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Modulating effect of ginger extract on rats with ulcerative colitis
Abstract
Ginger rhizomes are used traditionally for management of different gastrointestinal disturbances. Several studies proved that the rhizome possesses diverse biological activities such as cytotoxic, antioxidant, and anti-inflammatory effects. Recently, interest in ginger for treatment of chronic inflammatory conditions has been renewed.
The purpose of the present study is to evaluate the potential role of ginger extract [GE] in modulating the extent and severity of ulcerative colitis (UC), a chronically recurrent inflammatory bowel disease of unknown origin.
Male Wistar rats received 3 different doses of GE, sulfasalazine, or vehicle for 3 consecutive days before induction of UC by intra-rectal acetic acid administration, and continued further for 7 days after the induction. The colonic mucosal injury was assessed by macroscopic scoring, and histological examination. Furthermore, the mucosal content of malondialdehyde (MDA), protein carbonyl (PCO), and reduced glutathione (GSH) with the catalase (CAT) and superoxide dismutase (SOD) activity, were appraised as parameters of the redox state. Acute inflammatory response was determined by measuring myeloperoxidase (MPO), tumor necrosis factor (TNF-alpha), and prostaglandin E2 (PGE2).
All parameters were altered in ulcerated rats, and improved in animals receiving GE, an effect that was comparable to that of the standard sulfasalazine, especially at the highest dose level. Colonic mucosal injury parallels with the histological and biochemical evaluations.
Results showed a valuable effect of ginger extract against acetic acid-induced ulcerative colitis possibly by its antioxidant and anti-inflammatory properties.
... The presence of these antigens leads to recruitment of lymphocytes and macrophages, which further release inflammatory mediators and other soluble cytokines [10]. Studies have demonstrated a relative increase in the expression of T helper-associated cytokines (Th1-, Th2-, and Th17), IL-1β, IL-6, TNF-α, and IFN-γ in the intestinal tissues of IBD patients [11,12]. Conventional therapy for colitis patients mainly includes immunosuppressants, glucocorticoids, aminosalicylic acids, and biological agents [9]. ...
... The level of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β [11] and MPO [12] is relatively high in the intestinal tissues of colitis patients. Moringa oleifera extract significantly reduced their expression. ...
... It is released extracellularly by neutrophils, monocytes, and some tissue macrophages, where it catalyzes the reaction of halide and pseudo-halide ions with hydrogen peroxide (H 2 O 2 ) to generate hypohalous acids [62]. MPO is an indirect indicator of inflammation, especially in experimental studies of different colitis models, and is an enzyme that responds rapidly in the acute phase [12,63]. High MPO activity indicates neutrophil infiltration and tissue damage [64,65]. ...
... Ao observar os resultados de um experimento realizado por El-Abhar, Hammad & Gawad (2008), com 48 ratos machos Wistar, que foram tratados durante três dias com extrato de gengibre via oral em diversas doses (100mg/kg, 200mg/kg, 400mg/kg) ou sulfasalazina (500mg/kg) via oral, foi possível concluir que os rizomas do Zingiber officinale possuem propriedades anti-inflamatórias e antioxidantes comparáveis aos efeitos farmacológicos da sulfassalazina. Também foi possível observar que o uso oral de extrato de gengibre diminuiu a produção de TNF-α, através de sua inibição ou se seu fator de transcrição regulador, e de PGE2 devido à sua habilidade de inibir as enzimas da ciclooxigenase (COX). ...
... Também foi possível observar que o uso oral de extrato de gengibre diminuiu a produção de TNF-α, através de sua inibição ou se seu fator de transcrição regulador, e de PGE2 devido à sua habilidade de inibir as enzimas da ciclooxigenase (COX). Contatou-se também uma redução na infiltração de neutrófilos e a restauração do estado redox, que é um padrão preciso da habilidade da célula de responder o meio extracelular oxidante, da mucosa do cólon, que acontece por conta da capacidade do gengibre de inibir a produção de radicais livres (El-Abhar et al., 2008). ...
... Portanto, o tratamento da colite ulcerativa com o Zingiber officinale pode se tornar uma opção de tratamento complementar, oferecendo uma forma alternativa para modular o processo inflamatório gerado pela doença (El-Abhar et al., 2008). ...
A colite ulcerativa é uma doença inflamatória intestinal caracterizada pelo sangramento retal, dor abdominal, febre, perda de peso e diarreia, é uma doença crônica e tende a ser progressiva, afetando de maneira drástica a qualidade de vida. Seu tratamento convencional consiste na administração de aminossalicilatos orais ou tópicos e também corticoterapia, onde seu objetivo principal é o controle sintomatológico, equilíbrio nutricional e a melhora da qualidade de vida do paciente. Apesar de ser eficiente, é muito oneroso e também pode apresentar efeitos colaterais importantes, que acabam diminuindo a adesão ao tratamento. O propósito desta revisão narrativa, foi analisar estudos que utilizaram o gengibre para o tratamento da colite ulcerativa, e também, avaliar os estudos sobre as propriedades do Zingiber officinale, que são amplamente conhecidas pela capacidade anti-inflamatória e antioxidante. Apesar de literaturas limitadas, porém em crescimento, que explorem o uso do gengibre no tratamento da colite ulcerativa, bons resultados foram apresentados, como seus efeitos antioxidante e anti-inflamatório, além da facilidade de obter acesso, baixo custo e toxicidade nula comparada ao tratamento padrão, apesar de ainda mostrar-se necessário novas pesquisas utilizando-se essa planta.
... Non Commercial Use health problems, since it may be due to the presence of agents that promote inflammation as well as genetic issues (El-Abhar et al., 2008;He et al., 2021;Lee et al., 2017). Currently, the application of microencapsulated compounds has been proposed to treat long-term problems or pathologies related to inflammation (Table 5.3). ...
... This topic has gained significant relevance in recent years due to its increasing occurrence in society. The disease is characterized by localized inflammation in the intestine, overexpression of proinflammatory cytokines, and morphological changes at the cellular and molecular level (Carrasco-Avino, 2019;El-Abhar et al., 2008). By employing microencapsulation techniques, bioactive compounds can achieve greater stability and resistance to the digestive conditions that typically degrade them, thereby limiting or nullifying their anti-inflammatory effects (Grgić et al., 2020). ...
Bioactive compounds have a wide variety of activities or effects that are of interest to human health. Unfortunately, a large amount of the foods that are consumed, despite containing a high content of bioactive compounds, lose their functions after being subjected to digestive processes or different environmental conditions. This limits or eliminates their potential. Microencapsulated products have a great advantage in this regard, as they possess a large number of different characteristics, with stability in various environments being a standout feature. The following document presents a review of the different types of processes to encapsulate bioactive compounds, along with necessary considerations for their formulation, advantages of their bioavailability, and applications as an alternative to treat problems related to inflammation.
... Based on the literature review, some natural products were introduced with anti-UC effects. El-Abhar et al. [53] evaluated the modulating effects of ginger extract on the extent and severity of UC in rats; they found out that ginger extract (GE) had valuable and beneficial effects, comparable with those of sulfasalazine [53]. Han et al. suggested that Cordyceps militaris extract had a downregulatory effect on the production and expression of inflammatory mediators from macrophages, which was found to suppress acute-induced colitis in mice. ...
... Based on the literature review, some natural products were introduced with anti-UC effects. El-Abhar et al. [53] evaluated the modulating effects of ginger extract on the extent and severity of UC in rats; they found out that ginger extract (GE) had valuable and beneficial effects, comparable with those of sulfasalazine [53]. Han et al. suggested that Cordyceps militaris extract had a downregulatory effect on the production and expression of inflammatory mediators from macrophages, which was found to suppress acute-induced colitis in mice. ...
Objectives:
Ulcerative colitis is a common subtype of persistent inflammatory bowel disease with high morbidity consequences. Despite unknown definite pathogenesis, multiple anti-inflammatory medications are used for its treatment. Traditionally, Quercus brantii (QB), mostly available in the Middle East, has been used for gastrointestinal disorders. Other beneficial effects associated with QB include reduction of oxidative stress, inflammations, homeostatic instability, and improvement in clinical conditions.
Materials and methods:
This experimental study was designed to assess the possible therapeutic effects of QB on UC and compare its effects with those of sulfasalazine. Of the 70 Wistar rats clustered in seven groups, ten received only alcohols and sixty were confirmed to be suffering from trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Four groups received different dosages of QB extract via oral and rectal routes, one received sulfasalazine, and the other remaining two groups received nothing. The effects of QB were evaluated by assessing macroscopic and histologic scoring, measuring inflammatory mediators, and determining oxidative stress markers.
Results:
Comparing to the untreated TNBS-induced control groups, QB-treated groups showed a dose- and route-dependent improvement comparable with sulfasalazine. Treating rats with QB reduced the microscopic and macroscopic damage, decreased TNF-α, IL-6, NO, MPO activity, and MDA content, increased superoxide dismutase (SOD) activity, and reduced body weight loss.
Conclusions:
Our data recommended the anti-inflammatory and antioxidant effects of QB extract in a dose-dependent manner.
... In inflammatory bowel diseases (IBD) which include ulcerative colitis and Crohn's disease, an elevated level of TNF and PGE2 has been observed (Nakamura et al., 2006) because both diseases are responsible for inflammation (Kawahara et al., 2015). Ginger shows a protective effect against IBD by decreasing the level of both TNF and PGE2 (El-Abhar et al., 2008). In one study, TNF-α expression was compared in two groups of rats. ...
... Ulcerative colitis (UC) is a prevalent type of Inflammatory Bowel Disease (IBD) characterized by chronic inflammation, ulcers in the distal part of the intestine, and clinically recurrent phases of aggravation and remission [1]. Although the etiology of UC is poorly elucidated, growing evidence has revealed that interactions between several components, including genetic variations in the intestinal microbiome, immune responses, and environmental factors, may play a role [2][3][4][5], UC represents an underlying cause of various other disorders, including intermittent diarrhea and constipation, cramping, abdominal, rectal, or joint pain, bleeding, and/or anemia [6][7][8]. Thus, identifying and treating pathophysiological factors can play an indispensable role in reducing UCrelated complications. ...
Aim
We conducted a randomized placebo-controlled trial to assess the efficacy of Spirulina (SP) supplementation on disease activity, health-related quality of life, antioxidant status, and serum pentraxin 3 (PTX-3) levels in patients with ulcerative colitis (UC).
Methods
Eighty patients with UC were randomly assigned to consume either 1 g/day (two 500 mg capsules/day) of SP (n = 40) or control (n = 40) for 8 weeks. Dietary intakes, physical activity, disease activity, health-related quality of life, antioxidant status, erythrocyte sedimentation rate (ESR), and serum PTX-3 levels were assessed and compared between groups at baseline and post-intervention.
Results
Seventy-three patients (91.3%) completed the trial. We observed increases in serum total antioxidant capacity levels in the SP supplementation group compared to the control group after 8 weeks of intervention (p ≤ 0.001). A within-group comparison indicated a trend towards a higher health-related quality of life score after 8 weeks of taking two different supplements, SP (p < 0.001) and PL (p = 0.012), respectively. However, there were no significant changes in participant’s disease activity score in response to SP administration (p > 0.05). Similarly, changes in ESR and PTX-3 levels were comparable between groups post-intervention (p > 0.05).
Conclusions
SP improved antioxidant capacity status and health-related quality of life in patients with UC. Our findings suggest that SP supplementation may be effective as an adjuvant treatment for managing patients with UC. Larger trials with longer interventions periods are required to confirm our findings.
... Motawea et al. reported an increase in oxidative factors such as MPO and MDA and a decrease in antioxidants such as GPX and SOD in ulcerative colitis [79]. In addition, El-Abhar et al. showed an increase in two parameters of MPO and TNF-α in ulcerative colitis [80]. A decrease in SOD in this disease was also reported by Al-Rejaie [81]. ...
Introduction
Ulcerative colitis (UC) is a chronic recurrent inflammatory disease of the large intestine and rectum. The disease is characterized by oxidative stress and severe inflammation. Research has shown the anti-oxidative and anti-inflammatory effects induced by consuming the Acacia arabia and Ocimum basilicum. The present study aimed to evaluate the effect of treatment with O. basilicum together with A. arabica on healing, inflammation, and oxidative stress in the course of experimental colitis in rats.
Methods
A total number of 50 male rats were selected and randomly assigned to five groups of 10 rats each. Colitis was induced in rats by enemas with a 4 % acetic acid solution. Four days after the colitis induction, the rats were orally treated for the next 4 days with saline or a combination of A. arabica and O. basilicum (1000 mg/kg) or sulfasalazine (100 mg/kg).
Results
Acetic acid-induced colitis increased the colon's macroscopic and histopathological damage scores; increased colon levels of MDA (Malondialdehyde), MPO (Myeloperoxidase), TNF-α (Tissue necrosis factor α), IL6 (Interleukin 6), and IL17 (Interleukin 17); and decreased SOD (Superoxide Dismutase), GPx (Glutathione Peroxidase), and IL10 (Interleukin 10) levels in the treated rats compared with the control group (P < 0.001). Overall, a combination of A. arabica and O. basilicum reduced macroscopic and histopathological damage scores (P < 0.01) of the colon, and MDA, MPO, TNF-α, IL6 (P < 0.001), and IL17 (P < 0.01) levels of the colon. Furthermore, it increased SOD, GPx, and IL10 levels compared to the colitis group (P < 0.01).
Conclusion
A. arabica and O. basilicum have improving effects on UC by reducing inflammation and oxidative stress.
... The resulting injury has symptoms and characteristics similar to UC in humans [40]. In this regard, rats treated with DSS in their drinking water demonstrated a significant decrease in clinical parameters such as food intake, water consumption, body weight gain, and colonic length/weight due to severe tissue edema, necrosis, goblet cell hyperplasia, and inflammatory cell infiltration [41], but an increase in the DAI. MESA and AEUD treatment significantly improved these symptoms. ...
Abstract
Background and Objectives: Urtica dioica, a source of bioactive functional compounds, provides nutritional and gastrointestinal therapeutic benefits. This study attempted to investigate the prophylactic coloprotective action of an aqueous extract of Urtica dioica (AEUD) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Materials and Methods: Phenolic compounds, total sugar, and mineral levels were determined in AEUD. Then, AEUD at different doses (50, 100, and 200 mg/kg, BW, p.o.) and mesalazine (MESA) as a standard treatment (100 mg/kg, BW, p.o.) were given orally for 21 days. Acute colitis was induced by administering drinking water with 5% (w/v) DSS for 7 days. Body weight variation, fecal occult blood, and stool consistency were determined daily. The severity of colitis was graded according to colon length, disease activity index (DAI), histological evaluations, and biochemical alterations. Rats orally administered DSS regularly developed clinical and macroscopic signs of colitis. Results: Due to its richness in phenolic and flavonoid compounds (247.65 ± 2.69 mg EAG/g MS and 34.08 ± 0.53 mg EQt/g MS, respectively), AEUD markedly ameliorated DAI, ulcer scores, colon length shortening, colonic histopathological changes, and hematological and biochemical modifications. Taken together, AEUD treatment notably (p < 0.01) suppressed DSS-induced UC by reducing oxidative stress via lowering MDA/H2O2 production and stimulating the effect of enzyme antioxidants as well as attenuating inflammation by decreasing CRP levels by 79.5% between the DSS and DSS + AEUD-50 groups compared to the MESA group (75.6%). Conclusions: AEUD was sufficient to exert a coloprotective effect that might be influenced by its bioactive compounds’ anti-inflammatory and antioxidant capabilities.
Keywords: Urtica dioica; ulcerative colitis; oxidative stress; antioxidants; phenolic compounds
... The ingredients; such as shogaol and gingerol in ginger have been reported to possess antiemetic and gastroprotective effects 13 . Anti-inflammations of Java long pepper, ginger, and chilli have also been reported [14][15][16] . Concert action of YGBNR would support the indicative for diarrhea, nausea, and vomiting. ...
Objective: This study aimed to determine the physicochemical properties of Ya-Gae-Bid-Na-Ron (YGBNR); according to the Thai Herbal Pharmacopoeia (THP) guidelines.Material and Methods: Kratom, ginger, Java long pepper, and chilli were collected from different sources, authenticated, and prepared for crude drugs. From this, twelve YGNBR recipes were formulated, and the physicochemical properties of the raw materials and recipes were determined. The thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) fingerprints were investigated, and the microbial limits and heavy metal contamination were determined.Results: YGBNR was prepared by mixing dry powders of kratom: ginger: Java long pepper; chilli in the ratio of 72:5:13:10. The phytochemical properties; including loss on drying, total ash, acid-insoluble ash, ethanol (80% v/v)-soluble extractive, water-soluble extractive, volatile oil, and mitragynine content were: 7.68±0.04%w/w, 5.72±0.06%w/w, 0.26±0.02%w/w, 28.99±0.17%w/w, 21.98±0.21%w/w, 0.40±0.00%v/w, and 0.58±0.28 %w/w, respectively. The microbial limits and heavy metal contaminations were under the THP requirements. Conclusion: The physicochemical properties of YGNBR, an antidiarrheal recipe, was determined according to THP. The specification is essential information for the establishment for the herbal monograph of YGBNR.
... The ensuing damage has symptoms and characteristics that are comparable to those of UC in humans [40]. In this respect, rats treated with DSS in the drinking water showed a significantly decrease in the clinical parameters such as food intake, water consumption, body weight gain, and colon length/weight due to severe tissue oedema, necrosis, goblet cell hyperplasia, and inflammatory cell infiltration [41],but, an increase in the DAI. MESA and AEUD treatment significantly improved these symptoms. ...
Background and Objectives:Urticadioica, a source of bioactive functional compounds, provides nutritional and gastrointestinal therapeutic benefits.The recent study attempted to investigate the prophylactic coloprotective action of aqueous extract of Urticadioica (AEUD) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Materials and Methods: Phenolic compounds, total sugar, and mineral levels were determined in AEUD. Then, AEUD at different doses (50, 100, and 200 mg/kg, BW, p.o.) and Mesalazine (MESA), as a standard treatment (100 mg/kg, BW, p.o.), were given orally for 21 days. Acute colitis was induced by administering drinking water with 5% (w/v) DSS for 7 days. Body weight variation, fecal occult blood, and stool consistency were determined daily. The severity of colitis was graded by colon length, disease activity index (DAI), histological evaluations, and biochemical alterations. Rats orally administered with DSS regularly developed clinical and macroscopic signs of colitis.Results: Due to its richness in phenolic and flavonoid compounds (247.65±2.69 mg EAG/g MS and 34.08±0.53 mg EQt/g MS, respectively),AEUD markedly ameliorated DAI, ulcer scores, colon length shortening, colonic histopathological changes, and hematological and biochemical modifications. Taken together, AEUD-treatment suppressed notably (p< .01) DSS-induced UC by reducing oxidative stress via lowering MDA/H2O2 generation and stimulating effect of enzyme antioxidants as well as attenuating inflammation by decreasing CRP levels by 79.5% between DSS and DSS+AEUD-50 groups compared to MESA-group (75.6%).Conclusions: AEUD was sufficient to exert its coloprotectiveeffect which might be influenced by its bioactive compounds’ anti-inflammatory and antioxidant capabilities.
... The mucosal immune system is mainly affected by cytokines, which majorly produce inflammation. 28 It is a well-known fact that TNF-α is abundantly expressed in the gut of IBD patients, 29 and the findings proved that mucosal and sub-mucosal inflammation following initial injury was associated with activating arachidonic acid pathways. It leads to the activation of COX-2, which results in more than PGE2. ...
... Gingers extract inhibited hydroxyl radicals by 79.6% at 37 C and 74.8% at 80 C which showed a higher antioxidant activity than quercetin [13] . In rats ginger extract also ameliorated acetic acidinduced ulcerative colitis, likely due to antioxidant actions [14] . ...
... It is also used to treat nausea after surgery and same has been proved in several randomised clinical trials. This effect is seen due to its action on the 5-HT3 receptor ( [23,55,4,22,46] . Hematologic (platelets) effects of ginger Scientific evidence is still pending; however it was found that ginger is having antithrombotic and strong antiinflammatory effect due to increased fibrinolytic activity when same has been taken at about 5 g. ...
... In inflammatory bowel diseases (IBD) which include ulcerative colitis and Crohn's disease, an elevated level of TNF and PGE2 has been observed (Nakamura et al., 2006) because both diseases are responsible for inflammation (Kawahara et al., 2015). Ginger shows a protective effect against IBD by decreasing the level of both TNF and PGE2 (El-Abhar et al., 2008). In one study, TNF-α expression was compared in two groups of rats. ...
There is a multitude of life-threatening and widespread health issues worldwide, regarding weak immunity, severe inflammation, viral infections, bacterial infections as well as antimicrobial resistance (AMR), high free radicals generation, and cancer. Ginger, a perennial plant of the Zingiberaceae family with several authentic nutritional and medicinal values used in many countries as traditional medicine. That is why, the study was designed to highlight recent studies about medicinally most efficacious bio-active compounds of ginger along their biological significance related to immuno-stimulatory, anti-inflammatory, anti-viral, anti-bacterial, anti-oxidant, and anti-cancer effects. Our study also recognized future gaps in research. The study included professional research data under duration from 2001-2022 appearing in books and scholarly journals, collected from scientific database platforms via PubMed, Web of Science, Google Scholar, Springer Nature, Science Direct and Scopus. The present study includes the medicinal effects of almost 44 most influential ginger compounds like phenolics, terpenoids, flavonoids, and vinyllyl ketonic compounds etc. Our results revealed the strong alleviating effects of gingerols, shogaols, paradols, and polyphenols. Moreover, the ginger essential oil has proven to be very effective both for antiviral and antibacterial activity. However, no data is available in previous literature for components of ginger involved in immuno-stimulatory, effects. There is also a need to explore components for antibacterial activity. However, research has been conducted on ginger for only a few viruses despite its strong alleviating effects. Besides this, more study is needed to comprehend the comprehensive mechanism of action (especially at the molecular level) regarding the anti-bacterial and anti-viral activity of ginger and its constituents.
... As evidenced by numerous studies, ginger extract has a protective activity against ulcerative colitis, a chronic IBD of unknown pathology [168][169][170]. Recently Guo et al. [127] identified the mechanism by which ginger ameliorates dextran sulfate sodium (DSS) induced ulcerative colitis. ...
Colorectal cancer (CRC) is the second most frequent cause of cancer-related mortality among all types of malignancies. Sedentary lifestyles, obesity, smoking, red and processed meat, low-fiber diets, inflammatory bowel disease, and gut dysbiosis are the most important risk factors associated with CRC pathogenesis. Alterations in gut microbiota are positively correlated with colorectal carcinogenesis, as these can dysregulate the immune response, alter the gut’s metabolic profile, modify the molecular processes in colonocytes, and initiate mutagenesis. Changes in the daily diet, and the addition of plant-based nutraceuticals, have the ability to modulate the composition and functionality of the gut microbiota, maintaining gut homeostasis and regulating host immune and inflammatory responses. Spices are one of the fundamental components of the human diet that are used for their bioactive properties (i.e., antimicrobial, antioxidant, and anti-inflammatory effects) and these exert beneficial effects on health, improving digestion and showing anti-inflammatory, immunomodulatory, and glucose- and cholesterol-lowering activities, as well as possessing properties that affect cognition and mood. The anti-inflammatory and immunomodulatory properties of spices could be useful in the prevention of various types of cancers that affect the digestive system. This review is designed to summarize the reciprocal interactions between dietary spices and the gut microbiota, and highlight the impact of dietary spices and their bioactive compounds on colorectal carcinogenesis by targeting the gut microbiota.
... [9,35]. Therefore, various native and non-native plants such as Tragopogon graminifolius DC. [36], Cucumis sativus L. [37], Hibiscus rosa-sinensis L. [38], Zingiber officinale Rosccoe [39] have been studied to their effectiveness in the treatment of UC. Dundar and co-workers showed that Origanum onites L. (Lamiaceae) essential oil ameliorated the 2,4,6-trinitrobenzenesulfonic (TBS)-induced UC through reducing the gene expression of intercellular adhesion molecule-1 and myeloperoxidase (MPO) as two critical mediators of inflammation and oxidative stress [40]. ...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, which has a global prevalence. Also, the plants of the Cupressaceae family have prominent anti-inflammatory and wound healing effects, so they can be considered as promising candidates for the treatment of UC. In this study, the therapeutic effects of extract and essential oil of Cupressus arizonica Greene (C. arizonica) fruits in the animal model of UC were investigated. Total of 35 Wistar male rats were treated with essential oil and hydroalcoholic extract for one week after induction of colitis by acetic acid. The colonic segment cut for macroscopic and histological analysis. The total amount of extract phenol and flavonoid content was assayed by Folin–Ciocalteu and aluminum chloride colorimetric method, respectively. The essential oil was analyzed by gas chromatography/mass spectrometer (GC/MS). The extract at doses of 100 mg/kg and 250 mg/kg and essential oil at doses of 0.5 mg/kg showed significant effects on UC (P < 0.05). The total phenolic content of hydroalcoholic extract in terms of mg of gallic acid/ g of extract was 191.625 ± 7.04 and the amount of total flavonoids in terms of mg of rutin/g of extract was 66.52 ± 6.51. Also, according to the results of GC/MS analysis, α-pinene was the major constituent of essential oil. Our results revealed that the extract and essential oil of C. arizonica fruits had therapeutic effects on UC, and this effect may be related to the presence of polyphenolic and terpene compounds.
... The macroscopic observation of the intestinal content in treated animals revealed well-formed fecal pellets with no visible sign of blood or mucus. This may result from an uncompromised mucus layer leading to the inhibition of excessive blood loss, indicating the therapeutic success of anti-ulcerative agents [60][61][62]. Our results showed an increase in histopathological score, as well as the shortening of the length of the colon of non-treated colitis rats. ...
Moringa oleifera decoction is believed to alleviate gastrointestinal tract diseases. This study investigated anti-oxidant and anxiolytic activities of its leaves aqueous extract on acetic acid-induced colitis in rats. Rats (36) were randomly divided into six groups and received (20 days) distilled water, 10 mL/kg; Moringa oleifera leaf-aqueous extract (25, 50, and 100 mg/kg) or Loperamide (5 mg/kg). On days 1, 8, 17, and 20, behavioral parameters were evaluated. Colitis was induced (day 15, except in normal group) through acetic acid (4%, 1 mL) intra-rectal administration. After sacrifice (day 21), lesion number, weight/length ratio of the colon were recorded. Oxidative stress biomarkers were evaluated. On day 20, Moringa oleifera (100 mg/kg) reduced the number of head dipping and the duration in opened arms, respectively 2.00 ± 0.37 and 5.00 ± 0.37 s against 14.50 ± 0.72 and 2.17 ± 0.48 s in the control. It decreased colon weight/length ratio: 112.29 ± 9.46 against 185.93 ± 5.28 mg/cm in the control; malondialdehyde level (P < 0.01) and nitric oxide concentration (P < 0.001), in the brain: respectively 25.60 ± 0.60 and 36.34 ± 1.19 against 34.00 ± 0.33 and 46.17 ± 3.25 µmol/mg of tissue in the control. In the serum, the extract (50 mg/kg) significantly (P < 0.05) increased the catalase activity (0.10 ± 0.00 against 0.03 ± 0.00 µmol/mg of protein in the negative control group). At 100 mg/kg, it increased (P < 0.001) reduced glutathione concentration to 5.07 ± 0.31 against 3.26 ± 0.08 µmol/mg of protein in the negative control group. The improvement on colitis pathophysiology, the antioxidant and the anxiolytic effects noted therefore suggest that Moringa oleifera can be a potential source of drugs alleviating anxiety and oxidative stress associated to ulcerative colitis.
... On other side, Abu-El-Saad [53] found no change in the hepatic CAT activity in S. mansoni infected mice because CAT activity in liver was affected before the deposition of parasite eggs in the organ and then progressed. Also the present study showed an increase in the level of GSH, SOD and CAT in infected treated mice comes with ginger in comparison with infected group and this in agreement with many studies which have also showed that ginger enhances the levels of these antioxidant enzymes [10,[54][55][56][57]. ...
The effect of ginger extract on schistosomiasis
... In recent years, a large number of studies have been conducted on the ulcer protective effects of many biologically active substances as curcumin, a phenolic natural product isolated from the rhizome of Curcuma longa (turmeric), which has been used for centuries in China and Southeast Asia [29], glabridin, an isoflavonoid from Glycyrrhiza glabra [26], quercetin [11] and hesperidin [45], flavonoids in citrus fruits, hydroxytyrosol, a polyphenolic compound from extra virgin olive oil (EVOO) etc. [37,38]. Extracts from Camellia sinensis [31], Crataegi fructus [15], Zingiber officinale [12], Nigella sativa [2,13,23,27], Panax notoginseng [44] etc. have also been investigated for their protective effects on the gastrointestinal tract. Pharmacological mechanisms of action of these plant products have been elucidated. ...
... The findings from the current study are in harmony with those revealed in prior studies using the AA-induced UC rat model [39,40]. Pretreatment with miconazole at two different dose levels (20 or 40 mg/kg/day) for 7 days was shown to restore the histopathological deterioration of colon tissue, compared to colitis rats, and markedly alleviated the severity of the gross lesion score as compared to the UC group ( Figure 1). ...
Simple Summary
The protective effect of miconazole, sulfasalazine (as a reference drug) and their combination on acetic acid (AA)-induced ulcerative colitis (UC) in a rat model was investigated. Pretreatment with miconazole significantly reduced wet colon weight and macroscopic scores, accompanied by a significant amelioration of the colonic architecture disorder. Miconazole and/or sulfasalazine revealed protective effects on AA-induced ulcerative colitis via activation of the Nrf2 pathway that improved the antioxidant defense system against oxidative stress and inflammation in UC, as demonstrated by the alleviation of colonic immunopathology, suppression of malondialdehyde (MDA) and elevation in GSH, SOD and HO-1, as well as downregulation of the levels of TNF-α, IL-6 and CRP and upregulation of the IL-10 level. Therefore, miconazole alone—particularly the high dose—or in combination treatment with sulfasalazine was the most efficient candidate compared with sulfasalazine alone and may be an alternative strategy for the treatment of UC.
Abstract
Ulcerative colitis (UC) is the most common type of inflammatory bowel disease, characterized by oxidative stress and elevated pro-inflammatory cytokines. Miconazole is an azole antifungal that stimulates the expression of antioxidant enzymes via Nrf2 activation, which consequently inhibits ROS formation and NF-κB activation. Hence, the present study aimed to investigate the protective effect of miconazole, sulfasalazine (as a reference drug) and their combination on acetic acid (AA)-induced UC in a rat model which was induced by intra-rectal administration of 4% AA. Rats were pretreated with miconazole (20 and 40 mg/kg, orally) or sulfasalazine (100 mg/kg, orally), or their combination (20 mg/kg miconazole and 50 mg/Kg of sulfasalazine, orally). Pretreatment with miconazole significantly reduced wet colon weight and macroscopic scores, accompanied by a significant amelioration of the colonic architecture disorder. Moreover, the treatment also significantly decreased the malondialdehyde (MDA) level and prevented the depletion of superoxide dismutase (SOD) activity and GSH content in inflamed colons. Additionally, the treatment showed suppressive activities on pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP), and upregulated the anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, the treatment upregulated the protein levels of Nrf-2 and heme oxygenase-1 (HO-1) in the colon tissue. Taken together, miconazole is effective in alleviating AA-induced colitis in rats, and the mechanism of its action is associated with the activation of Nrf2-regulated cytoprotective protein expression.
... Macroscopic changes of the colonic mucosa in ulcerative colitis can be credited to extreme oedema of the skin, necrosis, hyperplasia of goblet cells and inflammatory invasion of cells. 43,44 Well-formed faecal pellets without visible blood or mucus stains were observed upon macroscopic analysis of the intestinal content of diosmetintreated rats, thus denoting the significance of unblemished mucus layers of the colon in these groups. The effect of diosmetin on the colon mucosa may be further responsible for the prevention of abnormal bleeding in faecal pellets indicating towards the successful demonstration of antiulcerative potential of the drug. ...
Introduction
Ulcerative colitis (UC) is a chronic inflammation of colon in which the innermost tissue of colon and rectum develops deep-rooted inflammation. Diosmetin is the aglycone of the flavonoid glycoside diosmin, commonly found in citrus fruits. Therapeutically diosmetin is indicated to demonstrate anticancer, antimicrobial, antioxidant, oestrogenic and anti-inflammatory activity.
Methods
In this research, we studied the action of diosmetin on TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced UC in rats. Male Wister rats were anesthetised with pentobarbital and TNBS introduced by performing an enema. Diosmetin treatment was provided through oral gavage for the next 28 days. Animals were sacrificed on the 29 th day and colon tissues were collected for further examinations.
Results
Diosmetin treatment decreased colonic ulceration dramatically and decreased the percentage of inflammation in the colonic mucosa. Depletion of the TNBS assisted of superoxide dismutase and catalase was substantially restricted, while lipid peroxidation was recorded in the colonic tissue as malondialdehyde content was also decreased. After treatment with diosmetin, the occurrence of TNF-α, IL-6and NF-κB was considerably lowered and the number of apoptotic cells observed was significantly reduced.
Conclusion
Taken together, these observations demonstrated the potential of diosmetin against ulcer formation and development.
... Additionally, liquorice has been manifesting to have chemo preventive results between determining Bcl-2/Bax and inhibiting carcinogenesis [60][61] . Zingiber Officinale Roscoe (Zingiberaceae): The authors El-Abhar et al., [62] suggested possible part of Zingiber Officinale Roscoe (Zingiberaceae) extract was characterized by regulating the expanse and seriousness of ulcerative colitis. The effects of that work manifest a precious outcome of ginger extract abutting acetic acid convince ulcerative colitis feasibly by its antioxidant and anti-inflammatory properties. ...
The Ulcerative colitis is a chronic comprehensive disease of the digestive tract, exhibited by abdominal pain, mucopurulent bloody stool, diarrhea and tenesmus among the pathological transmute of inflammation of the colic mucosa and submucous layer and ulceration. The conventional therapy for ulcerative colitis essentially involves amino salicylic acid, immune-regulatory medications, steroid hormones and it can assist in conserving limited revocation and this treatment indicate serious side effects. To overcome the side effects of chemical drugs herbal medicines are the best choice to treat the ulcerative colitis. The several herbs show an anti-inflammatory property for treatment of ulcerative colitis and this are covered in this review. However, the herbal remedies are not lacking of risk, they still be safe than chemical or synthetic drugs. The possible advantage of herb could lie in their elevated assumption by patients, effectiveness, safety and moderately inexpensive. For the quality and safety of herbal medicines in the treatment of ulcerative colitis there is requirement for further controlled clinical trials of the possible effectiveness of herbal medicines.
... Ulcerative colitis (UC) is a chronic or life-long idiopathic bowel disorder, also called inflammatory bowel disease (IBD). It may cause swelling, inflammation, irritation, and ulcers on the inner sides of the large intestine, which comprise of cyclic episodes of rectal bleeding, diarrhea, bloating, and abdominal cramp (El-Abhar et al., 2008). N. sativa contains TQ which has antiinflammatory and antioxidant proprieties that may be effective against UC (Nikkhah-Bodaghi et al., 2019). ...
Nigella sativa possesses many active constituents and properties which mankind has been using since several decades for improving health conditions and fighting against various diseases, including dyspepsia, ulcers, inflammation, diabetes, and even cancers among many. Thymoquinone (TQ) is one of the main active components of N. sativa which is majorly responsible for its therapeutic activities. N. sativa is reported to inhibit the production of gastric acid and maintains the permeability of mucosal membrane, thus has potential to be successfully used against gastrointestinal disorders (GID). N. sativa seeds, extract, and oil have been studied by several scientists for their effects in various GID and have been found to be effective, alone, as well as in combination with other active agents. N. sativa extract has also been successfully incorporated in various nanoformulations such as nanostructured lipid carrier (NLC), to achieve various goals like controlled release, targeted delivery to colon, etc.
... Ulcerative colitis (UC) is a chronic or life-long idiopathic bowel disorder, also called inflammatory bowel disease (IBD). It may cause swelling, inflammation, irritation, and ulcers on the inner sides of the large intestine, which comprise of cyclic episodes of rectal bleeding, diarrhea, bloating, and abdominal cramp (El-Abhar et al., 2008). N. sativa contains TQ which has antiinflammatory and antioxidant proprieties that may be effective against UC (Nikkhah-Bodaghi et al., 2019). ...
... Increased in macroscopic score (extent of tissue damage), colon weight and colon thickness in colitis group can also be due to severe tissue oedema, necrosis and inflammatory cell infiltration 38,39 . Macroscopic score and colon thickness showed no significance difference in Allium cepa + colitis group when compared with control which shows that the Allium cepa treatment reduced the inflammation in the treated group. ...
Colitis and coagulation influence each other and patients with colitis have been reported to have an increased risk of thromboembolic events. Allium cepa has been reported to have anti-coagulative activity and anti-inflammatory activity. This research was carried out to investigate the effect of Allium cepa on coagulation changes in colitis Twenty eight rats weighed 180 ± 20g were used for this study. They were divided into four groups; Control group, Colitis group, Allium Cepa + Colitis group and Allium Cepa group. Allium Cepa + Colitis group and Allium Cepa were given 1ml/100g body weight of Allium cepa extract daily for 28days orally. Colitis was induced by a single dose of intra-rectal administration of 1ml/100g body weight of 6% acetic acid. Forty eight hours after the colitis induction, blood was taken by cardiac puncture for clotting time test, Prothrombin time (PT), Partial thromboplastin time with kaolin test (PTT.K), platelet count, Calcium ion and Potassium ion test. Calcium ion was significantly decreased while potassium ion, platelet count, significantly increased and partial thromboplastin time shortened in colitis animals when compared with control. Calcium ion, potassium ion, platelet count and partial thromboplastin time showed no significant difference in Allium Cepa + Colitis group when compared with control. It can be concluded that Allium cepa has potential to reduced the risk of thromboembolism in colitis Keywords: Colitis, Allium cepa, thromboembolism
... Treatment with ginger extract and GNPs in the different experimental groups increased the activity of the hepatic tissue CAT significantly as compared to the infected non treated mice group (G2) (P < 0.001), which is in agreement with many researches, which have also shown that ginger enhances the level of antioxidant enzyme [8,35,36,37] In the present study, the level of MDA, lipid peroxidation end product, was notably elevated in the liver of the positive control mice group (G2). This elevated MDA level indicates strong lipid peroxidation with a failure of the host antioxidant defense mechanisms to prevent excessive free radical formation and tissue damage [38,39]. ...
Background
Nanotechnology has been manufactured from medicinal plants to develop safe, and effective antischistosmal alternatives to replace today’s therapies. The aim of the study is to evaluate the prophylactic effect of ginger-derived nanoparticles (GNPs), and the therapeutic effect of ginger aqueous extract, and GNPs on Schistosoma mansoni (S. mansoni) infected mice compared to praziquantel (PZQ), and mefloquine (MFQ).
Methodology/principal findings
Eighty four mice, divided into nine different groups, were sacrificed at 6th, 8th, and 10th week post-infection (PI), with assessment of parasitological, histopathological, and oxidative stress parameters, and scanning the worms by electron microscope. As a prophylactic drug, GNPs showed slight reduction in worm burden, egg density, and granuloma size and number. As a therapeutic drug, GNPs significantly reduced worm burden (59.9%), tissue egg load (64.9%), granuloma size, and number at 10th week PI, and altered adult worm tegumental architecture, added to antioxidant effect. Interestingly, combination of GNPs with PZQ or MFQ gave almost similar or sometimes better curative effects as obtained with each drug separately. The highest therapeutic effect was obtained when ½ dose GNPs combined with ½ dose MFQ which achieved 100% reduction in both the total worm burden, and ova tissue density as early as the 6th week PI, with absence of detected eggs or tissue granuloma, and preservation of liver architecture.
Conclusions/significance
GNPs have a schistosomicidal, antioxidant, and hepatoprotective role. GNPs have a strong synergistic effect when combined with etiological treatments (PZQ or MFQ), and significantly reduced therapeutic doses by 50%, which may mitigate side effects and resistance to etiological drugs, a hypothesis requiring further research. We recommend extending this study to humans.
... Neuroprotective [153] Inhibit the activation of NF-κB and limits the inflammatory response, such as ICAM-1, MCP-1, Cox-2, TNF-α, IL-1β, and IL-6 ...
Nutraceuticals are essential food constituents that provide nutritional benefits as well as medicinal effects. The benefits of these foods are due to the presence of active compounds such as carotenoids, collagen hydrolysate, and dietary fibers. Nutraceuticals have been found to positively affect cardiovascular and immune system health and have a role in infection and cancer prevention. Nutraceuticals can be categorized into different classes based on their nature and mode of action. In this review, different classifications of nutraceuticals and their potential therapeutic activity, such as anti-cancer, antioxidant, anti-inflammatory and anti-lipid activity in disease will be reviewed. Moreover, the different mechanisms of action of these products, applications, and safety upon consumers including current trends and future prospect of nutraceuticals will be included.
... The observed findings showed an increased DAI score, histopathological score, and shortening of colon length in AA-induced colitis rats. The observed increased colon and spleen weight/length ratio in the UC animals might be due to severe edema, necrosis, and inflammatory cell infiltration [19,47]. However, pre-treatment of colitis rats with oral administration of OF.Cr at both doses (200 and 400 mg/kg) resulted in a significant decrease in the DAI score, and restored the colon length. ...
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes irritation, inflammation, and ulceration in the linings of the colon and rectum. Otostegia fruticosa is traditionally used to treat various disorders in different parts of the Middle East and sub-Saharan Africa. In the present study, we evaluated the ameliorative effects of crude leaves extract of O. fruticosa (OF.Cr) on acetic acid (AA)-induced UC model in Wistar albino rats. Wistar rats were administered orally with either vehicle (10 mL/kg), OF.Cr (200 and 400 mg/kg), or prednisolone (2 mg/kg) once a day for 6 days. On day 6, UC was induced in rats by intrarectal administration of a single dose of 5% AA (1.0 mL). Disease activity index (DAI) was recorded after one day of colitis induction by assessing the symptoms of colitis and then the rats were euthanized by cervical dislocation, and colon tissues were isolated for the histopathological examination and biochemical analysis of oxidative stress parameters and cytokines (Interleukin-6 and Tumor Necrosis Factor-α). OF.Cr pretreatment exhibits significant prevention against UC, as confirmed by a significant decrease of DAI, colonic ulceration, and reduced inflammatory score as compared to the AA-induced colitis rats. Depletion of total glutathione (GSH) levels and catalase (CAT) activities in the colitis group was significantly restored in the OF.Cr treated groups, while increased lipid peroxidation in the colon tissues was significantly reduced. OF.Cr prevented the activation of the IL-6 and TNF-α pathways in the colonic tissues, which were clearly observed by the decreased levels of IL-6 and TNF-α in the OF.Cr treated animals. Hence, OF.Cr could be developed in the future for the treatment of UC.
... We also found profound mucosal ulceration, transmural inflammation, haemorrhage, oedema, crypt damage, and necrosis in colitis-induced untreated rats. Our findings are in accordance with previous studies investigating therapeutic options for IBD [37,38]. It has also been reported that sulfasalazine (500 mg/kg) pretreatment substantially mitigated the biochemical and microscopic changes of acetic acid-induced colitis [39]. ...
Background
Ulcerative colitis is a gut inflammatory disorder due to altered immune response to gut microbiome, with interplay of environmental and genetic factors. TNF-α activates inflammatory response through a cascade of immune responses, augmenting pro-inflammatory mediators and proteases, activating chemotaxis, and infiltration of inflammatory cells, leading to ulceration and haemorrhage through cytotoxic reactive oxygen species. 6-Paradol, a dietary component in several plants belonging to the Zingiberaceae family, has shown anti-inflammatory and antioxidant activities. Current study evaluates the effect of 6-paradol in amelioration of ulcerative colitis in rats for the first time.
Methods
6-Paradol (95% purity) was obtained from seeds of Aframomum melegueta. Rats were divided randomly into six groups ( n = 8). Group one was administered normal saline; group two was treated with the vehicle only; group three, sulfasalazine 500 mg/kg; and groups four, five, and six, were given 6-paradol (50, 100, 200, respectively) mg/kg orally through gastric gavage for 7 days. Colitis was induced on 4th day by intrarectal administration of 2 ml acetic acid (3%), approximately 3 cm from anal verge. On 8th day, rats were sacrificed, and distal one-third of the colon extending proximally up to 4 cm from anal orifice was taken for biochemical and gross examination. Two centimetres of injured mucosal portion was taken for histopathological investigations. SPSS (ver.26) was used for statistical analysis.
Results
Colonic and serum glutathione (GSH) levels decreased, while colonic and serum malondialdehyde (MDA), colonic myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6), serum tumour necrosis factor-α (TNF-α) levels, and colon weight to length ratio were increased significantly in the colitis untreated group compared to normal control. Treatment with 6-paradol considerably improved all these parameters, especially at a dose of 200 mg/kg ( p < 0.001), revealing non-significant differences with sulfasalazine 500 mg/kg and normal control ( p = 0.998). Sulfasalazine and 6-paradol in a dose dependent manner also markedly reversed mucosal oedema, atrophy and inflammation, cryptic damage, haemorrhage, and ulceration. There were non-significant differences between low and medium doses and between medium and high doses of 6-paradol for IL-6 and serum MDA levels.
Conclusion
6-Paradol demonstrated protection against acetic acid-induced ulcerative colitis, probably by anti-inflammatory and antioxidant actions.
... Shokyo is the powdered rhizome of ginger (Zingiber offinale Roscoe), whereas, kankyo is the steamed and powdered rhizome of ginger. Many reports demonstrated that ginger has anti-inflammatory effects in human (Afzal et al., 2001;Lakhan et al., 2015), animal (Thomson et al., 2002;Aimbire et al., 2007;El-Abhar et al., 2008), and in vitro models (Ara and Sogawa, 2016;Podlogar and Verspohl, 2012). Shokyo contains gingerols such as 6-, 8-, and 10-gingerols. ...
Previously, we revealed that several kampo medicines that are used for patients with excess and/or medium patterns [kakkonto (TJ-1), shosaikoto (TJ-9), hangeshashinto (TJ-14), and orento (TJ-120)] reduced prostaglandin (PG)E< 2 levels using LPS-treated human gingival fibroblasts (HGFs). Recently, we examined other kampo medicines used for patients with the deficiency pattern [bakumondoto (TJ-29), shinbuto (TJ-30), ninjinto (TJ-32), and hochuekkito (TJ-41)] and the herbs comprising shinbuto and ninjinto using the same experimental model. Shinbuto and ninjinto concentration-dependently reduced LPS-induced PGE 2 production by HGFs, whereas hochuekkito weakly reduced and bakumondoto did not reduce PGE 2 production. Shinbuto and ninjinto did not alter cyclooxygenase (COX) activity or the expression of molecules involved in the arachidonic acid cascade. Therefore, we next examined which herbs compromising shinbuto and ninjinto reduce LPS-induced PGE 2 production. Among these herbs, shokyo ( Zingiberis Rhizoma ) and kankyo ( Zingiberis Processum Rhizoma ) strongly and concentration-dependently decreased LPS-induced PGE 2 production. However, both shokyo and kankyo increased the expression of cytosolic phospholipase (cPL)A 2 but did not affect annexin1 or COX-2 expression. These results suggest that shokyo and kankyo suppress cPLA 2 activity. We demonstrated that kampo medicines suppress inflammatory responses in patients with the deficiency pattern, and in those with excess or medium patterns. Moreover, kampo medicines that contain shokyo or kankyo are considered to be effective for the treatment of inflammatory diseases.
... Shokyo is the powdered rhizome of ginger (Zingiber offinale Roscoe), whereas, kankyo is the steamed and powdered rhizome of ginger. Many reports demonstrated that ginger has anti-inflammatory effects in human (Afzal et al., 2001;Lakhan et al., 2015), animal (Thomson et al., 2002;Aimbire et al., 2007;El-Abhar et al., 2008), and in vitro models (Ara and Sogawa, 2016;Podlogar and Verspohl, 2012). Shokyo contains gingerols such as 6-, 8-, and 10-gingerols. ...
Previously, we revealed that several kampo medicines that are used for patients with excess and/or medium patterns [kakkonto (TJ-1), shosaikoto (TJ-9), hangeshashinto (TJ-14), and orento (TJ-120)] reduced prostaglandin (PG)E< 2 levels using LPS-treated human gingival fibroblasts (HGFs). Recently, we examined other kampo medicines used for patients with the deficiency pattern [bakumondoto (TJ-29), shinbuto (TJ-30), ninjinto (TJ-32), and hochuekkito (TJ-41)] and the herbs comprising shinbuto and ninjinto using the same experimental model. Shinbuto and ninjinto concentration-dependently reduced LPS-induced PGE 2 production by HGFs, whereas hochuekkito weakly reduced and bakumondoto did not reduce PGE 2 production. Shinbuto and ninjinto did not alter cyclooxygenase (COX) activity or the expression of molecules involved in the arachidonic acid cascade. Therefore, we next examined which herbs compromising shinbuto and ninjinto reduce LPS-induced PGE 2 production. Among these herbs, shokyo ( Zingiberis Rhizoma ) and kankyo ( Zingiberis Processum Rhizoma ) strongly and concentration-dependently decreased LPS-induced PGE 2 production. However, both shokyo and kankyo increased the expression of cytosolic phospholipase (cPL)A 2 but did not affect annexin1 or COX-2 expression. These results suggest that shokyo and kankyo suppress cPLA 2 activity. We demonstrated that kampo medicines suppress inflammatory responses in patients with the deficiency pattern, and in those with excess or medium patterns. Moreover, kampo medicines that contain shokyo or kankyo are considered to be effective for the treatment of inflammatory diseases.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.
Gastrointestinal (GI) diseases are those that affect the digestive tract. This may include sections from the esophagus to the rectum and the liver, gallbladder, and pancreas digestive organs. Gastrointestinal diseases may be acute, chronic, or recurrent. Natural products show the potential ability to treat the causes and decrease the GI tract production systems. This chapter is to present some of the medicinal plants that are used to treat and minimize signals of GI disease pathogenesis.
This study was designed to determine the effects of pomegranate peel on various antioxidiants measurements in liver cirrhosis of rats induced by thioacetamide.Fifty-seven male rats aged 13–15 weeks were randomly divided into 15 categories containing 5 rats per category, and were treated with either TAA, PP, or PP plus TAA or Selenium plus TAA or administered with 0.9% physiological saline solution as a control. The hepatoprotective effect of herbs was evaluated by measuring levels of antioxidiant marker enzymes such as Glutathione Peroxidase (GSH-Px) and Superoxide Dismutase (SOD) and measurement Malondialdehyde (MDA). The histological studies were also carried out to support the above parameters by using special stain Haemotoxlin & eosin and using immunofluorescent staining to examine the distribution of DDR2 in the liver. The study found that the supplementation of pomegranate peel significantly (p< 0.05) reduced the damaging effects on the liver by TAA. GSH, SOD increased in the treatment group, but serum MDA level was declined due to the hepatic injury induced. A comparative histopathological research of the liver between different groups demonstrated that pomegranate peel, drive to normal liver architecture suggesting they may use as a hepatoprotective alternative medication
Gastrointestinal (GI) diseases are those that affect the digestive tract. This may include sections from the esophagus to the rectum and the liver, gallbladder, and pancreas, associated digestive organs. Gastrointestinal diseases may be acute, chronic, or recurrent. Natural products show the potential ability to treat the causes and decrease the GI tract production systems. This chapter presents some of the medicinal plants that are used to treat and minimize signals of GI disease pathogenesis.
Ulcerative colitis (UC) manifests as chronic inflammation of the colon. The bowel inflammation is due to alteration in the immune response to gut micro flora, oxidative stress and hereditary genetic factors. Leaf extract of papaya Carica papaya Linn. contain vitamin A, C, alkaloids, saponins, glycosides, tannins and flavonoids which have antispasmodic, analgesic, antibacterial and antioxidant properties. The main aim of the study was to detect the efficacy of Carica papaya leaf extract (PLE) on ulcerative colitis in Wistar Albino rats with objectives to explore the possible mechanism involved in its efficacy and to look for prebiotic activity. The project was initiated after the approval of Institutional Animal Ethics Committee. Thirty adult Wistar rats were randomly assigned into seven groups of six rats each. Group I-control, Group II-UC disease control, Group III-Disease with standard Sulfasalazine 100mg/kg, Group IV and Group V, UC disease model receiving PLE of 250mg/kg and 500 mg/kg respectively. Ulcerative colitis was not induced in Group VI and Group VII which received PLE of 500mg/kg and 700 mg/kg respectively. All the drugs were administered orally for 15 days. UC was induced by acetic acid on the 8th day. Blood sample was collected for biochemical analysis for antioxidant levels. Histopathological analysis of distal colon was performed to look for inflammatory features. Microbial analysis was done for group VI and group VII. There was significant reduction in body weight in UC induced groups when compared to control. The weight loss in Group IV and V (PE1 and PE2) was not as extreme as seen in the UC alone group. The treatment groups IV and V showed significant increase in protein levels, increased catalase and decreased malondialdehyde levels when compared to Group I, II and III. On histopathological analysis, the severity and extent of inflammation was less in 500mg/kg dose of leaf extract (Group V) than 250mg/kg of leaf extract (Group IV) and 100mg/kg of sulfasalazine (Group III). Tissue sections of Group V showed only few inflammatory infiltrates with absence of oedema and crypt abscess in the submucosal area. On examining the pathogenic versus beneficial bacterial load in the control and Group VI (PE 3) and Group VII (PE 4), papaya leaf extracts depicted antibacterial property and probiotic activity. In the present study, 500mg/kg of papaya leaf extract was efficacious in relieving oxidative stress and reducing inflammation in acetic acid induced ulcerative colitis in rats. Carica papaya leaf extracts have a potential role to modify gut microbe with respect to its prebiotic activity.
Ulcerative colitis (UC) is an inflammatory disease of the large intestine that is characterized by diarrhea, bloody stools, abdominal pain and mucosal ulceration. UC is treated with nonsteroidal anti-inflammatory drugs, corticosteroids or immunosuppressants, but long-term use of these drugs can cause adverse effects. Arum maculatum is used as a traditional treatment for digestive system disorders, but its use for treatment of UC has not been investigated rigorously. We investigated the possible protective effect of a methanol extract of A. maculatum against dextran sulfate sodium (DSS) induced experimental UC in rats. Total phenolic and flavonoid contents of the extract were 32.919 ± 1.125 mg gallic acid equivalent (GAE)/g and 52.045 ± 7.902 µg rutin equivalent (RE)/mg, respectively. The half-maximal inhibitory concentration (IC50) for the extract was 105.76 µg/ml according to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity assay. Effects of A. maculatum extract on UC induced by DSS were assessed both macroscopically and histologically. We also investigated effects of A. maculatum extract on malondialdehyde (MDA) levels and the oxidative stress index (OSI) in normal rats and rats with UC. We found that treatment with A. maculatum extract protected the colon against DSS induced UC in a dose-dependent manner.
Emerging literature suggests that diet plays an important modulatory role in inflammatory bowel disease (IBD) through the management of inflammation and oxidative stress. The aim of this narrative review is to evaluate the evidence collected up till now regarding optimum diet therapy for IBD and to design a food pyramid for these patients. The pyramid shows that carbohydrates should be consumed every day (3 portions), together with tolerated fruits and vegetables (5 portions), yogurt (125 ml), and extra virgin olive oil; weekly, fish (4 portions), white meat (3 portions), eggs (3 portions), pureed legumes (2 portions), seasoned cheeses (2 portions), and red or processed meats (once a week). At the top of the pyramid, there are two pennants: the red one means that subjects with IBD need some personalized supplementation and the black one means that there are some foods that are banned. The food pyramid makes it easier for patients to decide what they should eat.
Inflammatory bowel disease (IBD) is a term used for a variety of conditions involving persistent inflammation of the digestive system. Ulcerative colitis (UC) and Crohn’s disease (CD) are examples of IBD. There were some treatments like Amino salicylates, glucocorticoids, immunosuppressants, antibiotics, and surgery which have been used for treating IBD. However, the short and long-term disabling adverse effects, like nausea, pancreatitis, elevated liver enzymes, allergic reactions, and other life-threatening complications remain a significant clinical problem. On the other hand, herbal medicine, believed to be safer, cheaper, and easily available, has gained popularity for treating IBD. Nowadays, Ginger, the Rizhome of Z. officinale from the Zingiberaceae family, one of the most commonly used fresh spices and herbs, has been proposed as a potential option for IBD treatment. According to upper issues, IBD treatment has become one of the society’s concerns. So, this review aims to summarize the data on the yin and yang of ginger use in IBD treatment.
This study investigated the biochemical and histological changes associated with administering a methanolic extract of Zingiber officinale (MEZO) in Wistar rats. Fifteen (15) female rats with weights ranging from 120 - 160 g were randomly divided into three (3) groups (A-C). Group A received no treatment and served as the control group. Groups B and C received 200 and 400 mg/kg of MEZO orally for 21 days, respectively. There were no significant changes in the SOD, GSH, and CAT levels in all the groups treated with MEZO compared to the control (p < 0.05). There was no difference in the expression of inflammatory cytokines in the duodenum of rats treated with MEZO compared to the control. Histopathological studies showed acute duodenitis with intense inflammatory cell infiltrations and an eroded villus. This study shows that MEZO causes no significant oxidative changes in the female rat duodenum. However, it could elicit transient and non-dose-dependent proinflammatory potentials in the female duodenum of Wistar rats at a low dose which could not be explained by the tissue antioxidants and expression of IL1α and IL4. There is a need for reevaluation of the safety of ginger extracts in the female rat duodenum.
Ethnopharmacological relevance
Inflammatory bowel disease (IBD) is pathologically characterized by an immune response accommodative insufficiency and dysbiosis accompanied by persistent epithelial barrier dysfunction, and is divided into ulcerative colitis (UC) and Crohn's disease (CD). Its progression increases the susceptibility to colitis-associated cancer (CAC), as well as other complications. The Xiao-Jian-Zhong (XJZ) formula has a historical application in the clinic to combat gastrointestinal disorders.
Aim of the study
The investigation aimed to explore the molecular and cellular mechanisms of XJZ.
Materials and methods
Dextran sodium sulfate (DSS) was diluted in drinking water and given to mice for a week to establish murine models of experimental colitis, and the XJZ solution was administered for two weeks. Network pharmacology analysis and weighted gene co-expression network analysis (WGCNA) were utilized to predict the therapeutic role of XJZ against UC and CAC. 16S rRNA sequencing and untargeted metabolomics were conducted utilizing murine feces to examine the changes in the microbiome profile. Biochemical experiments were conducted to confirm the predicted functions.
Results
XJZ treatment markedly attenuated DSS-induced experimental colitis progression, and the targets were enriched in inflammation, infection, and tumorigenesis, predicted by network pharmacology analysis. Based on The Cancer Genome Atlas (TCGA) database, the XJZ-targets were related to the survival probability in patients with colorectal cancer, underlying a potential therapeutic value in cancer intervention. Moreover, the XJZ therapy successfully rescued the decreased richness and diversity of microbiota, suppressed the potentially pathogenic phenotype of the gut microorganisms, and reversed the declined linoleic acid metabolism and increased cytochrome P450 activity in murine colitis models. Our in-vitro experiments confirmed that the XJZ treatment suppressed Caspase1-dependent pyroptosis and increased peroxisome proliferators-activated receptor-γ(PPAR-γ) expression in the colon, facilitated the alternative activation of macrophages (Mφs), inhibited tumor necrosis factor-α (TNFα)-induced reactive oxygen species (ROS) level in intestinal organoids (IOs), thereby favoring the mucosal healing.
Conclusion
The XJZ formula is efficacious for colitis by a prompt resolution of inflammation and dysbiosis, and by re-establishing a microbiome profile that favors re-epithelization, and prevents carcinogenesis.
Background
Ulcerative colitis (UC) is considered one of the most prevalent inflammatory bowel diseases (IBDs). However, due to the lack of satisfying efficacy of conventional therapies and their side effects, there is still a need for more efficient therapeutic agents. Melittin is a small peptide derived from bee venom, which shows potent anti-inflammatory activity. The present investigation aimed to assess the anti-inflammatory effect of melittin peptide alone and in co-therapy with sulfasalazine as a standard therapy on dextran sulfate sodium (DSS)-induced colitis models.
Material and methods
We used DSS to induce UC in C57BL/6 male mice. We investigated the effect of melittin peptide alone and in combination with sulfasalazine on improving the clinical symptoms among DSS-induced colitis models. Finally, we employed histological investigation to show the therapeutic effect of melittin on attenuating the pathological damage of colon tissue caused due to DSS-induced inflammation in colitis models.
Results
Our findings demonstrated that melittin peptide alone and in combination with sulfasalazine dramatically cured the clinical UC. Moreover, we observed that this peptide almost eliminated the histological damage of colon tissue in colitis, while significantly reducing the inflammation in colon tissue. Meanwhile, our results demonstrated that this peptide had an antioxidant effect through the disruption of the oxidant/antioxidant balance.
Conclusion
All these findings suggest that melittin peptide has an anti-inflammatory effect and can probably be considered a novel therapeutic agent for UC. Furthermore, our results demonstrated that this peptide can enhance the therapeutic effects of conventional therapy while attenuating the adverse effects of conventional agents.
In the present study, we characterised 25 compounds in the extract of Nitraria Tangutorum Bobr. fruits by using the HPLC/MS/MS method. We determined the antioxidant activities of ethanol, petroleum ether, chloroform (CE), ethyl acetate, n-butanol, and water extracts of N. Tangutorum fruits. All extracts were found to exhibit the antioxidant activity and significantly enhance the activities of antioxidant enzymes in H2O2-induced HepG-2 cells. Furthermore, the anti-inflammatory effect and molecular mechanism of the CE of N. Tangutorum Bobr. fruits were evaluated using the dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) mouse model. CE significantly restored the body weight reduction, colon shortening, DAI elevation, and histological score in DSS-induced UC mice (P < 0.01). In addition, CE could remarkably decrease the levels of MPO, IL-1β, TNF-α, and IL-6 and increase the levels of superoxide dismutase, catalase, glutathione, and IL-10 in the colon of DSS mice (P < 0.01). According to western blot analysis, CE inhibited the MAPK/NF-κB signalling pathway activation. The results indicated that CE exerts a protective effect on DSS-induced UC mice, which may be related to the MAPK/NF-κB signalling pathway activation. In conclusion, CE can be used as a therapeutic drug for UC.
Inflammatory bowel diseases (IBD), with obscure etiology, are rising and are of worldwide concern. Of the various components of IBD pathogenesis and progression, irritation appears to play a major part. Investigations on the molecular and cellular pathways that activate the IBD provide the focus for the development of useful therapies. Ginger (the rhizome of Zingiber officinale) has a broad spectrum of clinical applications due to its anti‐inflammatory and anti‐oxidative functions. Inflammation and oxidative stress are the key pathogenic factors in many diseases, including IBD. The most established components of ginger are phenolic compounds called gingerols. A wide range of pharmacological activities of the potential therapeutic benefit of Z. officinale have been detailed. In this regard, the anti‐inflammatory activity of ginger has been documented by many researchers. It was shown that ginger is a potent inhibitor of the nuclear factor kappa B (NF‐κB), signal transducer of activators of transcription (STATs), Nod‐like receptor family proteins (NLRPs), toll‐like receptors (TLRs), mitogen‐activated protein kinase (MAPKs), and mTOR (mTOR) pathways, as well as inhibiting various pro‐inflammatory cytokines. In the present report, the potential application of ginger in the management of IBD is reviewed in detail, with an emphasis on the relevant properties of ginger and its bioactive components. The significance of the functions, side effects, and delivery of ginger to the digestive system for particular application in IBD are also considered.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with intestinal epithelial barrier impairment. Polydatin (PD), a natural product isolated from Polygonum cuspidatum , is known to have an anti-inflammatory, antioxidant, and antiapoptotic effect. We attempted to compare the protective impact of PD pretreatment on alterations to the intestinal epithelial barrier and the colonic wall’s ultrastructure accompanying ulcerative colitis to other conventional drugs in practice, primarily L-carnosine, which has not been addressed before. The rats were divided into 5 groups; 3 of them were treated with sulphasalazine (500 mg/kg), L-carnosine (30 mg/kg), and PD (45 mg/kg). All groups were administered their respective drugs 3 days before the UC was induced by acetic acid intra-rectally, and the treatment was continued until the 11th day. The disease activity index (DAI) was estimated, and a macroscopic scoring was established for the harvested colonic tissue. The tissues were extracted and processed for hematoxylin and eosin staining, caspase-3 immunohistochemical staining, electron microscopy, and biochemical analysis evaluating proinflammatory markers (IL-1β, TNF-α, and IL-6), myeloperoxidase (MPO), oxidative stress, and lipid peroxidation. Histopathological examination of colonic tissue showed that PD pretreatment effectively restored mucosal epithelial cells, intercellular tight junctions, goblet cells, and maintained the intestinal epithelial and endothelial barriers. PD suppressed MPO, proinflammatory markers, and malondialdehyde but enhanced superoxide dismutase and glutathione levels. It also hampered apoptosis, as evidenced by a reduction in caspase-3 expression. PD showed a significantly better response in preserving the intestinal epithelial barrier against acetic acid-induced colitis as compared to sulphasalazine and L-carnosine. These findings demonstrate the therapeutic role of PD for patients with UC.
Background
An emerging body of evidence has highlighted the protective role of spirulina in human health. Thus, we conducted a randomized controlled trial to discern the effects of spirulina supplementation on anthropometric indices, blood pressure, sleep quality, mood, fatigue status, and quality of life among ulcerative colitis patients.
Methods
Eighty participants with ulcerative colitis were randomly allocated to receive, either, 1 g/day (two 500 mg capsules) spirulina (n=40) or placebo (n=40), in a clinical trial for eight weeks. Dietary intake, physical activity, sleep quality, mental health, fatigue status, and quality of life were assessed for each participant at baseline and trial cessation. Anthropometric indices and blood pressure were also assessed.
Results
Seventy-three participants completed the intervention. Our results revealed that spirulina supplementation significantly reduced sleep disturbances (p=0.03), while no significant changes occurred in the sleep quality score or other sleep parameters, vs. the placebo group (p> 0.05). Furthermore, a significant reduction in stress score (p=0.04) and increase in quality of life (p=0.03) was detected; but not anxiety, depression, or fatigue scores (p> 0.05). Additionally, anthropometric indices and blood pressure did not significantly change (p> 0.05).
Conclusion
An improved quality of life was observed among ulcerative colitis patients following spirulina supplementation, which could be attributed to improved sleep disturbance and stress status. Further clinical studies, with longer duration interventions and suitably powered sample sizes, are necessary to elucidate the veracity of our findings.
The inflammatory disease’s increased prevalence leads to a major concern around the world. Still, there is a lack of effective and successful therapy in the reversal of Inflammatory Bowel Disease (IBD) symptoms. Whereas, reactive oxygen species (ROS) production and muddled defense capacity of antioxidants in IBD subjects reported several times. Many proton pump inhibitors have been reported previously for their anti-inflammatory effect. The present study is aimed to assess the ameliorative effect of lansoprazole in experimentally induced IBD in rats. Thirty-six female Sprague Dawley rats were divided equally into six groups based on their body weight. Lansoprazole (1, 5, and 10 mg/kg, p.o.) and 5-aminosalicylate (5-ASA, 100 mg/kg, p.o.) served as standard control respectively, given for 18 days once a day. On the 11th day of the study, colitis was induced by intrarectal instillation of 2, 4-Dinitrobenzene sulfonic acid (DNBS), and treatment was continued for the next 7 days. Administration of lansoprazole (at 5 and 10 mg/kg) significantly reduced DAI (Disease Activation Index) and CMDI (Colon Macroscopic Damage Index); which further justifies a reduction in colon inflammation grades, as well as histopathological changes, and reflected by the stalling of body weight. The anti-inflammatory effects were indicated by lowered MPO (myeloperoxidase) and SOD (superoxide dismutase) in colon tissue as well as restores colonic NO (nitric oxide) level. The study shows lansoprazole improved DAI and CMDI scores, reduction of neutrophil infiltration, and an improved antioxidant status indicating an anti-ulcerative effect in DNBS-induced experimental colitis that is comparable with 5-ASA treatment.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that increases the risk of colorectal cancer. UC is highly associated with the disturbance of the immune system leading to oxidative stress and chronic inflammation of intestine. Therefore, the current study was conducted to investigate the potential anti-oxidant and anti-inflammatory effects of MMF against acetic acid-induced UC that might be associated with the regulation of Nrf-2 and NLRP3 inflammasome signaling. UC was induced in Sprague-Dawley rats by intracolonic instillation of acetic acid. Forty-eight hours post UC induction, MMF (50 mg/kg/day, orally) was given for 8 consecutive days. Then, colon tissues and blood samples were collected. Results showed that MMF significantly attenuated the acetic acid-induced functional, biochemical, and inflammatory injuries in colon. MMF significantly decreased oxidative stress as indicated by the decreased malondialdehyde concentration and the increased total antioxidant capacity, glutathione, catalase, and superoxide dismutase concentrations in colon tissues. MMF also significantly increased Nrf-2 and decreased NLRP3 inflammasome expressions. Moreover, MMF decreased expression of interferon-gamma and increased expression of interferon-alpha. MMF also significantly decreased expression of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18. These results suggest that MMF has antioxidant and anti-inflammatory effects against acetic acid-induced UC through the upregulation of Nrf-2, and INF-α expression in addition to the suppression of NLRP3 inflammasome and subsequent release of IL1β, IL-18 and INF-γ.
The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which non-specifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Such recent advances in the understanding of the pathogenesis of IBD created a recent trend of novel biological therapies which specifically inhibit the molecules involved in the inflammatory cascade. Major targets for such treatment are inflammatory cytokines and their receptors, and adhesion molecules. A chimeric anti-TNF-α monoclonal antibody, infliximab, has become a standard therapy for CD and it is also likely to be beneficial for UC. Several anti-TNF reagents have been developed but most of them seem to not be as efficacious as infliximab. A humanized anti-TNF monoclonal antibody, adalimumab may be useful for the treatment of patients who lost responsiveness or developed intolerance to infliximab. Antibodies against IL-12 p40 and IL-6 receptor could be alternative new anti-cytokine therapies for IBD. Anti-interferon-γ and anti-CD25 therapies were developed, but the benefit of these agents has not yet been established. The selective blocking of migration of leukocytes into intestine seems to be a nice approach. Antibodies against α4 integrin and α4β7 integrin showed benefit for IBD. Antisense oligonucleotide of intercellular adhesion molecule 1 (ICAM-1) may be efficacious for IBD. Clinical trials of such compounds have been either recently reported or are currently underway. In this article, we review the efficacy and safety of such novel biological therapies for IBD.
We assessed the possible protective effects of N-acetylcysteine (NAC) against toxic damage in the rat colon. Two doses of NAC (20 mg/kg and 100 mg/kg) given for 2 days and 7 days after acetic acid administration (to induce colitis) were tested. NAC was dissolved in saline and administered locally (intracolonic), systemically (intraperitoneal) or in a combination (intracolonic and intraperitoneal). Several parameters, including macroscopic and histopathological scores and myeloperoxidase, glutathione and nitric oxide concentrations were measured using standard assay procedures. Treatment with 100 mg/kg NAC for 7 days significantly decreased tissue myeloperoxidase, glutathione and nitric oxide concentrations. The 20 mg/kg dose had no protective effects. The data indicate that NAC substantially reduced the degree of colonic injury, probably by regulating free radical production and inhibiting inflammation. It may, therefore, have a role in the treatment of inflammatory bowel disease.
Ulcerative colitis is a chronic recurrent inflammatory bowel disease in which oxidative stress has been implicated. The aim of the present study was to evaluate possible protective effects of N-acetylcysteine against acetic acid-induced colitis in a rat model. Rats were administered intrarectal saline (control group) or acetic acid (colitis model group). Rats with acetic acid-induced colitis were treated by intraperitoneal or intrarectal administration of N-acetylcysteine (500 mg/kg) (treated group). Another series of rats were pre-treated by intraperitoneal or intrarectal administration of N-acetylcysteine, then administered intrarectal acetic acid (pre-treated group). The degree of tissue injuries was assessed by macroscopical and histopathological scores of the colonic mucosa. Malondialdehyde, myeloperoxidase, reduced glutathione, superoxide dismutase, and catalase levels were measured in tissue extracts of the dissected colon. Administration of N-acetylcysteine intraperitoneally or intrarectally ameliorated macroscopic score alterations produced by acetic acid in treated groups. In addition, microscopical improvement was observed in all N-acetylcysteine-treated rats compared to untreated animals with colitis. In the colonic tissues of the acetic acid-induced colitis, myeloperoxidase activity and malondialdehyde levels were elevated, while the reduced glutathione levels and superoxide dismutase and catalase activities were decreased. However, intraperitoneal or intrarectal treatment with N-acetylcysteine reversed these parameters, compared to the untreated colitis group. Notably, intrarectal administration of N-acetylcysteine elevated the reduced glutathione levels more markedly compared to the other treatment groups. Superoxide dismutase levels were increased in intraperitoneally or intrarectally N-acetylcysteine-treated groups significantly compared to the control, colitis and pre-treated groups. But there was no significant increase in catalase activity. In conclusion, N-acetylcysteine could be beneficial as a complementary agent in treatment of ulcerative colitis.
Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.
Cissus quadrangularis (family: Vitaceae) is well known for the treatment of gastric disorders in traditional medicine, owing to its rich source of carotenoids, triterpenoids and ascorbic acid, and has received considerable attention regarding its role in human nutrition. In the search of new potential antiulcer agents, the present study evaluated the ethanol extract of Cissus quadrangularis (CQE) against the gastric toxicity induced by aspirin in rats. The optimum protective dose of 500 mg/kg of extract was selected by the pretreatment of gastric ulcers with different doses of CQE (250, 500 and 750 mg/kg) for 7 days which showed ulcer protection by 40, 71.2 and 72.6%, respectively, as compared to ranitidine (RTD) (30 mg/kg) by 71.9% in the aspirin model. In addition, results have shown that administration of aspirin increases lipid peroxidation status, xanthine oxidase (XO), myeloperoxidase and decrease in selenium-glutathione peroxidase activities in the gastric mucosa, resulting in mucosal damage at both cellular and subcellular level. Pretreatment with CQE ameliorated the observed effect significantly in the gastric mucosa of ulcerated rats. These findings suggest that the gastroprotective activity of CQE could be mediated possibly through its antioxidant effect as well as by the attenuation of the oxidative mechanism and neutrophil infiltration.
Intestinal inflammatory states, regardless of specific initiating events, share common immunologically mediated pathways of tissue injury and repair. The efficacy of various drugs used to treat ulcerative colitis (UC) was investigated. The aim of the present study is to evaluate the effects of ginkgo biloba extract on the extent and severity of UC caused by intracolonic administration of acetic acid in rats. The inflammatory response was assessed by histology and measurement of myeloperoxidase activity (MPO), reduced glutathione (GSH), tumor necrosis factor (TNF-alpha) and interleukin-1beta (IL-1beta) levels in colon mucosa. Oral pretreatment with Ginkgo biloba in doses of (30, 60, 120 mg kg(-1) body weight) and sulfasalazine in a dose of (500 mg kg(-1) body weight used as reference) for 2 days before induction of colitis and continued for 5 consecutive days, significantly decreased colonic MPO activity, TNF-alpha, and IL-1beta levels and increased GSH concentration. Moreover, Ginkgo biloba attenuated the macroscopic colonic damage and the histopathological changes-induced by acetic acid. These results suggest that Ginkgo biloba may be effective in the treatment of UC through its scavenging effect on oxygen-derived free radicals.
Recently, the role of oxidative stress in the pathogenesis of ulcerative colitis has been investigated. This study was designed to evaluate the possible beneficial effects of L-carnitine on tissue injury and oxidative stress in acetic acid-induced colitis in rats. Acetic acid administration induced severe damage macroscopically and histopathologically in colon and significantly increased the levels of malondialdehyde and myeloperoxidase in colonic tissue. Supplementation of L-carnitine to acetic acid-treated rats did not prove to induce any improvements in macroscopic scores, while L-carnitine administration improved histopathologic scores and significantly decreased malondialdehyde and myeloperoxidase levels in treatment groups. Acetic acid administration significantly decreased reduced glutathione, superoxide dismutase, and catalase levels in colonic homogenate. Supplementation of L-carnitine prevented the depletion of reduced glutathione levels but significantly increased superoxide dismutase levels. On the other hand, no significant change in catalase activity was observed. In conclusion, these results may reflect that L-carnitine could be beneficial as a complementary agent in treatment of ulcerative colitis.
The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which non-specifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Such recent advances in the understanding of the pathogenesis of IBD created a recent trend of novel biological therapies which specifically inhibit the molecules involved in the inflammatory cascade. Major targets for such treatment are inflammatory cytokines and their receptors, and adhesion molecules. A chimeric anti-TNF-alpha monoclonal antibody, infliximab, has become a standard therapy for CD and it is also likely to be beneficial for UC. Several anti-TNF reagents have been developed but most of them seem to not be as efficacious as infliximab. A humanized anti-TNF monoclonal antibody, adalimumab may be useful for the treatment of patients who lost responsiveness or developed intolerance to infliximab. Antibodies against IL-12 p40 and IL-6 receptor could be alternative new anti-cytokine therapies for IBD. Anti-interferon-gamma and anti-CD25 therapies were developed, but the benefit of these agents has not yet been established. The selective blocking of migration of leukocytes into intestine seems to be a nice approach. Antibodies against alpha4 integrin and alpha4beta7 integrin showed benefit for IBD. Antisense oligonucleotide of intercellular adhesion molecule 1 (ICAM-1) may be efficacious for IBD. Clinical trials of such compounds have been either recently reported or are currently underway. In this article, we review the efficacy and safety of such novel biological therapies for IBD.
The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which non-specifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Such recent advances in the understanding of the pathogenesis of IBD created a recent trend of novel biological therapies which specifically inhibit the molecules involved in the inflammatory cascade. Major targets for such treatment are inflammatory cytokines and their receptors, and adhesion molecules. A chimeric anti-TNF-alpha monoclonal antibody, infliximab, has become a standard therapy for CD and it is also likely to be beneficial for UC. Several anti-TNF reagents have been developed but most of them seem to not be as efficacious as infliximab. A humanized anti-TNF monoclonal antibody, adalimumab may be useful for the treatment of patients who lost responsiveness or developed intolerance to infliximab. Antibodies against IL-12 p40 and IL-6 receptor could be alternative new anti-cytokine therapies for IBD. Anti-interferon-gamma and anti-CD25 therapies were developed, but the benefit of these agents has not yet been established. The selective blocking of migration of leukocytes into intestine seems to be a nice approach. Antibodies against alpha 4 integrin and alpha 4 beta 7 integrin showed benefit for IBD. Antisense oligonucleotide of intercellular adhesion molecule 1 (ICAM-1) may be efficacious for IBD. Clinical trials of such compounds have been either recently reported or are currently underway. In this article, we review the efficacy and safety of such novel biological therapies for IBD. (c) 2006 The WJG Press. All rights reserved.
Inflammatory bowel disease (IBD) is associatedwith increased activation of intestinal immune cells,whose overproduction of proinflammatory cytokines suchas tumor necrosis factor-a (TNF-a) and interleukin-1ß (IL-1ß) is implicatedin mediating the sustained inflammatory response.Studies to date have largely reported qualitativedifferences in cytokine gene expression between IBD andcontrols. Our aim was to perform quantitative analysis ofintestinal mucosal mRNA expression in colonic biopsiesfrom pediatric IBD patients using a competitivepolymerase chain reaction. IL-1ß and TNF-awere expressed in all IBD and control biopsies.Compared to controls, IL-1ß mRNA levels wereincreased in involved tissue from Crohn's disease (CD)patients, but not in histologically uninvolved CD or in ulcerative colitis (UC) mucosa. IL-1ßexpression in the latter groups were equivalent to thosefound in tissue from patients with eosinophilic colitis(EOC). Significantly higher levels of IL-1ß mRNA were found in uninvolved mucosa from CDpatients who presented with a relapse of diseaseactivity, as compared to newly diagnosed cases withhistological features of CD at an early stage.TNF-a mRNA transcripts were also significantly elevated ininvolved CD mucosa, but not in the other groups.TNF-a gene expression in CD-involved tissuedecreased with disease duration. Follow-up of thepatients revealed that high cytokine expression inuninvolved CD tissue correlated with an early clinicalrelapse. In conclusion, quantitative determination ofproinflammatory cytokine gene expression revealsdifferences between the type, severity, and clinical coursein patients with IBD.
Virtually all inflammatory mediators investigated to date seem to be dysregulated in the inflamed intestinal mucosa of patients with inflammatory bowel disease. However, which of these are actually involved in the initiation and perpetuation of intestinal tissue damage is still not fully understood. Amongst these mediators are the reactive oxygen metabolites, produced in large amounts by the massively infiltrating leucocytes. These reactive oxygen metabolites are believed to constitute a major tissue-destructive force and may contribute significantly to the pathogenesis of inflammatory bowel disease.
This paper provides a concise overview of reactive oxygen metabolite biochemistry, the types of cell and tissue damage potentially inflicted by them, and the endogenous antioxidants which should prevent these harmful effects. An up-to-date summary of the available human experimental data suggests that reactive oxygen metabolite-mediated injury is important in both the primary and downstream secondary pathophysiological mechanisms underlying intestinal inflammation. Nonetheless, how the individual components of the mucosal antioxidant enzymatic cascade respond to inflammatory conditions is a neglected area of research. This particular aspect of intestinal mucosal oxidative stress therefore merits further study, in order to provide a sound, scientific basis for the design of antioxidant-directed treatment strategies for inflammatory bowel disease patients.
The perpetuation of inflammation in ulcerative colitis and Crohn's disease may be regulated in part by an increased secretion of proinflammatory cytokines due to either an appropriate response to initial stimulating agents, and/or due to an impaired down-regulalion of cylokine secretion. The aim of this study was to determine the secretion patterns of the proinflammatory cytokines tumour necrosis factor-alpha (TNF-), IL-6 and IL-lβ, from isolated lamina propria mononuclear cells (LPMNC) isolated from colonic biopsies from patients with untreated ulcerative colitis or Crohn's disease. LPMNC isoiated from involved inflammatory bowel disease (lBD) mucosa spontaneously produced increased amounts of TNF-, IL-6, and IL-lβ. The TNF- secretion from IBD LPMNC could be further enhanced by pokeweed mitogen stimulation. The secretion patterns of TNF- and IL-1β by LPMNC from patients with either uicerative colitis or Crohn's disease demonstrated a close correlation with the degree of tissue involvement and mucosal inflammation. LPMNC from noninvolved ulcerative colitis mucosa secreted markedly increased leveis of IL-6 compared with noninvolved Crohn's disease mucosa or control mucosa. The heightened lL-6 secretion from LPMNC from non-involved ulcerative colitis mucosa without visible or microscopic signs of inflammation indicates that the pathophysiologie mechanisms involved in the initiation of inflammation may differ between ulceralive colitis and Crohn's disease. The determination of proinflammatory cytokine secretion by isolated LPMNC from colonoseopic biopsies may be a sensitive method for monitoring the severity of mucosal inflammation in IBD patients.
The autoxidation of pyrogallol was investigated in the presence of EDTA in the pH range 7.9–10.6.
The rate of autoxidation increases with increasing pH. At pH 7.9 the reaction is inhibited to 99% by superoxide dismutase, indicating an almost total dependence on the participation of the superoxide anion radical, O2·−, in the reaction. Up to pH 9.1 the reaction is still inhibited to over 90% by superoxide dismutase, but at higher alkalinity, O2·− -independent mechanisms rapidly become dominant.
Catalase has no effect on the autoxidation but decreases the oxygen consumption by half, showing that H2O2 is the stable product of oxygen and that H2O2 is not involved in the autoxidation mechanism.
A simple and rapid method for the assay of superoxide dismutase is described, based on the ability of the enzyme to inhibit the autoxidation of pyrogallol.
A plausible explanation is given for the non-competitive part of the inhibition of catechol O-methyltransferase brought about by pyrogallol.
Alternative medicine is used extensively by patients with chronic pain due to e.g., osteoarthritis. Only few of these drugs have be tested in a controlled setting and the present study was undertaken to examine the effect of ginger extract, one of the most popular herbal medications.
Ginger extract was compared to placebo and Ibuprofen in patients with osteoarthritis of the hip or knee in a controlled, double blind, double dummy, cross-over study with a wash-out period of one week followed by three treatment periods in a randomized sequence, each of three weeks duration. Acetaminophen was used as rescue medication throughout the study. The study was conducted in accordance with Good Clinical Practice (European Guideline for GCP).
A ranking of efficacy of the three treatment periods: Ibuprofen>ginger extract>placebo was found for visual analogue scale of pain (Friedman test: 24.65, P< 0.00001) and the Lequesne-index (Friedman test: 20.76, P< 0.00005). In the cross-over study, no significant difference between placebo and ginger extract could be demonstrated (Siegel-Castellan test), while explorative tests of differences in the first treatment period showed a better effect of both Ibuprofen and ginger extract than placebo (Chi-square, P< 0.05). There were no serious adverse events reported during the periods with active medications.
In the present study a statistically significant effect of ginger extract could only be demonstrated by explorative statistical methods in the first period of treatment before cross-over, while a significant difference was not observed in the study as a whole.
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.
The reaction of lipid peroxides in animal tissues with thiobarbituric acid was dependent on pH of the reaction mixture as was the case for linoleic acid hydroperoxide. The optimum pH was found to be 3.5. Taking this fact into consideration, a standard procedure for the assay of lipid peroxide level in animal tissues by their reaction with thiobarbituric acid was developed as follows. Ten percent ( tissue homogenate was mixed with sodium dodecyl sulfate, acetate buffer (pH 3.5), and aqueous solution of thiobarbituric acid. After heating at 95°C for 60 min, the red pigment produced was extracted with n-butanol-pyridine mixture and estimated by the absorbance at 532nm. As an external standard, tetramethoxy-propane was used, and lipid peroxide level was expressed in terms of nmol malondialdehyde. Using this method, the liped peroxide level in the liver of rats suffering from carbon tetrachloride intoxication was investigated. The results were in good agreement with previously reported data obtained by measuring diene content.
Oxygen-centered radicals, such as superoxide (O2-) and hydroxyl radicals (.OH) generated by phagocytes have been suggested to be involved in the pathogenesis of chronic inflammations of the bowel, such as Crohn's disease and colitis ulcerosa. Recently, sulfasalazine (SASP) and its metabolites have been reported to exert their effects as a direct scavenger of oxygen-centered radicals in the bowel. To scavenge oxygen-centered radicals in vivo, however, SASP and its metabolites have to react with O2- and/or .OH in vitro very rapidly, furthermore they have to reach an appropriate (possible millimolar) concentration range at the site of inflammation. To test this possibility, we investigated the direct O2- and .OH scavenging activity of SASP and its metabolites using the specific electron paramagnetic resonance/spin trapping method, and we compared the 50% inhibition rates of SASP and its metabolites with their known concentrations in the bowel and in the human plasma. It was found that SASP and its metabolites, such as 5-amino-salicylic acid (5-ASA), and acetyl-5-amino-salicylic acid (AC-5-ASA), but not sulfapyridine (SP) and acetyl-sulfapyridine (Ac-SP) have a direct O2- and .OH scavenging activity in vitro systems. Among the compounds, SASP and 5-ASA can reach a concentration which is appropriate to scavenge oxygen-centered radicals in the bowel but not in the human plasma. It was concluded that the in vivo antiinflammatory effects of SASP and its metabolites are, at least partly, due to the direct oxygen-centered scavenging activity of these drugs.
Publisher Summary This chapter discusses methods to determine carbonyl content in oxidatively modified proteins. The methods described are (1) reduction of the carbonyl group to an alcohol with tritiated borohydride; (2) reaction of the carbonyl group with 2,4-dinitrophenylhydrazine to form the 2,4-dinitrophenylhydrazone; (3) reaction of the carbonyl with fluorescein thiosemicarbazide to form the thiosemicarbazone; and (4) reaction of the carbonyl group with fluorescein amine to form a Schiff base followed by reduction to the secondary amine with cyanoborohydride. Van Poelje and Snell have also quantitated protein-bound pyruvoyl groups through formation of a Schiff base with p-aminobenzoic acid followed by reduction with cyanoborohydride. Although a systematic investigation has not appeared, this method should also be useful in detecting other protein-bound carbonyl groups. Carbonyl content of proteins is expressed as moles carbonyl/mole subunit for purified proteins of known molecular weight. For extracts, the results may be given as nanomoles carbonyl/milligram protein. For a protein having a molecular weight of 50,000, a carbonyl content of 1 mol carbonyl/mol protein corresponds to 20 nmol carbonyl/mg proteins.
An assay was devised to quantitate acute intestinal inflammation based on the assessment of myeloperoxidase activity. Myeloperoxidase is an enzyme found in neutrophils and, in much smaller quantities, in monocytes and macrophages. Myeloperoxidase was solubilized with hexadecyltrimethylammonium bromide and myeloperoxidase activity was measured with a dianisidine-H2O2 assay. In neutrophil suspensions, myeloperoxidase activity was directly related to cell number down to as few as 500 cells. Myeloperoxidase activity was assayed in two animal models of inflammation: acetic acid-induced colitis in rats and Clostridium difficile enterotoxin-induced enteritis in hamsters. In both models, the activity of myeloperoxidase solubilized from the inflamed tissue was directly proportional to the number of neutrophils seen in histologic sections. Histologic evaluation of neutrophil accumulation was performed by counting the number of neutrophils in a histologic section 0.18 mm long and 5 micron thick. In both animal models, myeloperoxidase activity was linearly related to neutrophil number from 400 and 4000 cells/mm. Myeloperoxidase activity from chronically inflamed colon, in which both neutrophils and histiocytes were present, was directly related to neutrophil content. Histiocytes did not contribute significantly to myeloperoxidase activity. The determination of myeloperoxidase activity in the intestine is a simple biochemical assay that can be used to quantitate inflammation.
The perpetuation of inflammation in ulcerative colitis and Crohn's disease may be regulated in part by an increased secretion of proinflammatory cytokines due to either an appropriate response to initial stimulating agents, and/or due to an impaired down-regulation of cytokine secretion. The aim of this study was to determine the secretion patterns of the proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-1 beta, from isolated lamina propria mononuclear cells (LPMNC) isolated from colonic biopsies from patients with untreated ulcerative colitis or Crohn's disease. LPMNC isolated from involved inflammatory bowel disease (IBD) mucosa spontaneously produced increased amounts of TNF-alpha, and IL-6, and IL-1 beta. The TNF-alpha secretion from IBD LPMNC could be further enhanced by pokeweed mitogen stimulation. The secretion patterns of TNF-alpha and IL-1 beta by LPMNC from patients with either ulcerative colitis or Crohn's disease demonstrated a close correlation with the degree of tissue involvement and mucosal inflammation. LPMNC from non-involved ulcerative colitis mucosa secreted markedly increased levels of IL-6 compared with non-involved Crohn's disease mucosa or control mucosa. The heightened IL-6 secretion from LPMNC from non-involved ulcerative colitis mucosa without visible or microscopic signs of inflammation indicates that the pathophysiologic mechanisms involved in the initiation of inflammation may differ between ulcerative colitis and Crohn's disease. The determination of proinflammatory cytokine secretion by isolated LPMNC from colonoscopic biopsies may be a sensitive method for monitoring the severity of mucosal inflammation in IBD patients.
Experimental approaches designed to define the role of reactive oxygen and nitrogen species generated by inflammatory cells in the tissue injury seen in inflammatory bowel disease rarely consider the chemical antioxidant defences against such increased oxidant stress in the mucosa. In this investigation, we have analysed components of the aqueous and lipid phase antioxidant mucosal defences by measuring the total peroxyl radical scavenging capacity and the levels of urate, glutathione, alpha-tocopherol, and ubiquinol-10 in paired noninflamed and inflamed mucosal biopsies from inflammatory bowel disease patients. Compared to paired noninflamed mucosa, decreases were observed in inflamed mucosa for total peroxyl radical scavenging capacity (55%, p = 0.0031), urate [Crohn's disease (CD), 62.2%, p = 0.066; ulcerative colitis (UC), 47.3%, p = 0.031], glutathione (UC, 59%, 7/8 patients, ns), total glutathione (UC 65.2%, 6/8 patients, ns), ubiquinol-10 (CD, 75.7%, p = 0.03; UC, 90.5%, p = 0.005). The mean alpha-tocopherol content was unchanged. These observations support our earlier findings of decreased reduced and total ascorbic acid in inflamed IBD mucosa and demonstrate that the loss of chemical antioxidant defences affects almost all the major components. The decreased antioxidant defences may severely compromise the inflamed mucosa, rendering it more susceptible to oxidative tissue damage, hindering recovery of the mucosa and return of epithelial cell layer integrity. The loss of chemical antioxidant components provides a strong rational for developing novel antioxidant therapies for the treatment of inflammatory bowel disease.
Keratinocyte growth factor (KGF) is known to enhance tissue repair in the skin; however, its role in the gastrointestinal tract is largely unknown. The aim of this study was to evaluate the effects of exogenous KGF in an experimental model of colitis in rats.
KGF was administered before or after induction of colitis with 2,4,6-trinitrobenzenesulfonic acid/ethanol. In the first two study groups, KGF (5 mg/kg) was administered intraperitoneally 24 hours and 1 hour before induction of colitis; animals were killed 8 hours (n=10) and 1 week (n=10) after injury. In subsequent study groups, KGF or vehicle treatment was begun 24 hours after the induction of colitis at doses of 5 (n=20), 1 (n=10), and 0.1 (n=10) mg/kg intraperitoneally and continued once daily for 1 week. Colonic tissue samples were evaluated macroscopically and microscopically for mucosal injury and assayed for myeloperoxidase activity.
Administration of KGF after but not before induction of colitis significantly ameliorated tissue damage. Macroscopic necrosis and microscopic ulcerations were reduced by 40%-50% at KGF doses of 1 and 5 mg/kg.
Exogenous KGF has a key role in mucosal healing in an experimental model of colitis in rats.
Reactive oxygen species may mediate tissue injury in inflammatory bowel disease. Aminosalicylates have antioxidant activity and the antioxidants, superoxide dismutase and allopurinol, are of reported benefit in inflammatory bowel disease.
To develop a convenient technique for testing the antioxidant potential of standard and novel therapeutic agents for use in inflammatory bowel disease.
Amplified chemiluminescence was used to measure reactive oxygen species production by colonic biopsy specimens from rats with acetic acid induced colitis and to assess the in vitro effect of conventional antioxidants, standard therapies and proposed novel therapies for inflammatory bowel disease.
The model was validated by demonstrating that the profile of effects on chemiluminescence of acetic acid induced colitis biopsy specimens given by conventional antioxidants (sodium azide, catalase, copper-zinc superoxide dismutase, dimethyl sulphoxide, N-acetylcysteine and ascorbate) and standard therapies (5-aminosalicylate and hydrocortisone) resembled that previously reported using biopsy specimens from ulcerative colitis. Human recombinant manganese superoxide dismutase did not alter chemiluminescence. Two novel compounds, LY231617 (10 mM) and amflutizole (20 mM), reduced chemiluminescence by 98% (n = 5, p = 0.009) and 88% (n = 5, p = 0.03), respectively.
The similarity of the chemiluminescence responses of colonic biopsy specimens from acetic acid induced colitis and ulcerative colitis to a range of conventional antioxidants and standard treatments suggests that this model is a useful method for testing the antioxidant potential of new therapies for inflammatory bowel disease. The antioxidant actions of dimethyl sulphoxide, ascorbate, and the novel compounds, amflutizole and LY231617 in this model suggest that these agents merit further assessment in the treatment of inflammatory bowel disease.
Inflammatory bowel disease (IBD) is associated with increased activation of intestinal immune cells, whose overproduction of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) is implicated in mediating the sustained inflammatory response. Studies to date have largely reported qualitative differences in cytokine gene expression between IBD and controls. Our aim was to perform quantitative analysis of intestinal mucosal mRNA expression in colonic biopsies from pediatric IBD patients using a competitive polymerase chain reaction. IL-1 beta and TNF-alpha were expressed in all IBD and control biopsies. Compared to controls, IL-1 beta mRNA levels were increased in involved tissue from Crohn's disease (CD) patients, but not in histologically uninvolved CD or in ulcerative colitis (UC) mucosa. IL-1 beta expression in the latter groups were equivalent to those found in tissue from patients with eosinophilic colitis (EOC). Significantly higher levels of IL-1 beta mRNA were found in uninvolved mucosa from CD patients who presented with a relapse of disease activity, as compared to newly diagnosed cases with histological features of CD at an early stage. TNF-alpha mRNA transcripts were also significantly elevated in involved CD mucosa, but not in the other groups. TNF-alpha gene expression in CD-involved tissue decreased with disease duration. Follow-up of the patients revealed that high cytokine expression in uninvolved CD tissue correlated with an early clinical relapse. In conclusion, quantitative determination of proinflammatory cytokine gene expression reveals differences between the type, severity, and clinical course in patients with IBD.
The inflammatory bowel diseases (IBDs) are characterized by intestinal inflammation of unknown etiology. Two distinct disorders, Crohn's disease and ulcerative colitis, have been identified. Three theories of IBD etiology are currently under consideration: 1) reaction to a persistent intestinal infection, 2) existence of a defective mucosal barrier to luminal antigens, and 3) a dysregulated host immune response to ubiquitous antigens. In each of these theories, either pathogenic or resident luminal bacteria constantly stimulate the mucosal and systemic immune systems to perpetuate the inflammatory cascade. Chronicity of inflammation results from an interaction of the persistent stimulus of microbial antigens with genetically determined host susceptibility factors that determine the individual's immune response or mucosal barrier function. The pathogenesis of IBD involves a series of steps, beginning with the breach of the intestinal mucosal barrier by infectious agents or toxins. The defective barrier exposes lamina propria immune cells to the continual presence of resident luminal bacteria, bacterial products, or dietary antigens, which perpetuates the inflammatory cascade. Many immunoregulatory abnormalities are noted in IBD, including the ratio of proinflammatory to immunosuppressive cytokines, selective activation of T(H) lymphocyte subsets, and abnormalities in epithelial antigen presentation. When activated during the initial inflammatory process, macrophages and T lymphocytes secrete a host of cytokines, which recruit other inflammatory cell types, thereby continuing the process. Tissue injury is the net result of the soluble products of the activated inflammatory cells. Knowledge of the pathogenesis in IBD suggests that the ultimate goals of therapy should be to block the proinflammatory mediators toward the proximal, rather than the distal, end of the cascade, to decrease the constant antigenic drive of luminal bacteria, and to correct the dysregulated immune response.
Ginger is well known in the form of ginger sticks or ginger ale. If these are consumed during travel, the traveler imbibes, albeit subconsciously, a healing plant for motion sickness. The efficacy of ginger rhizome for the prevention of nausea, dizziness, and vomiting as symptoms of motion sickness (kinetosis), as well as for postoperative vomiting and vomiting of pregnancy, has been well documented and proved beyond doubt in numerous high-quality clinical studies. The use of this ancient medicine for gastrointestinal problems (stimulation of digestion) has been given scientific approval. Today, medicinal ginger is used mainly for prevention of the symptoms of travel sickness.
Virtually all inflammatory mediators investigated to date seem to be dysregulated in the inflamed intestinal mucosa of patients with inflammatory bowel disease. However, which of these are actually involved in the initiation and perpetuation of intestinal tissue damage is still not fully understood. Amongst these mediators are the reactive oxygen metabolites, produced in large amounts by the massively infiltrating leucocytes. These reactive oxygen metabolites are believed to constitute a major tissue-destructive force and may contribute significantly to the pathogenesis of inflammatory bowel disease. This paper provides a concise overview of reactive oxygen metabolite biochemistry, the types of cell and tissue damage potentially inflicted by them, and the endogenous antioxidants which should prevent these harmful effects. An up-to-date summary of the available human experimental data suggests that reactive oxygen metabolite-mediated injury is important in both the primary and downstream secondary pathophysiological mechanisms underlying intestinal inflammation. Nonetheless, how the individual components of the mucosal antioxidant enzymatic cascade respond to inflammatory conditions is a neglected area of research. This particular aspect of intestinal mucosal oxidative stress therefore merits further study, in order to provide a sound, scientific basis for the design of antioxidant-directed treatment strategies for inflammatory bowel disease patients.
Intestinal inflammation is accompanied by excessive production of reactive oxygen and nitrogen metabolites. In order to counteract their harmful effects, the intestinal mucosa contains an extensive system of antioxidants. It has previously been shown that the levels of and the balance between the most important antioxidants are seriously impaired within the intestinal mucosa from inflammatory bowel disease (IBD) patients compared with normal mucosa. The present study investigated the consequences of this antioxidative imbalance by evaluating parameters of oxidative stress-related mucosal damage in the same tissue samples. The extent of apoptosis, peroxynitrite-mediated protein nitration (3-NT), and lipid peroxidation were assessed in relation to the expression of nitric oxide synthase (NOS) and the superoxide-producing enzyme xanthine oxidase (XO). In addition, bi- and multi-variate regression analyses were performed to associate these parameters with the levels of the antioxidants assessed previously. Apoptotic cell death was visualized by TUNEL staining in luminal epithelium of normal controls, and in IBD additionally in the inflammatory infiltrate and in deeper parts of the crypts, but its frequency was unrelated to the severity of inflammation. In Crohn's disease (CD), epithelial apoptosis levels were strongly associated with the expression of XO, implying a role for this enzyme in the regulation of epithelial cell homeostasis, although its levels were unaffected by intestinal inflammation and were comparable to those in normal control mucosa. 3-NT immunoreactivity was substantially increased in luminal crypt cells, neutrophils, and mononuclear cells in the inflamed mucosa of ulcerative colitis (UC) patients. The inflamed IBD luminal epithelium, but not the inflammatory cells, also contained increased amounts of NOS. The immunoreactivity of both 3-NT and NOS was significantly higher in UC than in CD. Unexpectedly, the increased 3-NT expression in UC was associated with neutrophilic myeloperoxidase and not with NOS, which suggests that 3-NT is formed in areas with a dense neutrophilic infiltrate via a peroxynitrite-independent oxidation pathway. Lipid peroxidation, as estimated by the malondialdehyde (MDA) concentration, was elevated in both the inflamed CD and the inflamed UC mucosa, and was identified in the luminal epithelium using a histochemical technique. In CD, lipid peroxidation was independently associated with the concentration of metallothionein and with Mn-superoxide dismutase activity, suggesting the involvement of hydroxyl radicals and superoxide anions. In UC, however, the amount of MDA was associated with epithelial catalase expression and neutrophilic myeloperoxidase activity, suggesting a hydrogen peroxide- and/or hypochlorous acid-mediated mechanism. The present study underlines the importance of oxidative stress in the pathogenesis of IBD and provides clues regarding the (anti)oxidants involved which indicate that this process evolves through diverging pathways in CD and UC.
1. A rapid colorimetric and apparently specific micromethod for the determination of total glutathione in small amounts of tissue is described. Generally, less than 30mg. of tissue is sufficient and this is homogenized in ice-cold 3% metaphosphoric acid. The product is filtered through sintered glass and neutralized or diluted before being added to a cuvette containing phosphate buffer, pH7.1, 5,5'-dithiobis-(2-nitrobenzoic acid), EDTA and glutathione reductase. Addition of NADPH(2) to the system initiates a progressive reduction of 5,5'-dithiobis-(2-nitrobenzoic acid) by catalytic amounts of GSH, and this causes a colour increase at 412mmu. The rate of this change, calculated over 5min., is proportional to the total amount of glutathione present, and consequently unknown concentrations may be determined by reference to standards. 2. A preparation (based on that of Racker, 1955) of a suitable sample of glutathione reductase from yeast is described. 3. A less specific and less sensitive determination of extracted thiol groups with 5,5'-dithiobis-(2-nitrobenzoic acid) at pH8.0, based on observations of Ellman (1959) and Jocelyn (1962), is also described. 4. Although the precise nature of the reaction is not known, evidence is put forward to support a process of cyclo-reduction. GSSG is reduced enzymically to GSH, which reacts with 5,5'-dithiobis-(2-nitrobenzoic acid) to produce a coloured ion: [Formula: see text] (E(max.) 412mmu) and a mixed disulphide. This disulphide reacts with further quantities of GSH to liberate another ion and GSSG, which then re-enters the cycle.
The pathogenic roles of reactive oxygen species (ROS) have been implicated in ulcerative colitis (UC). The aim of this study was to examine the effects of ecabet sodium on ROS produced by human neutrophils, particularly after being primed by bacterial lipopolysaccharides (LPS). Neutrophils were isolated from six healthy volunteers. Each well of a 96-well microplate received neutrophil suspension (1.0 x 10(5) cells) and the plates were incubated at 37 degrees C for 30 min with or without E. coli LPS (f.c. 0.001 ng/ micro L). Ecabet sodium (f.c. 0-5.0 mg/mL) was added before starting or after finishing the incubation. Neutrophils were stimulated by opsonized zymosan (OZ; 1.0 mg/mL) or calcium ionophore (A21837; 0.3 micro mol/L) and luminol-dependent chemiluminescence response was measured using a Lumi Box H-1000. Ecabet sodium attenuated ROS production at a concentration of 5.0 mg/mL (p < 0.05) in LPS-primed neutrophils. However, attenuating effects were not significantly different when ecabet sodium was added before or after the incubation with E. coli LPS. Ecabet sodium may have some attenuating effects on ROS produced by human neutrophils even after neutrophils are primed by bacterial LPS. These results may explain, in part, the therapeutic effects of ecabet sodium for UC.
Since 1922 when Wu proposed the use of the Folin phenol reagent for
the measurement of proteins (l), a number of modified analytical pro-
cedures ut.ilizing this reagent have been reported for the determination
of proteins in serum (2-G), in antigen-antibody precipitates (7-9), and
in insulin (10).
Although the reagent would seem to be recommended by its great sen-
sitivity and the simplicity of procedure possible with its use, it has not
found great favor for general biochemical purposes.
In the belief that this reagent, nevertheless, has considerable merit for
certain application, but that its peculiarities and limitations need to be
understood for its fullest exploitation, it has been studied with regard t.o
effects of variations in pH, time of reaction, and concentration of react-
ants, permissible levels of reagents commonly used in handling proteins,
and interfering subst.ances. Procedures are described for measuring pro-
tein in solution or after precipitation wit,h acids or other agents, and for
the determination of as little as 0.2 y of protein.