Ulcerative colitis (UC) is a chronic and non-specific inflammatory bowel disease (IBD). Huanglian Ganjiang decoction (HGD), derived from ancient book Beiji Qianjin Yao Fang, has demonstrated efficacy in treating UC patients traditionally. Previous research established that the compatibility of cold herb Coptidis Rhizoma + Phellodendri Chinensis Cortex (CP) and hot herb Angelicae Sinensis Radix + Zingiberis Rhizoma (AZ) in HGD synergistically improved colitis mice. This study investigated the compatibility mechanisms through which CP and AZ regulated inflammatory balance in colitis mice. The experimental colitis model was established by administering 3% dextran sulphate sodium (DSS) to mice for 7 days, followed by CP, AZ and CPAZ treatment for an additional 7 days. M1/M2 macrophage polarization levels, glucose metabolites levels and pyruvate dehydrogenase kinase 4 (PDK4) expression were analyzed using flow cytometry, Western blot, immunofluorescence and targeted glucose metabolomics. The findings indicated that CP inhibited M1 macrophage polarization, decreased inflammatory metabolites associated with tricarboxylic acid (TCA) cycle, and suppressed PDK4 expression and pyruvate dehydrogenase (PDH) (Ser-293) phosphorylation level. AZ enhanced M2 macrophage polarization, increased lactate axis metabolite lactate levels, and upregulated PDK4 expression and PDH (Ser-293) phosphorylation level. TCA cycle blocker AG-221 and adeno-associated virus (AAV)-PDK4 partially negated CP's inhibition of M1 macrophage polarization. Lactate axis antagonist oxamate and PDK4 inhibitor dichloroacetate (DCA) partially reduced AZ's activation of M2 macrophage polarization. In conclusion, the compatibility of CP and AZ synergistically alleviated colitis in mice through M1/M2 macrophage polarization balance via PDK4-mediated glucose metabolism reprogramming. Specifically, CP reduced M1 macrophage polarization by restoration of TCA cycle via PDK4 inhibition, while AZ increased M2 macrophage polarization through activation of PDK4/lactate axis.
Animals ; Drugs, Chinese Herbal/chemistry* ; Mice ; Macrophages/immunology* ; Glucose/metabolism* ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics* ; Male ; Mice, Inbred C57BL ; Humans ; Colitis/drug therapy* ; Disease Models, Animal ; Colitis, Ulcerative/drug therapy* ; Metabolic Reprogramming

Objective To investigate the anti-inflammatory effect of artemisinin (ART) encapsulated by β-lactoglobulin (BLG) nanoparticles on Winnie spontaneous ulcerative colitis mouse model. Methods BLG-ART nanoparticles were prepared and their effects on the solubility and stability of ART were evaluated. A mouse model of colitis induced by dextran sulfate sodium (DSS) was used to compare the therapeutic effects of artemisinin (ART) administered by direct gavage and artemisinin encapsulated by β-lactoglobulin nanoparticles (BLG-ART) administered by gavage. Winnie mice were randomly divided into blank group, ART group and BLG-ART group. Mice in the ART group were given 50 mg/kg ART by gavage; mice in the BLG-ART group were given the same dose of BLG-ART nanoparticle PBS dispersion by gavage; mice in the blank group were given the same amount of PBS by gavage, for 16 days. The body mass and disease activity index (DAI) of each group of mice were measured. HE staining was used to observe the pathological changes of mouse intestinal tissue, and real-time quantitative PCR was used to detect the mRNA expression levels of TNF-α, interleukin 1β (IL-1β), IL-10 and IL-17 in mouse colon tissue. Results Compared with the ART group and the blank group, the body mass of the BLG-ART group increased and the DAI decreased after 16-day treatment; the crypt structure of the proximal and distal colon regions of the mice recovered; goblet cell loss decreased; neutrophil infiltration decreased and the mRNA expression levels of pro-inflammatory and anti-inflammatory cytokines were significantly down-regulated. Conclusion ART-BLG can alleviate intestinal inflammation in spontaneous ulcerative colitis mice.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Nanospheres ; Inflammation ; Administration, Oral ; Artemisinins ; Disease Models, Animal ; RNA, Messenger

Objective To investigate the immunomodulatory effect of mare's milk on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. Methods Kunming mice were randomly divided into a blank group(0.8 mL/day saline by gavage) and a DSS modeling group. After modeling, the DSS modeling group was further divided into a control group (0.8 mL/day saline), a salazosulfapyridine (SASP) treated group(430 mg/(kg.d)) and a mare's milk group(0.8 mL/day), with 16 mice in each group. After 10 days of gavage administration, HE staining was performed to observe colonic inflammation, and the disease activity index (DAI) and colonic mucosal damage index (CMDI) were scored. ELISA was used to determine the levels of interleukin 1β (IL-1β), IL-6, and IL-10 in mouse colonic tissues, and flow cytometry was used to detect the percentages of CD4⁺ and CD8⁺ T lymphocytes in peripheral blood. Results Compared to the blank group, all indexes in mice of the control group indicated that DSS successfully induced UC. Compared to the control group, colon shortening in UC mice was attenuated in the mare's milk group; inflammation and ulcer formation in colonic tissues were inhibited; DAI and CMDI scores were lowere; IL-1β and IL-6 levels in mouse colonic tissues were significantly reduced; IL-10 levels were increased and the CD4⁺/CD8⁺ T cell ratio was reduced. Conclusion Mare's milk can inhibit the inflammation of DSS-induced UC mice through immune regulation.
Mice ; Animals ; Female ; Horses ; Colitis, Ulcerative/drug therapy* ; Interleukin-10 ; Dextran Sulfate ; Interleukin-6 ; Milk ; Signal Transduction ; Disease Models, Animal ; Inflammation ; Colon

The effect of Tujia medicine Berberidis Radix on endogenous metabolites in the serum and feces of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) was analyzed by metabolomics technology to explore the metabolic pathway and underlying mechanism of Berberidis Radix in the intervention of UC. The UC model was induced in mice by DSS. Body weight, disease activity index(DAI), and colon length were recorded. The levels of tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10) in colon tissues were determined by ELISA. The levels of endogenous metabolites in the serum and feces were detected by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were employed to characterize and screen differential metabolites. The potential metabolic pathways were analyzed by MetaboAnalyst 5.0. The results showed that Berberidis Radix could significantly improve the symptoms of UC mice and increase the level of the anti-inflammatory factor IL-10. A total of 56 and 43 differential metabolites were identified in the serum and feces, respectively, belonging to lipids, amino acids, fatty acids, etc. After the intervention by Berberidis Radix, the metabolic disorder gradually recovered. The involved metabolic pathways included biosynthesis of phenylalanine, tyrosine, and tryptophan, linoleic acid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. Berberidis Radix can alleviate the symptoms of mice with DSS-induced UC, and the mechanism may be closely related to the re-gulation of lipid metabolism, amino acid metabolism, and energy metabolism.
Mice ; Animals ; Colitis, Ulcerative/drug therapy* ; Interleukin-10 ; Metabolomics/methods* ; Chromatography, High Pressure Liquid

This study aims to explore the effect of tryptanthrin on potential metabolic biomarkers in the serum of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) based on liquid chromatography-mass spectrometry(LC-MS) and predict the related metabolic pathways. C57BL/6 mice were randomly assigned into a tryptanthrin group, a sulfasalazine group, a control group, and a model group. The mouse model of UC was established by free drinking of 3% DSS solution for 11 days, and corresponding drugs were adminsitrated at the same time. The signs of mice were observed and the disease activity index(DAI) score was recorded from the first day. Colon tissue samples were collected after the experiment and observed by hematoxylin-eosin(HE) staining. The levels of interleukin-4(IL-4), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-8(IL-8) in the serum were measured by enzyme linked immunosorbent assay(ELISA). The serum samples were collected from 6 mice in each group for widely targeted metabolomics. The metabolic pathways were enriched by MetaboAnalyst 5.0. The results showed that compared with the model group, tryptanthrin treatment decreased the DAI score(P<0.05), alleviated the injury of the colon tissue and the infiltration of inflammatory cells, lowered the levels of proinflammatory cytokines, and elevated the levels of anti-inflammatory cytokines in the serum. The metabolomic analysis revealed 28 differential metabolites which were involved in 3 metabolic pathways including purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. Tryptanthrin may restore the metabolism of the mice with UC induced by DSS to the normal level by regulating the purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. This study employed metabolomics to analyze the mechanism of tryptanthrin in the treatment of UC, providing an experimental basis for the utilization and development of tryptanthrin.
Mice ; Animals ; Colitis, Ulcerative/drug therapy* ; Tryptophan ; Arachidonic Acid/metabolism* ; Mice, Inbred C57BL ; Colon ; Cytokines/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/metabolism* ; Metabolomics ; Purines/therapeutic use* ; Dextran Sulfate/metabolism* ; Disease Models, Animal ; Colitis/chemically induced*

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Ursodeoxycholic Acid/adverse effects* ; Berberine/pharmacology* ; Interleukin-6 ; Tumor Necrosis Factor-alpha/pharmacology* ; Drugs, Chinese Herbal/pharmacology* ; Colon ; Nanoparticles ; Dextran Sulfate/adverse effects* ; Disease Models, Animal ; Colitis/chemically induced*

Platycodon grandiflorus polysaccharide (PGP) is one of the main components of P. grandiflorus, but the mechanism of its anti-inflammatory effect has not been fully elucidated. The aim of this study was to evaluate the therapeutic effect of PGP on mice with dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) and explore the underlying mechanisms. The results showed that PGP treatment inhibited the weight loss of DSS-induced UC mice, increased colon length, and reduced DAI, spleen index, and pathological damage within the colon. PGP also reduced the levels of pro-inflammatory cytokines and inhibited the enhancement of oxidative stress and MPO activity. Meanwhile, PGP restored the levels of Th1, Th2, Th17, and Treg cell-related cytokines and transcription factors in the colon to regulate colonic immunity. Further studies revealed that PGP regulated the balance of colonic immune cells through mesenteric lymphatic circulation. Taken together, PGP exerts anti-inflammatory and anti-oxidant effect and regulates colonic immunity to attenuate DSS-induced UC through mesenteric lymphatic circulation.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Platycodon ; Colon/pathology* ; Cytokines ; Anti-Inflammatory Agents/therapeutic use* ; Polysaccharides/therapeutic use* ; Dextran Sulfate ; Disease Models, Animal ; Colitis/chemically induced* ; Mice, Inbred C57BL

OBJECTIVE: To elucidate the mechanism of Lizhong Decoction (LZD) in treating dextran sodium sulfate (DSS)-induced colitis in mice based on metabonomics. METHODS: Thirty-six mice were randomly divided into 6 groups, including normal, model, low- (1.365 g/kg), medium- (4.095 g/kg) and high dose (12.285 g/kg) LZD and salazosulfadimidine (SASP) groups, 6 mice in each group. Colitis model mice were induced by DSS admistration for 7 days, and treated with low, medium and high dose LZD extract and positive drug SASP. Metabolic comparison of DSS-induced colitis and normal mice was investigated by using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass (UPLC-Q-TOF/MS) combined with Metabolynx™ software. RESULTS: The metabolic profiles of plasma and urine in colitis mice were distinctly ameliorated after LZD treatment (P<0.05). Potential biomarkers (9 in serum and 4 in urine) were screened and tentatively identified. The endogenous metabolites were mainly involved in primary bile acid, sphingolipid, linoleic acid, arachidonic acid, amino acids (alanine, aspartate, and glutamate), butanoate and glycerophospholipid metabolism in plasma, and terpenoid backbone biosynthesis, glycerophospholipid and tryptophan metabolism in urine. After LZD treatment, these markers notably restored to normal levels. CONCLUSIONS The study revealed the underlying mechanism of LZD on amelioration of ulcerative colitis based on metabonomics, which laid a foundation for further exploring the pathological and physiological mechanism, early diagnosis, and corresponding drug development of colitis.
Mice ; Animals ; Colitis, Ulcerative/drug therapy* ; Tryptophan/adverse effects* ; Aspartic Acid ; Dextrans/adverse effects* ; Drugs, Chinese Herbal/adverse effects* ; Colitis/drug therapy* ; Biomarkers/metabolism* ; Amino Acids/adverse effects* ; Glycerophospholipids/therapeutic use* ; Sphingolipids/adverse effects* ; Bile Acids and Salts/adverse effects* ; Glutamates/adverse effects* ; Alanine/adverse effects* ; Arachidonic Acids/adverse effects* ; Linoleic Acids/adverse effects* ; Terpenes

Inflammatory bowel disease(IBD) is a chronic and recurrent inflammatory disorder of the gut, including Crohn's disease(CD) and ulcerative colitis(UC). The occurrence and development of IBD involves multiple pathogenic factors, and the dybiosis of gut flora is recognized as an important pathogenic mechanism of IBD. Therefore, restoring and maintaining the balance of gut flora including bacteria and fungi has become an effective option for IBD treatment. Based on the theoretical basis of the interaction between gut flora and IBD, this paper followed the principle of clinical syndrome differentiation for IBD therapy by traditional Chinese medicine(TCM), and summarized several Chinese medicinal formulae commonly used in IBD patients with large intestine damp-heat syndrome, intermingled heat and cold syndrome, spleen deficiency and dampness accumulation syndrome, spleen and kidney yang deficiency syndrome, liver stagnation and spleen deficiency syndrome, and severe heat poisoning syndrome. The therapeutic and regulatory effects of Shaoyao Decoction, Qingchang Suppository, Wumei Pills, Banxia Xiexin Decoction, Shenling Baizhu Powder, Lizhong Decoction, Sishen Pills, Tongxie Yaofang, Baitouweng Decoction, Gegen Qinlian Decoction, and Houttuyniae Herba prescriptions on gut flora of IBD patients were emphasized as well as the mechanisms. This study found that Chinese medicinal formulae increased the abundance of Bacteroidetes, Bifidobacteria, Lactobacillus, and other beneficial bacteria producing short-chain fatty acids, and reduced the abundance of Enterobacteriaceae and other harmful bacteria to restore the balance of gut flora, thus treating IBD. Confronting the recalcitrance and high recurrence of IBD, Chinese medicinal formulae provide new opportunities for IBD treatment through intervening dysbiosis of gut flora.
Humans ; Gastrointestinal Microbiome ; Inflammatory Bowel Diseases/drug therapy* ; Dysbiosis/drug therapy* ; Colitis, Ulcerative/drug therapy* ; Bacteria/genetics* ; Homeostasis ; China

Ulcerative colitis(UC) is a continuous inflammatory bowel disease with the main clinical manifestations of abdominal pain, diarrhea, and mucous bloody stools, mainly attacking the colorectal mucosa and submucosa. It is characterized by high recurrence rate, difficult cure, and clustering and regional occurrence. Chinese medicinal prescriptions for the treatment of UC have good therapeutic effect, multi-target regulation, slight toxicity, and no obvious side effects. In particular, the classical prescriptions highlight the characteristics and advantages of traditional Chinese medicine theory and have attracted much attention in recent years. To enable researchers to timely and comprehensively understand the classical prescriptions in the treatment of UC, we reviewed the studies about the pharmacodynamic material basis, quality control, action mechanism, and clinical application of relevant classical prescriptions. We first introduced the latest research progress in the active components such as alkaloids, polysaccharides, saponins, and flavonoids in relevant classical prescriptions. Then, we reviewed the latest research achievements on the quality control of classical prescriptions for the treatment of UC by gas chromatography, liquid chromatography, mass spectrometry, liquid chromatography-mass spectrometry and the like. Further, we summarized the research advances in the mechanisms of relevant prescriptions in the treatment of UC based on network pharmacology, molecular docking, integrated pharmacology platform, and animal experiments. Finally, we generalized the clinical application of the classical prescriptions for clearing heat and removing dampness, mildly regulating cold and heat, soothing liver and regulating spleen, strengthening spleen and invigorating Qi, and tonifying spleen and stomach. By systematic summary of the research progress in relevant classical prescriptions, we hope to promote the application and development of such prescriptions in UC treatment.
Animals ; Colitis, Ulcerative/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Molecular Docking Simulation ; Gas Chromatography-Mass Spectrometry ; Medicine, Chinese Traditional ; Drug Prescriptions