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Frontiers in Pharmacology 2023Qing Hua Chang Yin (QHCY) is a famous formula of traditional Chinese medicine (TCM) and has been proven to have protective effect on ulcerative colitis. However, its...
Qing Hua Chang Yin (QHCY) is a famous formula of traditional Chinese medicine (TCM) and has been proven to have protective effect on ulcerative colitis. However, its protective effect and potential therapeutic mechanisms in chronic colitis remain unclear. The purpose of this study is to explore the effects and underlying mechanisms of QHCY on dextran sulfate sodium (DSS)-induced chronic colitis mice model. The chronic colitis model was established by administration of 2% DSS for three consecutive cycles of 7 days with two intervals of 14 days for recovery by drinking water. The experiment lasted 49 days. The DSS + QHCY group received QHCY administration by oral gavage at doses of 1.6 g/kg/d, DSS + Mesalazine group was administrated Mesalazine by oral gavage at doses of 0.2 g/kg/d. The control and DSS group were given equal volume of distilled water. The body weight, stool consistency and blood in stool were monitored every 2 days. The disease activity index (DAI) was calculated. The colon length was measured after the mice were sacrificed. The histomorphology of colonic tissues was checked by the HE and PAS staining. Immunohistochemistry was performed to detect the expressions of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), tight junction proteins (ZO-1, occludin) and Mucin2 (MUC2). 16S rRNA sequencing analysis was conducted to study the diversity and abundance of gut microbiota changes. QHCY treatment not only significantly attenuated DSS-induced the weight loss, DAI score increase, colon shortening and histological damage in mice, but also decreased the expression of pro-inflammatory cytokines in colonic tissues and increased the expression of ZO-1, occludin, and MUC2. Furthermore, QHCY enhanced the diversity of gut microbes and regulated the structure and composition of intestinal microflora in mice with chronic colitis. QHCY has a therapeutic effect on a murine model of chronic colitis. It can effectively reduce the clinical and pathological manifestations of colitis and prevent alterations in the gut microbiota.
PubMed: 37576825
DOI: 10.3389/fphar.2023.1176579 -
Respiratory Medicine Case Reports 2023Pulmonary involvement associated with inflammatory bowel disease (IBD) are a rare extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), we herein...
Pulmonary involvement associated with inflammatory bowel disease (IBD) are a rare extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), we herein presented two cases. Case 1: 53-year-old man with Crohn's disease treated with mesalazine and azathioprine. Pulmonary nodular shadows were incidentally detected on chest imaging, and revealed granulomas through transbronchial lung biopsy. Case 2: 68-year-old man with ulcerative colitis treated with mesalazine. He presented with fever and respiratory symptoms, and chest imaging showed multiple nodular infiltrates. He was diagnosed with organizing pneumonia by lung biopsy. Both cases were diagnosed to have pulmonary involvement associated with inflammatory bowel disease (IBD) according to multidisciplinary examination including positron emission tomography-computed tomography (FDG-PET) and pathological test. Pulmonary manifestations with IBD may not always require discontinuation of drugs or additional use of steroids or immunosuppressants.
PubMed: 37719886
DOI: 10.1016/j.rmcr.2023.101914 -
The Medical Letter on Drugs and... Jul 2023
Topics: Humans; Inflammatory Bowel Diseases; Immunosuppressive Agents; Colitis, Ulcerative
PubMed: 37418332
DOI: 10.58347/tml.2023.1680d -
European Review For Medical and... Oct 2023Ulcerative colitis (UC), a chronic inflammatory disease of the colon with unknown etiology, is characterized by remission and recurrence. At present, a considerable...
OBJECTIVE
Ulcerative colitis (UC), a chronic inflammatory disease of the colon with unknown etiology, is characterized by remission and recurrence. At present, a considerable number of UC cases are misdiagnosed or delayed in diagnosis and treatment. We aimed to identify UC-related genes to aid the development of drugs for this condition.
PATIENTS AND METHODS
Transcriptome data of 362 patients with UC and 126 control subjects were obtained from the Gene Expression Omnibus. The 362 patients with UC were subgrouped using unsupervised machine learning. R software was used to analyze the clinical characteristics of the subgroups, screen subgroup-specific genes, assess the relationships between gene modules and clinical characteristics using weighted gene co-expression network analysis, and perform Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the subgroups.
RESULTS
Patients with UC were classified into two subgroups. Genes specific to subgroup I included IL21R, ATP8B2, and PLEKHO1. Severe disease tended to be associated with immune cell infiltration; anti-tumor necrosis factor (TNF)-α antibodies and ustekinumab may have been effective in this subgroup. Subgroup II-specific genes included SLC4A4, EPB41L4B, and PLCE1. Patients in this subgroup had mild clinical conditions; however, their disease was more likely to progress to colorectal cancer. Thus, 5-aminosalicylic acid-based drugs may be effective for the treatment of UC in these patients.
CONCLUSIONS
We divided UC into two molecular subgroups based on transcriptome data, providing molecular evidence for the development of diagnostic methods and individualized treatment strategies for UC.
Topics: Humans; Colitis, Ulcerative; Mesalamine; Gene Expression Profiling; Tumor Necrosis Factor-alpha; Intracellular Signaling Peptides and Proteins
PubMed: 37843347
DOI: 10.26355/eurrev_202310_33961 -
World Journal of Gastroenterology Apr 2024The treatment of patients with inflammatory bowel disease (IBD), especially those with severe or refractory disease, represents an important challenge for the clinical... (Review)
Review
The treatment of patients with inflammatory bowel disease (IBD), especially those with severe or refractory disease, represents an important challenge for the clinical gastroenterologist. It seems to be no exaggeration to say that in these patients, not only the scientific background of the gastroenterologist is tested, but also the abundance of "gifts" that he should possess (insight, intuition, determination, ability to take initiative, ) for the successful outcome of the treatment. In daily clinical practice, depending on the severity of the attack, IBD is treated with one or a combination of two or more pharmaceutical agents. These combinations include not only the first-line drugs (., mesalazine, corticosteroids, antibiotics, ) but also second- and third-line drugs (immunosuppressants and biologic agents). It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied. Therefore, a part of these patients are going to surgery. In recent years, several small-size clinical studies, reviews, and case reports have been published combining not only biological agents with other drugs ( immunosuppressants or corticosteroids) but also the combination of two biological agents simultaneously, especially in severe cases. In our opinion, it is at least a strange (and largely unexplained) fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few. As mentioned above, there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations. The appropriate dosage, the duration of the administration, the suitable timing for checking the clinical and laboratory outcome, as well as the treatment side-effects, should be the subject of intense clinical research shortly. In this editorial, we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients. We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.
Topics: Humans; Drug Therapy, Combination; Immunosuppressive Agents; Treatment Outcome; Inflammatory Bowel Diseases; Adrenal Cortex Hormones; Gastrointestinal Agents; Severity of Illness Index; Anti-Bacterial Agents; Biological Products
PubMed: 38681984
DOI: 10.3748/wjg.v30.i15.2068 -
Phytomedicine : International Journal... Jul 2023Current antidepressant therapy remains unsatisfactory due to the complex pathogenesis. Emerging evidence suggested that depression is associated with inflammatory bowel...
BACKGROUND
Current antidepressant therapy remains unsatisfactory due to the complex pathogenesis. Emerging evidence suggested that depression is associated with inflammatory bowel disease (IBD), intestinal inflammation is an increasingly accepted factor that influences depression, but the mechanism is unclear.
PURPOSE
In the current study, we determined whether Pulsatilla chinensis saponins (PRS), a phytomedicine from Pulsatilla chinensis (Bunge) Regel with excellent anti-IBD effect, could improve the depression. Furthermore, we investigated the mechanisms to explore the relationship between IBD and depression and provide new source for the urgent development of antidepressants from phytomedicine.
METHODS
The antidepressant activity of PRS was accessed by behavioral test and multichannel technology in depression mice induced by Chronic Unpredictable Mild Stress (CUMS). 16S rDNA-based microbiota and RNA-seq in colon was used to explore potential intestinal metabolism affected by PRS. To illustrate the underlying mechanisms of anti-depression effect of PRS, targeted metabolomics, ELISA assay, immunofluorescence staining, Western Blot, and qPCR were carried out.
RESULTS
The results clarified that CUMS induced depression with tryptophan (Trp) metabolism and intestinal inflammation. PRS effectively suppressed the depression and acted as a regulator of Trp/kynurenine (Kyn) metabolic and intestinal inflammation confirmed by analysis of microflora and colon RNA. Meanwhile PRS reduced interferon gamma (IFN-γ), inhibited JAK1-STAT1 phosphorylation, decreased IDO1 levels to protect against the overactivity of Trp/kyn path, suggesting that IFN-γ activated IDO1 probably a significant target for PRS to exert anti-depression effects. To further confirm the mechanism, this research expressed that PRS improved IDO1 activity and depressive behavior in mice with IFN-γ-induced depression. Furthermore, the therapeutic effect of 1-methyl-tryptophan (1-MT) well known as an IDO1 inhibitor in depression and clinically used anti-UC drug Mesalazine (MS) was demonstrated to confirm the potential mechanism.
CONCLUSION
The study is the first to reveal the antidepressant effect of PRS and further demonstrate its potential therapeutic targets. In addition, it also clarifies that the Trp/kyn pathway is the crosstalk between IBD and depression and provides new choice for depression treatment. And it also provides an important basis for the follow-up development and exploration of anti-intestinal antidepressants.
Topics: Mice; Animals; Tryptophan; Pulsatilla; Saponins; Inflammatory Bowel Diseases; Antidepressive Agents; Interferon-gamma; Inflammation; Indoleamine-Pyrrole 2,3,-Dioxygenase
PubMed: 37167824
DOI: 10.1016/j.phymed.2023.154852 -
Journal of Gastroenterology and... Jul 2023
Topics: Humans; Colitis, Ulcerative; Mesalamine; Proctitis
PubMed: 37170628
DOI: 10.1111/jgh.16216 -
Journal of Ethnopharmacology May 2024Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be...
Anchang Yuyang Decoction inhibits experimental colitis-related carcinogenesis by regulating PPAR signaling pathway and affecting metabolic homeostasis of host and microbiota.
ETHNOPHARMACOLOGICAL RELEVANCE
Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties.
AIM OF THE STUDY
This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches.
MATERIALS AND METHODS
A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting.
RESULTS
AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-β/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]).
CONCLUSIONS
This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.
Topics: Rats; Animals; Mice; Peroxisome Proliferator-Activated Receptors; RNA, Ribosomal, 16S; Chromatography, Liquid; Tandem Mass Spectrometry; Colitis; Inflammation; Signal Transduction; Inflammatory Bowel Diseases; Carcinogenesis; Azoxymethane; Gastrointestinal Microbiome; Colorectal Neoplasms; Homeostasis; Adenoma; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Colon
PubMed: 38428656
DOI: 10.1016/j.jep.2024.117995 -
Journal of Crohn's & Colitis Dec 2023The benefit of continuing 5-aminosalicylic acid [5-ASA] treatment when escalating to advanced therapies in patients with inflammatory bowel disease [IBD] is unclear....
BACKGROUND AND AIMS
The benefit of continuing 5-aminosalicylic acid [5-ASA] treatment when escalating to advanced therapies in patients with inflammatory bowel disease [IBD] is unclear. Vedolizumab is a gut-selective monoclonal anti-α4β7-integrin antibody used to treat moderate to severe IBD. Clinical trial data were analysed post hoc to assess the impact of 5-ASA co-treatment on vedolizumab efficacy and safety in patients with IBD.
METHODS
Data were analysed from patients aged 18-80 years with moderate to severe ulcerative colitis [UC]/Crohn's disease [CD] receiving intravenous [IV]/subcutaneous [SC] vedolizumab. Efficacy data were from four studies [GEMINI 1 and 2 and VISIBLE 1 and 2]; safety data were from seven studies [GEMINI 1‒3 and long-term, VISIBLE 1, 2, and open-label extension]. The impact of 5-ASA co-treatment on clinical and endoscopic outcomes at Weeks 6 and 52 was assessed using multivariate analysis (adjusted odds ratios [aORs] with 95% confidence intervals [CIs]).
RESULTS
There were no significant differences in UC clinical remission [Mayo score ≤2, no subscore >1] rates with vs without 5-ASA at Week 6 [20.7% vs 20.4%, respectively; aOR 0.77, 95% CI 0.43-1.38] or at Week 52 [45.1% vs 40.6%; aOR 1.14, 0.70-1.86], and in CD clinical remission [CD activity index score ≤150] rates at Week 6 [41.4% vs 35.1%; 1.26, 0.86-1.85] or at Week 52 [49.6% vs 37.8%; 1.35, 0.91-1.99]. The incidence of enteric and all infections in vedolizumab IV/SC-treated patients was low with and without 5-ASA.
CONCLUSION
Continuation of concomitant oral 5-ASA after starting vedolizumab had no significant impact on clinical and endoscopic outcomes.
CLINICAL TRIAL IDENTIFIERS
GEMINI 1: NCT00783718, EudraCT 2008-002782-32; GEMINI 2: NCT00783692, EudraCT 2008-00278-33; GEMINI 3: NCT01224171, EudraCT 2009-016488-12; GEMINI long-term safety study: NCT00790933, EudraCT 2008-002784-14; VISIBLE 1: NCT02611830, EudraCT 2015-000480-14; VISIBLE 2: NCT02611817, EudraCT 2015-000481-58; VISIBLE open-label extension: NCT02620046, EudraCT 2015-000482-31.
Topics: Humans; Mesalamine; Gastrointestinal Agents; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Treatment Outcome; Antibodies, Monoclonal, Humanized
PubMed: 37492976
DOI: 10.1093/ecco-jcc/jjad113 -
EClinicalMedicine Nov 2023Previous studies have demonstrated the tolerability and efficacy of multimatrix mesalamine in inducing and maintaining remission in adults with mild-to-moderate...
BACKGROUND
Previous studies have demonstrated the tolerability and efficacy of multimatrix mesalamine in inducing and maintaining remission in adults with mild-to-moderate ulcerative colitis (UC). We evaluated the safety and efficacy of low-dose and high-dose once-daily multimatrix mesalamine in children and adolescents with mild-to-moderate UC or those in remission.
METHODS
This prospective, randomised, parallel-group, phase 3 study (8-week double-blind acute [DBA] phase; 26-week double-blind maintenance [DBM] phase; and an additional 8-week, open-label acute [OLA] phase) was conducted in 33 sites across North America, Europe, and the Middle East between December 12, 2014, and November 28, 2018. Eligible patients aged 5-17 years and weighing 18-90 kg were randomised 1:1 to either low (900-2400 mg) or high (1800-4800 mg) oral doses of multimatrix mesalamine once daily, stratified by body weight. Interactive response technology was used for randomisation. The primary efficacy outcome was to estimate the clinical response of multimatrix mesalamine (two doses) in different weight groups. Efficacy and safety analyses were conducted in the safety analysis set (Clinicaltrials.gov: NCT02093663; Study completed).
FINDINGS
Overall, 107 patients were randomised into the DBA (n = 54) or DBM phase (n = 88; directly or after completing the double-blind or OLA phases); the overall safety analysis set included 105 patients. In the DBA phase, the high-dose group (n = 17; 65.4%) achieved a higher clinical response rate than the low-dose (n = 10; 37.0%) group; difference 28.3% (95% CI: 2.5-54.2; p = 0.039), odds ratio (OR) 3.21 (95% CI: 1.04-9.88). In the DBM phase at Week 26, similar proportions of patients maintained clinical response in the low-dose (n = 23; 54.8%) and high-dose (n = 24; 53.3%) groups: OR 0.99 (0.42-2.34); p = 0.981. Overall, 246 treatment-emergent adverse events (TEAEs) were reported in 73 patients (69.5%); 23 TEAEs in 14 patients (13.3%) were considered related to the study drug. No treatment-related deaths were reported.
INTERPRETATION
Our findings suggested that the benefit-risk ratio of once-daily multimatrix mesalamine in paediatric patients was favourable and comparable with that reported in adults with mild-to-moderate UC.
FUNDING
Shire Development LLC, a Takeda company.
PubMed: 37855022
DOI: 10.1016/j.eclinm.2023.102232