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Drug Development and Industrial Pharmacy Apr 2023A novel formulation for Ulcerative Colitis (UC) treatment by rectal administration with budesonide liposomes (Bud ) and thermosensitive gel (Gel) was developed for...
PURPOSE
A novel formulation for Ulcerative Colitis (UC) treatment by rectal administration with budesonide liposomes (Bud ) and thermosensitive gel (Gel) was developed for future clinical use. To evaluate the anti-inflammatory activity and colon mucosal protection of this novel formulation compared with the other three in mice.
METHODS
Bud was prepared by reverse evaporation method and then dispersed in solutions with PL407 and PL188 by a cold method. Male mice were induced to UC by dextran sulfate sodium (DSS) and were treated for 14 days by rectal administration, as follows: Bud (a conventional suspension formulation); Bud ; Bud ; Bud ; saline. And a negative control without colitis was also used. Disease activity index (DAI), and macroscopic and microscopic damage scores in colon tissues were used to evaluate the effect of therapy. The levels of IL-6 and IL-10 in serum and the concentrations of TNF-α and IL-10 and myeloperoxidase (MPO) activity in colon tissue were also introduced.
RESULTS
In UC mice model, Bud showed inflammation was alleviated significantly, and the treatment was highly associated with lower DAI, less macroscopic and microscopic colonic damage and downregulation of pro-inflammatory cytokines TNF-α, IL-6 and MPO. Bud had advantages over Bud, Bud , Bud in the treatment of active UC.
CONCLUSION
Novel Bud liposomes complex in thermosensitive Gel effectively mitigated symptoms, alleviated macroscopic and microscopic colon damage, and reduced inflammatory reaction in UC mice, which might be a potential strategy for UC treatment.
Topics: Male; Animals; Mice; Colitis, Ulcerative; Interleukin-10; Liposomes; Tumor Necrosis Factor-alpha; Budesonide; Interleukin-6; Inflammation
PubMed: 37272387
DOI: 10.1080/03639045.2023.2212789 -
Therapeutische Umschau. Revue... Jan 2019Perianal fistulas in CED: from mouse model to clinic Abstract. Fistulas are one of the most severe complications in Crohn's disease patients (CD). More than one third of... (Review)
Review
Perianal fistulas in CED: from mouse model to clinic Abstract. Fistulas are one of the most severe complications in Crohn's disease patients (CD). More than one third of Crohn's disease patients will suffer from mainly perianal fistulas during the course of their disease. Options for fistula treatment are scarce and their efficacy is often insufficient. In particular, complex fistulas often can only insufficiently be treated and complete and longstanding fistula closure occurs only in about one third of the patients. One of the big challenges in this area is that, on the one hand, fistula pathogenesis is only partially understood, and, on the other, no well-established in vivo model for Crohn's fistula exists that could be used for preclinical studies. From a histopathologic perspective, a fistula is a tube-like formation that is covered by epithelial-like cells. Our current research findings suggests that fistulas development in Crohn's disease patients due to epithelial-to-mesenchymal transition (EMT) which occurs during wound healing and invasive cell growth. Cytokines and growth factors, such as TNF, IL-13 and TGFβ, seem to play a prominent role during fistula development. Current treatment strategies for Crohn's fistula include medcial treatment as well as surgical approaches, often used in combination. Routinely used medications mainly include antibiotics, immunosuppressives and anti-TNF antibodies. Recent studies also indicate that adipose tissue-derived or bone marrow-derived mesenchymal stem cells might be a promising novel approach for fistula therapy. However, often available medications are insufficient and surgery is needed what often also does not provide durable relief. So, it is obvious that novel treatment approaches are urgently needed to improve our understanding of fistula pathogenesis and to develop novel therapeutic strategies for the patients.
Topics: Animals; Crohn Disease; Humans; Immunosuppressive Agents; Mice; Rectal Fistula; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 30700244
DOI: 10.1024/0040-5930/a001000 -
Medical Oncology (Northwood, London,... Sep 2023The CYLD gene is a tumor suppressor, reduced in many cancers. Here, we aimed to investigate CYLD protein level and NF-κβ/TNF-α signaling pathway in rectal cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
The CYLD gene is a tumor suppressor, reduced in many cancers. Here, we aimed to investigate CYLD protein level and NF-κβ/TNF-α signaling pathway in rectal cancer patients with Lactobacillus acidophilus (L. acidophilus) consumption. One hundred ten patients with non-metastatic rectal cancer were randomly divided into L. acidophilus probiotic (500 mg, three times daily) and placebo groups for 13 weeks. The expression of CYLD, TNF-α, and NF-κB proteins and the genes involved in the NF-κβ/TNF-α pathway were evaluated using ELISA and qPCR techniques. The survival rate was measured after five years. Unlike the placebo group, the results showed a significant increase in the expression of CYLD protein and tumor suppressor genes, including FOXP3, ROR-γ, Caspase3, GATA3, T-bet, and a considerable decrease in the expression of NF-ҝβ and TNF-α proteins and oncogenes, including STAT3, 4, 5, 6, and SMAD 3, in the probiotic group. A higher overall survival rate was seen after L. acidophilus consumption compared to the placebo group (P < 0.05). L. acidophilus consumption can reduce inflammation factors by affecting CYLD protein and its downstream signaling pathways. A schematic plot of probiotic consumption Effects on the CYLD protein in regulating the NF-ĸβ signaling pathway in colorectal cancer. NF-ĸβ can be activated by canonical and noncanonical pathways, which rely on IκB degradation and p100 processing, respectively. In the canonical NF-κβ pathway, dimmers, such as p65/p50, are maintained in the cytoplasm by interacting with an IκBα protein. The binding of a ligand to a cell-surface receptor activates TRAF2, which triggers an IKK complex, containing -α, -β, -g, which phosphorylates IKK-β. It then phosphorylates IκB-α, leading to K48-ubiquitination and degradation of this protein. The p65/p50 protein freely enters the nucleus to turn on target genes. The non-canonical pathway is primarily involved in p100/RelB activation. It differs from the classical pathway in that only certain receptor signals activate this pathway. It proceeds through an IKK complex that contains two IKK-α subunits but not NEMO. Several materials including peptidoglycan, phorbol, myristate, acetate, and gram-positive bacteria such as probiotics inhibit NF-κB by inducing CYLD. This protein can block the canonical and noncanonical NF-κβ pathways by removing Lys-63 ubiquitinated chains from activated TRAFs, RIP, NEMO, and IKK (α, β, and γ). Moreover, TNF-α induces apoptosis by binding caspase-3 to FADD.
Topics: Humans; Tumor Necrosis Factor-alpha; Deubiquitinating Enzyme CYLD; Lactobacillus acidophilus; NF-kappa B; Signal Transduction; Probiotics; Neoplasms
PubMed: 37725175
DOI: 10.1007/s12032-023-02170-y -
Gut Jan 2018Radiation proctitis (RP) is a complication of pelvic radiotherapy which affects both the host and microbiota. Herein we assessed the radiation effect on microbiota and...
OBJECTIVE
Radiation proctitis (RP) is a complication of pelvic radiotherapy which affects both the host and microbiota. Herein we assessed the radiation effect on microbiota and its relationship to tissue damage using a rectal radiation mouse model.
DESIGN
We evaluated luminal and mucosa-associated dysbiosis in irradiated and control mice at two postradiation time points and correlated it with clinical and immunological parameters. Epithelial cytokine response was evaluated using bacterial-epithelial co-cultures. Subsequently, germ-free (GF) mice were colonised with postradiation microbiota and controls and exposed to radiation, or dextran sulfate-sodium (DSS). Interleukin (IL)-1β correlated with tissue damage and was induced by dysbiosis. Therefore, we tested its direct role in radiation-induced damage by IL-1 receptor antagonist administration to irradiated mice.
RESULTS
A postradiation shift in microbiota was observed. A unique microbial signature correlated with histopathology. Increased colonic tumor necrosis factor (TNF)α, IL-1β and IL-6 expression was observed at two different time points. Adherent microbiota from RP differed from those in uninvolved segments and was associated with tissue damage. Using bacterial-epithelial co-cultures, postradiation microbiota enhanced IL-1β and TNFα expression compared with naïve microbiota. GF mice colonisation by irradiated microbiota versus controls predisposed mice to both radiation injury and DSS-induced colitis. IL-1 receptor antagonist administration ameliorated intestinal radiation injury.
CONCLUSIONS
The results demonstrate that rectal radiation induces dysbiosis, which transmits radiation and inflammatory susceptibility and provide evidence that microbial-induced radiation tissue damage is at least in part mediated by IL-1β. Environmental factors may affect the host via modifications of the microbiome and potentially allow for novel interventional approaches via its manipulation.
Topics: Animals; Coculture Techniques; Colitis; Cytokines; Disease Susceptibility; Dysbiosis; Fecal Microbiota Transplantation; Feces; Female; Gastrointestinal Microbiome; Germ-Free Life; Intestinal Mucosa; Mice, Inbred C57BL; Proctitis; Radiation Injuries; Rectum
PubMed: 28438965
DOI: 10.1136/gutjnl-2017-313789 -
The Lancet. Gastroenterology &... Feb 2022Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission... (Randomized Controlled Trial)
Randomized Controlled Trial
Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial.
BACKGROUND
Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents.
METHODS
HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov, NCT02100696.
FINDINGS
HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114).
INTERPRETATION
HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14.
FUNDING
F Hoffmann-La Roche.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Asia; Colitis, Ulcerative; Europe; Female; Gastrointestinal Agents; Humans; Injections, Subcutaneous; Male; Middle Aged; Middle East; North America; Oceania; Remission Induction; Severity of Illness Index; South America; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Young Adult
PubMed: 34798039
DOI: 10.1016/S2468-1253(21)00298-3 -
Journal of Gastrointestinal Cancer Mar 2022While the treatment for early stage rectal cancer is surgery, when a diagnosis is made at a locally advanced stage, it is recommended to start treatment with neoadjuvant...
BACKGROUND/AIM
While the treatment for early stage rectal cancer is surgery, when a diagnosis is made at a locally advanced stage, it is recommended to start treatment with neoadjuvant chemoradiotherapy. Therefore, it is important to determine which patients will respond best to neoadjuvant treatment. The aim of this study was to investigate which hematological, histopathological, and radiological parameters can predict the response to chemoradiotherapy.
METHODS AND MATERIAL
A retrospective examination was made of 43 patients who underwent surgery following neoadjuvant chemoradiotherapy because of locally advanced stage rectal cancer. Demographic data were collected from the patient files, and the radiological, histopathological, and laboratory findings before neoadjuvant chemoradiotherapy were compared with the findings after treatment.
RESULTS
In the postoperative evaluation, a pathological complete response was determined in 25.50% of the patients. Lymphovascular invasion, perineural invasion, and absence of necrosisis were seen to be statistically related to major response (p < 0.05), and in patients where the tumor was closer than 6 cm to the anal verge, the response was better CONCLUSION: When the findings were examined, histopathological lymphovascular invasion, perineural invasion, the presence of necrosis, and the anal verge distance were evaluated as parameters predicting the response to neoadjuvant chemoradiotherapy in rectal cancer.
Topics: Chemoradiotherapy; Demography; Humans; Neoadjuvant Therapy; Rectal Neoplasms; Retrospective Studies; Treatment Outcome
PubMed: 34472012
DOI: 10.1007/s12029-021-00697-9 -
International Journal of Surgery Case... 2018Incarceration and necrosis of rectal prolapse is rare but when it occurs it requires urgent management. Perineal rectosigmoidectomy (Altemeier's procedure) may be a...
INTRODUCTION
Incarceration and necrosis of rectal prolapse is rare but when it occurs it requires urgent management. Perineal rectosigmoidectomy (Altemeier's procedure) may be a reasonable approach for the treatment of this condition. In some cases, a diverting stoma may be necessary.
METHODS
We report two cases of incarcerated massive rectal prolapse, one of which also manifested tissue necrosis, that were successfully treated with perineal rectosigmoidectomy. In one case a diverting colostomy was required. Both patients recovered uneventfully.
RESULTS
A literature review was performed to determine the optimal management of incarcerated and necrotic rectal prolapse, and to determine the indication for fecal diversion.
CONCLUSION
Perineal rectosigmoidectomy (Altemeier's procedure) can be utilized in emergency circumstances and, in our experience, the procedure was both safe and effective. The need for fecal diversion depends on the condition of the patient and the experience and judgement of the surgeon.
PubMed: 30360238
DOI: 10.1016/j.ijscr.2018.08.057 -
Tidsskrift For Den Norske Laegeforening... Dec 2023Fluoropyrimidines have been linked to cardiovascular toxicity.
BACKGROUND
Fluoropyrimidines have been linked to cardiovascular toxicity.
CASE PRESENTATION
A woman in her forties with locally advanced rectal cancer received curative-intent treatment according to the RAPIDO protocol. Shortly after starting the first 5-fluorouracil infusion she developed chest/epigastric pain, nausea and vomiting. Electrocardiogram showed mild ST elevation in multiple contiguous leads. Troponin I was elevated. Transthoracic echocardiogram (TTE) displayed signs suggestive of myocardial infarction. Coronary angiogram indicated no obstructive coronary artery disease. Ventriculography demonstrated apical hypokinesia and basal hyperkinesia. MRI revealed no signs of myocardial infarction or myocarditis. The patient was diagnosed with Takotsubo syndrome, possibly induced by 5-fluorouracil. Follow-up TTE three weeks later was normal. Subsequently, she received treatment with tegafur/gimeracil/oteracil (Teysuno®) in place of 5-fluorouracil, combined with oxaliplatin. No further cardiotoxicity was observed during three cycles.
INTERPRETATION
The patient was diagnosed with Takotsubo syndrome following 5-fluorouracil infusion, likely to represent 5-fluorouracil-induced cardiotoxicity. Following replacement of 5-fluorouracil with Teysuno®, she experienced no signs of cardiotoxicity.
Topics: Female; Humans; Cardiotoxicity; Electrocardiography; Fluorouracil; Myocardial Infarction; Takotsubo Cardiomyopathy; Adult; Middle Aged
PubMed: 38088292
DOI: 10.4045/tidsskr.23.0338 -
Biochimica Et Biophysica Acta.... Apr 2024Colorectal cancer (CRC) has been the third most common malignancy and the second cause of cancer-related mortality. As the core of volume-sensitive chloride currents,...
Colorectal cancer (CRC) has been the third most common malignancy and the second cause of cancer-related mortality. As the core of volume-sensitive chloride currents, leucine-rich repeat-containing 8A (LRRC8A) contributes to tumor progression but is not consistent, especially for whom the roles in colon carcinoma metastasis were not fully elucidated. Herein, LRRC8A proteins were found highly expressed in hematogenous metastasis from human colorectal cancer samples. The oxaliplatin-resistant HCT116 cells highly expressed LRRC8A, which was related to impaired proliferation and enhanced migration. The over-expressed LRRC8A slowed proliferation and increased migration ex vivo and in vivo. The elevated LRRC8A upregulated the focal adhesion, MAPK, AMPK, and chemokine signaling pathways via phosphorylation and dephosphorylation. Inhibition of LRRC8A impeded the TNF-α signaling cascade and TNF-α-induced migration. LRRC8A binding to PIP5K1B regulated the PIP2 formation, providing a platform for LRRC8A to mediate cell signaling transduction. Importantly, LRRC8A self-regulated its transcription via NF-κB1 and NF-κB2 pathways and the upregulation of NIK/NF-κB2/LRRC8A transcriptional axis was unfavorable for colon cancer patients. Collectively, our findings reveal that LRRC8A is a central mediator in mediating multiple signaling pathways to promote metastasis and targeting LRRC8A proteins could become a potential clinical biomarker-driven treatment strategy for colon cancer patients.
Topics: Humans; Colonic Neoplasms; Membrane Proteins; NF-kappa B p52 Subunit; Rectal Neoplasms; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 38350542
DOI: 10.1016/j.bbadis.2024.167066 -
Nutrients Jul 2022A leaky gut is closely connected with systemic inflammation and psychiatric disorder. The rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induces gut...
A leaky gut is closely connected with systemic inflammation and psychiatric disorder. The rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induces gut inflammation and cognitive function in mice. Therefore, we selected NK219, NK209, and NK210, which induced claudin-1 expression in TNBS- or lipopolysaccharide (LPS)-stimulated Caco-2 cells, from the fecal bacteria collection of humans and investigated their effects on cognitive function and systemic inflammatory immune response in TNBS-treated mice. The intrarectal injection of TNBS increased cognitive impairment-like behaviors in the novel object recognition and Y-maze tests, TNF-α, IL-1β, and IL-17 expression in the hippocampus and colon, and LPS level in the blood and feces, while the expression of hippocampal claudin-5 and colonic claudin-1 decreased. Oral administration of NK209, NK210, and NK219 singly or together decreased TNBS-impaired cognitive behaviors, TNF-α and IL-1β expression, NF-κBIba1 cell and LPSIba1 cell numbers in the hippocampus, and LPS level in the blood and feces, whereas BDNFNeuN cell and claudin-5 cell numbers and IL-10 expression increased. Furthermore, they suppressed TNBS-induced colon shortening and colonic TNF-α and IL-1β expression, while colonic IL-10 expression and mucin protein-2 cell and claudin-1 cell numbers expression increased. Of these, NK219 most strongly alleviated cognitive impairment and colitis. They additively alleviated cognitive impairment with colitis. Based on these findings, NK209, NK210, NK219, and their combinations may alleviate cognitive impairment with systemic inflammation by suppressing the absorption of gut bacterial products including LPS into the blood through the suppression of gut bacterial LPS production and alleviation of a leaky gut by increasing gut tight junction proteins and mucin-2 expression.
Topics: Animals; Caco-2 Cells; Claudin-1; Claudin-5; Cognitive Dysfunction; Colitis; Humans; Inflammation; Interleukin-10; Lipopolysaccharides; Mice; NF-kappa B; Probiotics; Tight Junction Proteins; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha
PubMed: 35889931
DOI: 10.3390/nu14142975