02811953

October 05, 2021, 19:42

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Comments to Urotensin II levels in patients with inflammatory bowel disease Yan Zhang(a) and Guoxun Chen(b)* aDepartment of Gastroenterology, Affiliated Puren Hospital of Wuhan University of Science and Technology, Wuhan, Hubei, P.R. China bDepartment of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA Background Inflammatory bowel disease (IBD) is a condition of relapsing chronic inflammation in the gastrointestinal tract with an unpredictable course [1]. IBD includes two disorders: Crohn’s disease (CD) and ulcerative colitis (UC). The etiology of IBD is considered to be multifactorial as complex interrelations among extrinsic factors, genetic predispositions, immunological imbalance and microbiota disturbances. Urotensin II (U-II) is a pleotropic peptide that was discovered 40 years ago. U-II is the most potent vasoconstrictor identified so far, and its effect is 10-fold stronger than that of endothelin-1[2]. The action of U-II is mediated by the activity of the U-II receptor (UTR), a G-protein-coupled receptor also known as GPR14 [3]. U-II and UTR are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal, and metabolic systems. Upon the binding of U-II, the activation of UTR induces calcium mobilization into cytosol, smooth muscle cells proliferation and regulation of the inflammation process [4, 5]. More and more studies have indicated that patients with IBD have a high cardiovascular risk [6-8]. Therefore, the authors of the commented paper performed this observational study to investigate clinically the possible association between IBD and U-II levels. Study summary Here, the authors compared the serum levels of U-II between patients with IBD and healthy controls, and investigated the association of serum U-II levels with the anthropometric, clinical and biochemical parameters. The study included 50 adult patients with pre-diagnosed IBD (24 patients with UC and 26 patients with CD) and 50 healthy, age and gender matched controls. IBD patients had significantly higher U-II levels than control subjects. Significant positive correlations between serum U-II levels and high sensitivity C reactive peptide (hsCRP) levels, UC Endoscopic Index of Severity and Simple Endoscopic Score for CD scores were observed. The clinical data above suggested interestingly that U-II could be involved in the pathophysiology of IBD, especially in the inflammation severity and disease activity. Clinical significance According to the authors’ observations, there is an obvious correlation between the increase in the blood U-II level and development of IBD. The possible mechanism is attributed to the elevation of inflammatory factors such as hsCRP. So far, studies of U-II have been mainly focused on cardiovascular diseases [9]. With the progress of research in the fields, more and more investigators have found that U-II level is also closely related to liver, pancreas and intestinal tumor diseases (eg. colon cancer) [10]. Up to now, studies only show the association between U-II and IBD, whereas the underlying mechanisms remain to be identified and confirmed. Therefore, this observational study fills the knowledge gap and further elaborates the possible mechanisms through which the extraintestinal manifestations (cardiovascular events) of IBD occur frequently. Further confirmation of this line of evidence could guide clinical diagnosis and treatment of IBD in the future. Research limitations Some limitations exist and could be resolved to further strengthen the research. 1) The sample size of this clinical observation is relatively small (50 IBD patients and 50 healthy subjects as controls). It is a single center investigation. If authors could further expand the sample size (＞100) and include additional investigators from multi centers, the research data and conclusions would be more convincing and relevant. 2) This clinical research found the association of the increased serum U-II levels with IBD occurrence and progression, and the possible role of hsCRP as a responsible inflammatory effector in the process. However, they did not measure other inflammatory factors and clarify their involvement in the elevation of serum U-II level in IBD patients. As far as the current research findings are concerned, U-II can trigger a series of inflammatory responses by releasing various inflammatory mediators, such as interleukin-6, interleukin-8, tumor necrosis factor-α and etc. The signals of these cytokines are mediated by the molecular regulation systems comprising of EPK1/2, NF-κB and Rho/ROCK [11-13]. It is still unclear whether these signaling systems form a network and how they influence each other. In the future work, researchers could further explore how U-II level is influenced by other inflammatory factors, and how U-II potentiates the IBD severity by interacting with those signal pathways using in vivo and in vitro models. By doing so, more data can be accumulated, which will provide theoretical and practical guidance for the prevention and treatment of cardiovascular events in IBD. In addition, it may be worth to develop potential U-II antagonists to modulate UTR activity, which may help treat IBD clinically in the future. References 1. Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol 2014; 20: 91-99 [PMID: 24415861 DOI: 10.3748/wjg.v20.i1.91] 2. Svistunov AA, Tarasov VV, Shakhmardanova SA, Sologova SS, Bagaturiya ET, Chubarev VN, Galenko-Yaroshevsky PA, Avila-Rodriguez MF, Barreto GE, Aliev G. Urotensin II: Molecular Mechanisms of Biological Activity. Curr Protein Pept Sci 2018; 19: 924-934 [PMID: 28875851 DOI: 10.2174/1389203718666170829 162335] 3. Ross B, McKendy K, Giaid A. Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol. 2010; 298(5):R1156-72. [PMID: 20421634. doi: 10.1152/ajpregu.00706.2009] 4. Sun SL, Liu LM. Urotensin II: an inflammatory cytokine. J Endocrinol 2019 [PMID: 30601760 DOI: 10.1530/joe-18-0505] 5. Liang DY, Liu LM, Ye CG, Zhao L, Yu FP, Gao DY, Wang YY, Yang ZW. Inhibition of UII/UTR system relieves acute inflammation of liver through preventing activation of NF-κB pathway in ALF mice. PLoS One 2014; 8: e64895 [PMID: 23755157 DOI: 10.1371/journal.pone.0064895] 6. Bigeh A, Sanchez A, Maestas C, Gulati M. Inflammatory bowel disease and the risk for cardiovascular disease: Does all inflammation lead to heart disease? Trends Cardiovasc Med 2020; 30: 463-469 [PMID: 31653485 DOI: 10.1016/ j.tcm.2019.10.001] 7. Singh S, Kullo IJ, Pardi DS, Loftus EV Jr. Epidemiology, risk factors and management of cardiovascular diseases in IBD. Nat Rev Gastroenterol Hepatol 2015; 12: 26-35 [PMID: 25446727 DOI: 10.1038/nrgastro.2014.202] 8. Zivkovic PM, Matetic A, Tadin Hadjina I, Rusic D, Vilovic M, Supe-Domic D, Borovac JA, Mudnic I, Tonkic A, Bozic J. Serum Catestatin Levels and Arterial Stiffness Parameters Are Increased in Patients with Inflammatory Bowel Disease. J Clin Med 2020; 9 [PMID: 32110996 DOI: 10.3390/jcm9030628] 9. Pereira-Castro J, Brás-Silva C, Fontes-Sousa AP. Novel insights into the role of urotensin II in cardiovascular disease. Drug Discov Today. 2019; 24(11):2170-2180. [PMID: 31430542. doi: 10.1016/j.drudis.2019.08.005] 10. Zappavigna S, Abate M, Cossu AM, Lusa S, Campani V, Scotti L, Luce A, Yousif AM, Merlino F, Grieco P, De Rosa G, Caraglia M. Urotensin-II-Targeted Liposomes as a New Drug Delivery System towards Prostate and Colon Cancer Cells. J Oncol. 2019; 2019:9293560.[PMID: 31929800; PMCID: PMC6942863. doi: 10.1155/2019/ 9293560] 11. Yang Y, Zhang J, Chen X, Wu T, Xu X, Cao G, Li H, Li Y. UII/GPR14 is involved in NF-κB-mediated colonic inflammation in vivo and in vitro. Oncol Rep. 2016; 36(5):2800-2806. [PMID: 27600191. Doi: 10.3892/or.2016.5069] 12. Li J, Zhao PP, Hao T, Wang D, Wang Y, Zhu YZ, Wu YQ, Zhou CH. Urotensin II inhibitor eases neuropathic pain by suppressing the JNK/NF-κB pathway. J Endocrinol.2017; 232(2):165-174. [PMID: 27895138. doi: 10.1530/JOE-16-0255] 13. Lu D, Peng F, Li J, Zhao J, Ye X, Li B, Ding W. Urotensin II promotes secretion of LTB4 through 5-lipoxygenase via the UT-ROS-Akt pathway in RAW264.7 macrophages. Arch Med Sci. 2019; 15(4):1065-1072. [PMID: 31360201; PMCID: PMC6657259. doi: 10.5114/aoms.2019.85197]

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03580207

September 26, 2021, 12:07

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It is an interesting research article talking about that Urotensin II is involved in the complex pathophysiology of cardiovascular complications in IBD patients, and its purpose should be investigated in further studies.

Thank you very much for your comments.