the colon, starting in the rectum. 5-Aminosalicylic acid (5-ASA) is the main therapy for ulcerative colitis; however, it has side effects. Physical exercise effectively increases the number of anti-inflammatory and anti-immune cells in the body. In the current study, the effects of simultaneous treatment of treadmill exercise and 5-ASA were compared with monotherapy with physical exercise or 5-ASA in UC mice. To induce the UC animal model, the mice consumed 2% dextran sulfate sodium dissolved in drinking water for 7 days. The mice in the exercise groups exercised on a treadmill for 1 h once a day for 14 days after UC induction. The 5-ASA-treated groups received 5-ASA by enema injection using a 200 μL polyethylene catheter once a day for 14 days. Simultaneous treatment improved histological damage and increased body weight, colon weight, and colon length, whereas the disease activity index score and collagen deposition were decreased. Simultaneous treatment with treadmill exercise and 5-ASA suppressed pro-inflammatory cytokines and apoptosis following UC. The benefits of this simultaneous treatment may be due to inhibition on nuclear factor-κB/mitogen-activated protein kinase signaling activation. Based on this study, simultaneous treatment of treadmill exercise and 5-ASA can be considered as a new therapy of UC.

Ulcer colitis (UC) is a chronic, nonspecific, and noninfectious inflammatory bowel disease. Recently, Toll-like receptors (TLRs) have been found to be closely associated with clinical inflammatory diseases. Achieving complete remission in patients with intermittent periods of activity followed by dormancy is challenging. Moreover, no study has explored the mechanism by which Kuicolong-yu enema decoction retains traditional Chinese medicine enemas to attenuate the inflammatory response in UC.

To explore the mechanism by which Kuicolong-yu enema decoction retains traditional Chinese medicine enemas to attenuate the inflammatory response in UC.

This prospective clinical study included patients who met the exclusion criteria in 2020 and 2021. The patients with UC were divided into two groups (control and experimental). The peripheral blood of the experimental and control groups were collected under aseptic conditions. The expression of TLR4 protein, NF-κB, IL-6, and IL-17 was detected in the peripheral blood of patients in the experimental group and control group before and 1 month after taking the drug. Linear correlation analysis was used to analyze the relationship between the expression level of TLR4 protein and the expression levels of downstream signal NF-κB and inflammatory factors IL-6 and IL-17, and P < 0.05 was considered statistically significant.

There were no significant differences in the patient characteristics between the control and experimental groups. The results showed that the expression levels of TLR4 and NF-κB in the experimental group were significantly lower than those in the control group (P < 0.05). The levels of IL-6 and IL-17 in the experimental group were significantly lower than those in the control group (P < 0.05). The TLR4 protein expression in the experimental group was positively correlated with the expression level of downstream signal NF-κB and was positively correlated with the levels of downstream inflammatory cytokines IL-6 and IL-17 (r = 0.823, P < 0.05).

Kuicolong-yu enema decoction retains traditional Chinese medicine enema attenuates the inflammatory response of UC through the TLR4/NF-κB signaling pathway.

The increasing global prevalence of ulcerative colitis (UC) underscores the imperative to explore novel therapeutic approaches. Traditional Chinese medicine has historically shown potential in addressing this ailment. The current study aimed to elucidate the functional attributes and underlying mechanisms of isofraxidin, a coumarin derivative from Acanthopanax, in the context of UC.

A murine model of dextran sodium sulfate (DSS)-induced UC was established, and we conducted a comprehensive assessment of the influence of isofraxidin on UC symptomatology, colonic histopathological manifestations, the inflammatory response, and apoptosis. The potential receptor of isofraxidin was initially identified through the Target database and molecular docking analysis. Subsequent in vivo and in vitro experiments were conducted to determine the effects of isofraxidin on the identified receptor and associated signaling pathways. Transfection was used to examine the receptor's role in the regulatory mechanism of isofraxidin.

Isofraxidin reduced UC symptoms and colonic histopathological impairments. Furthermore, isofraxidin ameliorated the DSS-induced inflammatory response and apoptosis in tissues. S1PR1 was identified as a target of isofraxidin and effectively suppressed activation of the IL-17 signaling pathway. Intriguingly, cellular experiments indicated that overexpression of S1PR1 counteracted the protective effect of isofraxidin.

In summary, our investigation revealed that isofraxidin could modulate S1PR1 and regulate the IL-17 signaling pathway, thus ameliorating DSS-induced UC. These findings establish a robust foundation for considering isofraxidin as a prospective therapeutic intervention to treat UC.

The mechanisms underlying chronic inflammatory diseases remain unclear. Therefore, researchers have explored the mechanisms underlying colitis using diverse materials. Recently, there has been an increasing interest in fermented products and bioconversion materials, their potential efficacy is being actively studied. Gochujang, a traditional Korean fermented product, is crafted by blending fermented Meju powder, gochu (Korean chili) powder, glutinous rice, and salt. In our study, we explored the effectiveness of Gochujang (500 mg/kg; Cheongju and Hongcheon, Korea) in dextran sulfate sodium (DSS)-induced colitis mice model. Gochujang was orally administered for 2 weeks, followed by the induction of colitis using 3% DSS in the previous week. During our investigation, Gochujang variants (TCG22-25, Cheongju and TCG22-48, Hongcheon) did not exhibit significant inhibition of weight reduction (p = 0.061) but notably (p = 0.001) suppressed the reduction in large intestine length in DSS-induced colitis mice. In the serum from colitis mice, TCG22-48 demonstrated reduced levels of the inflammatory cytokines interleukin (IL)-6 (p = 0.001) and tumor necrosis factor (TNF)-α (p = 0.001). Additionally, it inhibited the phosphorylation of Erk (p = 0.028), p38, and NF-κB (p = 0.001) the inflammatory mechanism. In our study, TCG22-25 demonstrated a reduction in the IL-6 level (p = 0.001) in serum and inhibited the phosphorylation of p38 and NF-κB (p = 0.001). Histological analysis revealed a significant (p = 0.001) reduction in the pathological score of the large intestine from TCG22-25 and TCG22-48. In conclusion, the intake of Gochujang demonstrates potent anti-inflammatory effects, mitigating colitis by preventing the large intestine length reduction of animals with colitis, lowering serum levels of TNF-α and IL-6 cytokines, and inhibiting histological disruption and inflammatory mechanism phosphorylation.

Naringin is a natural flavonoid with therapeutic properties found in citrus fruits and an active natural product from herbal plants. Naringin has become a focus of attention in recent years because of its ability to actively participate in the body's immune response and maintain the integrity of the immune barrier. This review aims to elucidate the mechanism of action and therapeutic efficacy of naringin in various inflammatory diseases and to provide a valuable reference for further research in this field. The review provided the chemical structure, bioavailability, pharmacological properties, and pharmacokinetics of naringin and found that naringin has good therapeutic potential for inflammatory diseases, exerting anti-inflammatory, anti-apoptotic, anti-oxidative stress, anti-ulcerative and detoxifying effects in the disease. Moreover, we found that the great advantage of naringin treatment is that it is safe and can even alleviate the toxic side effects associated with some of the other drugs, which may become a highlight of naringin research. Naringin, an active natural product, plays a significant role in systemic diseases' anti-inflammatory and antioxidant regulation through various signaling pathways and molecular mechanisms.

(-)-Syringaresinol (SYR), a natural lignan with significant antioxidant and anti-inflammatory activities, possesses various pharmacological benefits including cardio-protective, antibacterial, anticancer, and anti-aging effects. It was shown that the effectiveness of (+)-syringaresinol diglucoside on the ulcerative colitis (UC) was attributed to the active metabolite (+)-syringaresinol (the enantiomor of SYR). However, the efficacy of SYR against UC remains unclear, and the associated molecular mechanism has not been revealed yet PURPOSE: This study aimed to assess the protective effect of SYR in UC and its underlying mechanism STUDY DESIGN AND METHODS: We examined SYR's protective impact on the intestinal epithelial barrier and its ability to inhibit inflammatory responses in both a lipopolysaccharide (LPS)-induced Caco-2 cell model and a dextran sodium sulfate (DSS)-induced UC mouse model. We also explored the potential signaling pathways regulated by SYR using transcriptome analysis and western blot assay RESULTS: In Caco-2 cells, SYR significantly increased trans-epithelial electrical resistance, reduced tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ), and cyclooxygenase-2 (COX-2) levels, and enhanced cellular tight junction protein expression and distribution. In mice with UC, oral treatment with SYR (10, 20, 40 mg·kg-1) dose-dependently increased body weight, colon length, and expression of tight junction proteins, decreased disease activity index score, spleen coefficient, cytokine serum levels, bacterial translocation, and intestinal damage, and also preserved the ultrastructure of colonic mucosal cells. Transcriptomics indicated that the anti-UC effect of SYR is mediated via the PI3K-Akt/MAPK/Wnt signaling pathway.

In summary, SYR effectively mitigated the development of UC by enhancing the intestinal epithelial barrier function and attenuating the inflammatory response. The plant-derived product SYR might be a potentially effective therapeutical agent against UC.

A polysaccharide from Artocarpus heterophyllus Lam. (jackfruit) pulp (JFP-Ps) is known for its excellent bioactivities. However, its impact on small intestinal barrier function is still largely unexplored. The study aimed to examine the protection effect of JFP-Ps against dextran sodium sulfate-induced enteritis and its underlying mechanism. This research revealed that JFP-Ps mitigated small intestinal tissue damage by reducing the expression of pro-inflammatory cytokines and promoting the expression of the anti-inflammatory cytokine interleukin-10 in the small intestine. JFP-Ps diminished oxidative stress by bolstering the activity of antioxidant enzymes and reducing the concentration of malondialdehyde in the small intestine. In addition, JFP-Ps may restore the mechanical barrier and inhibit intestinal structure damage by augmenting the expression of short-chain fatty acids (SCFAs) receptors (GPR41/43) and up-regulating the expression of tight junction proteins (occludin). In conclusion, JFP-Ps may positively influence intestinal health by relieving oxidative stress in the small intestine, improving mechanical barrier function, activating the SCFA-GPR41/GPR43 axis, and inhibiting TLR4/MAPK pathway activation. The results augment our comprehension of the bioactivities of JFP-Ps, corroborating its great potential as a functional food.

Xiao Cheng Qi (XCQ) decoction, an ancient Chinese herbal mixture, has been used in treating slow-transit constipation (STC) for years. The underlying action mechanism in relieving the clinical symptoms is unclear. Several lines of evidence point to a strong link between constipation and gut microbiota. Short-chain fatty acids (SCFAs) and microbial metabolites have been shown to affect 5-HT synthesis by activating the GPR43 receptor localized on intestinal enterochromaffin cells, since 5-HT receptors are known to influence colonic peristalsis. The objective of this study was to evaluate the efficacy of XCQ in alleviating clinical symptoms in a mouse model of STC induced by loperamide. The application of loperamide leads to a decrease in intestinal transport and fecal water, which is used to establish the animal model of STC. In addition, the relationship between constipation and gut microbiota was determined. The herbal materials, composed of Rhei Radix et Rhizoma (Rhizomes of Rheum palmatum L., Polygonaceae) 55.2 g, Magnoliae Officinalis Cortex (Barks of Magnolia officinalis Rehd. et Wils, Magnoliaceae) 27.6 g, and Aurantii Fructus Immaturus (Fruitlet of Citrus aurantium L., Rutaceae) 36.0 g, were extracted with water to prepare the XCQ decoction. The constipated mice were induced with loperamide (10 mg/kg/day), and then treated with an oral dose of XCQ herbal extract (2.0, 4.0, and 8.0 g/kg/day) two times a day. Mosapride was administered as a positive drug. In loperamide-induced STC mice, the therapeutic parameters of XCQ-treated mice were determined, i.e., (i) symptoms of constipation, composition of gut microbiota, and amount of short-chain fatty acids in feces; (ii) plasma level of 5-HT; and (iii) expressions of the GPR43 and 5-HT4 receptor in colon. XCQ ameliorated the constipation symptoms of loperamide-induced STC mice. In gut microbiota, the treatment of XCQ in STC mice increased the relative abundances of Lactobacillus, Prevotellaceae_UCG_001, Prevotellaceae_NK3B31_group, Muribaculaceae, and Roseburia in feces and decreased the relative abundances of Desulfovibrio, Tuzzerella, and Lachnospiraceae_ NK4A136_group. The levels of SCFAs in stools from the STC group were significantly lower than those the control group, and were greatly elevated via treatment with XCQ. Compared with the STC group, XCQ increased the plasma level of 5-HT and the colonic expressions of the GPR43 and 5-HT4 receptor, significantly. The underlying mechanism of XCQ in anti-constipation could be related to the modulation of gut microbiota, the increase in SCFAs, the increase in plasma 5-HT, and the colonic expressions of the GPR43 and 5-HT4 receptor. Our results indicate that XCQ is a potent natural product that could be a therapeutic strategy for constipation.

Food intake is a basic need to sustain life, but foodborne pathogens and food-related xenobiotics are also the main health concerns regarding intestinal barrier homeostasis. With a predominant role in the well-being of the entire human body, intestinal barrier homeostasis is strictly regulated by epithelial and immune cells. These cells are also the main intervenients in oxidative stress and inflammation-related diseases in the intestinal tract, triggered, for example, by genetic/epigenetic factors, food additives, pesticides, drugs, pathogens, and their metabolites. Nevertheless, the human diet can also be seen as a solution for the problem, mainly via the inclusion of functional foods or nutraceuticals that may act as antioxidant/anti-inflammatory agents to prevent and mitigate acute and chronic oxidative damage and inflammation. A literature analysis of recent advances in this topic highlights the significant role of Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways in these biological processes, with many natural products and phytochemicals targeting endogenous antioxidant systems and cytokine production and balance. In this review, we summarized and discussed studies using in vitro and in vivo models of the intestinal tract used to reproduce oxidative damage and inflammatory events, as well as the role of natural products as modulators of Nrf2 and NK-kB pathways.

The diet during pregnancy, or antenatal diet, influences the offspring's intestinal health. We previously showed that antenatal butyrate supplementation reduces injury in adult murine offspring with dextran sulfate sodium (DSS)-induced colitis. Potential modulators of butyrate levels in the intestine include a high fiber diet or dietary supplementation with probiotics. To test this, we supplemented the diet of pregnant mice with high fiber, or with the probiotic bacteria Lactococcus lactis subspecies cremoris or Lactobacillus rhamnosus GG. We then induced chronic colitis with DSS in their adult offspring. We demonstrate that a high fiber antenatal diet, or supplementation with Lactococcus lactis subspecies cremoris during pregnancy diminished the injury from DSS-induced colitis in offspring. These data are evidence that antenatal dietary interventions impact offspring gut health and define the antenatal diet as a therapeutic modality to enhance offspring intestinal health.

The flavonoid Naringin (Nar) has been extensively investigated and found to have multiple pharmacological properties, including neuroprotection. Although recent reports have shown that Nar can effectively treat spinal cord injury (SCI), its potential mechanism remains unknown. This study aimed to investigate the effects of Nar on motor recovery and inflammatory responses after SCI and to elucidate its mechanism.

SCI rat models were established using Allen's weight-drop method. The rats were intragastrically given Nar (40 mg/kg) for 21 d, and their motor function before surgery and on the 1st, 3rd, 7th, 14th, 21st days after surgery was assessed by the Basso-Beattie-Bresnahan (BBB) scale and examined by the grid walking test (GWT). The enzyme linked immunosorbent assay (ELISA) was used to detect the interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 levels in rat spinal cord tissues, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure the mRNA expression levels of microglial activation markers CD68 and ionized calcium binding adaptor molecule 1 (Iba-1), M1 markers inducible nitric oxide synthase (iNOS) and IL-6, and M2 markers CD206 and Arginase 1 (Arg1). The expression levels of peroxisome proliferator-activated receptor gamma/nuclear factor kappa B (PPAR-γ/NF-κB) pathway-related proteins in rat spinal cord tissues were determined using western blotting.

Nar significantly increased the BBB score and decreased the mean error rate of GWT in SCI rats. Additionally, Nar effectively inhibited microglial activation and expression of M1 markers in spinal cord tissues. It also elevated M2 polarization-related gene expression and significantly lowered the levels of inflammatory factors. Further investigation showed that Nar enhanced the expression of PPAR-γ protein and inhibited NF-κB pathway activity.

Nar promotes functional recovery by regulating microglial polarization and inhibiting the inflammatory response in SCI, and its mechanism may be related to the PPAR-γ/NF-κB signaling pathway activity.

Ulcerative colitis (UC) is one of the most common subtypes of inflammatory bowel disease (IBD) that affects the colon and is characterized by severe intestinal inflammation. Canagliflozin is a widely used antihyperglycemic agent, a sodium-glucose cotransporter-2 (SGLT2) inhibitor that enhances urinary glucose excretion. This study aims to provide insights into the potential benefits of canagliflozin as a treatment for UC by addressing possible cellular signals. Acetic acid (AA; 4% v/v) was administered intrarectally to induce colitis. Canagliflozin is given orally at a dose of 10 mg/kg/day. Canagliflozin attenuates inflammation in AA-induced colitis, evidenced by significant and dose-dependently downregulation of p38 MAPK, NF-κB-p65, IKK, IRF3, and NADPH-oxidase as well as colonic levels of IL-6 and IL-1β and MPO enzymatic activity. Canagliflozin mitigates colonic oxidative stress by decreasing MDA content and restoring SOD enzymatic activities and GSH levels mediated by co-activating of Nrf2, PPARγ, and SIRT1 pathways. Moreover, an in-silico study confirmed that canagliflozin was specific to all target proteins in this study. Canagliflozin's binding affinity with its target proteins indicates and confirms its effectiveness in regulating these pathways. Also, network pharmacology analysis supported that canagliflozin potently attenuates UC via a multi-target and multi-pathway approach.

Roughly 10 -15% of global populace suffer from Chronic Kidney Disease(CKD). A major secondary disease that can progress to end-stage renal disease (ESRD) is obesity-associated kidney disease (ORG). Although clinical management strategies are currently available, morbidity and mortality rates are increasing. Thus, new solutions are needed. Intestinal permeability, systemic inflammation, and aberrant intestinal metabolites have all been linked to ORG.

ACT001 has anti-inflammatory, redox-regulatory and antitumour activities. The current study was designed to examine how ACT001 affects ORG and analyze the fundamental processes.

A high-fat diet (HFD) was used to generate ORG in female C57BL/6 J mice. ORG mice were divided into three groups at random: HFD, HFD + ACT001, HFD + polyphosphocholine (PPC). To assess renal and colonic damage, periodic acid-Schiff (PAS) and hematoxylin-eosin (HE) staining were used. Following that, renal inflammation, oxidative stress, lipid deposition, colonic inflammation, and intestinal permeability were evaluated by protein blotting, polymerase chain reaction (PCR), immunohistochemistry, and immunofluorescence staining. Lastly, the SCFAs content was assessed by gas chromatographymass spectrometry.

Mice in the HFD group displayed more severe albuminuria, glomerular hypertrophy, renal oxidative damage, inflammation, and lipid accumulation than mice with the normal diet (ND) group, as well as lower levels of intestinal SCFA valproic acid, colonic inflammation, and tight junction protein downregulation. ACT001 treatment restores the content of valproic acid in intestinal SCFAs, promotes the binding of SCFAs to renal GPR43, activates the AMPK signalling pathway. Therefore, it promotes the Nrf2-Keap1 signalling pathway and inhibits the NF-κB signalling pathway. SCFAs, additionally, augment colonic GPR43 concentrations, diminishing NLRP3 inflammasome expression and restoring ZO-1 and occludin protein levels.

This study is the first to look at ACT001's potential as a treatment for obesity-related kidney disease. Regulating GPR43 and AMPK signalling pathways, By controlling the GPR43 and AMPK signalling pathways, ACT001 improves colitis and the intestinal mucosal barrier, decreases renal lipid deposition, and suppresses inflammation and oxidative stress in the kidneys. According to this study, ACT001 could be a viable ORG therapy option.