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Ginger (Zingiber officinale Roscoe) for the treatment and prevention of necrotizing enterocolitis

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... The obtained powder was stored at −80°C until the need for use. This powder was solved in required volume of distilled water (prepared by cold maceration of 100 g of powdered in 400 ml of distilled water for 24 hr) for the preparation of gavaged extract (Cakir et al., 2018;Sadrefozalayi & Farokhi, 2014;Speijers et al., 2010). After that, a volume of 10 microliters was analyzed by Ultra high-performance liquid chromatography with a tandem mass spectrometric (LC-MS/MS, Shimadzu-8030) device (Cakir et al., 2018;Isik et al., 2019). ...
... This powder was solved in required volume of distilled water (prepared by cold maceration of 100 g of powdered in 400 ml of distilled water for 24 hr) for the preparation of gavaged extract (Cakir et al., 2018;Sadrefozalayi & Farokhi, 2014;Speijers et al., 2010). After that, a volume of 10 microliters was analyzed by Ultra high-performance liquid chromatography with a tandem mass spectrometric (LC-MS/MS, Shimadzu-8030) device (Cakir et al., 2018;Isik et al., 2019). ...
... Pups in the Group 1 and Group 2 were administered oral distilled water (0.8 ml/kg) from the first day till the end of the study. However, pups in the Group 3 group were administered FV once a day from the beginning to the end of the study (Cakir et al., 2018;Sadrefozalayi & Farokhi, 2014). ...
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We aimed to understand the efficacy of fennel (Foeniculum vulgare : FV) extract in an experimental necrotizing enterocolitis (NEC) model. Forty‐two rat pups were divided into three groups as NEC, NEC treated with fennel extract, and control. At the end of the experiment, tissue samples were taken from the proximal colon and ileum for biochemical and immuno‐histological studies including hematoxylin‐eosin and Caspase‐3‐8‐9 immunohistochemical staining. Bowel damage and apoptosis were found to be less in the NEC + FV group. Oxidant stress, caspase 3, TNF‐α, and IL‐6 levels were considerably decreased in the NEC + FV group. Antioxidants were significantly higher in the NEC + FV group more than in the NEC group. Moreover, protein, DNA damage, and lipid peroxidation were found to be decreased in the NEC + FV group compared to the NEC group. Practical applications Intense inflammation, oxidant stress, apoptosis, and infection are important in the development of NEC. Fennel has anti‐oxidant, anti‐inflammatory, antibacterial, antifungal, antiviral, immunomodulatory effects. Fennel extract might be a novel option in the treatment of NEC through its anti‐oxidant, anti‐inflammatory, anti‐apoptotic, and cytoprotective features.
... Bacteroides fragilis ZY-312 [113] Lactobacillus reuteri DSM 17938 [68,69] Lactobacillus reuteri ATCC PTA 4659 [68] Lactobacillus reuteri biofilm on unloaded microspheres [71,72] Lactobacillus reuteri biofilm on MRS loaded microspheres [71] Lactobacillus reuteri biofilm on sucrose loaded microspheres [72] Lactobacillus reuteri biofilm on maltose loaded microspheres [72] Bifidobacterium microcapsules [114] Bifidobacterium mixture [115] Bifidobacterium adolescentis [76] Bifidobacterium infantis [116] Bifidobacterium bifidum OLB6378 [74] Bifidobacterium breve M-16V [117] Lactobacillus rhamnosus HN001 (live) [39] Lactobacillus rhamnosus HN001 (dead) [39] Lactobacillus rhamnosus isolated DNA [39] Probiotic mixture (Bifidobacterium animalis DSM15954, Lactobacillus acidophilus DSM13241, Lactobacillus casei ATCC55544, Lactobacillus pentosus DSM14025 and Lactobacillus plantarum DSM13367) [77] CpG-DNA [39] Other interventions Bovine milk exosomes [118] Native human breast milk exosomes [78,119] Pasteurized human breast milk exosomes [119] Preterm human breast milk exosomes [120] Ginger [121] Fennel seed extracts [122] Amniotic fluid [40,63,123] Curcumin [124] Sesamol [125] Astragaloside iv [126] Resveratrol [127] Berberine [79] Surfactant protein a [80] Human β-defensin-3 [81] PUFA, polyunsaturated fatty acids; MPL milk polar lipids; MFGM, milk fat globule membrane; HMO, human milk oligosaccharides; DSLNT, disialyllacto-N-tetraose; 2 -FL, 2 -fucosyllactose; 6 -SL, 6 -sialyllactose; GOS: galacto-oligosaccharides; GD3, ganglioside D3; OPN, osteopontin; EGF, epidermal growth factor; HB-EGF, hemoglobin-binding EGF-like growth factor; HGF, hepatocyte growth factor; TGF-β1, transforming growth factor β1; TGF-β2, transforming growth factor β2; ATRA, all-trans retinoic acid. Table 3. Enteral feeding interventions reducing clinical disease score or signs and symptoms in experimental animal models of NEC. ...
... Lactobacillus reuteri DSM17938 [70] Bifidobacterium infantis-longum strain CUETM 89-215 [130] Bifidobacterium adolescentis [76] Bacteroides fragilis ZY-312 [113] Lactobacillus rhamnosus HN001 (live) [39] Lactobacillus rhamnosus HN001 (dead) [39] Lactobacillus rhamnosus isolated DNA [39] Other interventions Ginger [121] Fennel seed extracts [122] Amniotic fluid [123] Sesamol [125] Human β-defensin-3 [81] DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MFGM, milk fat globule membrane; MPL milk polar lipids; 2 -FL, 2 -fucosyllactose; 6 -SL, 6 -sialyllactose; GD3, ganglioside D3; CGMP, caseinoglycomacropeptide; OPN, osteopontin; EGF, epidermal growth factor; HB-EGF, hemoglobin-binding EGF-like growth factor; IGF1, insulin-like growth factor 1. Protein/amino acid-based interventions Lactadherin [51] Lysozyme [131] rPAF-AH [52] Hormone/growth factor/vitamin-based interventions HB-EGF [41,58,59,62,105] Probiotic interventions ...
... Finally, several other food components have been linked to immune modulatory effects within the context of NEC. Ginger intake by rats with NEC reduces intestinal protein concentrations of IL1β, IL6, TNFα and myeloperoxidase (MPO) [121]. Enteral administration of fennel seed extracts reduces intestinal protein concentrations of MPO, TNFα and IL6 [122]. ...
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Necrotizing enterocolitis (NEC), which is characterized by severe intestinal inflammation and in advanced stages necrosis, is a gastrointestinal emergency in the neonate with high mortality and morbidity. Despite advancing medical care, effective prevention strategies remain sparse. Factors contributing to the complex pathogenesis of NEC include immaturity of the intestinal immune defense, barrier function, motility and local circulatory regulation and abnormal microbial colonization. Interestingly, enteral feeding is regarded as an important modifiable factor influencing NEC pathogenesis. Moreover, breast milk, which forms the currently most effective prevention strategy, contains many bioactive components that are known to support neonatal immune development and promote healthy gut colonization. This systematic review describes the effect of different enteral feeding interventions on the prevention of NEC incidence and severity and the effect on pathophysiological mechanisms of NEC, in both experimental NEC models and clinical NEC. Besides, pathophysiological mechanisms involved in human NEC development are briefly described to give context for the findings of altered pathophysiological mechanisms of NEC by enteral feeding interventions.
... Hence, our experimental study confirmed findings in previously studies that hypoxia was an important risk factor for intestinal injury. Many investigators reported that increased pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, had been found in cases with NEC, and that these cytokines might be played a role in mediating intestinal injury [8,[17][18][19]. Moreover, it was reported that the metabolites of oxidative stress produced during reperfusion had also been proposed to play a critical role in the pathophysiology of NEC [10,16,[19][20][21][22]. ...
... Many investigators reported that increased pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, had been found in cases with NEC, and that these cytokines might be played a role in mediating intestinal injury [8,[17][18][19]. Moreover, it was reported that the metabolites of oxidative stress produced during reperfusion had also been proposed to play a critical role in the pathophysiology of NEC [10,16,[19][20][21][22]. In the presented study, we also showed that the highest levels of TNF-α, IL-6, and OSI were detected in H/R-induced groups when compared to control group. ...
... The first line of defense of the body's antioxidant system is responsible for inhibiting the generation of excess oxygen free radicals and lipid peroxidation. The defense of cells against oxidative stress is mediated by SOD and GSH [43]. SOD and GSH can neutralize oxygen free radicals to resist oxidative stress [44,45]. ...
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Objective: Necrotizing enterocolitis (NEC) is one of the commonest gastrointestinal critical diseases in newborns. Several researches have proven the efficacy of melatonin (MEL) on NEC, but the latent mechanisms were ambiguous. We designed the current research to evaluate the function and mechanism of MEL on NEC in a neonatal mouse model. Methods: The newborn mice were subjected to formula milk containing LPS and hypoxia to establish a NEC model and also intraperitoneally injected with MEL. During the experiment, all mice were closely monitored and weighed. The effect of MEL on the histopathological injury of the terminal ileum tissues, inflammation, and oxidative stress of serum in NEC mice was examined by hematoxylin-eosin (H&E) staining and ELISA. The effect of MEL on the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome was assessed via quantitative real-time PCR and Western blot. Results: MEL intensified the survival rate and body weight in NEC mice. The H&E staining illustrated that MEL improved the histopathological injury in NEC mice. Moreover, MEL repressed the IL-1β, TNF-α, and MDA levels of serum and enhanced the SOD and GSH-Px levels of serum in NEC mice. We also discovered that MEL attenuated the mRNA and protein levels of NLRP3, Toll-like Receptor 4 (TLR4), NF-κB, and caspase-1 of the terminal ileum tissues in NEC mice. Conclusion: Our research illuminated that MEL attenuated the severity of NEC via weakening the activation of the NLRP3 inflammasome.
... It is widely distributed and used in Asian countries as a traditional medicine for a wide array of conditions, including nausea, vomiting, colds, fever, and rheumatic disorders [15]. Several studies report that ginger and its active components have antimicrobial [16], antioxidant [17], and anti-inflammatory properties [18]. Ginger extract showed its protective effects by reducing lipid peroxidation and enhancing antioxidant enzyme activities in mycotoxin-treated HepG2 cell lines [19]. ...
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Ginger (Zingiber officianale), the most widely consumed species, is traditionally used as a folk medicine to treat some inflammatory diseases in China and Korea. However, the functional activity of steamed ginger extract on gastric ulcers has not been previously explored. The present study aimed to investigate antiulcer activity of steamed ginger extract (GGE03) against ethanol (EtOH)/HCl-induced gastric ulcers in a rat model. GGE03 (100 mg/kg) was orally administered for 14 days to rats before oral intubation of an EtOH/HCl mixture to induce gastric damage. Pretreatment with GGE03 markedly protected the formation of microscopic pathological damage in the gastric mucosa. Further, administration of GGE03 significantly increased mucosal total nitrate/nitrite production in gastric tissues, and elevated total GSH content, catalase activity and superoxide dismutase (SOD) expression as well as decreasing lipid peroxidation and myeloperoxidase (MPO) activity. Underlying protective mechanisms were examined by assessing inflammation-related genes, including nuclear factor-κB (NF-κB), prostaglandin E2 (PGE2), and pro-inflammatory cytokines levels. GGE03 administration significantly reduced the expression of NF-κB and pro-inflammatory cytokines. Our findings suggest that GGE03 possesses antiulcer activity by attenuating oxidative stress and inflammatory responses.
... Intestinal inflammation is an important contributing factor in the pathogenesis of NEC [5][6][7]. Activation of pro-inflammatory cytokines such as TNF-α and IL-1β has been shown to play a major role in the onset and progression of NEC [5][6][7]32,34,36]. TNF-α plays a key role in triggering a series of inflammatory events. ...
Article
Necrotizing enterocolitis (NEC) is a major neonatal health problem that especially affects preterm infants and causes severe morbidity and mortality. Although its pathogenesis is not fully understood, important risk factors include prematurity, oxidative stress, inflammation, and apoptosis. Ankaferd Blood Stopper® (ABS) has antioxidant, antiinflammatory, antimicrobial, antiapoptotic, and wound healing accelerant properties. In this study, we aimed to investigate whether treatment with ABS reduced the severity of NEC in rat pups in an experimental NEC model. Thirty-six newborn Wistar albino rat pups were randomly assigned to the control, NEC + saline, or NEC + ABS groups. NEC was induced by intraperitoneal injection of lipopolysaccharide, feeding with hyperosmolar enteral formula, and exposure to hypoxia/hyperoxia and cold stress. ABS was administered intraperitoneally to the pups in the NEC + ABS group daily starting on day 1 of the study at a dose of 2 ml/kg by diluting 2 ml with saline at a ratio of 1:3. All pups were sacrificed on day 4. The terminal ileum including the proximal colon was removed for histopathological and immunohistochemical examination and biochemical analysis. Macroscopic assessment and intestinal injury scores were lower in NEC + ABS group compared to the NEC + saline group (p
... These results demonstrate that QE effectively enhances antioxidant activity, limits oxidative stress, reduces intestinal epithelial injury, and prevents the progression of NEC [40]. In recent studies, other antioxidant agents, such as sesamol or ginger and an antioxidant peptide from the tuna backbone protein, had a similar protective effect on experimental NEC [41][42][43]. Intestinal microbiota plays a very important role in the development of NEC [44]. Therefore, in recent years, some scholars have tried to prevent or treat NEC through fecal microbiota transplantation (FMT). ...
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Necrotizing enterocolitis (NEC) is one of the most severe diseases of preterm neonates and has a high mortality rate. With the development of inspection techniques and new biomarkers, the diagnostic accuracy of NEC is constantly improving. The most recognized potential risk factors include prematurity, formula-feeding, infection, and microbial dysbiosis. With further understanding of the pathogenesis, more effective prevention and therapies will be applied to clinical or experimental NEC. At present, such new potential prevention and therapies for NEC are mainly focused on the Toll-like receptor 4 inflammatory signaling pathway, the repair of intestinal barrier function, probiotics, antioxidative stress, breast-feeding, and immunomodulatory agents. Many new studies have changed our understanding of the pathogenesis of NEC and improve our approaches for preventing and treating of NEC each year. This review provides an overview of the recent researches focused on clinical or experimental NEC and highlights the advances made within the past 5 years toward the development of new potential preventive approaches and therapies for this disease.
... The protective activity on muscle was discussed as being related to the antioxidant activity of phenolic components in sumac juice (Alghadir & Gabr, 2016). The most important goal in NEC treatment is to reduce oxidant stress (Cakir et al., 2018;Lim et al., 2015;Tayman et al., 2012). In this sense, TOS and OSI, which are indicators of oxidant damage in NEC, are decreased significantly due to the antioxidant properties of sumac (Erel, 2005). ...
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Leukotrienes, free oxygen radicals, tumor necrosis factor‐alpha, and inflammatory mediators play major roles in the development of necrotizing enterocolitis (NEC). Rhus coriaria (RC: sumac) extracts may enhance cell viability by reinforcing defenses against free radical species in several progressive diseases as well as inflammatory diseases. The aim of the present study was to evaluate the effects of RC in a rat NEC model in terms of intestinal damage. Newborn pups were separated into three groups: control, NEC, and NEC treated with RC. Mortality and clinical sickness scores were evaluated. At the end of the study, ileum and proximal colon were obtained from all rats and histopathological and immunohistochemical studies were performed. In this study, the anti‐inflammatory, antioxidant, immunomodulatory, and anti‐apoptotic activities of RC were demonstrated in a rat NEC model, which suggests RC as a promising treatment option for preventing intestinal tissue damage. Practical applications Free oxygen radicals, tumor necrosis factor‐alpha, and inflammatory mediators play major roles in the development of NEC. Intestinal tissue damage is caused by necrosis and apoptosis as a result of intestinal inflammation and release of pro‐inflammatory cytokines. Anti‐inflammatory, antioxidant, immunomodulatory, and anti‐apoptotic activities of RC are especially due to its phenolic compounds. In this study, the anti‐inflammatory, antioxidant, immunomodulatory, and anti‐apoptotic activities of RC were demonstrated in a rat NEC model. RC can suggest as a new treatment option for preventing intestinal injury.
... Ginger (Zingiber officinale ROSCOE) which is a perennial rhizomatous herb of family Zingiberaceae is native to Southeast Asia and has been used as a cooking spice and condiment worldwide [1,2]. Ginger has effective health effects and has positive effect on the treatment of asthma, gingivitis, toothache, stroke, diabetes and rheumatism [3,4]. As a functional dietary agent, ginger also has been shown to help control body weight and prevent metabolic disorders [5]. ...
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Three bioactive components (6-gingerol, zingerone and sesquiterpenes) in essential oil from ginger were successfully separated and purified by high-speed counter-current chromatography (HSCCC), and their proliferation inhibition on cancer cells was further investigated. The HSCCC was performed using n-hexane–ethyl acetate–methanol–water (7:3:5:5, v/v), n-hexane–methanol–water (3:2:1, v/v), and n-hexane–chloroform–acetonitrile (6:2:5, v/v) in 600 μl samples severally, yielding 35 mg 6-gingerol, 23 mg zingerone, and 105 mg sesquiterpenes with the purities of 98.6%, 99.4%, and 99.2% determined by high-performance liquid chromatography (HPLC). Their relative contents reached 84.07%, 94.67%, and 95.17%. MTT results showed that the three compounds caused cytotoxicity on the A549, HepG2 and MDA-MB-231 cells and 6-gingerol had the strongest anti-proliferation activity. Moreover, Hoechst 33342/PI staining confirmed that 6-gingerol could induce A549 cells to exhibit some typical features of apoptosis and Annexin V-FITC/PI verified that the cells induced by 6-gingerol underwent apoptosis rather than necrosis during this process. The HSCCC could be used to prepare bioactive substance with anti-tumor activities.
... Intestinal inflammation is an important contributing factor in the pathogenesis of NEC [5][6][7]. Activation of pro-inflammatory cytokines such as TNF-α and IL-1β has been shown to play a major role in the onset and progression of NEC [5][6][7]32,34,36]. TNF-α plays a key role in triggering a series of inflammatory events. ...
Article
Full-text available
Necrotizing enterocolitis (NEC) is a major neonatal health problem that especially affects preterm infants and causes severe morbidity and mortality. Although its pathogenesis is not fully understood, important risk factors include prematurity, oxidative stress, inflammation, and apoptosis. Ankaferd Blood Stopper® (ABS) has anti-oxidant, antiinflammatory, antimicrobial, antiapoptotic, and wound healing accelerant properties. In this study, we aimed to investigate whether treatment with ABS reduced the severity of NEC in rat pups in an experimental NEC model. Thirty-six newborn Wistar albino rat pups were randomly assigned to the control, NEC + saline, or NEC + ABS groups. NEC was induced by intraperitoneal injection of lipopolysaccharide, feeding with hyper-osmolar enteral formula, and exposure to hypoxia/hyperoxia and cold stress. ABS was administered in-traperitoneally to the pups in the NEC + ABS group daily starting on day 1 of the study at a dose of 2 ml/kg by diluting 2 ml with saline at a ratio of 1:3. All pups were sacrificed on day 4. The terminal ileum including the proximal colon was removed for histopathological and immunohistochemical examination and biochemical analysis. Macroscopic assessment and intestinal injury scores were lower in NEC + ABS group compared to the NEC + saline group (p < 0.05). Immunohistochemical evaluations of caspase-3,-8, and-9 revealed significantly reduced apoptosis in the NEC + ABS group compared to the NEC + saline group (p = 0.001). Total oxidant status, oxidative stress index, tumor necrosis factor α and interleukin-1β levels, and lipid, protein, and deoxyribonucleic acid oxidation products were significantly lower in the NEC + ABS group compared to NEC + saline group (p < 0.001 for all), while total antioxidant status, glutathione, and superoxide dismutase levels were higher in the NEC + ABS group (p < 0.001, p < 0.001, p = 0.01, respectively). ABS treatment has the potential to effectively reduce the severity of intestinal damage in NEC due to its antioxidant, antiin-flammatory, and antiapoptotic properties. Therefore, NEC may be an alternative option for treatment.
... In a study, orally administered ginger to newborn rats with necrotizing enterocolitis showed a reduction in TNF-α, IL-1β, and IL-6, which indicated a significant reduction in the inflammation [150], as well as inhibiting the acute inflammatory response in ulcerative colitis [151]. Furthermore, cinnamon extracts were able to inhibit more than 90% of the expression of IL-1 at the concentration of 50 µg/mL, and peppermint extracts were capable of reducing 90% of the expression of IL-6 at the concentration of 50 µg/mL; both indicated potent levels of anti-inflammatory activity [152]. Table 3 summarizes anti-inflammatory modes of action. ...
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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.
... Studies show that ginger has anti-inflammatory, antioxidants, anti-carcinogenic and antiangiogenic effects and can help reduce the lipid profile due to bioactive compounds such as gingerols, shogaols, paradols, and zingerone. Zingerone is one of the main compounds from the ginger root, and it is a non-toxic, antioxidant, antimicrobial, anti-inflammatory, and antithrombotic compound [4,[42][43][44][45]. ...
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Background: The use of medicinal plants may have an effective action on the performance of athletes. Aims: This review aimed to evaluate the effects of the use of medicinal plants and some phytocompounds on physical performance. Methodology: MEDLINE/PUBMED and EMBASE were consulted following the PRISMA guidelines. Results: Panax ginseng increases the anti-fatigue effect, decreases the stress promoted by the physical exercise, and improves muscular function through gene expression enhancement. Arnica Review Article Dias et al.; EJMP, 32(1): 1-21, 2021; Article no.EJMP.65049 2 montana has a crucial anti-inflammatory action showing relief of muscular pain a. Zingiber officinale has an anti-inflammatory and analgesic role on muscular pain, and it can be used to speed up the recovery of muscular strength after intense activity. Ephedra sinica is related to thermogenic and sympathomimetic effects, being able to increase the energetic state. Capsaicin increases the energetic expenditure due to fat oxidation, promotes the anti-fatigue effect, and enhances the athlete's resistance. Caffeine has ergogenic importance related to its antioxidant capacity, and it improves mental alertness condition. Conclusion: The nutritional supplementation with products derived from medicinal plants may be an efficient alternative to improve the athlete's performance, being a natural substitute for synthetic supplements, which usually are forbidden in competitions.
... Finally, the use of antioxidants to treat NEC has been widely validated. Using antioxidants in vivo such as NAC, Ginger (Zingiber officinale Roscoe), Nigella sativa oil (NSO), and caffeic acid phenethyl ester (CAPE) is effective in the treatment of NEC [55][56][57][58]. ...
Article
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High concentration oxygen is widely used in the treatment of neonates, which has a significant effect on improving blood oxygen concentration in neonates with respiratory distress. The adverse effects of hyperoxia therapy on the lung, retina, and neurodevelopment of newborns have been extensively studied, but less attention has been paid to intestinal damage caused by hyperoxia therapy. In this review, we focus on the physical, immune, and microorganism barriers of the intestinal tract and discuss neonatal intestinal tract damage caused by hyperoxia therapy and analyze the molecular mechanism of intestinal damage caused by hyperoxia in combination with necrotizing enterocolitis.
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Ginger is a spice type used by rhizome. Ginger has long been used to heal various diseases, including inflammation and digestive disorders. As the development of science, the food and health sector, mostly use ginger as functional food and medicine because of its usefulness. Ginger's role as food and medicine has been recognized as safe, classified in Generally Recognized as Safe (GRAS) by the Food Drug and Administration (FDA). The content of bioactive compounds in ginger classified as volatile and non-volatile compounds contributes positively to food and health. Ginger can be used as fresh, dried, essential oils, oleoresin, extracts, or powders. Oleoresin and essential ginger oil are extracts used extensively in food and health fields. To obtain the extract, an extraction that multiplies thermal and non-thermal processes can be performed. Many use gingers as a condiment for food. Ginger gives a spicy taste that's typical of food and drink. It also contributes to a natural antioxidant, extends food products' shelf-life, and improves the organoleptic quality of food products. Whereas ginger consumption can help decrease blood glucose in type 2 diabetes mellitus, analgesics, reduce uric acid, lessen muscle pain, and increase the body's immune system. In this study, we have reviewed ginger, the red ginger extraction process, and functional compounds, food, and health benefits.
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The effects of ginger on gastrointestinal disorders such as ulcerative colitis have been widely investigated using experimental models; however, the mechanisms underlying its therapeutic actions are still unknown. In this study, we investigated the correlation between the therapeutic effects of ginger and the regulation of the gut microbiota. We used dextran sulfate sodium (DSS) to induce colitis and found that ginger alleviated colitis-associated pathological changes and decreased the mRNA expression levels of interleukin-6 and inducible nitric oxide synthase in mice. 16s rRNA sequencing analysis of the feces samples showed that mice with colitis had an intestinal flora imbalance with lower species diversity and richness. At the phylum level, a higher abundance of pathogenic bacteria, Proteobacteria and firmicutes , were observed; at the genus level, most samples in the model group showed an increase in Lachnospiraceae_NK4A136_group . The overall analysis illustrated an increase in the relative abundance of Lactobacillus_murinus , Lachnospiraceae_bacterium_615 , and Ruminiclostridium_ sp ._KB18. These increased pathogenic bacteria in model mice were decreased when treated with ginger. DSS-treated mice showed a lower abundance of Muribaculaceae , and ginger corrected this disorder. The bacterial community structure of the ginger group analyzed with Alpha and Beta indices was similar to that of the control group. The results also illustrated that altered intestinal microbiomes affected physiological functions and adjusted key metabolic pathways in mice. In conclusion, this research presented that ginger reduced DSS-induced colitis severity and positively regulated the intestinal microbiome. Based on the series of data in this study, we hypothesize that ginger can improve diseases by restoring the diversity and functions of the gut microbiota.
Article
Ethnopharmacological relevance Based on ancient records and previous studies, many parts of Rhus chinensis Mill., including the fruits, have good preventive and therapeutic effects on inflammation, malaria, diarrhea, and gastrointestinal diseases. Rhus plants and Galla chinensis produced from R. chinensis leaves can also prevent or cure intestinal diseases. However, the preventive effect and molecular mechanisms of R. chinensis fruits on necrotizing enterocolitis (NEC) have not been comprehensively studied. Aim of the study This article aims to estimate the effect of the 80% ethanol extract of R. chinensis fruits (RM) on alleviating NEC in rat pups and illustrate the potential molecular mechanisms. Materials and methods Rat pups were subjected to formula feeding, intermittent hypoxic, and cold stresses to establish the NEC model. The preventive effects of RM on NEC were evaluated through survival rate; clinical sickness index; macroscopic conditions; histopathology; and expression levels of inflammatory factors (i.e., tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6]), oxidative stress indicators (i.e., total antioxidant status [TAS], total oxidant status [TOS], superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], myeloperoxidase [MPO], malondialdehyde [MDA]), and tight junction proteins (i.e., Zonula Occludens 1 [ZO-1], Occludin). Moreover, the expression levels of several key proteins involved in oxidative stress (i.e., nuclear factor erythroid 2-related factor 2 [Nrf2], NAD(P)H–quinone oxidoreductase-1 [NQO1]), inflammation (i.e., Toll-like receptor 4 [TLR4], phosphorylated-nuclear factor kappa-B [p-NF-κB], inducible nitric oxide synthase [iNOS]), and apoptosis (i.e., cleaved cysteinyl aspartate specific proteinase-3 [cleaved Caspase-3], Bcl-2-associated X [Bax], B-cell lymphoma-2 [Bcl-2]) in intestinal tissues were analyzed to clarify the molecular mechanisms. Results The extract particularly high doses could remarkably reduce the mortality and clinical sickness score and improve the macroscopic condition and histopathological injury of the intestine in NEC pups. After RM administration, the levels of TOS, TNF-α, IL-6, MPO, and MDA in the bowel tissue decreased, whereas the levels of TAS, SOD, and GSH-Px were significantly enhanced. The expression levels of ZO-1 and Occludin proteins were dramatically augmented in RM-treated groups to maintain intestinal barrier integrity. Further analyses revealed that RM might prevent NEC pups by improving some pivotal proteins involved in oxidative stress, inflammation, and apoptosis of enterocytes, namely, by down-regulating the levels of TLR4, p-NF-κB, iNOS, cleaved Caspase-3, and Bax and up-regulating the levels of Bcl-2, NQO1, and Nrf2. Conclusions The RM prevented the intestinal inflammation and damage caused by NEC by regulating the expression of several pivotal proteins involved in oxidative stress, inflammation, and apoptosis. This study might provide a scientific basis for R. chinensis fruits as a traditional herbal medicine to prevent and/or alleviate NEC.
Article
Endometriosis was induced (autotransplant) in Wistar rats. After 21 days, the rats were randomly divided into two groups (16 female rats each). Control group was forced-fed 0.9% sodium chloride solution, and the ginger group was forced-fed 0.5 mg/100 g of Zingiber officinale Roscoe fresh extract, both by gavage, for 14 days, in addition to their normal diet. After that, an anesthetic dose (ketamine/xylazine) was administered until euthanasia. Peritoneal lavage fluid was collected to evaluate tumor necrosis factor (TNF)-α and interleukin (IL)-6, and autotransplant was measured and excised to evaluate histology. The final mean volumes were larger in the control group (120.92 mm3 ± 78.91) than in the ginger group (40.50 mm3 ± 19.57) (P = .01). The endometriosis foci increased in the control group from 45.10 mm3 ± 29.96 at 21 days postimplantation to 120.92 mm3 ± 78.91 on the day of euthanasia (P = .02). In the ginger group, a slight increase was observed from 38.43 mm3 ± 19.96 to 40.50 mm3 ± 19.57, without statistical difference (P = .83). In addition, a greater increase in growth of the endometriosis foci was found when compared with the control (75.81 mm3 ± 58.95) and ginger groups (2.07 mm3 ± 18.87) (P = .004). No difference was found in TNF-α (P = .51) and in IL-6 (P = .12). The degree of lesion atrophy was higher in the ginger group (1 ± 0.92) than in the control group (2.25 ± 1.16) (P = .03). The ginger extract reduced and atrophied autotransplanted endometriosis foci, but did not reduce IL-6 and TNF-α in the peritoneal lavage fluid.
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Background Activated inflammation and oxidant stress during cerebral ischemia reperfusion injury (IRI) lead to brain damage. Astaxanthin (ASX) is a type of carotenoid with a strong antioxidant effect. Objective The aim of this study was to investigate the role of ASX on brain IRI. Methods A total of 42 adult male Sprague-Dawley rats were divided into 3 groups as control (n=14) group, IRI (n=14) group and IRI + ASX (n=14) group. Cerebral ischemia was instituted by occluding middle cerebral artery for 120 minutes and subsequently, reperfusion was performed for 48 hours. oxidant parameter levels and protein degradation products were evaluated. Hippocampal and cortex cell apoptosis, neuronal cell count, neurological deficit score were evaluated. Results In the IRI group, oxidant parameter levels and protein degradation products in the tissue were increased compared to control group. However, these values were significantly decreased in the IRI + ASX group (p<0.05). There was a significant decrease in hippocampal and cortex cell apoptosis and a significant increase in the number of neuronal cells in the IRI + ASX group compared to the IRI group alone (p<0.05). The neurological deficit score which was significantly lower in the IRI group compared to the control group was found to be significantly improved in the IRI + ASX group (p<0.05). Conclusion Astaxanthin protects the brain from oxidative damage and reduces neuronal deficits due to IRI injury.
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Objective: To investigate the protective effect of L. reuteri DSM17938 strain against oxidative stress in a neonatal mouse model of necrotizing enterocolitis (NEC) and explore the possible mechanism. Methods: Ninety-six 10-day-old neonatal C57BL/6J mice were equally randomized into control group, NEC group, and NEC+ L. reuteri group. The pathological changes of the ileocecal intestinal tissue were evaluated with HE staining and double-blind pathological scoring. The mRNA and protein expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the intestinal tissues were detected using quantitative real-time PCR and ELISA, respectively. Colorimetric assays were used to determine the activity of superoxide dismutase (SOD) and its inhibition rate, malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), and GSSG/ GSH ratio. Results: Compared with those in the control group, the neonatal mice in NEC group showed significant weight loss (P < 0.05), obvious intestinal injury, increased pathological scores (P < 0.05), increased expressions of TNF-α and IL-1β mRNA and proteins (P < 0.05), decreased SOD activity and inhibition rate, decreased GSH, and significantly increased MDA, GSSG, and GSSG/GSH ratios (P < 0.05). Treatment with L. reuteri obviously decreased the pathological scores, expressions of TNF-α and IL-1β (P < 0.05), MDA, GSSG, and GSSG/GSH ratio (P < 0.05), and significantly increased SOD activity, its inhibition rate, and GSH level in the mice with NEC, but the survival rate was not significantly different between NEC and L. reuteri-treated groups (P > 0.05). Conclusions: L. reuteri DSM17938 can offer protection against NEC in mice by reducing oxidative stress and increasing antioxidant capacity of the intestinal tissue to suppress intestinal inflammations.
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Intestinal epithelial cells (IEC) are important parts of the mucosal barrier, whose function can be impaired upon various injury factors such as lipopolysaccharide. Although food-derived exosomes are preventable against intestinal barrier injuries, there have been few studies on the effect of yak milk–derived exosomes and the underlying mechanism that remains poorly understood. This study aimed to characterize the effect of exosomal proteins derived from yak and cow milk on the barrier function of IEC-6 treated with lipopolysaccharide and the relevant mechanism involved. Proteomics study revealed 392 differentially expressed proteins, with 58 higher expressed and 334 lower expressed in yak milk–derived exosomes than those in cow exosomes. Additionally, the top 20 proteins with a relatively consistent higher expression in yak milk exosomes than cow milk exosomes were identified. Protein CD46 was found to be a regulator for alleviating inflammatory injury of IEC-6. In vitro assay of the role of yak milk exosomes on survival of IEC-6 in inflammation by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay confirmed the effectiveness of yak milk exosomes to increase IEC-6 survival up to 18% for 12 h compared with cow milk exosomes (up to 12%), indicating a therapeutic effect of yak milk exosomes in the prevention of intestinal inflammation. Furthermore, yak and cow milk exosomes were shown to activate the PI3K/AKT/C3 signaling pathway, thus promoting IEC-6 survival. Our findings demonstrated an important relationship between yak and cow milk exosomes and intestinal inflammation, facilitating further understanding of the mechanisms of inflammation-driven epithelial homeostasis. Interestingly, compared with cow milk exosomes, yak milk exosomes activated the PI3K/AKT/C3 signaling pathway more to lower the incidence and severity of intestine inflammation, which might represent a potential innovative therapeutic option for intestinal inflammation.
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Background Ginger oil poses various pharmacological properties corresponding to its terpene composition which depends upon the preparation method along with the sample variety. Objecive This work aims to explore the variability in the oil derived associated with the hydrodistillation settings i.e. sample freshness/dryness, size reduction process, and heating duration using chemometric approaches. Methods The extraction process was evaluated with a two-level full factorial design where the volatile oils were hydrodistillated and characterized by gas chromatographic-mass spectrometry. The multivariate dataset ascertained was further explored with principal component analysis. Results According to the outcomes from the design, the yield could be quantitatively improved by using fresh sample, with reduced particle thickness and longer extraction cycle. The clastering patterns from principal component analysis revealed the domination of monoterpenes in the extracts from fresh samples; sesquiterpenes in the grated samples; whereas heating duration demonstrated antagonistic effect between monoterpenes and sesquiterpenes. Conclusion These findings suggest the importance of experimental conditions in driving the yield and quality of ginger extracts according to the requirement of the industries.
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Necrotizing enterocolitis (NEC) is a serious intestinal disease associated with a high mortality (40-60%) in newborn infants. Cronobacter sakazakii is an important factor for NEC. However, studies regarding NEC pathogenesis and therapeutic treatments are still limited. Here, a C. sakazakii-induced mouse neonatal intestinal inflammation model was employed to determine the effects of trans-cinnamaldehyde (TC) on infections. TC treatment reduced the number of C. sakazakii colony-forming units in the ileal tissues and mitigated the morphological damage in intestinal tissues. Additionally, it reduced the mRNA transcription of inflammatory genes and production of interleukin 6 and tumor necrosis factor-α in mice infected with C. sakazakii. Moreover, TC treatment suppressed caspase-3 activity, modulated enterocyte apoptosis, and inhibited the nuclear factor-kappa B signaling pathway activation induced by C. sakazakii. These findings suggest that TC has protective effects on C. sakazakii-induced murine intestinal inflammation and that it may be a potential agent for preventing NEC.
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In recent years, there is an increasing interest of using the essential oils (EOs) based nanoemulsions as natural antioxidants candidates for wide range of food applications. The upsurge in this current trend is a clear indication highlighting the consumer’s demand for healthier food products with improved stability, safety and fresh-like sensory properties. The prominence of biopolymers in the field of nanotechnology cannot be denied. In this perspective, possessing unique properties, biopolymers such as carbohydrates, proteins and lipids have been fetched much attentions as emulsifiers and stabilizers. In this regard, biopolymer based nanoemulsions loaded with EOs offer great avenues to achieve the desired characteristics such as oxidative stability, thermo-stability, shelf-life and biological activity in food products as well as minimize the choice of applications of synthetic preservatives at the same time. This review presents an update of recent literature on major sources of EOs, their chemical compositions, as well as highlights the formulation and fabrication of biopolymer based nanoemulsions entrapped with EOs. Our effort encompasses the discussion on feasibility of loading of EOs into the nanoemulsion delivery systems embedded with diverse kinds of biopolymers, their antioxidant potential as a preservation strategy to delay and/or halt the oxidation process in wide range of food product applications.
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Zingiber officinale Rosc. (Zingiberacae), commonly known as ginger, is a perennial and herbaceous plant with long cultivation history. Ginger rhizome is one of the most popular food spices with unique pungent flavor and is prescribed as a well-known traditional Chinese herbal medicine. To date, over 160 constituents, including volatile oil, gingerol analogues, diarylheptanoids, phenylalkanoids, sulfonates, steroids, and monoterpenoid glycosides compounds, have been isolated and identified from ginger. Increasing evidence has revealed that ginger possesses a broad range of biological activities, especially gastrointestinal-protective, anti-cancer, and obesity-preventive effects. In addition, gingerol analogues such as 6-gingerol and 6-shogaol can be rapidly eliminated in the serum and detected as glucuronide and sulfate conjugates. Structural variation would be useful to improve the metabolic characteristics and bioactivities of lead compounds derived from ginger. Furthermore, some clinical trials have indicated that ginger can be consumed for attenuating nausea and vomiting during early pregnancy; however, there is not sufficient data available to rule out its potential toxicity, which should be monitored especially over longer periods. This review provides an up-to-date understanding of the scientific evidence on the development of ginger and its active compounds as health beneficial agents in future clinical trials.
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A growing body of research suggests daily low-dose aspirin (ASA) reduces heart diseases and colorectal cancers. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. Preclinical studies have shown that ginger constituents ameliorate ASA-induced gastric ulceration. We here report the design and synthesis of a novel prodrug of aspirin, [6]-gingerol aspirinate (GAS). Our data show that GAS exerts enhanced anti-cancer properties in vitro and superior gastroprotective effects in mice. GAS was also able to survive stomach acid and decomposed in intestinal linings or after absorption to simultaneously release ASA and [6]-gingerol. We further present that GAS inactivates both COX-1 and COX-2 equally. Our results demonstrate the enhanced anticancer properties along with gastroprotective effects of GAS, suggesting that GAS can be a therapeutic equivalent for ASA in inflammatory and proliferative diseases without the deleterious effects on stomach mucosa.
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Background Herbal materials should be stored at optimal conditions in order to retain their nutritional quality. Proper storage has a significant impact on the quality of the herbs and spices. Methods The effects of storage temperature (5 and 15 °C) and time (4 and 8 months) on the phytochemical constituents associated with the antioxidant and antibacterial activities of ginger varieties (Halia bentong and Halia bara) were evaluated to determine the optimal storage conditions for ginger rhizomes. Total flavonoid content (TFC) and Total phenolic content (TPC) were measured using the spectrophotometric method. Individual phenolic acids and flavonoids, 6-gingerol and 6-shogaol were identified by ultra-high performance liquid chromatography. Ferric reducing antioxidant potential (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays were used for evaluation of antioxidant activities. An antibacterial property of ginger varieties was evaluated using well diffusion method. ResultsDry matter, TPC, TFC and individual phenolics and flavonoids content, 6-gingerol and 6-shogaol content noticeably decreased at 5 and 15 °C during the storage times from 4 to 8 months. Highest content of flavonoids, phenolic acids, 6-gingerol, and 6-shogaol was observed in fresh samples followed by rhizomes stored at 5 °C for 4 months. Storage at 15 °C for 4 months reduced the phytochemical content significantly. Cinnamic acid and tannic acid were not detected in those variety stored at 15 °C for 4 and 8 months. Polyphenol oxidase (PPO) activity was associated significantly with storage time and temperature. Highest and lowest PPO activity was observed in stored and fresh rhizomes respectively. Antioxidant and antimicrobial activities gradually declined with the increase of storage temperature (from 5 to 15 °C) and duration (from 4 to 8 months) in both the varieties. Freshly harvested Halia bara variety had higher antioxidant and antibacterial activity compared to the Halia bentong variety. Conclusions Halia bara exhibited valuable phytochemical content and antioxidant and antibacterial activities at higher levels compared to that exhibited by Halia bentong rhizomes. In general, storage of Malaysian ginger varieties at temperature of 5 °C is recommended and the storage time should be not more than 4 months. This storage condition will provide greater stability to the concentration of the phytochemical constituents more similar to the fresh material.
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Necrotizing enterocolitis (NEC) is the most frequent and lethal disease of the gastrointestinal tract of preterm infants. At present, NEC is thought to develop in the premature host in the setting of bacterial colonization, often after administration of non-breast milk feeds, and disease onset is thought to be due in part to a baseline increased reactivity of the premature intestinal mucosa to microbial ligands as compared with the full-term intestinal mucosa. The increased reactivity leads to mucosal destruction and impaired mesenteric perfusion and partly reflects an increased expression of the bacterial receptor Toll-like receptor 4 (TLR4) in the premature gut, as well as other factors that predispose the intestine to a hyper-reactive state in response to colonizing microorganisms. The increased expression of TLR4 in the premature gut reflects a surprising role for this molecule in the regulation of normal intestinal development through its effects on the Notch signalling pathway. This Review will examine the current approach to the diagnosis and treatment of NEC, provide an overview of our current knowledge regarding its molecular underpinnings and highlight advances made within the past decade towards the development of specific preventive and treatment strategies for this devastating disease.
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Aim: To undertake a systematic review and meta-analysis of prospective studies to determine the effect of ginger supplementation on serum C-reactive protein (CRP), lipid profile, and glycaemia. Method: PubMed-MEDLINE, Web of Science, Cochrane Database, and Google Scholar databases were searched (up until July 2016) to identify prospective studies evaluating the impact of ginger supplementation on serum CRP. Random-effects model meta-analysis was used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I(2) index. Systematic review registration: CRD42016035973. Results: From a total of 265 entries identified via searches, 9 studies were included in the final selection. The meta-analysis indicated a significant reduction in serum CRP concentrations following ginger supplementation [weighted mean difference (WMD)-0.84 mg/L (95% CI -1.38 to -0.31, I(2) 56.3%)]. The WMD for fasting blood glucose and HbA1c was -1.35 mg/dl (95% CI -2.04 to -0.58, I(2) 12.1%) and -1.01 (95% CI -1.28 to -0.72, I(2) 9.4%), respectively. Moreover, high-density lipoprotein and triglyceride significantly improved after ginger administration [1.16 mg/dl (95% CI 0.52 to 1.08, I(2) 12.3%) and -1.63 mg/dl (95% CI -3.10 to -0.17, I(2) 8.1%), respectively]. These findings were robust in sensitivity analyses. Random-effects meta-regression revealed that changes in serum CRP levels were independent of the dosage of ginger supplementation (slope -0.20; 95% CI -0.95 to 0.55; p=0.60). Conclusions: This meta-analysis suggests that ginger supplementation significantly reduces serum CRP and improves glycaemia indexes and lipid profile. Randomized control trials with larger sample size and with a longer-term follow-up period should be considered for future investigations.
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The innate immune response is characterized by activation of transcription factors, nuclear factor kappa B and activator protein-1 and their downstream targets, the pro-inflammatory cytokines including interleukin 1β and interleukin 6. Normal development of this response in the intestine is critical to survival of the human neonate and delays can cause the onset of devastating inflammatory diseases such as necrotizing enterocolitis. Previous studies have addressed the role of nuclear factor kappa B in the development of the innate immune response in the enterocyte, however despite its central role in the control of multiple pro-inflammatory cytokine genes, little is known on the role of Activator Protein 1 in this response in the enterocyte. Here we show that the canonical Activator Protein 1 members, cJun and cFos and their upstream kinases JNK and p38 play an essential role in the regulation of interleukin 6 in the immature enterocyte. Our data supports a model whereby the cFos/cJun heterodimer and the more potent cJun homodimer downstream of JNK are replaced by less efficient JunD containing dimers, contributing to the decreased responsiveness to interleukin 1β and decreased interleukin 6 secretion observed in the mature enterocyte. The tissue specific expression of JunB in colonocytes and colon derived tissues together with its ability to repress Interleukin-1β induction of an Interleukin-6 gene reporter in the NCM-460 colonocyte suggests that induction of JunB containing dimers may offer an attractive therapeutic strategy for the control of IL-6 secretion during inflammatory episodes in this area of the intestine.
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In the present study, the chemical composition and antioxidant potential of an essential oil of ginger rhizomes from Ecuador was elucidated. The analysis of the essential oil by GC/FID/MS resulted in identification of 71 compounds, of which the main are citral (geranial 10.5% and neral 9.1%), α-zingiberene (17.4%), camphene (7.8%), α-farnesene (6.8%) and β-sesquiphellandrene (6.7%). The in vitro antioxidant activity of the essential oil expressed by IC50 in descending order is: hydroxyl radical (OH*) scavenging (0.0065 μg/mL) > chelating capacity (0.822 μg/mL) > 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS*+) scavenging (3.94 μg/mL) > xanthine oxidase inhibition (138.0 μg/mL) > oxygen radical (O2*) scavenging (404.0 μg/mL) > 2,2- diphenyl-1-picrylhydrazyl radical (DPPH*) scavenging (675 μg/mL). Lipid peroxidation inhibition of the essential oil was less efficient than butylhydroxytoluol (BHT) in both stages, i.e. hydroperoxide and malondialdehyde formation. In vivo studies in Saccharomyces cerevisiae demonstrated a significant dose-dependent increase in antioxidant marker enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), blocking the oxidation processes in yeast cells. Moreover, ginger essential oil in concentrations of 1.6 mg/mL increases the viability of cells to oxidative stress induced by H2O2.
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Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. This heme enzyme uses hydrogen peroxide and chloride to catalyze the production of hypochlorous acid, which is the major strong oxidant generated by neutrophils in appreciable amounts. In addition to chlorination, myeloperoxidase displays several other activities. It readily oxidizes thiocyanate to hypothiocyanite, converts a myriad of organic substrates to reactive free radicals, and hydroxylates aromatic compounds. Depending on the concentration of its competing substrates and the conditions of the local environment, myeloperoxidase could substantially affect oxidant production by neutrophils. Superoxide is undoubtedly a physiological substrate for myeloperoxidase. Its interactions with the enzyme are key factors in determining how neutrophils use superoxide to kill pathogens and promote inflammatory tissue damage. Superoxide modulates the chlorination and peroxidation activities of myeloperoxidase. It also reacts with the enzyme to form oxymyeloperoxidase which is catalytically active and hydroxylates phenolic substrates. Myeloperoxidase reacts rapidly with nitric oxide and peroxynitrite so that at sites of inflammation there is a strong possibility that these reactions will impact on oxidative damage caused by neutrophils. Under certain conditions, many substrates of myeloperoxidase act as inhibitors and regulate oxidant production by the enzyme. Given the numerous reactions of myeloperoxidase, all its activities should be considered when assessing the injurious oxidants produced by neutrophils.
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Humans have been using natural products for medicinal use for ages. Natural products of therapeutic importance are compounds derived from plants, animals, or any microorganism. Ginger is also one of the most commonly used condiments and a natural drug in vogue. It is a traditional medicine, having some active ingredients used for the treatment of numerous diseases. During recent research on ginger, various ingredients like zingerone, shogaol, and paradol have been obtained from it. Zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) is a nontoxic and inexpensive compound with varied pharmacological activities. It is the least pungent component of Zingiber officinale. Zingerone is absent in fresh ginger but cooking or heating transforms gingerol to zingerone. Zingerone closely related to vanillin from vanilla and eugenol from clove. Zingerone has potent anti-inflammatory, antidiabetic, antilipolytic, antidiarrhoeic, antispasmodic, and so forth properties. Besides, it displays the property of enhancing growth and immune stimulation. It behaves as appetite stimulant, anxiolytic, antithrombotic, radiation protective, and antimicrobial. Also, it inhibits the reactive nitrogen species which are important in causing Alzheimer’s disease and many other disorders. This review is written to shed light on the various pharmacological properties of zingerone and its role in alleviating numerous human and animal diseases.
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The current mode of treatment based on synthetic drugs is expensive and also causes genetic and metabolic alterations. However, safe and sound mode of treatment is needed to control the diseases development and progression. In this regards, medicinal plant and its constituents play an important role in diseases management via modulation of biological activities. Ginger, the rhizome of the Zingiber officinale, has shown therapeutic role in the health management since ancient time and considered as potential chemopreventive agent. Numerous studies based on clinical trials and animal model has shown that ginger and its constituents shows significant role in the prevention of diseases via modulation of genetic and metabolic activities. In this review, we focused on the therapeutics effects of ginger and its constituents in the diseases management, and its impact on genetic and metabolic activities.
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We investigated the mechanism underlying the protective effects of ginger against gastric damage induced by aspirin in rats. Gastric mucosal lesions were produced by orally administering 200 mg/kg aspirin suspended in 1% carboxymethylcellulose solution to pyloric-ligated male Wistar rats. Ginger powder (200 mg/kg) markedly reduced the aspirin-induced gastric hemorrhagic ulcer area. The total acidity of gastric juice was not significantly influenced by aspirin or ginger. Ginger powder did not affect the aspirin-induced reduction in mucosal prostaglandin E2 (PGE2) content; however, it did ameliorate the aspirin-induced increases in mucosal activity of the inducible form of NO synthase (iNOS) and plasma tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels. In the next experiment, high and low doses of 6-gingerol and 6-shogaol were used instead of ginger powder in the same experimental model to examine their roles in the anti-ulcer mechanism of ginger. Both 6-gingerol and 6-shogaol reduced aspirin induced ulcer formation, mucosal iNOS and plasma TNF-α and IL-1β levels. In conclusion, ginger powder prevents the aspirin induced gastric ulcer formation by reducing mucosal iNOS activity and the plasma levels of inflammatory cytokines but does not affect gastric juice or acid production or mucosal PGE2 content. This protective effect of ginger powder against gastric ulcers may be attributable to both gingerol and shogaol.
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Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4-dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4-dependent up-regulation of CD14 membrane expression.
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The aim was to investigate whether or not glutamine, an antioxidant effective amino acid, improves the reperfusion-induced oxidative injury of abdominal hypertension. Wistar Albino rats were used. Group 1: Abdominal compartment syndrome alone: With the rats under anesthesia, intraabdominal pressure was obtained. Three days later, the rats were sacrificed, and intestine, lung and liver samples were removed for determination of tissue malondialdehyde (MDA) and glutathione (GSH) levels as oxidative injury parameters and of myeloperoxidase (MPO) activity as an inflammatory parameter. Trunk blood was analyzed for the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Group 2: Abdominal compartment syndrome and glutamine: intragastric glutamine was given for seven days before and three days following establishment of the abdominal compartment syndrome model. The same examination procedure was then performed. Group 3: Glutamine administration alone. Group 4: Control group. Intraabdominal pressure significantly increased the intestine, lung and liver MDA levels and MPO activities in comparison to the control group. Glutamine was associated with decreased MDA levels and MPO activities and increased GSH levels. Glutamine appears to have protective effects against reperfusion-induced oxidative damage via its anti-inflammatory and antioxidant effect.
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Ginger (Zingiber officinale Roscoe) is a well known and widely used herb, especially in Asia, which contains several interesting bioactive constituents and possesses health promoting properties. In this study, the antioxidant activities of methanol extracts from the leaves, stems and rhizomes of two Zingiber officinale varieties (Halia Bentong and Halia Bara) were assessed in an effort to compare and validate the medicinal potential of the subterranean part of the young ginger. The antioxidant activity and phenolic contents of the leaves as determined by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and the total amounts of phenolics and flavonoids were higher than those of the rhizomes and stems. On the other hand, the ferric reducing/antioxidant potential (FRAP) activity of the rhizomes was higher than that of the leaves. At low concentration the values of the leaves' inhibition activity in both varieties were significantly higher than or comparable to those of the young rhizomes. Halia Bara had higher antioxidant activities as well as total contents of phenolic and flavonoid in comparison with Halia Bentong. This study validated the medicinal potential of the leaves and young rhizome of Zingiber officinale (Halia Bara) and the positive relationship between total phenolics content and antioxidant activities in Zingiber officinale.
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Oxygen-derived free radicals, particularly superoxide anion, are considered important mediators of intestinal injury induced by ischemia/reperfusion based on the protective effects of superoxide dismutase and allopurinol. A role for free radicals was investigated in a model of necrotizing enterocolitis (NEC) which was initiated by a luminal, as opposed to a vascular, insult. Intestinal loops of weanling rabbits received either saline (control loops) or a solution of 10 mg/ml casein and 50 mg/ml calcium gluconate acidified to pH 4 with proprionic acid (treated loops). When the animals were sacrificed 3 hours later, severe damage was noted in the treated loops, which included blunting of villi and edema, with all animals surviving. At 16 hours only 5 of 8 rabbits survived, and 3 had hemorrhagic necrosis. Control loops were normal in each case. Intravenous infusion of superoxide dismutase (4 mg/kg/hr), commencing 15 minutes after NEC induction, totally prevented intestinal injury. On the other hand, pretreatment with allopurinol, an inhibitor of xanthine oxidase, for 2 days (30 and 60 mg/kg by mouth) was not protective against intestinal damage. A cellular infiltration in treated loops was not histologically evident in the majority of animals at 3 hours after treatment, a finding confirmed by the minimal accumulation of 111In-labeled leukocytes in damaged and intact intestinal tissue. These results suggest that superoxide generated locally from sources other than xanthine oxidase play a critical and early role in experimental NEC and that superoxide dismutase may prove to be an effective therapy in this devastating neonatal disease.
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Lipid peroxidation (LPO) is a free radical-related process that in biologic systems may occur under enzymatic control, e.g., for the generation of lipid-derived inflammatory mediators, or nonenzymatically. This latter form is associated mostly with cellular damage as a result of oxidative stress, which also involves cellular antioxidants in this process. This article focuses on the relevance of two LPO products, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), to the pathophysiology of human disease. The former has been studied in human serum samples of hepatitis C virus-infected adults and human immunodeficiency virus-infected children. In these two cases it is shown that the specific assay of serum MDA is useful for the clinical management of these patients. The presence of MDA in subretinal fluid of patients with retinal detachment suggests the involvement of oxidative stress in this process. Moreover, we were able to report the dependence of this involvement on the degree of myopia in these patients. The assay of MDA contents in the peripheral nerves of rats fed a chronic alcohol-containing diet or diabetic mice also confirms the pathophysiologic role of oxidative stress in these experimental models. In these two cases, associated with an increase in tissue LPO products content, we detected a decrease of glutathione peroxidase (GSHPx) activity in peripheral nerve, among other modifications. We have demonstrated that in vitro HNE is able to inhibit GSHPx activity in an apparent competitive manner, and that glutathione may partially protect and/or prevent this inactivation. The accumulation of LPO products in the brain of patients with Alzheimer's disease has also been described, and it is on the basis of this observation that we have tried to elucidate the role of oxidative stress and cellular antioxidants in beta-amyloid-induced apoptotic cell death of rat embryo neurons. Finally, we discuss the possible role of the observed vascular effects of HNE on human arteries.
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Since time immortal, ginger as an ancient herb has been used throughout the world in foods and beverages due to its typical strong and pungent flavor. Besides its use as a spice, it also serves as an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Gingerols constitute as key ingredients in fresh ginger with the most abundant being 6-gingerol, 8-gingerol and 10-gingerol. Many studies have investigated the various valuable pharmacological properties of its ingredients and experimentally verified their mechanistic aspects of the health effects; however, to date, most research on the anti-cancerous activities of gingerols have focused largely on 6-gingerol. Thus, the present article deals with the number of recent studies which have indicated and highlighted the role of 10-gingerol with respect to its cancer preventive attributes in particular and its anti-inflammatory, anti-oxidant, anti-microbial and gastrointestinal tract protective potential in general. The purpose of this review is to provide an overview of all the experimentally validated health benefits of 10-gingerol for its nutraceutical application. The various findings warranted the further investigation of 10-gingerol for its possible use in the various cancer treatments as well as its promising role as a chemo preventive agent
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Diabetes is the most common endocrine disorder in humans with multiple complications including nervous system damages. The aim of the present study was to determine the effect of ginger extract on apoptosis of the neurons of hippocampus, via evaluation of BAX and Cyclin D1 and also histological analysis, in male diabetic rats. In this experimental study, 60 Wistar rats (220 ± 30gr) were conducted in 5 groups as follow: diabetic group treated with saline (group 1), normal group treated with saline (group 2), diabetic group treated with ginger (group 3), diabetic group treated with ginger-insulin (group 4), diabetic group treated with insulin (group 5). STZ (60 mg/kg) was intraperitoneally used to induce the diabetes. Expression levels of BAX and Cyclin D1 were examined using Real-Time PCR technique and the normality of neurons was evaluated using H&E staining method. The results showed that blood glucose level significantly decreased in group 4 when compared to group 1. In molecular analysis, there was no significant difference between groups regarding the expression of BAX gens, while, the expression of Cyclin D1 were significantly decreased in group 4 compared with group 1. Histological analysis revealed that pathological symptoms were lower in group 4 than the other diabetic groups. The results of present study showed that the ginger in addition to lowering blood sugar level, changes the expression of Cyclin D1 gene and histological characteristics in a positive manner. This means that the ginger may protects neurons of the hippocampus from apoptosis in diabetic patients.
Article
The anti-cancerous activity of 6-gingerol extracted from Tongling White Ginger was investigated. 6-Gingerol inhibited the growth of HeLa cells with IC50 (96.32 μM) and IC80 (133.01 μM) and led to morphological changes, induced the cell cycle arrest in G0/G1-phase and ultimately resulted into apoptosis. Among cell cycle-related genes and proteins, the expression of cyclin (A, D1, E1) reduced, while of CDK-1, p21 and p27 showed slight decrease, except cyclin B1 and E1 (protein). Western blotting reported the induction of apoptosis with an increased Bax/Bcl-2 ratio, release of cytochrome c, cleavage of caspase-3, -8, -9 and PRPP in treated cells. 6-Gingerol activated AMPK, but inhibited PI3K/AKT phosphorylation with reduced P70S6K expression and also suppressed the mTOR phosphorylation. 6-Gingerol with 5-FU and Ptx resulted in 83.2% and 52% inhibition respectively, this synergy have stimulated apoptosis proteins more efficiently as compared to 6-Gingerol alone (10.75%) under in vitro conditions.
Article
With an aim to evaluate anti-cancerous activities of 10-gingerol (10-G) against Hela cells, it was purified and identified from Tongling White Ginger by HSCCC, UPLC-TOF-MS/MS and NMR analysis, respectively. 10-G inhibited the proliferation of HeLa cells at IC50 (29.19 μM) and IC80 (50.87 μM) with altered cell morphology, increased cytotoxicity and arrested cell cycle in G0/G1-phase. The most cell cycle related genes and proteins expression significantly decreased, followed by slight decrease in few and without affecting cyclin B1 and cyclin E1 (protein). Both death receptors significantly upregulated and activated apoptosis indicators (caspase family). Furthermore, significant changes in mitochondria dependent pathway markers were observed and led to cell death. 10-G led to PI3K/AKT inhibition and AMPK activation to induce mTOR mediated cell apoptosis in Hela cells. Our results can be an asset to exploit 10-G with other medicinal plant derivatives for future applications.
Article
Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.
Article
Natural compounds containing phenoxyl groups or/and Michael acceptor units appear to possess antioxidant and cytoprotective properties. The ginger principal constituent 6-shogaol (6-S) represents one of such compounds. In this study, we reported that 6-S efficiently scavenges various free radicals in vitro, and displays remarkable cytoprotection against oxidative stress-induced cell damage in the neuron-like rat pheochromocytoma cell line, PC12 cells. Pretreatment of PC12 cells with 6-S significantly upregulates a series of phase II antioxidant molecules, such as glutathione, Heme oxygenase 1, NAD(P)H: quinone oxidoreductase 1, thioredoxin reductase 1, and thioredoxin 1. Mechanistic study revealed that 6-S enhanced the translocation of Nrf2 from cytosol to nucleus and knockdown of Nrf2 abolished such protection, indicating that this cytoprotection is mediated by the activation of transcription factor Nrf2. Another ginger constituent 6-gingerol (6-G), having the similar structure of 6-S but lacking the alpha, beta-unsaturated ketone structure (Michael acceptor moiety), failed to shelter PC12 cells from oxidative insults. Our results demonstrate that 6-S is a novel small molecule activator of Nrf2 in PC12 cells, and suggest that 6-S might be a potential candidate for the prevention of oxidative stress-mediated neurodegenerative disorders.
Article
Although necrotizing enterocolitis (NEC) is the most lethal gastrointestinal disease in the neonatal population, its pathogenesis is poorly understood. Risk factors include prematurity, bacterial colonization, and formula feeding. This review examines how mucosal injury permits opportunistic pathogens to breach the gut barrier and incite an inflammatory response that leads to sustained overproduction of mediators such as nitric oxide and its potent adduct, peroxynitrite. These mediators not only exacerbate the initial mucosal injury, but they also suppress the intestinal repair mechanisms, which further compromises the gut barrier and culminates in bacterial translocation, sepsis, and full-blown NEC.
Article
Gingerols are phenolic compounds in ginger (Zingiber officinale), which have been reported to exhibit antiinflammatory, antioxidant, and anticancer properties. The present study aimed at evaluating the possible pharmacologic activity of 6-gingerol in a mouse model of dextran sulphate sodium (DSS)-induced ulcerative colitis. Adult male mice were exposed to DSS in drinking water alone or co-treated with 6-gingerol orally at 50, 100, and 200 mg/kg for 7 days. Disease activity index, inflammatory mediators, oxidative stress indices, and histopathological examination of the colons were evaluated to monitor reatment-related effects of 6-gingerol in DSS-treated mice. Administration of 6-gingerol significantly reversed the DSS-mediated reduction in body weight, diarrhea, rectal bleeding, and colon shrinkage to near normal. Moreover, 6-gingerol significantly suppressed the circulating concentrations of interleukin-1β and tumor necrosis factor alpha and restored the colonic nitric oxide concentration and myeloperoxidase activity to normal in DSS-treated mice. 6-Gingerol efficiently prevented colonic oxidative damage by increasing the activities of antioxidant enzymes and glutathione content, decreasing the hydrogen peroxide and malondialdehyde levels, and ameliorated the colonic atrophy in DSS-treated mice. 6-Gingerol suppressed the induction of ulcerative colitis in mice via antioxidant and antiinflammatory activities, and may thus represent a potential anticolitis drug candidate
Article
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature neonates. The pathogenesis of NEC remains poorly understood. The present study aimed to investigate the dynamic change and role of cyclooxygenase-2 (COX-2) in neonatal rats with intestinal injury. Wistar rats, <24 h in age, received an intraperitoneal injection with 5 mg/kg lipopolysaccharide (LPS). Ileal tissues were collected at 1, 3, 6, 12 and 24 h following the LPS challenge for histological evaluation of NEC and for measurements of COX-2 mRNA. The correlation between the degree of intestinal injury and expression of COX-2 mRNA was determined. The LPS-injected pups showed a significant increase in injury scores compared to the control, and the most deteriorating change was at 12 h. COX-2 mRNA expression was upregulated following LPS injection. There was a significantly positive correlation between COX-2 mRNA and the grade of intestinal injury within 12 h, whereas COX-2 mRNA expression had a significantly negative correlation with the severity of intestinal injury at 24 h. COX-2 plays an important role in LPS-induced intestinal injury and the repair processes. Caution should be exerted concerning the potential therapeutic uses of COX-2 inhibitors or promoters in NEC.
Article
Unlabelled: The cellular endogenous antioxidant system plays pivotal roles in counteracting or retarding the pathogenesis of many neurodegenerative diseases. Molecules with the ability to enhance the antioxidant defense thus are promising candidates for neuroprotective drugs. 6-Dehydrogingerdione (6-DG), one of the major components of dietary ginger, has received increasing attention due to its multiple pharmacological activities. However, how this pleiotropic molecule works on the neuronal system has not been studied. This paper reports that 6-DG efficiently scavenges various free radicals in vitro and displays remarkable cytoprotection against oxidative stress-induced neuronal cell damage in the neuron-like rat pheochromocytoma cell line, PC12 cells. Pretreatment of PC12 cells with 6-DG significantly up-regulates a panel of phase II genes as well as the corresponding gene products, such as glutathione, heme oxygenase, Nad(p)h: quinone oxidoreductase, and thioredoxin reductase. Mechanistic study indicates that activation of the Keap1-Nrf2-ARE pathway is the molecular basis for the cytoprotection of 6-DG. This is the first revelation of this novel mechanism of 6-DG as an Nrf2 activator against oxidative injury, providing the potential therapeutic use of 6-DG as neuroprotective agent.
Article
Stress can lead to the manifestation of functional gastrointestinal disorders, the most prominent being irritable bowel disorder. The present study investigated the impact zingerone in ameliorating chronic water stress induced irritable bowel disorder, brain gut axis dysfunction and dysregulation of the intestinal barrier due to oxidative stress. Rats were randomly allocated to groups and subjected to chronic water stress for a period of 21 days for 1h and the fecal pellet output was measured. At the end of chronic stress, behavioral assessment for anxiety like behavior was recorded and plasma corticosterone levels were measured 60min after water stress. The colonic transit was determined, levels of oxidative and antioxidant biomarkers were measured in the colon homogenate. Myeloperoxidase activity was determined as an indirect index of neutrophil infiltration. Chronic water stress increased the rate of colonic transit, fecal output, induced behavioral changes, and decreased antioxidant levels. An increase in lipid peroxide levels, catalase and corticosterone was observed. Mast cell infiltration was evident in the stressed group. Zingerone significantly reduced colonic transit, fecal output, neutrophil infiltration, and lipid peroxide formation. The levels of catalase were not altered; however, a marginal increase in the levels of glutathione peroxidase was observed. Zingerone significantly enhanced the levels of superoxide dismutase, glutathione and decreased the levels of corticosterone. Zingerone produced marked improvement in stress induced irritable bowel disorder which could be attributed to the powerful antioxidant nature, direct effect on the intestinal smooth muscle and adaptogenic nature.
Article
The pathogenesis of necrotizing enterocolitis (NEC) is complex and its speed of progression is variable. To gain understanding of the disease, researchers have examined tissues resected from patients with NEC; however, as these are obtained at late stages of the disease, they do not yield clues about the early pathogenic events leading to NEC. Therefore, animal models are used and have helped identify a role for several mediators of the inflammatory network in NEC. In this article, we discuss the evidence for the role of these inflammatory mediators and conclude with a current unifying hypothesis regarding NEC pathogenesis.
Chapter
Ginger (Zingiber officinale Roscoe, Zingiberaceae) is one of the most commonly consumed dietary condiments in the world (Surh et al. 1999). The oleoresin (i.e., oily resin) from the rhizomes (i.e., roots) of ginger contains many bioactive components, such as [6]-gingerol (1-[4′-hydroxy-3′- methoxyphenyl]-5-hydroxy-3-decanone; Figure 7.1), which is the primary pungent ingredient that is believed to exert a variety of remarkable pharmacological and physiological activities. Although ginger is generally considered to be safe (Kaul and Joshi 2001), the lack of a complete understanding of its mechanisms of action suggests caution in its therapeutic use (Wilkinson 2000a). Previous reviews (Barrett, Kiefer, and Rabago 1999; Ness, Sherman, and Pan 1999; Talalay and Talalay 2001) have emphasized the importance of careful scientific research in establishing the safety and efficacy of potential therapeutic plant remedies and in defining the risks and benefits of herbal medicine. Ginger has been used for thousands of years for the treatment of numerous ailments, such as colds, nausea, arthritis, migraines, and hypertension. The medicinal, chemical, and pharmacological properties of ginger have been extensively reviewed (Surh, Lee, and Lee 1998; Ernst and Pittler 2000; Afzal et al. 2001; Bode and Dong 2004; Boone and Shields 2005; Borrelli et al. 2005; Chrubasik and Pittler 2005; Chrubasik, Pittler, and Roufogalis 2005; Grzanna, Lindmark, and Frondoza 2005; Thompson and Potter 2006; Eliopoulos 2007; Shukla and Singh 2007; White 2007; Ali et al. 2008; Nicoll and Henein 2009). Over the last few years, interest in ginger or its various components as valid preventive or therapeutic agents has increased markedly, and scientific studies focusing on verification of ginger’s pharmacological and physiological actions have likewise increased (Ali et al. 2008). The primary purpose of this chapter is to comprehensively examine the available scientific evidence regarding ginger’s proven effectiveness in preventing or treating a variety of pathologic conditions.
Article
Aim: The aim of this study was to determine the beneficial effects of Nigella sativa oil (NSO) on rats with necrotizing enterocolitis (NEC). Material and methods: Thirty newborn Sprague-Dawley rats were randomly divided into three groups as NEC, NEC + NSO, and control. NEC was induced by enteral formula feeding, exposure to hypoxia-hyperoxia and cold stress. Pups in the NEC + NSO group were administered NOS at a dose of 2 ml/kg daily by intraperitoneal route from the first day until the end of the study. Proximal colon and ileum were excised for histopathologic, apoptosis (TUNEL) and biochemical evaluation, including xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malonaldehyde (MDA), and myeloperoxdase (MPO) activities. Results: Pups in the NEC + NOS group had better clinical sickness scores and weight gain compared to the NEC group (p < 0.05). In the macroscopic assessment, histopathologic and apoptosis evaluation (TUNEL), severity of bowel damage was significantly lower in the NEC + NOS group compared to the NEC group (p < 0.05). Tissue GSH-Px and SOD levels were significantly preserved in the NEC + NSO group (p < 0.05), whereas, tissue MDA, MPO levels of the NEC + NSO group were significantly lower than those in the NEC group (p < 0.05). Conclusion: NSO significantly reduced the severity of intestinal damage in NEC.
Article
This review will examine the unique susceptibility of premature infants to oxidative stress, the role of reactive oxygen species (ROS) in the pathogenesis of common disorders of the preterm infant, and potential for therapeutic interventions using enzymatic and/or nonenzymatic antioxidants. Oxidative stress is caused by an imbalance between the production of ROS and the ability to detoxify them with the help of antioxidants. The premature infant is especially susceptible to ROS-induced damage because of inadequate antioxidant stores at birth, as well as impaired upregulation in response to oxidant stress. Thus, the premature infant is at increased risk for the development of ROS-induced diseases of the newborn, such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and periventricular leukomalacia. Potential therapies for ROS-induced disease include both enzymatic and nonenzymatic antioxidant preparations. More research is required to determine the beneficial effects of supplemental antioxidant therapy.
Article
Contemporary medications used in the treatment of gastric ulcers involve the use of novel mucosal protective drugs. The present study aimed to investigate the gastroprotective effect of ginger extract and polaprezinc in a rat model of acetic acid-induced gastric ulcer. 'Kissing' ulcers were induced in male Sprague-Dawley rats by using 60% acetic acid. Rhizoma Zingiber officinale (ginger) extract (1.5-5 g/kg) or polaprezinc (30 and 60 mg/kg) was orally given to the animals once daily for three consecutive days after ulcer induction. All animals were killed on day 5 by an overdose of ketamine. Both ginger extract and polaprezinc significantly reduce the gastric ulcer area in a dose-dependent manner, with concomitant attenuation of the elevated activities of xanthine oxidase and myeloperoxidase, as well as malondialdehyde level in the ulcerated mucosa. Nevertheless, only polaprezinc could restore the mucosal glutathione level. Polaprezinc also causes the overexpression of basic fibroblast growth factor, vascular endothelial growth factor and ornithine decarboxylase, whereas ginger extract only increases the expression of the two growth factors in the gastric mucosa. Furthermore, polaprezinc could consistently downregulate the protein expression of tumor necrosis factor (TNF)-α, interleukin-1β, macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant-2α that have been activated in the ulcerated tissues, whereas ginger extract mainly inhibits the expression of the chemokines and to some extent TNF-α. Ginger extract and polaprezinc both show anti-oxidation that consequently alleviates gastric mucosal damage and promotes ulcer healing, which together serve as effective mucosal protective agents.
Article
Zingiber officinale Roscoe, popular name ginger, is grown naturally in many parts of the world, including Brazil. Ginger is used in pharmaceutical, cosmetic, and food and beverage industries and the essential oil has been used in folk medicine for manifold conditions including as an analgesic, anti-inflammatory, and antirheumatic. The purpose of this study was to investigate the effects of ginger (Zingiber officinale Roscoe) essential oil (GEO) in an in vitro chemotaxis assay and on leukocyte-endothelial interactions in vivo. GEO was analyzed by GC-MS and the main components identified were ar-curcumene (59%), β-myrcene (14%), 1,8-cineol (8%), citral (7.5%), and zingiberene (7.5%). Oral administration of GEO (200-500 mg/kg) reduced the rolling and leukocyte adherence after 2 h of carrageenan injection (100 μg) into the scrotal chamber. The number of leukocytes migrated to the perivascular tissue 4 h after the irritant stimulus was also diminished. GEO in all doses tested (10(-4), 10(-3), or 10(-2) μL/mL) caused a significant reduction of leukocyte chemotaxis (35.89 ± 4.33, 30.67 ± 0.70, and 35.85 ± 3.83%, respectively) toward casein stimuli. The data presented showed direct and systemic effects of GEO on leukocyte migration as an important mechanism of the anti-inflammatory action of ginger.
Article
Eryngium creticum, Nigella sativa, and Teucrium polium have been traditionally used for the treatment of inflammations, liver disorders, and arthritis. Various studies on these plants revealed anti-inflammatory, hepatoprotective and antimutagenic activities. Previous results of our research group, however, indicate that aqueous extracts prepared as for the traditional use (tea) have neither cytoprotective nor antimutagenic activity. Instead, there is evidence for a mutagenic potential. Since the described antimutagenic activity may not be present in effective amounts in the aqueous extracts this study focuses on ethanolic extracts. Ethanolic extracts of the three plant species were prepared and tested against N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a directly acting mutagen. Since it cannot be excluded that the active constituents of the plant extracts require biotransformation or induce metabolic enzymes, causing antimutagenic or detoxifying effects, primary cultures of rat hepatocytes were used for this study. Plant ethanolic extracts were applied along with MNNG in three protocols: pre-treatment, combined treatment and post-treatment. The results of this investigation clearly indicate an inhibitory effect of the plant extracts on MNNG mutagenicity, while the extracts had no effect on cytotoxicity indicators such as necrosis and apoptosis. The effects obtained can be attributed to a direct antimutagenic activity and an increased recovery at the chromosomal level. In order to identify the responsible compounds extracts will in a next step have to be fractionated, tested and chemically analyzed.
Article
A neonatal rat model of necrotizing enterocolitis (NEC) is useful to investigate this devastating and obscure disease. The aim of this study was to assess a neonatal rat model of NEC to evaluate whether the histological appearance of the damaged intestine could be predicted by the clinical behaviour of the animals and the macroscopic appearance of the gut. Neonatal rats were delivered at term and assigned either to a control group consisting of breastfeeding and no stress factors, or to a NEC group in which NEC was induced by gavage feeding + hypoxia + oral lipopolysaccharide (4 mg/kg/day once daily for the first 2 days of life). Clinical status was assessed on day 4 using a clinical sickness score (general appearance, response to touch, natural activity, body colour; 0 - 3 for each variable). Neonatal rats were sacrificed at 4 different time points: day 1, day 2, day 3, and day 4. At sacrifice, a macroscopic assessment of the gut was performed using a new scoring system based on: colour (0 - 2), consistency (0 - 2) and degree of dilatation (0 - 2). The resected gut was stained with haematoxylin/eosin, and evaluated microscopically by 2 independent blinded scorers, including a consultant histopathologist. The histology results were used to validate the macroscopic gut assessment. Results were compared by ANOVA and linear regression analysis. Ethics Committee and Home Office approvals were obtained. In the control group NEC was not present either macroscopically or histologically. The clinical sickness score was higher in the NEC group (median = 4.5; range = 2 - 6) compared to controls (median = 0; range = 0 - 1; p < 0.0001). In the NEC group the macroscopic appearance (from day 2) and histological score (from day 1) increased significantly (p < 0.0001) and were strongly correlated (r (2) = 0.74, p < 0.0001). The clinical behaviour and macroscopic appearance of the intestine are valid tools to assess gut damage in our neonatal rat model of NEC. This allows future studies that are not exclusively based on histology.
Article
Xanthine oxidase was decreased 2- to 10-fold in all examined rat hepatomas irrespective of the malignancy; growth rate and degrees of histological differentiation of the neoplasms. The affinity to substrate (KM=6-8 muM) and the pH optimum (8.0) of the liver and hepatoma enzymes were the same. The reprogramming of gene expression, as manifested in the decreased activity of this key purine metabolizing enzyme, appears to be specific to neoplastic transformation. Since glutamine PRPP amidotransferase activity was increased but the opposing enzyme, xanthine oxidase, was decreased in all the hepatomas, the reprogramming of gene expression results in an imbalance that favors synthesis against catabolism. This enzymatic imbalance should confer selective advantages to the cancer cells.
Article
This chapter describes the malondialdehyde (MDA) as index of lipid peroxidation. The determination of malondialdehyde (MDA) has attracted widespread interest, because it appears to offer a facile means of assessing lipid peroxidation in biological materials. Malondialdehyde occurs in biological materials in free state and in various covalently bound forms. Urine also contains small amounts of MDA adducts with guanine, the phospholipid bases serine and ethanolamine, and other unidentified reactants. Free MDA is a minor and variable excretory product. It is apparent from the occurrence of these derivatives in urine that MDA forms adducts with proteins, nucleic acids, and other substances in vivo, and this compromises the assessment of lipid peroxidation in the tissues based on the determination of free MDA. The pH required for maximum yield of MDA varies among biological materials depending on the nature of the derivatives present. MDA may be generated during hydrolysis by the oxidation of polyunsaturated fatty acids (PUFA) in the sample and by the degradation of preexisting oxidation products. Pigments present in the sample, or generated during hydrolysis, also can interfere in the colorimetric assessment of MDA. These problems, and possibilities for their resolution, are discussed in the chapter.
Article
This assay for superoxide dismutase (SOD, EC 1.15.1.1) activity involves inhibition of nitroblue tetrazolium reduction, with xanthine-xanthine oxidase used as a superoxide generator. By using a reaction terminator, we can determine 40 samples within 55 min. One unit of activity of pure bovine liver Cu,ZnSOD and chicken liver MnSOD was expressed by 30 ng and 500 ng of protein, respectively. The mean concentrations of Cu,ZnSOD as measured by this method in blood from normal adults were 242 (SEM 4) mg/L in erythrocytes, 548 (SEM 20) micrograms/L in serum, and 173 (SEM 11) micrograms/L in plasma. The Cu,ZnSOD concentrations in serum and plasma of patients with cancer of the large intestine tended to be less and greater than these values, respectively, but not statistically significantly so.
Article
Necrotizing enterocolitis (NEC) is a common gastrointestinal disorder affecting premature infants. To investigate critically the importance of the purported risk factors of NEC (formula feeding, asphyxia, bacteria, and prematurity), we developed a neonatal rat model that closely mimics the human disease. Full-term and premature newborn rats were stressed with formula feeding, asphyxia, and/or exogenous bacterial colonization and subsequently evaluated grossly and histologically for the development of intestinal injury. We found that most animals treated with asphyxia, formula feeding, and bacteria developed NEC (77%) and died (86%) by 96 h. All maternally fed animals treated with asphyxia and bacterial colonization survived and had normal intestinal histology. Furthermore, asphyxia was a critical instigating factor, because formula and bacterial exposure without asphyxia resulted in normal intestine and minimal mortality (12%). Enteral bacterial colonization was not a significant determinant of NEC in this model. We conclude that the neonatal rat model is an excellent test system for the study of NEC. As in the human disease, asphyxia and formula feeding play an important role in the pathophysiology of experimental NEC.
Article
Newborn intestine is uniquely prone to vasoconstriction in response to a wide variety of perturbations. To test the hypothesis that endothelin (ET)-1 is an important factor in this process, we determined the effects of exogenous ET-1 administration and blockade of endogenous ET-1 in vivo and in vitro in 3- and 35-day-old swine. Intramesenteric artery administration of exogenous ET-1 to vascularly isolated in vivo gut loops (10(-9) M/kg bolus) caused vasoconstriction and reduced gut O(2) uptake similarly in these age groups. Selective blockade of ET(A) or ET(B) receptors with BQ-610 or BQ-788, respectively, in vascularly isolated in vivo gut loops had no effect on gut vascular resistance or O(2) uptake in either age group; within in vitro gut loops, BQ-610 significantly increased vasoconstriction when perfusion pressure was reduced below baseline, but only in 3-day-old animals; i.e., it impaired the autoregulatory response to perfusion pressure reduction. Exogenous ET-1 significantly decreased capillary perfusion within in vitro gut loops, as evidenced by a decrease in capillary filtration coefficient, but only in 3-day-old animals; furthermore, blockade of endogenous ET-1 activity with BQ-610 significantly enhanced capillary filtration coefficient in 3-day-old animals and increased O(2) extraction ratio. ET-1 did not depress intestinal metabolic rate, as evidenced by its effect on the O(2) uptake-blood flow relationship; it did compromise tissue oxygenation because of its effects on intestinal O(2) transport. ET-1 concentration in mesenteric venous effluent exceeded arterial concentration, but only in 3-day-old intestine, suggesting production of ET-1 by newborn intestine. We conclude that ET-1 exerts an age-dependent effect on intestinal hemodynamics in postnatal intestine, having a greater impact in 3- than in 35-day-old intestine.
Article
Neonatal necrotizing enterocolitis (NEC) is a major cause of morbidity in preterm infants. We hypothesize that the intestinal injury in this disease is a consequence of synergy among three of the major risk factors for NEC: prematurity, enteral feeding, and bacterial colonization. Together these factors result in an exaggerated inflammatory response, leading to ischemic bowel necrosis. Human milk may decrease the incidence of NEC by decreasing pathogenic bacterial colonization, promoting growth of nonpathogenic flora, promoting maturation of the intestinal barrier, and ameliorating the proinflammatory response.
Article
The present study investigated the effects of the herbal medicine Dai-kenchu-to (DKCT) and its 4 individual ingredients on intestinal blood flow (IBF) in rats by laser Doppler flowmetry. Intraduodenal administration of DKCT (30, 100 and 300 mg/kg) increased IBF in a dose-dependent manner, whereas the mean arterial blood pressure was not affected. One of the ingredients in DKCT is dried ginger rhizome (150 mg/kg), whose main component is [6]-shogaol (2 mg/kg), both of which showed similar effects to those shown by DKCT, while the other ingredients in DKCT only slightly increased IBF or had no effect. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP (8-37), completely abolished the hyperemia induced by DKCT, dried ginger rhizome and [6]-shogaol. However, the vasoactive intestinal polypeptide (VIP) receptor antagonist, [4-Cl-DPhe6, Leul7]-VIP, and atropine were less inhibitory than CGRP (8-37), and the substance P (SP) receptor antagonist, spantide, had no effect. The present study demonstrated that DKCT and one of its active components, [6]-shogaol, produced an increase in IBF which was mainly mediated by CGRP and suggests that DKCT may be useful in the treatment of intestinal ischemia-related diseases.
Article
The histopathology of necrotizing enterocolitis (NEC) is characterized by destruction of the mucosal layer in initial stages and by transmural necrosis of the intestinal wall in advanced stages of the disease. To test the hypothesis that enhanced epithelial apoptosis is an initial event underlying the gross histologic changes, we analyzed epithelial apoptosis and tissue morphology in an animal model of NEC and evaluated the effect of caspase inhibition on the incidence of experimental NEC in this model. Apoptosis was analyzed with terminal deoxynucleotidyltransferase-mediated dUTP-FITC nick end labeling (TUNEL) staining in intestinal sections and by measuring caspase 3 activity from intestinal lysates of neonatal rats subjected to formula feeding and cold/asphyxia stress (FFCAS) and from mother-fed (MF) controls. Morphologic evaluation was based on hematoxylin and eosin staining of intestinal sections. FFCAS resulted in histologic changes consistent with NEC, which were absent from MF animals. FFCAS was also associated with a significantly increased rate of nuclear DNA fragmentation in the small intestinal epithelium compared with MF. Elevated tissue caspase 3 activity confirmed the presence of apoptosis in samples with increased DNA fragmentation. Analysis of the coincidence of morphologic damage and apoptosis in corresponding tissue sections indicated that apoptosis precedes gross morphologic changes in this model. Furthermore, supplementation of formula with 8 boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, significantly reduced the incidences of apoptosis and experimental NEC. These findings indicate that in neonatal rats FFCAS induces epithelial apoptosis that serves as an underlying cause for subsequent gross tissue necrosis.
Article
The anti-inflammatory properties of ginger have been known and valued for centuries. During the past 25 years, many laboratories have provided scientific support for the long-held belief that ginger contains constituents with antiinflammatory properties. The original discovery of ginger's inhibitory effects on prostaglandin biosynthesis in the early 1970s has been repeatedly confirmed. This discovery identified ginger as an herbal medicinal product that shares pharmacological properties with non-steroidal anti-inflammatory drugs. Ginger suppresses prostaglandin synthesis through inhibition of cyclooxygenase-1 and cyclooxygenase-2. An important extension of this early work was the observation that ginger also suppresses leukotriene biosynthesis by inhibiting 5-lipoxygenase. This pharmacological property distinguishes ginger from nonsteroidal anti-inflammatory drugs. This discovery preceded the observation that dual inhibitors of cyclooxygenase and 5-lipoxygenase may have a better therapeutic profile and have fewer side effects than non-steroidal anti-inflammatory drugs. The characterization of the pharmacological properties of ginger entered a new phase with the discovery that a ginger extract (EV.EXT.77) derived from Zingiber officinale (family Zingiberaceae) and Alpina galanga (family Zingiberaceae) inhibits the induction of several genes involved in the inflammatory response. These include genes encoding cytokines, chemokines, and the inducible enzyme cyclooxygenase-2. This discovery provided the first evidence that ginger modulates biochemical pathways activated in chronic inflammation. Identification of the molecular targets of individual ginger constituents provides an opportunity to optimize and standardize ginger products with respect to their effects on specific biomarkers of inflammation. Such preparations will be useful for studies in experimental animals and humans.
Article
Ginger (rhizome of Zingiber officinale) has been widely used for centuries in gastrointestinal disorders, particularly dyspepsia, but its precise mode of action has yet to be elucidated. This study was undertaken to study the prokinetic action of ginger and its possible mechanism of action. Prokinetic activity of ginger extract (Zo.Cr) was confirmed in an in vivo test when it enhanced the intestinal travel of charcoal meal in mice. This propulsive effect of the extract, similar to that of carbachol, was blocked in atropine-pretreated mice, a standard cholinergic antagonist. Likewise, Zo.Cr showed an atropine-sensitive dose-dependent spasmogenic effect in vitro as well as in isolated rat and mouse stomach fundus tissues. In atropinized tissue, it showed spasmolytic activity as shown by the inhibition of 5-HT- and K+-induced contractions. A spasmolytic effect was also observed in other gut preparations either as noncompetitive inhibition of agonist dose-response curves, inhibition of high K+(80 mM)-induced contractions, or displacement of Ca2+ dose-response curves to the right, indicating a calcium antagonist effect. Phytochemical analysis revealed the presence of saponins, flavonoids, and alkaloids in the crude extract. These data indicate that Zo.Cr contains a cholinergic, spasmogenic component evident in stomach fundus preparations which provides a sound mechanistic insight for the prokinetic action of ginger. In addition, the presence of a spasmolytic constituent(s) of the calcium antagonist type may explain its use in hyperactive states of gut like colic and diarrhea.
Article
Necrotizing enterocolitis (NEC) is the most common intestinal disease of premature infants. Although increased mucosal permeability and altered epithelial structure have been associated with many intestinal disorders, the role of intestinal barrier function in NEC pathogenesis is currently unknown. We investigated the structural and functional changes of the intestinal barrier in a rat model of NEC. In addition, the effect of EGF treatment on intestinal barrier function was evaluated. Premature rats were divided into three groups: dam fed (DF), formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC + EGF); all groups were exposed to asphyxia/cold stress to develop NEC. Intestinal permeability, goblet cell density, mucin production, and composition of tight junction (TJ) proteins were evaluated in the terminal ileum, the site of NEC injury, and compared with the proximal jejunum, which was unaffected by NEC. Animals with NEC had significantly increased intestinal paracellular permeability compared with DF pups. Ileal goblet cell morphology, mucin production, and TJ composition were altered in animals with NEC. EGF treatment significantly decreased intestinal paracellular permeability, increased goblet cell density and mucin production, and normalized expression of two major TJ proteins, occludin and claudin-3, in the ileum. In conclusion, experimental NEC is associated with disruption of the intestinal barrier. EGF treatment maintains intestinal integrity at the site of injury by accelerating goblet cell maturation and mucin production and normalizing expression of TJ proteins, leading to improved intestinal barrier function.
Article
Reactive oxygen species (ROS) are involved in the pathogenesis of necrotizing enterocolitis (NEC) in premature infants. We have recently found that activation of multiple cellular signaling transduction pathways occurs during ROS-induced intestinal cell apoptosis; the phosphatidylinositol 3-kinase (PI3-K) pathway plays an anti-apoptotic role during this process. Insulin-like growth factor (IGF)-1 activates PI3-K pathway to promote cell survival; however, the effects of IGF-1 treatment during gut injury are not clearly defined. The purpose of this study was to determine whether IGF-1 protects intestinal cells from ROS-induced apoptosis. Rat intestinal epithelial (RIE)-1 cells were treated with either IGF-1 (100 nm), hydrogen peroxide (H2O2; 500 microm), or combination. Western blotting was performed to assess phosphorylation of Akt, a downstream effector of PI3-K. Cell Death Detection ELISA, DCHF, and JC-1 assays were performed to demonstrate protective effects of IGF-1. Wortmannin, an inhibitor of PI3-K, was used to show PI3-K-dependent mechanism of action for IGF-1. H2O2 treatment resulted in increased intestinal epithelial cell apoptosis with intracellular ROS generation and mitochondrial membrane depolarization; IGF-1 pre-treatment attenuated this response without affecting ROS production. H2O2-induced phosphorylation of Akt was further increased with IGF-1 treatment; wortmannin abolished these effects in RIE-1 cells. PI3-K pathway is activated during ROS-induced intestinal epithelial cell injury; IGF-1 exerted an anti-apoptotic effect during this response by PI3-K activation. A better understanding of the exact role of IGF-1-mediated activation of PI3-K may allow us to facilitate the development of novel therapy against NEC.
Article
The aim of this study was to evaluate changes in intestinal microcirculation during necrotizing enterocolitis (NEC) and to examine the effect of endothelin (ET)-1 on the intestinal microcirculation. Prematurely born rats were either hand-fed formula (NEC) or dam fed (DF) and were exposed to asphyxia and cold stress twice daily to induce disease. At 0, 2, 3, and 4 d after the birth, the microcirculation in the ileum was examined using in vivo microscopic methods. The nutritive microvascular perfusion in the NEC group was progressively compromised from d 3 to d 4 (35% and 50% decrease, respectively) when compared with DF rats. Concomitantly, intestinal blood flow assessed by laser Doppler flowmetry was significantly reduced at d 2, 3, and 4 (by 31%, 36%, and 73%, respectively). Levels of ET-1 mRNA in the ileum were increased 3.7-fold. Microvascular responses to topically applied ET-1 were significantly increased in the NEC group, which was associated with decreased expression of ETB receptor. These results suggest that microcirculatory dysfunction in the distal ileum of neonatal rats with NEC contributes to disease progression and that enhanced microvascular responsiveness to ET-1 may participate in these microcirculatory disturbances.
Article
Necrotizing enterocolitis (NEC) is the most common and lethal disease that affects the gastrointestinal (GI) tract of the premature infant. The etiology of NEC remains undefined. The only consistent epidemiological precursors for NEC are prematurity and enteral alimentation. Various inflammatory mediators, including tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, platelet-activating factor (PAF), and nitric oxide (NO) have been implicated in the pathogenesis of NEC, but the kinetics and role of these agents are ill-defined. Currently, there are no biomarker predictors of NEC risk and severity. Sera or tissue from early time points in the development of the disease may help delineate early inflammatory events that predispose an individual to NEC, thus providing an interventional opportunity. We suggest that the lack of diagnostic and therapeutic modalities for NEC are due to the absence of a systems view of the disease, which in turn is hindered by a lack of sensitive physiological measurements that predict perturbations in the intestinal tissue compartment and an inability to reliably test serial samples for the presence of inflammatory mediators in small volumes and in a high-throughput manner. Computational modeling is a useful tool in the study of complex systems such as the inflammatory process. Computation models provide an "existence proof" for a given mechanism, uncover subtle inconsistencies between the underlying hypotheses and quantitative data, and force one to ask how much is known. We suggest that a properly validated and calibrated mathematical model of inflammation and its pathologic consequences in NEC will be useful for predicting the physiologic and biologic response in infants suffering from the disease.