Morphological aspects of the protective effect of newly formulated rectal suppositories with turmeric extract in experimental Crohn’s disease

2021 ◽  
pp. 67-77
Author(s):  
М.В. Осиков ◽  
Е.В. Симонян ◽  
А.Е. Бакеева ◽  
Л.В. Астахова
Keyword(s):  
Tissue Damage ◽  
Activity Index ◽  
Curcuma Longa ◽  
Clinical Status ◽  
Damage Index ◽  
Disease Activity Index ◽  
The Novel ◽  
Turmeric Extract ◽  
Tnf Α ◽  
Rectal Suppositories

Введение. Востребованным для лечения болезни Крона (БК) является разработка новых, обоснованных с патогенетических позиций и безопасных лекарственных средств преимущественно локального действия эндогенного или растительного происхождения. В этом отношении привлекает внимание экстракт корневищ Куркумы длинной (Curcuma longa), содержащий куркуминоидный комплекс, обладающий плейотропными эффектами. Ранее нами показано, что экстракт куркумы в составе суппозиториев при экспериментальной БК обладaет иммуномодулирующим и местным антиоксидантным действием, что предполагает влияние экстракта куркумы на морфологию очага повреждения в кишечнике при БК. Цель работы - изучение влияния экстракта куркумы в составе оригинальных ректальных суппозиториев на динамику морфологических изменений, экспрессию миелопероксидазы (МПО) и TNF-a в очаге повреждения толстого кишечника при экспериментальной БК. Методика. Эксперимент выполнен на 49 половозрелых крысах-самцах Wistar. БК моделировали введением per rectum спиртового раствора тринитробензосульфоновой кислоты (ТНБС). Оригинальные ректальные суппозитории массой 300 мг на основе полиэтиленгликолей различной молекулярной массы, содержащие 0,075 мг куркумина из экстракта корневищ Curcuma longa L., вводили per rectum каждые 12 ч в течение 7 сут. Клинический статус оценивали по модифицированной шкале Disease activity index (DAI). Морфометрически в стенке кишечника оценивали размер язвенного дефект, выраженность клеточной инфильтрации, рассчитывали индекс тканевого повреждения (tissue damage index, TDI), оценивали экспрессию МПО и TNF-α. Результаты. При экспериментальной БК на 3-и, 5-е и 7-е сут наблюдения в толстом кишечнике обнаруживались язвенные дефекты, выраженный отек тканей, плотная нейтрофильно-лимфоцитарная инифильтрации с примесью эозинофилов, плазмоцитов, гистиоцитов, фибробластов, наблюдалось формирование грануляционной ткани. Индекс тканевого повреждения возрастал, повышалась экспрессия МПО и TNF-α. Размер язвенных дефектов, выраженность инфильтрации, индекс тканевого повреждения соответствовали клинической картине и индексу DAI. Применение оригинальных ректальных суппозиториев с экстрактом куркумы (0,075 мг) приводит к снижению выраженности клинических и морфологических признаков заболевания, максимальный эффект отмечен на 5-е и 7-е сут наблюдения. Заключение. Установленные протекторные свойства куркумина в составе оригинальных ректальных суппозиториев при БК на доклиническом этапе расширяют современные представления о плейотропных эффектах экстракта куркумы и являются предпосылкой для проведения дальнейших исследований и внедрения новой лекарственной формы в клиническую практику. The development of safe, new, pathogenetically justified medicines, mainly with local effects and of endogenous or plant origin, is of great interest for treatment of Crohn’s disease (CD). In this regard, an extract of rhizomes of Curcuma longa, containing a curcuminoid complex with pleiotropic effects, has attracted attention. We showed previously that having turmeric extract in suppositories for treatment of experimental CD would produce immunomodulatory and antioxidant effects. This suggests that turmeric extract affects the morphology of the CD intestinal lesion. The aim of this work was to study the effect of turmeric extract in the composition of novel rectal suppositories on the morphology and expression of myeloperoxidase (MPO) and TNF- α in colon lesions of experimental CD. Methods. Experiments were performed on 49 sexually mature male Wistar rats. CD was modeled by administration per rectum of an alcohol solution of trinitrobenzenesulfonic acid. The newly formulated rectal suppositories weighing 300 mg and based on polyethylene glycols of various molecular weights and containing 0.075 mg of curcumin obtained from Curcuma longa L. rhizome extract were administered per rectum every 12 hours for 7 days. The clinical status was assessed with the modified disease activity index (DAI) scale. The ulcer defect diameter, cell infiltration, tissue damage index (TDI), MPO expression, and TNF-α expression were evaluated. Results. In experimental CD on the 3rd, 5th, and 7th days of observation, a morphometric assessment of the lesion in the large intestine revealed the presence of ulcerative defects, edema, thick neutrophilic lymphocytic infiltration with an admixture of eosinophils, plasmocytes, histiocytes, fibroblasts, the formation of granulation tissue, increased TDI, and increased expression of MPO and TNF-α. The size of ulcerative defects, the degree of wall infiltration by neutrophils, lymphocytes, plasmocytes, histiocytes, and fibroblasts were recorded. The TDI, the expression of MPO, and TNF-α were associated with the DAI. The use of the novel rectal suppositories produced a maximal effect on the 5th and 7th days of observation. The severity of clinical and morphological signs of the disease were reduced. These signs included ulcer size, TDI, intestinal wall infiltration with neutrophils, lymphocytes, eosinophils, plasmocytes, histiocytes, and fibroblasts, and expression of MPO and TNF-α. Conclusion. The results supplement available data on the pathogenesis, the role of the expression of MPO and TNF-α, and the morphology of the lesion in the clinical status in TNBS-induced CD in rats. The demonstrated, protective properties of curcumin in the composition of the novel rectal suppositories at the preclinical stage of CD expand modern understanding of the pleiotropic effects of turmeric extract and are a prerequisite for further research and the introduction of a new dosage form in clinical practice.

scholarly journals Effect of local use of extractum of curcumin in Сrohn’s disease experiment

2020 ◽  
pp. 133-140
Author(s):  
M. V. Osikov ◽  
E. V. Simonyan ◽  
A. E. Bakeeva
Keyword(s):  
Clinical Symptoms ◽  
Activity Index ◽  
Clinical Status ◽  
Clinical Signs ◽  
Disease Activity Index ◽  
Aminosalicylic Acid ◽  
Trinitrobenzenesulfonic Acid ◽  
Turmeric Extract ◽  
Local Use ◽  
Rectal Suppositories

The aim was to study the effectiveness of the use of turmeric extract in the composition of the original rectal suppositories in experimental Crohn’s disease (CD) based on the assessment of the clinical picture and indicators of the immune status.Materials and methods. The work was performed on 70 rats of the Wistar line. CD was unduced by the rectal administration of a trinitrobenzenesulfonic acid solution, rectal suppositories with 0.000075 mg of curcumin based on an alcohol solution of rhizome extract with turmeric roots were used after 12 hours for 7 days, in the comparison group rectal suppositories with 50 mg of 5-aminosalicylic acid were used (5-ASA). To assess the clinical status, the Disease activity index scale was used, the population spectrum of leukocytes, CD3 + and CD45RA + lymphocytes, the concentration of IgG, IgM, IL-23 on the 3, 5 and 7 days of the experiment were determined.Results: In CD, the clinical signs of the disease progress from 3 to 7 days, the total number of leukocytes in the blood increases due to monocytes, lymphocytes, including CD3 +, CD45RA +, the concentration of IL-23, IgM, Ig G. Local use of turmeric extract in CD reduces the severity of clinical symptoms on days 5 and 7, restores the total number of leukocytes, lymphocytes, including CD3 +, the concentration of IgM on days 3, 5, 7, and IL-23 on days 5 and 7, partially restores serum concentration of IgG on the 3-rd, 5th, 7th day, IL-23—on the 3-rd day of observation. The eff ect of CD in the composition of rectal suppositories of turmeric extract is comparable to the eff ect of 5-ASA on the 3-rd, 5th, 7th day of observation in relation to the severity of clinical symptoms, the number of leukocytes, lymphocytes, CD3 + in the blood, the concentration of IgM and IgG; less pronounced in relation to the concentration of IL-23 on day 3.Conclusion. The clinical and immunological efficacy of local application of turmeric extract every 12 hours as part of the original rectal suppositories in experimental CD has been demonstrated, comparable with the use of rectal suppositories with 5-ASA. 

scholarly journals Dynamics of lipid peroxidation in the large intestine during experimental Crohn's disease and the use of rectal suppositories with long turmeric extract

2020 ◽  
pp. 131-136
Author(s):  
М.В. Осиков ◽  
Е.В. Симонян ◽  
А.Е. Бакеева ◽  
О.И. Огнева
Keyword(s):  
Lipid Peroxidation ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Large Intestine ◽  
Clinical Symptoms ◽  
Activity Index ◽  
Disease Activity Index ◽  
Turmeric Extract ◽  
Rectal Suppositories

Цель исследования - проведение сравнительного анализа влияния экстракта куркумы длинной и 5-аминосалициловой кислоты (5-АСК) в составе ректальных суппозиториев на клиническую картину и содержание продуктов перекисного окисления липидов (ПОЛ) в слизистой оболочке толстого кишечника при экспериментальной болезни Крона (БК). Методика. Эксперимент выполнен на 70 белых крысах-самцах Wistar. БК моделировали ректальным введением тринитробензосульфоновой кислоты. Ректальные суппозитории (массой 0,3 г каждая) начинали применять через 12 ч. Содержание 5-АСК в суппозиториях составляло 50 мг, 10% экстракта куркумы длинной оригинального состава 0,000075 г. На 3-и, 5-е и 7-е сут после моделирования БК оценивали клинический статус по модифицированной шкале Disease activity index и содержание продуктов ПОЛ в слизистой оболочке толстого кишечника. Результаты. В динамике БК в толстом кишечнике увеличивается содержание первичных, вторичных и конечных продуктов ПОЛ в гептановой и изопропанольной фазах; тяжесть клинических признаков (снижение массы тела, диарея, кровь в каловых массах) нарастает по мере увеличения содержания продуктов ПОЛ. Применение при БК ректальных суппозиториев с экстрактом куркумы снижает выраженность клинических симптомов, уменьшает содержание продуктов ПОЛ преимущественно в изопропанольной фазе липидного экстракта толстого кишечника; установлена корреляция индекса клинической активности БК с содержанием продуктов ПОЛ в толстом кишечнике. Заключение. Эффективность локального применения экстракта куркумы в составе ректальных суппозиториев сопоставима по эффективности с применением ректальных суппозиториев с 5-АСК по показателям индекса клинической активности и по содержанию продуктов ПОЛ в слизистой толстого кишечника. Aim. To compare effects of turmeric extract and 5-aminosalicylic acid (5-ASA) formulated into rectal suppositories on clinical symptoms and content of lipid peroxidation products (LPP) in the mucous membrane of the large intestine in experimental Crohn’s disease (CD). Methods: Experiments were performed on 70 Wistar male rats. CD was modeled by rectal administration of trinitrobenzenesulfonic acid; rectal suppositories (0.3 g each) were used every 12 h. The suppositories contained 5-ASA (50 mg) or 10% turmeric extract with an original composition (0.000075 g). On days 3, 5, and 7 of CD, the clinical status was evaluated with a modified Disease Activity Index scale, and LPP concentrations were measured in the large intestine mucosa. Results. In the course of CD in the colon, concentrations of primary, secondary, and final LPP in the heptane and isopropanol phases increased; severity of clinical signs (weight loss, diarrhea, blood in fecal masses) increased with increasing LPP concentrations. The use of rectal suppositories with turmeric extract alleviated severity of clinical symptoms and reduced LPP content primarily in the isopropanol phase of colon lipid extract. The index of CD clinical activity of CD was correlated with the large intestinal LPP content. Conclusion. Effectiveness of the local application of turmeric extract formulated into rectal suppositories was comparable with that of rectal suppositories with 5-ASA as determined by the Disease Activity Index and the LPP content in the large intestine.

Severity of the acute phase response in experimental ulcerative colitis under conditions of the use of vitamin D3 in a novel rectal suppository

2021 ◽  
pp. 80-88
Author(s):  
М.В. Осиков ◽  
М.С. Бойко ◽  
Е.В. Симонян
Keyword(s):  
Disease Activity ◽  
Vitamin D3 ◽  
Activity Index ◽  
Clinical Manifestations ◽  
Disease Activity Index ◽  
Blood Leukocytes ◽  
Reducing Ability ◽  
Tnf Α ◽  
Blood Neutrophils ◽  
Rectal Suppositories

Цель - изучение влияния витамина D3 в составе оригинальных ректальных суппозиториев на выраженность острофазового ответа при экспериментальном язвенном колите Методика. Эксперимент выполнен на 49 половозрелых крысах-самцах Wistar. Язвенный колит (ЯК) моделировали двухэтапным (накожным, а затем ректальным) применением 3% спиртового раствора оксазолона. Оригинальные суппозитории на основе смеси полиэтиленгликолей массой 300 мг, содержащие 1500 ME витамина D3, вводили per rectum каждые 12 ч в течение 6 сут. Исследования проводили на 2-е, 4-е и 6-е сут заболевания. Клиническую картину оценивали по адаптированной для крыс шкале Disease activity index (DAI) с учетом массы тела, консистенции и наличия крови в каловых массах. Количество лейкоцитов и нейтрофилов определяли на гематологическом анализаторе и в мазках крови. Функциональную активность нейтрофилов исследовали по поглощению частиц монодисперсного латекса в спонтанном и индуцированном НСТ-тесте. Концентрацию в сыворотке крови C-реактивного белка (С-РБ), IL-6 и IL-8 определяли с помощью иммуноферментного анализа, экспрессию TNF-α в стенке толстой кишки - иммуногистохимическим методом. Результаты. При экспериментальном ЯК на 2-е, 4-е и 6-е сут наряду с прогрессивным повышением DAI зафиксированы изменения показателей острофазового ответа (ООФ): увеличивается экспрессия в толстой кишке TNF-α с максимальным уровнем на 4-е и 6-е сут, повышается концентрация в сыворотке крови IL-6 с максимальным уровнем на 4-е, IL-8 - на 6-е сут; в сыворотке возрастает концентрация С-РБ максимально на 6-е сут, в крови увеличивается общее количество лейкоцитов, число палочкоядерных и сегментоядерных нейтрофилов с максимальным уровнем на 2-е и 4-е сут. Возрастает поглотительная и НСТ-редуцирующая способность нейтрофилов крови с максимальными значениями на 4-е и 6-е сут эксперимента. Применение при экспериментальном ЯК ректальных суппозиториев с витамином D3 приводит на 4-е и 6-е сут наблюдения к снижению DAI, экспрессии TNF-α в толстой кишке и количества нейтрофилов, на 2-е, 4-е и 6-е сут - к уменьшению концентрации IL-6 и С-РБ в сыворотке, поглотительной и НСТ-редуцирующей способности нейтрофилов крови, на 6-е сут - к снижению концентрации IL-8 в сыворотке и общего количества лейкоцитов в крови. Заключение. Применение при экспериментальном ЯК оригинальных ректальных суппозиториев с витамином D3 приводит к снижению индекса активности болезни. Выраженность клинических проявлений ослабевает по мере снижения экспрессии в кишке TNF-α, снижения концентрации в сыворотке IL-6, количества в крови лейкоцитов и нейтрофилов, уменьшения НСТ-редуцирующей способности нейтрофилов. Aim. To study the effect of vitamin D3 in rectal suppositories on severity of the acute phase response (APR) in experimental ulcerative colitis (UC). Methods. Experiments were performed on 49 mature male Wistar rats. UC was induced by cutaneous followed by rectal applications of a 3% oxazolone alcohol solution. Novel polyethylene glycol suppositories (300 mg) containing 1500 IU of vitamin D3 were injected per rectum every 12 hrs for 6 days. Data were collected on days 2, 4, and 6 of UC. The clinical picture was assessed according to the Disease Activity Index (DAI) scale adapted for rats, taking into account body weight, consistency of, and the presence of blood in the feces. The number of blood leukocytes and neutrophils was determined on a hematological analyzer and in blood smears. The functional activity of neutrophils isolated from the blood was evaluated by the absorption of monodisperse latex particles and with the spontaneous and induced NBT test. Serum concentrations of C-reactive protein (CRP), IL-6 and IL-8 were measured by enzyme immunoassay. TNF-α expression in the colon wall was measured by an immunohistochemical method. Results. The following changes in APR variables along with a progressive increase in DAI were recorded on days 2, 4, and 6. Expression of colon TNF-α increased, with maximal values on days 4 and 6. Serum IL-6 increased and reached a maximal value on day 4; and serum IL-8 increased, with a maximum on day 6. Serum CRP increased, with a maximum on day 6. The total number of blood leukocytes and the number of stab and segmented neutrophils increased, with maximal values on days 2 and 4. The absorption and NBT-reducing ability of blood neutrophils increased, with maximal values on days 4 and 6. The use of rectal suppositories with vitamin D3 in experimental UC resulted in decreases in DAI, colon TNF-α expression, and the number of blood neutrophils on days 4 and 6; decreases in serum concentrations of IL-6 and CRP, and the absorption and NBT-reducing ability of blood neutrophils on days 2, 4, and 6; and decreases in the serum concentration of IL-8 and in the total number of blood leukocytes on day 6. Severity of clinical manifestations was alleviated with decreases in the expression of colon TNF-α, the serum concentration of IL-6, the number of blood leukocytes and neutrophils, and the NBT-reducing ability of neutrophils decreases. Conclusion. Application of the original rectal suppositories with vitamin D3 every 12 hours in experimental UC leads to a decrease in the disease activity index. The severity of clinical manifestations weakens as TNF-α expression, serum IL-6 concentration, number of leukocytes and neutrophils in blood, and decrease of neutrophil NST-reducing capacity decrease.

scholarly journals Immunotropic effect of rectal suppositories with vitamin D3 in dynamics of experimental ulcer colitis

2020 ◽  
pp. 141-145
Author(s):  
M. V. Osikov ◽  
E. V. Simonyan ◽  
M. S. Boyko ◽  
A. M. Bogomolova
Keyword(s):  
Serum Concentration ◽  
Vitamin D3 ◽  
Activity Index ◽  
Clinical Status ◽  
Disease Activity Index ◽  
Serum Concentrations ◽  
Aminosalicylic Acid ◽  
Experimental Ulcer ◽  
Specific Test ◽  
Rectal Suppositories

Purpose of the study—to develop a new dosage form—rectal suppositories with vitamin D3 and at the preclinical stage to analyze its clinical and immunological efficacy compared to 5-aminosalicylic acid (5-ASA) in the dynamics of experimental ulcerative colitis (UC) in rats.Materials and methods. UC was simulated by cutaneous and then rectal application of a 3% solution of oxazolone. Original rectal suppositories with 1500ME of vitamin D3 were administered per rectum every 12 hours, in the comparison group with the same interval, rectal suppositories with 50 mg of 5-ASA. To assess the clinical status, the Disease activity index (DAI) scale was used, the serum concentration of IgG, IgM, IL-6, IL-8 was determined by the enzyme immunoassay using rat-specific test systems on days 2 and 6 of the experiment.The results of the study. In experimental UC, DAI rises, and the concentration of IgG, IgM, IL-8 and IL-6 in serum increases on the 2nd and 6th day of the experiment. DAI increases as serum concentrations of IgG, IgM, IL-8 and IL-6 increase. The use of vitamin D3 in UC leads to a decrease in DAI and serum concentrations of IgG, IgM, IL-8, IL-6 mainly on the 6th day of observation. The use of rectal suppositories with 5-ASA in UC leads to a decrease in DAI and the concentration of IgM, IgG, IL-6, IL-8 on the 2nd and 6th day of observation.Conclusion. The efficacy of rectal suppositories containing 1500 IU of vitamin D3 in experimental UC was found to be comparable with the use of rectal suppositories with 5-ASA based on the assessment of the clinical status and serum concentration of IgM, IgG, IL-6, IL-8.

scholarly journals Clinical and morphological characteristics of experimental ulcerative colitis in the conditions of using original rectal suppositories with vitamin D3

2021 ◽  
Vol 20 (1) ◽  
pp. 8-15
Author(s):  
M. V. Osikov ◽  
M. S. Boyko ◽  
E. V. Simonyan ◽  
V. A. Ushakova
Keyword(s):  
Ulcerative Colitis ◽  
Vitamin D ◽  
Tissue Damage ◽  
Plasma Cells ◽  
Clinical Status ◽  
Damage Index ◽  
Clinical Signs ◽  
Morphological Characteristics ◽  
Colon Wall ◽  
Rectal Suppositories

Introduction. Vitamin D3 possesses antioxidant, anti-inflammatory, immunomodulatory, and other properties, has been shown to be effective in some autoimmune diseases, which is a prerequisite for studying its effect, when applied locally, on the clinical status and morphology of the site of injury in ulcerative colitis (UC).The aims was to study the effect of vitamin D3 in the composition of original rectal suppositories on the clinical status and morphology of the lesion of colon in experimental UC.Materials and methods. UC was modeled by two-stage administration of oxazolone. Rectal suppositories were prepared on the basis of a 10% aqueous solution of vitamin D3. The clinical status was assessed using the Disease activity index (DAI) scale. In the area of colon damage, the number of neutrophils, lymphocytes, eosinophils, histiocytes, plasmocytes and fibroblasts was examined per mm² d the tissue damage index (TDI) was calculated.Results and Discussion. In experimental UC, DAI increase an ulcerative defect is recorded in the colon, the number of neutrophils, lymphocytes, eosinophils, plasma cells, histiocytes, fibroblasts, TDI increases. The use of original rectal suppositories with vitamin D3 in experimental UC leads to a decrease in DAI, the size of the ulcer and TDI, a decrease in the infiltration of the intestinal wall by neutrophils, lymphocytes, eosinophils and plasma cells, an increase in the infiltration of histiocytes, fibroblasts.Conclusions. In experimental oxazolone-induced colitis, the clinical picture and morphology of the injury site characteristic of UC are recorded. The use of original rectal suppositories with vitamin D3 a total dose of 18,000 IU leads to a decrease in the severity of clinical signs and a decrease in the representation in the colon wall of cells involved in tissue destruction, an increase in the representation of cells mediating repair, which was reflected in a decrease in the area of the ulcer and tissue damage index , the severity of clinical signs according to DAI weakens as lymphocytes and plasma cells decrease in the area of damage to the colon, decrease in the size of the ulcer and decrease in TDI, increase in histiocytes and fibroblasts.

Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis

2010 ◽  
Vol 298 (2) ◽  
pp. G255-G266 ◽  
Author(s):  
Takashi Mizushima ◽  
Makoto Sasaki ◽  
Tomoaki Ando ◽  
Tsuneya Wada ◽  
Mamoru Tanaka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Activity Index ◽  
Body Weight Loss ◽  
Disease Activity Index ◽  
Wild Type ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Novel Target ◽  
Colitis Model

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to α4β7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R−/−) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-α, but did not inhibit phosphorylation of p38 MAPK or of IκB that modulate MAdCAM-1 expression. However, NF-κB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R−/− than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R−/− than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-κB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.

scholarly journals Brusatol-Enriched Brucea javanica Oil Ameliorated Dextran Sulfate Sodium-Induced Colitis in Mice: Involvement of NF-κB and RhoA/ROCK Signaling Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Xinghan Zheng ◽  
Liting Mai ◽  
Tongtong Wang ◽  
Ying Xu ◽  
Zireng Su ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Activity Index ◽  
Disease Activity Index ◽  
Protective Effects ◽  
Intestinal Epithelial ◽  
Colon Tissue ◽  
Epithelial Barrier Function ◽  
Brucea Javanica ◽  
Tnf Α ◽  
Brucea Javanica Oil

Brucea javanica oil (BJO) is beneficial for the treatment of ulcerative colitis (UC), and that quassinoids in particular brusatol are bioactive components. However, it is still uncertain whether or not other components in BJO, such as oleic acid and fatty acids, have an anti-UC effect. The present study is aimed at comparing the anti-UC effects between brusatol-enriched BJO (BE-BJO) and brusatol-free BJO (BF-BJO) and at exploring the effects and mechanisms of BE-BJO on colon inflammation and intestinal epithelial barrier function. Balb/C mice received 3% (wt/vol) DSS for one week to establish the UC model. Different doses of BE-BJO, BF-BJO, or BJO were treated. The result illustrated that BE-BJO alleviated DSS-induced loss of body weight, an increase of disease activity index (DAI), and a shortening of colon, whereas BF-BJO did not have these protective effects. BE-BJO treatment improved the morphology of colon tissue, inhibited the production and release of TNF-α, IFN-γ, IL-6, and IL-1β in the colon tissue, and reversed the decreased expressions of ZO-1, occludin, claudin-1, and E-cadherin induced by DSS but augmented claudin-2 expression. Mechanistically, BE-BJO repressed phosphorylation of NF-κB subunit p65, suppressed RhoA activation, downregulated ROCK, and prevented phosphorylation of myosin light chain (MLC) in DSS-treated mice, indicating that the protective effect of BE-BJO is attributed to suppression of NF-κB and RhoA/ROCK signaling pathways. These findings confirm that brusatol is an active component from BJO in the treatment of UC.

scholarly journals A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis

2009 ◽  
Vol 296 (6) ◽  
pp. G1167-G1179 ◽  
Author(s):  
Ryan Ungaro ◽  
Masayuki Fukata ◽  
David Hsu ◽  
Yasmin Hernandez ◽  
Keith Breglio ◽  
...  
Keyword(s):  
Activity Index ◽  
Disease Activity Index ◽  
Mucosal Healing ◽  
Transfer Model ◽  
Innate Immune Responses ◽  
Murine Colitis ◽  
Dss Colitis ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Intestinal Repair

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45Rbhi T cells into RAG1−/− mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1−/− mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing.

Clinical and Serologic Factors Associated with Lupus Pleuritis

2010 ◽  
Vol 37 (4) ◽  
pp. 747-753 ◽  
Author(s):  
SHIKHA MITTOO ◽  
ALLAN C. GELBER ◽  
CAROL A. HITCHON ◽  
EARL D. SILVERMAN ◽  
JANET E. POPE ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Disease Duration ◽  
Activity Index ◽  
Disease Onset ◽  
Damage Index ◽  
Disease Activity Index ◽  
Nuclear Antigen ◽  
Systemic Lupus ◽  
Factors Associated ◽  
American College Of Rheumatology

Objective.Pleuritis is a common manifestation and independent predictor of mortality in systemic lupus erythematosus (SLE). We examined the prevalence of pleuritis and factors associated with pleuritis in a multicenter Canadian SLE cohort.Methods.We studied consecutive adults satisfying the American College of Rheumatology (ACR) classification criteria for SLE who had a completed Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) score, at least 1 evaluable extractable nuclear antigen assay, and either a SLE Disease Activity Index (SLEDAI) or a SLE Activity Measure score. Pleuritis was defined as having pleuritis by satisfying the ACR criteria or the SLEDAI. Factors related to pleuritis were examined using univariate and multivariate logistic regression.Results.In our cohort of 876 patients, 91% were women, 65% Caucasian, mean age (± SD) was 46.8 ± 13.5 years, and disease duration at study entry was 12.1 ± 9.9 years; the prevalence of pleuritis was 34% (n = 296). Notably, greater disease duration (p = 0.002), higher SDI score (p ≤ 0.0001), age at SLE diagnosis (p = 0.009), and anti-Sm (p = 0.002) and anti-RNP (p = 0.002) seropositivity were significantly associated with pleuritis. In multivariate analysis with adjustment for disease duration, age at diagnosis, and SDI score, concomitant seropositivity for RNP and Sm were related to a nearly 2-fold greater prevalence of pleuritis (OR 1.98, 95% CI 1.31–2.82).Conclusion.Pleuritis occurred in one-third of this Canadian cohort. Concomitant Sm and RNP seropositivity, greater cumulative damage, longer disease duration, and younger age at SLE disease onset were related to a higher rate of SLE pleural disease.

scholarly journals Measuring Disease Activity and Damage with Validated Metrics: A Systematic Review on Mortality and Damage in Systemic Lupus Erythematosus

2018 ◽  
Vol 45 (10) ◽  
pp. 1448-1461 ◽  
Author(s):  
Stephanie O. Keeling ◽  
Ben Vandermeer ◽  
Jorge Medina ◽  
Trish Chatterley ◽  
Tatiana Nevskaya ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Damage Index ◽  
Disease Activity Index ◽  
Evaluation Methodology ◽  
Systemic Lupus ◽  
Increased Risk ◽  
Damage Accrual

Objective.To identify the effect of disease activity and damage, measured by validated indices, on mortality and damage accrual, in order to inform upcoming Canadian systemic lupus erythematosus (SLE) recommendations.Methods.Following GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology to fill in evidence-to-decision tables to create recommendations for “minimal investigations needed to monitor SLE patients at baseline and subsequent visits,” a systematic literature review was performed. The effect of disease activity and damage, measured by validated metrics, on mortality and damage was systematically reviewed, with metaanalyses performed when available.Results.A title/abstract screen of 5599 articles identified 816 articles for full paper review, with 102 meeting inclusion criteria and 53 with extractable data. Thirty-three articles describing outcomes related to disease activity and 20 articles related to damage were identified. Mortality was associated with higher SLE Disease Activity Index-2000 scores in 6 studies (HR 1.14, 95% CI 1.06–1.22) and higher Systemic Lupus International Collaborating Clinics/ACR Damage Index scores in 6 studies (HR 1.53, 95% CI 1.28–1.83). Higher SLE Activity Measure scores were associated with increased risk of damage in 3 studies (OR 1.06, 95% CI 1.04–1.08). British Isles Lupus Assessment Group was associated with mortality in 1 study with HR of 1.15.Conclusion.Active SLE disease and damage are associated with and predict greater mortality and damage. The use of validated disease activity and damage metrics is important in the assessment of disease activity and damage and will inform upcoming Canadian recommendations for the assessment of SLE.

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