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Molecules (Basel, Switzerland) Mar 2024Biocatalysis processes based on oxidoreductases, such as fungal laccase, are important for discovering new organic compounds with broad structures and potential...
Biocatalysis processes based on oxidoreductases, such as fungal laccase, are important for discovering new organic compounds with broad structures and potential applications. They include bioactive compounds, which can be obtained through laccase-mediated oxidation of organic substrates having hydroxyl and/or amino groups especially, e.g., 5-aminosalicylic acid (5-ASA) is characterised for its potential for oxidation by a fungal laccase obtained from a strain. The biotransformation process was optimised in terms of the buffer and co-solvent concentration, buffer pH value, and laccase activity. Selected crude dyes were analysed for their bioactive properties, toxicity, and suitability for the dyeing of wool fibres. The data obtained clearly indicated that a low concentration of the reaction buffer in the pH range from 5 to 6 and in the presence of 10% acetonitrile increased the rate of substrate oxidation and the amount of the product formed. The red-brown compound obtained via laccase-mediated oxidation of 5-aminosalicylic acid showed antioxidant properties and unique antimicrobial activity against and strains with the MIC value of 0.125 mg/mL detected for the purest dye. In addition, it was reported to have good wool fibre dyeing properties and no irritant effect after patch tests on a selected group with increased skin sensitivity.
Topics: Animals; Laccase; Mesalamine; Oxidation-Reduction; Antioxidants; Coloring Agents; Hydrogen-Ion Concentration
PubMed: 38542946
DOI: 10.3390/molecules29061310 -
Frontiers in Chemistry 2024A key challenge for the effective treatment of intestinal diseases, including inflammatory bowel disease (IBD), is to develop an oral drug delivery system that can...
A key challenge for the effective treatment of intestinal diseases, including inflammatory bowel disease (IBD), is to develop an oral drug delivery system that can resist gastric acid erosion and efficiently release drugs after rapid entry into the intestine. In the present work, we developed oral composite nanoparticles (MSZ@PRHS) consisting of a rough mesoporous silica (RHS) loaded with Mesalazine (MSZ) and a CAP polymer membrane for targeted relief of inflammation in colitis. At the pH values of the simulated stomach and small intestine, the release rate of MSZ from MSZ@PRHS was low, while at the pH values of the simulated colon, the release rate of MSZ was high. In dextran sulfate sodium salt (DSS)-induced acute colitis mouse model, compared with oral administration of the drug Mesalazine in the equivalent solution form, oral administration of PRHS loaded with drug-loaded nanoparticles can significantly alleviate the symptoms of inflammatory bowel disease, and improve the therapeutic effect. We propose that the intestinal microenvironment provides an interface for nanocomposites switch and a promising drug delivery platform for the management and treatment of many intestinal diseases, where controlled drug release and prolonged residence time are required.
PubMed: 38532806
DOI: 10.3389/fchem.2024.1365880 -
Trials Mar 2024The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC,... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial.
BACKGROUND
The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial.
DESIGN AND METHODS
The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life.
DISCUSSION
The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients.
TRIAL REGISTRATION
Dutch Trial Register (NTR) NTR2883 . Registered May 3, 2011. ISRCTN, ISRCTN60945764 . Registered August 12, 2019.
Topics: Humans; Colitis, Ulcerative; Appendectomy; Quality of Life; Remission Induction; Neoplasm Recurrence, Local; Mesalamine; Recurrence; Disease Progression
PubMed: 38532488
DOI: 10.1186/s13063-024-08037-5 -
Digestion 20245-aminosalicylic acid (5-ASA) is the first-line drug for the treatment of mild-to-moderate ulcerative colitis (UC). Three oral sustained-release formulations are often...
Analysis of the Medication Persistence Rate for and Adherence to Oral 5-Aminosalicylic Acid Preparations in Japanese Patients with Ulcerative Colitis: Study Using a Nationwide Claims Database.
INTRODUCTION
5-aminosalicylic acid (5-ASA) is the first-line drug for the treatment of mild-to-moderate ulcerative colitis (UC). Three oral sustained-release formulations are often used. However, no unified view of their actual use in routine medical practice has been presented to date.
METHODS
Using a health insurance claims database, we extracted patients with an initial diagnosis of mild-to-moderate UC during the period from December 1, 2017, to March 31, 2022. For the three types of oral 5-ASA formulation, we calculated and compared descriptive statistics of medication persistence rates (MPR), proportions of days covered (PDC), and adherence proportion (PDC ≥80%) in the extracted population.
RESULTS
An oral 5-ASA formulation was used in combination with a topical preparation (cohort 1) in 899 patients, and oral 5-ASA was used alone (cohort 2) in 1,829 patients. In cohort 1, MPR at days 151-180 with concomitant use of topical formulation was significantly higher for the Multi Matrix System™ (MMX) formulation (65.2%) compared with that for pH-dependent formulation (51.7%, p < 0.025), while MPR tended to be higher for MMX than for the time-dependent formulation (56.4%, not significant). During days 151-180 after starting the oral formulation, MPR for MMX (66.7% and 65.8%) was higher than for pH-dependent (55.9% and 55.3%) and time-dependent (57.6% and 55.9%) formulations in cohorts 1 + 2 and 2, respectively. In cohort 1, there was a significant difference between MMX (68.3%) and pH-dependent (57.1%) formulations, but no significant difference was seen with time-dependent formulations (61.8%). In terms of the proportion of adherence until day 180, MMX was significantly better than the other formulations.
CONCLUSION
The analyses of the three oral 5-ASA formulations suggested that both MPR and medication adherence were better for the MMX formulation than for time-dependent or pH-dependent formulations.
Topics: Humans; Colitis, Ulcerative; Mesalamine; Medication Adherence; Male; Female; Administration, Oral; Middle Aged; Adult; Japan; Anti-Inflammatory Agents, Non-Steroidal; Databases, Factual; Aged; Delayed-Action Preparations; Retrospective Studies; Young Adult; Administration, Topical; East Asian People
PubMed: 38527451
DOI: 10.1159/000538319 -
Advanced Biomedical Research 2024Ulcerative colitis (UC) is one of the inflammatory gastrointestinal diseases. It causes irritation, inflammation, and ulcers in the digestive tract. UC is distinguished...
BACKGROUND
Ulcerative colitis (UC) is one of the inflammatory gastrointestinal diseases. It causes irritation, inflammation, and ulcers in the digestive tract. UC is distinguished clinically by abdominal and rectal pain and intestinal secretion abnormalities. Mesenchymal stem cell (MSC) therapy could be the underlying treatment for UC. This study aimed to compare the results of MSC therapy with tretinoin and caffeine in an animal model.
MATERIALS AND METHODS
Sixty male BALB/c mice were randomly divided into six equal groups. Five groups were exposed to acetic acid-induced colitis, and one healthy negative control group was designed. The positive control group was UC-induced mouse model with no treatment. Besides, treatment groups were MSCs (n = 2×10) that received tretinoin and caffeine. The treatment group was given mesalazine orally. The decision to begin treatment was taken after monitoring the symptoms of the UC.
RESULTS
MSCs, tretinoin, and caffeine-treated MSCs significantly decrease inflammatory cytokines (interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α) and inflammatory mediators (myeloperoxidase (MPO) and nitric oxide (NO)) compared with the positive control group. However, the alleviated effects of tretinoin-treated MSCs significantly were more than those of MSCs and caffeine-treated MSCs.
CONCLUSION
MSC therapy is an effective option for UC and can prevent disease progression. The results represented a high developmental rate and simple cell application of MSC therapy in UC patients. Also, MSC therapy's ability for immunomodulation is strengthened by drugs that improve their microenvironment by binding to their receptors.
PubMed: 38525396
DOI: 10.4103/abr.abr_173_23 -
Journal of Translational Medicine Mar 2024Osteoarthritis (OA) is a multifactorial, hypertrophic, and degenerative condition involving the whole joint and affecting a high percentage of middle-aged people. It is... (Meta-Analysis)
Meta-Analysis
Identification of therapeutic targets in osteoarthritis by combining heterogeneous transcriptional datasets, drug-induced expression profiles, and known drug-target interactions.
BACKGROUND
Osteoarthritis (OA) is a multifactorial, hypertrophic, and degenerative condition involving the whole joint and affecting a high percentage of middle-aged people. It is due to a combination of factors, although the pivotal mechanisms underlying the disease are still obscure. Moreover, current treatments are still poorly effective, and patients experience a painful and degenerative disease course.
METHODS
We used an integrative approach that led us to extract a consensus signature from a meta-analysis of three different OA cohorts. We performed a network-based drug prioritization to detect the most relevant drugs targeting these genes and validated in vitro the most promising candidates. We also proposed a risk score based on a minimal set of genes to predict the OA clinical stage from RNA-Seq data.
RESULTS
We derived a consensus signature of 44 genes that we validated on an independent dataset. Using network analysis, we identified Resveratrol, Tenoxicam, Benzbromarone, Pirinixic Acid, and Mesalazine as putative drugs of interest for therapeutics in OA for anti-inflammatory properties. We also derived a list of seven gene-targets validated with functional RT-qPCR assays, confirming the in silico predictions. Finally, we identified a predictive subset of genes composed of DNER, TNFSF11, THBS3, LOXL3, TSPAN2, DYSF, ASPN and HTRA1 to compute the patient's risk score. We validated this risk score on an independent dataset with a high AUC (0.875) and compared it with the same approach computed using the entire consensus signature (AUC 0.922).
CONCLUSIONS
The consensus signature highlights crucial mechanisms for disease progression. Moreover, these genes were associated with several candidate drugs that could represent potential innovative therapeutics. Furthermore, the patient's risk scores can be used in clinical settings.
Topics: Middle Aged; Humans; Osteoarthritis
PubMed: 38491514
DOI: 10.1186/s12967-024-05006-z -
International Journal of Molecular... Feb 2024Chronic rhinosinusitis (CRS) is a disease characterised by the inflammation of the nasal and paranasal cavities. It is a widespread condition with considerable morbidity...
Chronic rhinosinusitis (CRS) is a disease characterised by the inflammation of the nasal and paranasal cavities. It is a widespread condition with considerable morbidity for patients. Current treatment for chronic rhinosinusitis consists of appropriate medical therapy followed by surgery in medically resistant patients. Although oral steroids are effective, they are associated with significant morbidity, and disease recurrence is common when discontinued. The development of additional steroid sparing therapies is therefore needed. Mesalazine is a commonly used therapeutic in inflammatory bowel disease, which shares a similar disease profile with chronic rhinosinusitis. This exploratory in vitro study aims to investigate whether mesalazine could be repurposed to a nasal wash, which is safe on human nasoepithelial cells, and retains its anti-inflammatory effects. CRS patients' human nasal epithelial cells (HNECs) were collected. HNECs were grown at an air-liquid interface (ALIs) and in a monolayer and challenged with mesalazine or a non-medicated control. Transepithelial electrical resistance, paracellular permeability, and toxicity were measured to assess epithelial integrity and safety. The anti-inflammatory effects of mesalazine on the release of interleukin (IL)-6 and tumour necrosis factor alpha (TNF-α) were analysed using human leukemia monocytic cell line (THP-1). mesalazine did not impact the barrier function of HNEC-ALIs and was not toxic when applied to HNECs or THP-1 cells at concentrations up to 20 mM. mesalazine at 0.5 and 1 mM concentrations significantly inhibited TNF-α release by THP-1 cells. mesalazine effectively decreases TNF-α secretion from THP-1 cells, indicating the possibility of its anti-inflammatory properties. The safety profile of mesalazine at doses up to 20 mM suggests that it is safe when applied topically on HNECs.
Topics: Humans; Mesalamine; Tumor Necrosis Factor-alpha; Cells, Cultured; Sinusitis; Nasal Mucosa; Interleukin-6; Anti-Inflammatory Agents; Chronic Disease; Epithelial Cells
PubMed: 38474043
DOI: 10.3390/ijms25052796 -
Functional & Integrative Genomics Mar 2024Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated...
Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated carcinogenesis (CAC) are still unclear. Therefore, we aimed to determine the beneficial effects of HQD on CAC in mice and to reveal the underlying mechanism involved. AOM/DSS was used to induce CAC in mice, and the effects of HQD on tumorigenesis in mice were examined (with mesalazine serving as a positive control). Mesalazine or HQD treatment alleviated body weight loss and decreased the disease activity index in mice induced by AOM/DSS. Mesalazine or HQD treatment also suppressed the shortening of colon tissue length, the number of tumors, and the infiltration of inflammatory cells. The genes targeted by HQD were predicted and verified, followed by knockout experiments. Elevated SLC6A4 and inhibited serotonin production and inflammation were observed in HQD-treated mice. HQD inhibited the NFκB and NLRP3/caspase1/GSDMD pathways. The therapeutic effect of HQD was diminished in SLC6A4-deficient AOM/DSS mice. Additionally, the downregulation of SLC6A4 mitigated the inhibitory effect of HQD-containing serum on MODE-K cell pyroptosis. Our findings suggest that SLC6A4 is a pivotal regulator of HQD-alleviated CAC via its modulation of the NLRP3/caspase1/GSDMD pathway.
Topics: Mice; Animals; Scutellaria baicalensis; Mesalamine; NLR Family, Pyrin Domain-Containing 3 Protein; Colitis; Carcinogenesis; Mice, Inbred C57BL
PubMed: 38467948
DOI: 10.1007/s10142-024-01334-x -
Cureus Feb 2024Patients who undergo restorative proctocolectomy and ileoanal anastomosis can develop pouchitis as a common chronic complication. A rare subset of patients fails to...
Patients who undergo restorative proctocolectomy and ileoanal anastomosis can develop pouchitis as a common chronic complication. A rare subset of patients fails to respond to multiple antibiotic therapies and develop chronic antibiotic-refractory pouchitis (CARP). We present a case of a 45-year-old male with pouchitis refractory to chronic antibiotic therapy and histology demonstrating chronic inflammatory changes. Management involved mesalamine and probiotics, resulting in a positive clinical response and symptom absence on follow-up. This case highlights the intricacies of treating chronic pouchitis post ileoanal anastomosis, showcasing the efficacy of a personalized approach using mesalamine and probiotics. CARP is emerging as an entity associated with poor quality of life and increased healthcare costs. CARP fails to respond to multiple courses of antibiotic therapy. Therefore, the management of CARP is difficult and limited. Current literature on the management of CARP is scarce and mainly involves immunomodulatory therapy and probiotics. It is essential to keep this differential diagnosis in mind in patients with recurrent pouchitis episodes and start them on immunomodulator treatment and probiotics rather than repeated courses of antibiotics.
PubMed: 38435148
DOI: 10.7759/cureus.53398 -
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