Alkaloids from Aconitum carmichaelii Alleviates DSS-Induced Ulcerative Colitis in Mice via MAPK/NF-κB/STAT3 Signaling Inhibition
Chuanqi HuangJunli DongLu ChengHaoran MaFuqian WangFeng YanShu ZhangYuling LiDan ZhangXiaoqi JinXin XiongJie JiangBin WuHongfeng XuGeng Zhang
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Abstract:
Fuzi (Aconitum carmichaelii Debx) has been traditionally used for the treatment of ulcerative colitis (UC) in China for thousands of years. The total alkaloids of A. carmichaelii (AAC) have been considered as the main medicinal components of fuzi, whereas its underlying anti-UC mechanisms remain elusive. In the present study, the dextran sulfate sodium (DSS)-induced UC mice model, which was consistent with the symptoms and pathological features of human UC, was established to comprehensively evaluate the anti-UC effects of AAC. The results indicated that AAC effectively improved the weight loss, disease activity index (DAI), spleen hyperplasia, and colon shortening, and thus alleviated the symptoms of UC mice. Meanwhile, AAC not only inhibited the MPO enzyme and the abnormal secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ, and IL-17A) and suppressed the overexpression of inflammatory mediators (TNF-α, IL-1β, and IL-6) of mRNA but also reduced the phosphorylation of p38 MAPK, ERK, and JNK, and the protein expressions of NF-κB, IκB-α, STAT3, and JAK2 in the colon tissue. Furthermore, the LC-MS/MS quantitative determination suggested that the three low toxic monoester alkaloids were higher in both contents and proportion than that of the three high toxic diester alkaloids. Additionally, molecular docking was hired to investigate the interactions between alkaloid-receptor complexes, and it suggested the three monoester alkaloids exhibited higher binding affinities with the key target proteins of MAPK, NF-κB, and STAT3. Our finding showcased the noteworthy anti-UC effects of AAC based on the MAPK/NF-κB/STAT3 signaling pathway, which would provide practical and edge-cutting background information for the development and utilization of A. carmichaelii as a potential natural anti-UC remedy.Keywords:
Docking (animal)
Proinflammatory cytokine
Fifteen patients with ulcerative colitis and 11 patients with ulcerative proctitis have been observed and studied for periods ranging from one to 15 years. It is suggested that the clinical course of the two disorders is quite distinct. Further, while the serum immunoglobulins were within normal limits in ulcerative proctitis, significant increases in the serum alpha(2)-, beta-, and gamma-globulins and in the IgA and IgG concentrations were found in ulcerative colitis. Despite total colectomy for ulcerative colitis, the serum IgG and IgA concentration remained high and even after subsequent rectal resection the relative IgA concentration continued to increase. The significance of these findings is discussed.
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Combined Signature of the Fecal Microbiome and Plasma Metabolome in Patients with Ulcerative Colitis
BACKGROUND Ulcerative colitis is a chronic, idiopathic inflammatory disease that destroys the colon structure. Nevertheless, the exact pathogenesis is not clear and needs to be fully elucidated. MATERIAL AND METHODS Stool and plasma samples were used for 16S ribosomal RNA sequencing and liquid chromatography mass spectrometry, respectively. In addition, we detected the level of trimethylamine N-oxide. Finally, we performed Pearson correlation analysis between the microbiome and the metabolome. RESULTS Twenty-three active ulcerative colitis, 25 inactive ulcerative colitis, and 30 control cases were included. Thirty-four significantly different metabolites were found between the active ulcerative colitis and control groups, 38 were found between the inactive ulcerative colitis and control groups, and only 1 was found between the active ulcerative colitis and inactive ulcerative colitis groups. The plasma trimethylamine N-oxide level of the inactive ulcerative colitis and active ulcerative colitis groups was significantly higher than that of the control group. Moreover, we identified significant changes in 24, 18, and 12 bacterial genera for active ulcerative colitis-control, inactive ulcerative colitis-control, and active ulcerative colitis-inactive ulcerative colitis, respectively. Cross-correlation indicated an association between sphingosine 1-phosphate and Roseburia, Klebsiella, and Escherichia-Shigella. Through the pathway analysis, we found sphingolipid metabolism was one of the most significantly increased pathways. CONCLUSIONS Although levels of trimethylamine N-oxide were higher in ulcerative colitis patients, they did not achieve statistical significance in active ulcerative colitis and inactive ulcerative colitis groups. Sphingosine 1-phosphate was increased in ulcerative colitis patients and there were several microbiota associated with it. Although further study is still needed, sphingosine 1-phosphate will probably become a new target for treatment of ulcerative colitis.
Metabolome
Gut microbiome
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IM To study the action and significance of serum tumor necrosis factorα (TNFα) and interleukin8 (IL8) in patients with ulcerative colitis. METHODS Serum TNFα (2622ng/L±20ng/L vs 1462ng/L±25ng/L, P005) and IL8 (1118ng/L±26ng/L vs 575ng/L±40ng/L, P005) in 33 patients with active ulcerative colitis and in 40 normal subjects were detected using a Sandwich ELISA. RESULTS Serum TNFα and IL8 levels in patients with ulcerative colitis were elevated significantly and related to the severity of the disease and area of lesions (P005).CONCLUSION Immune dysfunction exists in patients with ulcerative colitis. The increased serum TNFα and IL8 are related to the development of ulcerative colitis and may serve as an indicator of ulcerative colitis.
Interleukin 8
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Many studies have been conducted for the role of Ahara (~dietary habits), Vihara (~abnormal Physical activity) and Manas (~Psychological factors) and their association with pathogenesis of Ulcerative colitis, which is a subtype of inflammatory bowel disease, which pursue a protracted relapsing and remitting course, usually extending over years. The causes of relapsing of ulcerative colitis are not known. Dietary factors have been associated in the pathogenesis of ulcerative colitis as well as associated with an increased risk of relapse of ulcerative colitis. Here, we have reviewed the probable mechanisms of the role of diet and its association with pathogenesis of Ulcerative colitis (UC). In Ayurveda, on the basis of signs and symptoms ulcerative colitis can be best compared with Raktatisara. This article is an attempt to do critical review and put a light on the role of diet, faulty lifestyle and Psychological factors in occurrence and progression of Ulcerative colitis (UC), and try to explain Etiopathogenesis of Raktatisara in relation to ulcerative colitis by going through Ayurvedic texts, Google Scholar, PubMed journals etc.
Pathogenesis
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Objective To observe the levels of plasma P-selection(P-sel) and in patients with ulcerative colitis and to study the clinical significance of them. Methods the concentrations of P-sel in 18 patients with active ulcerative colitis and 13 relief ulcerative colitis were determined with ELISA method. Results The results shown that the levels of P-sel in active ulcerative colitis patients were markedly elevated and were correlated with the severity of the disease. But the levels of P-sel in relief ulcerative colitis patients have no difference with normal controls. Conclusion It is suggested that the occurrence and development of ulcerative colitis may be related to the increase of plasma P-sel. Measurement of levels of plasma P-sel and might therefore provide a tool for monitoring the clinical course and for gaiding the treatment of ulcerative colitis.
Clinical Significance
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Objective To investigate action and significance of serum nitric oxide(NO) in patients with ulcerative colitis.Methods Levels of serum NO in active stage of 33 patients with ulcerative colitis and 40 healthy controls were detected.Results Levels of serum NO in patients with ulcerative colitis were significantly high and related to severe degrees of the disease (P0.05).Conclusion Immune dysfunction exists in patients with ulcerative colitis, There are relationship between higher levels of serum NO and ulcerative colitis pathogenesis and elevation of serum NO level may be as an indicator of ulcerative colitis.
Pathogenesis
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Objective:To investigate the action of TNF-a,IL-6 and sIL-2R in the mechanism of ulcerative colitis.Methods:Bi-antibody radioimmune methods and ELISA methods were used to analysis the samples in TNF-a,IL-6 and sIL-2R of 25 cases with active ulcerative colitis.30 normal persons were assigned as the contrast group.The data of cytokines(TNF-a,IL-6,sIL-2R)among contrast group,the active and catabolic phases of ulcerative colitis were compared.That in catabolic phases of ulcerative colitis was also compared with that in contrast group,the difference were compared among slight,moderate and severe groups,The relativity among the serum level in TNF-a,IL-6 of active ulcerative colitis had been observed.Results:The level of serum TNF-a,IL-6 and sIL-2R in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant difference between catabolic ulcerative colitis and contrast group(P0.005).The level in severe group is higher than that in moderate and slight group(P0.05).Serum cytokines,TNF-a and IL-6 are positively related to active ulcerative colitis.(r=0.8476,P0.05).Conclusion:There is a severe disorders of cellular immunity in the patients with active ulcerative colitis.TNF-a,IL-6,sIL-2R etc play the very important roles in the genesis and development of ulcerative colitis.The serum level of the above cytokines not only reflected the development of ulcerative colitis but also could be used as biological index of the effect and estimate the prognosis.
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This paper discusses the treatment of ulcerative colitis with Traditional Chinese Medicine, and expounds the specific pathogenesis of ulcerative colitis. In addition, we put forward the application of some new technologies and methods for the scientific research on the treatment of ulcerative colitis, and summarizes the research hotspots of ulcerative colitis, hoping to provide reference for other scholars to study ulcerative colitis. Keywords: Chinese traditional; ulcerative colitis; techniques and methods; medicine treatment.
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Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, deregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually present with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. Treatment for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immune-suppressant. The therapeutic armamentarium for ulcerative colitis is expanding. A total of 60 respondents were interviewed and were investigated for ulcerative colitis. A predesigned and pretested was used to collect the information about the participants. For the research survey method was used for the collection of data. Results shows that mostly 70 (%) respondents were aware of ulcerative colitis and 30 (%) respondents were not aware of ulcerative colitis. In conclusion that studies ulcerative colitis.
Bloody
Pathogenesis
Genetic predisposition
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Objective To observe the severity correlation of TNF-α、IL-6 and IL-8 levels in plasma in patients with ulcerative colitis and investigate mechanism of ulcerative colitis.Methods TNF-α,IL-6 and IL-8 levels in plasma were measured with ELISA methods in 56 patients with ulcerative colitis and 20 normal persons as a control group.The active and catabolic phases of ulcerative colitis were compared and the difference were compared among slight,moderate and sever groups.Results The level of serum TNF-α,IL-6 and IL-8 in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant differences between catabolic ulcerative colitis and contrast group(P0.05).The level in severe group was higher than that in moderate and slight group(P0.05).Conclusions There is a sever disorders of cellular immunity in the patients with active ulcerative colitis.TNF-α,IL-6 and IL-8 play the very important roles in the genesis and development of ulcerative colitis.The measurement of TNF-α,IL-6 and IL-8 levels in plasma may contribute to predict the severity of ulcerative colitis.
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