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Li Z, Zeng L, Huang W, Zhang X, Zhang L, Xie Q. Angiogenic Factors and Inflammatory Bowel Diseases. Biomedicines 2025; 13:1154. [PMID: 40426981 PMCID: PMC12108873 DOI: 10.3390/biomedicines13051154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/29/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation and impaired epithelial barrier function. Emerging evidence highlights the critical role of vascular remodeling and angiogenesis in IBD pathogenesis. This review explores the intricate relationship between blood vessels and the intestinal epithelial barrier, emphasizing how aberrant vascularization contributes to barrier dysfunction and disease progression. In IBD, excessive angiogenesis is driven by hypoxia, immune cell infiltration, and pro-inflammatory cytokines, further perpetuating inflammation and tissue damage. Key angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietins, and platelet-derived growth factor (PDGF), are upregulated in IBD, promoting pathological vessel formation. These newly formed vessels are often immature and hyperpermeable, exacerbating leukocyte recruitment and inflammatory responses. Given the pivotal role of angiogenesis in IBD, anti-angiogenic therapies have emerged as a potential therapeutic strategy. Preclinical and clinical studies targeting VEGF and other angiogenic pathways have shown promise in reducing inflammation and promoting mucosal healing. This review summarizes current knowledge on vascular-epithelial interactions in IBD, the mechanisms driving pathological angiogenesis, and the therapeutic potential of anti-angiogenic approaches, providing insights for future research and treatment development.
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Affiliation(s)
- Zhiru Li
- Clinical Medical School, University of Electronic Science and Technology of China, Chengdu 610072, China;
| | - Li Zeng
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Wei Huang
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Xinxing Zhang
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Li Zhang
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Qin Xie
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
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Zhang L, Wang J, Rong S, Dong H. Elucidating novel mechanism of action of spiperone for drug repurposing to prevent and treat murine colitis and sepsis. Life Sci 2025; 361:123268. [PMID: 39580139 DOI: 10.1016/j.lfs.2024.123268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 11/25/2024]
Abstract
AIMS While Ca2+ signaling plays a vital role in maintaining normal endothelial function and vascular activity, aberrant Ca2+ signaling in endothelial dysfunction is involved in the pathogenesis of inflammation. As a safe anti-psychotic drug to mobilize Ca2+ signaling, we repurposed spiperone as a potential drug for two intestinal epithelial injury related diseases, colitis and sepsis. MATERIALS AND METHODS Spiperone-induced vasorelaxation of human submucosal arterioles and mesenteric arterioles from wide-type and TRPV4 KO mice was determined by Mulvany-style wire myograph. The action of spiperone in HUVEC was tested by Ca2+ imaging and patch clamp, and its action on murine mesenteric arterioles was measured in vivo. LPS- and CLP-induced septic mice and DSS-induced colitic mice were used to examine the anti-inflammatory effects of spiperone. KEY FINDINGS Spiperone induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of healthy arterioles with EC50 of ∼50 nM predominately via PLC/IP3/IP3R pathway to induce endoplasmic reticulum (ER) Ca2+ release and further to promote Ca2+ entry via TRPV4-constituted SOCE. In both LPS- and CLP-induced septic mice, spiperone effectively prevented and treated sepsis by reducing serum proinflammatory factors, alleviating multiple organ dysfunction, rescuing the impaired EDH-mediated vasorelaxation and improving murine survival rate. Similarly, spiperone could also protect against murine colitis. SIGNIFICANCE We reveal new action mode and mechanism of spiperone to induce EDH-mediated vasorelaxation of both human and murine arterioles to protect against colitis and sepsis by innovatively inducing PLC/IP3R/Ca2+ signaling rather than canonically antagonizing GPCR. Spiperone could be repurposed as a potential new drug for the prevention/treatment of colitis and sepsis.
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Affiliation(s)
- Luyun Zhang
- Department of Intensive Critical Care, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, Sichuan, China
| | - Jianxin Wang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Shaoya Rong
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Hui Dong
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
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Buehler A, Brown EL, Nedoschill E, Eckstein M, Ludwig P, Wachter F, Mandelbaum H, Raming R, Oraiopoulou M, Paulus L, Rother U, Friedrich O, Neurath MF, Woelfle J, Waldner MJ, Knieling F, Bohndiek SE, Regensburger AP. In Vivo Assessment of Deep Vascular Patterns in Murine Colitis Using Optoacoustic Mesoscopic Imaging. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404618. [PMID: 39439243 PMCID: PMC11615813 DOI: 10.1002/advs.202404618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 08/15/2024] [Indexed: 10/25/2024]
Abstract
The analysis of vascular morphology and functionality enables the assessment of disease activity and therapeutic effects in various pathologies. Raster-scanning optoacoustic mesoscopy (RSOM) is an imaging modality that enables the visualization of superficial vascular networks in vivo. In murine models of colitis, deep vascular networks in the colon wall can be visualized by transrectal absorber guide raster-scanning optoacoustic mesoscopy (TAG-RSOM). In order to accelerate the implementation of this technology in translational studies of inflammatory bowel disease, an image-processing pipeline for TAG-RSOM data has been developed. Using optoacoustic data from a murine model of chemically-induced colitis, different image segmentation methods are compared for visualization and quantification of deep vascular patterns in terms of vascular network length and complexity, blood volume, and vessel diameter. The presented image-processing pipeline for TAG-RSOM enables label-free in vivo assessment of changes in the vascular network in murine colitis with broad applications for inflammatory bowel disease research.
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Affiliation(s)
- Adrian Buehler
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Emma L. Brown
- Cancer Research UK Cambridge InstituteUniversity of CambridgeCB2 0RECambridgeUnited Kingdom
| | - Emmanuel Nedoschill
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Markus Eckstein
- Institute of PathologyFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Petra Ludwig
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Felix Wachter
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Henriette Mandelbaum
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Roman Raming
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | | | - Lars‐Philip Paulus
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Ulrich Rother
- Department of Vascular SurgeryUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Oliver Friedrich
- Institute of Medical BiotechnologyDepartment of Chemical and Biological EngineeringFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91052ErlangenGermany
| | - Markus F. Neurath
- Department of Medicine 1University Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91052ErlangenGermany
| | - Joachim Woelfle
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Maximilian J. Waldner
- Department of Medicine 1University Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91052ErlangenGermany
| | - Ferdinand Knieling
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
| | - Sarah E. Bohndiek
- Cancer Research UK Cambridge InstituteUniversity of CambridgeCB2 0RECambridgeUnited Kingdom
| | - Adrian P. Regensburger
- Department of Pediatrics and Adolescent MedicineUniversity Hospital ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐Nürnberg91054ErlangenGermany
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Romano L, Fonticelli M, Miranda A, Priadko K, Napolitano L, Crocetto F, Barone B, Arcaniolo D, Spirito L, Manfredi C, Gravina AG, Sciorio C, Compare D, Melina R, Sgambato D, Orlando A, Calderone S, Nardone OM, Nardone G, Caruso P, Esposito K, De Sio M, Romano M, Maiorino MI. Sexual dysfunctions in inflammatory bowel disease: role of Mediterranean diet and quality of life. Andrology 2024. [PMID: 39492590 DOI: 10.1111/andr.13791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 10/04/2024] [Accepted: 10/17/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Dietary factors and chronic gastrointestinal diseases are frequent determinants of sexual dysfunctions (SD). Whether inflammatory bowel diseases (IBD) are associated with SD is not well known as well as the role of diet and quality of life (QoL). OBJECTIVES To evaluate the prevalence of SD in a cohort of IBD patients and assess the role of clinical-demographic variables, adherence to Mediterranean diet (MD) and QoL. MATERIALS AND METHODS This is a cross-sectional observational study involving 301 patients (134 females and 167 males); 119 had Crohn's Disease and 182 had ulcerative colitis. SD were assessed through the Female Sexual Function Index (FSFI) and the International Index of Erectile Function (IIEF). Adherence to MD was evaluated by the MD Score. QoL was investigated by the 12-item Short-Form Health Survey (SF-12) which yields summary scores of physical (PCS) and mental (MCS) health. Multiple logistic regression was used to identify predictors of SD. RESULTS Prevalence of SD in females was 61.9%, while 52.1% of males had erectile dysfunction. No differences in the prevalence of SD were found between CD and UC in both males and females. IBD activity, as defined by patient-reported outcomes, was significantly associated with SD in both sexes. In females, MD adherence score (OR 0.8, 95% CI 0.653-0.974, p = 0.027), PCS (OR = 0.936, CI 95% = 0.891-0.983, p = 0.008), and MCS (OR 0.9, 95% CI 0.906-0.985, p = 0.008) were protective against SD, whereas in males a higher PCS was associated with a lower probability of SD (OR 0.9, 95% CI 0.891-0.978, p = 0.004) DISCUSSION: IBD patients had a significant prevalence of SD which occurred more frequently in females than in males. Disease activity is associated with a higher likelihood of SD in both sexes, whereas dietary factors are differentially associated with SD in males and females. A better QoL is associated with a lower risk of SD. CONCLUSION SD is prevalent among men and women with IBD. Adherence to MD, PCS and MCS in females as well as PCS in males were protective against SD. The assessment of sexual function in IBD patients could be relevant in order to reach an early diagnosis and a timely treatment.
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Affiliation(s)
- Lorenzo Romano
- Department of Neurosciences, Reproductive Sciences and Odontostomatology and Urology Unit, Federico II University, Naples, Italy
- Department of Woman, Child and General and Specialized Surgery and Urology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Mariano Fonticelli
- Department of Precision Medicine and Hepatogastroenterology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Kateryna Priadko
- Department of Precision Medicine and Hepatogastroenterology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luigi Napolitano
- Department of Neurosciences, Reproductive Sciences and Odontostomatology and Urology Unit, Federico II University, Naples, Italy
| | - Felice Crocetto
- Department of Neurosciences, Reproductive Sciences and Odontostomatology and Urology Unit, Federico II University, Naples, Italy
| | - Biagio Barone
- Department of Neurosciences, Reproductive Sciences and Odontostomatology and Urology Unit, Federico II University, Naples, Italy
| | - Davide Arcaniolo
- Department of Woman, Child and General and Specialized Surgery and Urology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Lorenzo Spirito
- Department of Woman, Child and General and Specialized Surgery and Urology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Celeste Manfredi
- Department of Woman, Child and General and Specialized Surgery and Urology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine and Hepatogastroenterology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Debora Compare
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | | | | | | | | | - Olga Maria Nardone
- Gastroenterology, Department of Public Health, Federico II University, Naples, Italy
| | - Gerardo Nardone
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Paola Caruso
- Division of Endocrinology and Metabolic Diseases, University Hospital of Campania "Luigi Vanvitelli", Naples, Italy
| | - Katherine Esposito
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco De Sio
- Department of Woman, Child and General and Specialized Surgery and Urology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco Romano
- Department of Precision Medicine and Hepatogastroenterology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Ida Maiorino
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania "Luigi Vanvitelli", Naples, Italy
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Jenkins SW, Grunz EA, Ramos KR, Boerman EM. Perivascular Adipose Tissue Becomes Pro-Contractile and Remodels in an IL10 -/- Colitis Model of Inflammatory Bowel Disease. Int J Mol Sci 2024; 25:10726. [PMID: 39409054 PMCID: PMC11476586 DOI: 10.3390/ijms251910726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/18/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Inflammatory Bowel Diseases (IBDs) are associated with aberrant immune function, widespread inflammation, and altered intestinal blood flow. Perivascular adipose tissue (PVAT) surrounding the mesenteric vasculature can modulate vascular function and control the local immune cell population, but its structure and function have never been investigated in IBD. We used an IL10-/- mouse model of colitis that shares features with human IBD to test the hypothesis that IBD is associated with (1) impaired ability of PVAT to dilate mesenteric arteries and (2) changes in PVAT resident adipocyte and immune cell populations. Pressure myography and electrical field stimulation of isolated mesenteric arteries show that PVAT not only loses its anti-contractile effect but becomes pro-contractile in IBD. Quantitative immunohistochemistry and confocal imaging studies found significant adipocyte hyperplasia and increased PVAT leukocytes, particularly macrophages, in IBD. PCR arrays suggest that these changes occur alongside the altered cytokine and chemokine gene expression associated with altered NF-κB signaling. Collectively, these results show that the accumulation of macrophages in PVAT during IBD pathogenesis may lead to local inflammation, which ultimately contributes to increased arterial constriction and decreased intestinal blood flow with IBD.
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Affiliation(s)
| | | | | | - Erika M. Boerman
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
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Zeng X, Tong L. Genetic and causal relationship between chronic gastrointestinal diseases and erectile dysfunction: a Mendelian randomization study. Front Med (Lausanne) 2024; 11:1422267. [PMID: 39144654 PMCID: PMC11322132 DOI: 10.3389/fmed.2024.1422267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/17/2024] [Indexed: 08/16/2024] Open
Abstract
Background Studies based on observations have indicated potential associations between chronic gastrointestinal diseases and an increased risk of erectile dysfunction (ED). However, the causality of these connections remains ambiguous. Methods Summary data for chronic gastrointestinal diseases were extracted from public data. Summary data on ED were extracted from three distinct sources. The genetic correlations between chronic gastrointestinal diseases and ED were explored using linkage disequilibrium score regression (LDSC). The causal associations between chronic gastrointestinal diseases and ED were evaluated using Mendelian randomization (MR) analysis, followed by a meta-analysis to determine the ultimate causal effect. Results The LDSC results suggested significant genetic correlations between Crohn's disease (CD) and ED. Inflammatory bowel disease (IBD), ulcerative colitis (UC), and liver cirrhosis (LC) were found to have potential genetic correlations with ED. The combined multiple MR results indicate that IBD and CD have significant causal relationships with ED, while colorectal cancer (CRC) may have a potential causal effect on ED. Conclusion This research provided evidence supporting a causal association between IBD, CD, CRC, and ED. The impact of chronic gastrointestinal diseases on ED warrants greater attention in clinical practice.
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Affiliation(s)
- Xiaoyan Zeng
- Qinghai University, Xining, China
- Qinghai Provincial Key Laboratory of Traditional Chinese Medicine Research for Glucolipid Metabolic Diseases, Xining, China
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi City, China
| | - Li Tong
- Qinghai University, Xining, China
- Qinghai Provincial Key Laboratory of Traditional Chinese Medicine Research for Glucolipid Metabolic Diseases, Xining, China
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Wang X, Li T, Chen Q. Causal relationship between ulcerative colitis and male infertility: A two-sample Mendelian randomization study. PLoS One 2024; 19:e0303827. [PMID: 38814907 PMCID: PMC11139326 DOI: 10.1371/journal.pone.0303827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 05/01/2024] [Indexed: 06/01/2024] Open
Abstract
AIMS To explore the causal relationship between ulcerative colitis (UC) and male infertility using Mendelian randomization method with single nucleotide polymorphism (SNP) as the instrumental variables. METHODS Genetic loci closely associated with UC were extracted as instrumental variables and male infertility was the outcome variable in pooled data from the gene-wide association study (GWAS),which was derived from European ethnic groups. The UC data(ebi-a-GCST003045) contained a total sample size of 27432 individuals and 110944 SNPs, and the male infertility data(finn-b-N14_MALEINFERT) contained a total sample size of 73479 individuals and 16377329 SNPs. The SNPs highly correlated with UC were screened from ebi-a-GCST003045(P<5×10-8 as the screening condition, the linkage disequilibrium coefficient was 0.001,and the width of the linkage disequilibrium area was 10000 kb).SNPs related to male infertility from finn-b-N14_MALEINFERT (the minimum r2>0.8,replacing the missing SNPs with SNPs with high linkage, and deleting SNPs without substitution sites) were extracted. MR analysis was performed using MR-Egger regression, the weighted median and the inverse-variance weighted (IVW) respectively, and the causal relationship between UC and male infertility was evaluated by OR and 95% CI, and the Egger-intercept method was used to test for horizontal multiplicity, and the sensitivity analysis was performed using "leave-one-out method". Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study. RESULTS A total of 86 SNPs were included as IVs, with OR and 95% CI of 1.095(0.820~1.462)、1.059(0.899~1.248)、1.125(1.002~1.264) for MR-Egger, the weighted median and IVW results respectively, and P value of less than 0.05 for IVW, indicating that a causal relationship between UC and male infertility was causally related. The results of MR analysis combined with BWMR analysis also showed positive genetic causal relationship between UC and male infertility.MR-Egger regression showed an intercept of -2.21×10-3 with a standard error of 0.006 and P = 0.751, there was no horizontal pleiotropy for the IVs of exposure factors. Heterogeneity tests showed no heterogeneity and the results of the "leave-one-out" sensitivity analysis were stable. CONCLUSION There is a causal association between UC and male infertility, which increases the risk of developing male infertility.
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Affiliation(s)
- Xia Wang
- Medical Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tongyi Li
- Medical Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiu Chen
- Medical Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Screm G, Mondini L, Salton F, Confalonieri P, Trotta L, Barbieri M, Romallo A, Galantino A, Hughes M, Lerda S, Confalonieri M, Ruaro B. Vascular Endothelial Damage in COPD: Where Are We Now, Where Will We Go? Diagnostics (Basel) 2024; 14:950. [PMID: 38732364 PMCID: PMC11083092 DOI: 10.3390/diagnostics14090950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) has higher rates among the general population, so early identification and prevention is the goal. The mechanisms of COPD development have not been completely established, although it has been demonstrated that endothelial dysfunction plays an important role. However, to date, the measurement of endothelial dysfunction is still invasive or not fully established. Nailfold video capillaroscopy (NVC) is a safe, non-invasive diagnostic tool that can be used to easily evaluate the microcirculation and can show any possible endothelial dysfunctions early on. The aim of this review is to evaluate if nailfold microcirculation abnormalities can reflect altered pulmonary vasculature and can predict the risk of cardiovascular comorbidities in COPD patients. METHODS A systematic literature search concerning COPD was performed in electronic databases (PUBMED, UpToDate, Google Scholar, ResearchGate), supplemented with manual research. We searched in these databases for articles published until March 2024. The following search words were searched in the databases in all possible combinations: chronic obstructive pulmonary disease (COPD), endothelial damage, vascular impairment, functional evaluation, capillaroscopy, video capillaroscopy, nailfold video capillaroscopy. Only manuscripts written in English were considered for this review. Papers were included only if they were able to define a relationship between COPD and endothelium dysfunction. RESULTS The search selected 10 articles, and among these, only three previous reviews were available. Retinal vessel imaging, flow-mediated dilation (FMD), and skin autofluorescence (AF) are reported as the most valuable methods for assessing endothelial dysfunction in COPD patients. CONCLUSIONS It has been assumed that decreased nitric oxide (NO) levels leads to microvascular damage in COPD patients. This finding allows us to assume NVC's potential effectiveness in COPD patients. However, this potential link is based on assumption; further investigations are needed to confirm this hypothesis.
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Affiliation(s)
- Gianluca Screm
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Lucrezia Mondini
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Francesco Salton
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Paola Confalonieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Liliana Trotta
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Mariangela Barbieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Antonio Romallo
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Alessandra Galantino
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Michael Hughes
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester & Salford Royal NHS Foundation Trust, Manchester M6 8HD, UK
| | - Selene Lerda
- Graduate School, University of Milan, 20149 Milan, Italy
| | - Marco Confalonieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
| | - Barbara Ruaro
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University of Trieste, Hospital of Cattinara, 34149 Trieste, Italy
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Park JS, Cresci GAM. Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00043. [PMID: 38818514 PMCID: PMC11136270 DOI: 10.1097/in9.0000000000000043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/01/2024] [Indexed: 06/01/2024]
Abstract
The intestinal microvascular endothelium plays a crucial role in orchestrating host responses to inflammation within the gastrointestinal tract. This review delves into the unique aspects of intestinal microvascular endothelial cells, distinct from those of larger vessels, in mediating leukocyte recruitment, maintaining barrier integrity, and regulating angiogenesis during inflammation. Specifically, their role in the pathogenesis of inflammatory bowel diseases, where dysregulated endothelial functions contribute to the disease progression, is reviewed. Furthermore, this review discusses the isolation technique for these cells and commonly used adhesion molecules for in vitro and in vivo experiments. In addition, we reviewed the development and therapeutic implications of a biologic agent targeting the interaction between α4β7 integrin on T lymphocytes and mucosal addressin cellular adhesion molecule-1 on gut endothelium. Notably, vedolizumab, a humanized monoclonal antibody against α4β7 integrin, has shown promising outcomes in inflammatory bowel diseases and other gastrointestinal inflammatory conditions, including chronic pouchitis, immune checkpoint inhibitor-induced colitis, and acute cellular rejection post-intestinal transplantation.
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Affiliation(s)
- Ji Seok Park
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gail A. M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s Hospital, Cleveland, OH, USA
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Dudek P, Talar-Wojnarowska R. Current Approach to Risk Factors and Biomarkers of Intestinal Fibrosis in Inflammatory Bowel Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:305. [PMID: 38399592 PMCID: PMC10889938 DOI: 10.3390/medicina60020305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/31/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024]
Abstract
Inflammatory bowel disease (IBD), especially Crohn's disease (CD), characterized by a chronic inflammatory process and progressive intestinal tissue damage, leads to the unrestrained proliferation of mesenchymal cells and the development of bowel strictures. Complications induced by fibrosis are related to high rates of morbidity and mortality and lead to a substantial number of hospitalizations and surgical procedures, generating high healthcare costs. The development of easily obtained, reliable fibrogenesis biomarkers is essential to provide an important complementary tool to existing diagnostic and prognostic methods in IBD management, guiding decisions on the intensification of pharmacotherapy, proceeding to surgical methods of treatment and monitoring the efficacy of anti-fibrotic therapy in the future. The most promising potential markers of fibrosis include cartilage oligomeric matrix protein (COMP), hepatocyte growth factor activator (HGFA), and fibronectin isoform- extra domain A (ED-A), as well as antibodies against granulocyte macrophage colony-stimulating factor (GM-CSF Ab), cathelicidin (LL-37), or circulatory miRNAs: miR-19a-3p and miR-19b-3p. This review summarizes the role of genetic predisposition, and risk factors and serological markers potentially contributing to the pathophysiology of fibrotic strictures in the course of IBD.
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11
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Wasuwanich P, So JM, Rajborirug S, Karnsakul W. Hepatitis A hospitalisations in the United States and risk factors for inpatient mortality: A nationwide population study, 1998-2020. J Viral Hepat 2024; 31:88-95. [PMID: 38062864 DOI: 10.1111/jvh.13902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/01/2023] [Accepted: 11/24/2023] [Indexed: 01/18/2024]
Abstract
Hepatitis A virus infections in the United States have been declining; however, recent widespread outbreaks have brought the disease back into the spotlight. We aim to describe the epidemiology of hepatitis A hospitalisations from 1998 to 2020 in the United States and investigate risk factors for inpatient mortality. We utilised the National Inpatient Sample database and identified hepatitis A-related hospitalisations using ICD-9 and ICD-10 diagnosis codes. Demographic and clinical data including death, coinfections, comorbidities and pregnancy status were extracted. Data were analysed by logistic and Poisson regression. We identified a total of 213,681 hepatitis A-related hospitalisations between 1998 and 2020, with hospitalisation rates ranging between 22.4 per 1,000,000 and 62.9 per 1,000,000. Between 1998 and 2015, the hospitalisation rate for hepatitis A was decreasing (IRR = 0.98; 95% CI: 0.97-0.98; p < .001); however, between 2015 and 2020, it increased overall (IRR = 1.22; 95% CI: 1.21-1.23; p < .001). The overall inpatient mortality rate was 2.7%. Age ≥55 years (OR = 1.84; 95% CI: 1.41-2.40; p < .001), alcoholic cirrhosis (OR = 2.53; 95% CI: 1.64-3.90; p < .001), ascites (OR = 2.65; 95% CI: 1.86-3.78; p < .001), hepatorenal syndrome (OR = 9.04; 95% CI: 5.93-13.80; p < .001), heart failure (OR = 1.76; 95% CI: 1.29-2.39; p < .001), pulmonary hypertension (OR = 2.02; 95% CI: 1.28-3.19; p = .003) and malignant neoplasm (OR = 1.75; 95% CI: 1.25-2.45; p = .001) were associated with increased odds of mortality. Tobacco use disorder (OR = 0.52; 95% CI: 0.38-0.70; p < .001) was associated with decreased odds of mortality. None of the hepatitis A-associated hospitalisations involving pregnant women resulted in death. Hepatitis A hospitalisations initially declined but increased rapidly after 2015. Certain risk factors can be used to predict prognosis of hospitalised patients.
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Affiliation(s)
- Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, Florida, USA
| | - Joshua M So
- University of Florida College of Medicine, Gainesville, Florida, USA
| | - Songyos Rajborirug
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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12
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Chen D, Zhou C, Luo Q, Chen C, Liu G. A Mendelian randomization study on causal effects of inflammatory bowel disease on the risk of erectile dysfunction. Sci Rep 2024; 14:2137. [PMID: 38272986 PMCID: PMC10811225 DOI: 10.1038/s41598-024-52712-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 01/23/2024] [Indexed: 01/27/2024] Open
Abstract
This study aimed to evaluate the causal effects of inflammatory bowel disease (IBD) and erectile dysfunction (ED) using Mendelian randomization (MR). All datasets were obtained from the public genome-wide association study database. In the exposure group, 12,882 IBD patients and 21,770 controls were included. A total of 1154 ED patients and 94,024 controls were included in the outcome group. Two-sample MR was conducted to estimate the causal effect of IBD on ED. Furthermore, Crohn's disease (CD) and ulcerative colitis (UC) were exposure factors in subgroup analyses. Weighted median, MR-egger, Inverse-variant weighted (IVW), weighted mode, and simple mode methods were used in MR analysis. Horizontal pleiotropy test, heterogeneity test, and leave-one-out method were utilized to evaluate the sensitivity and stability of results. After analysis, 62, 52, and 36 single nucleotide polymorphisms (SNPs) that IBD-ED, CD-ED, and UC-ED were included, respectively. The incidence of ED was increased by IBD (IVW: OR = 1.110, 95% CI = 1.017-1.211, P = 0.019; P-heterogeneity > 0.05) and, in addition, ED was affected by CD (IVW: OR = 1.085, 95% CI = 1.015-1.160, P = 0.016; P-heterogeneity > 0.05). However, there was no causal effect of UC on ED (IVW: OR = 1.018, 95% CI = 0.917-1.129, P = 0.743; P-heterogeneity < 0.05). All SNPs showed no significant horizontal pleiotropy (P > 0.05). These results indicate that IBD and CD can cause ED; However, UC did not cause ED. Additional research was required to determine causality and potential mechanisms further.
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Affiliation(s)
- Di Chen
- Department of Urology, The Frist Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chao Zhou
- Department of Assisted Reproduction, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Quanhai Luo
- Department of Urology, Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Changsheng Chen
- Department of Urology, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Gang Liu
- Department of Urology, Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
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13
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Rong S, Zhang L, Wang J, Dong H. Regulatory role of Piezo1 channel in endothelium-dependent hyperpolarization-mediated vasorelaxation of small resistance vessels and its anti-inflammatory action. Life Sci 2024; 336:122326. [PMID: 38056769 DOI: 10.1016/j.lfs.2023.122326] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/14/2023] [Accepted: 11/29/2023] [Indexed: 12/08/2023]
Abstract
AIMS Although endothelial Piezo1 channel is known to induce NO-mediated vasorelaxation of conduit vessels, it remains largely unknown if it can induce endothelial-dependent hyperpolarization (EDH)-mediated vasorelaxation of resistance vessels. Therefore, the present study aims to investigate Piezo1/EDH-mediated vasorelaxation in health and its involvement in ulcerative colitis (UC) and sepsis, two intractable and deadly inflammatory diseases. MAIN METHODS The tension of the second-order branch of mouse mesenteric artery was measured via the Danish DMT600M microvascular measurement system. The changes in cytoplasmic calcium ([Ca2+]cyt) signaling in vascular endothelial cells were detected by fluorescent calcium assay, and the membrane potential changes were monitored by patch clamp. Experimental murine models of UC and sepsis were induced by dextran sulfate sodium (DSS) and lipopolysaccharides (LPS), respectively. KEY FINDINGS A selective activator of Piezo1 channel, Yoda1, dose-dependently induced vasorelaxation of the second-order branch of mouse mesenteric artery in an endothelium-dependent manner. The endothelial Piezo1 channel mediated the vasorelaxation through EDH mechanism by a functional coupling of Piezo1 and TRPV4 channels. Their function and coupling were verified by [Ca2+]cyt imaging and patch clamp study in single endothelial cells. Moreover, while ACh-induced vasorelaxation played a major role in health, it was significantly impaired in the pathogenesis of UC and sepsis; however, Piezo1/EDH-mediated vasorelaxation remained intact. Finally, Piezo1/EDH-mediated vasorelaxation recovered ACh-induced vasorelaxation impaired in UC and sepsis. SIGNIFICANCE Piezo1/TRPV4/EDH-mediated vasorelaxation rescues the impaired ACh-induced vasorelaxation to likely recover hemoperfusion to organs, leading to organ protection against UC and sepsis. Our study not only suggests that endothelial Piezo1, TRPV4 and KCa channels are the potential therapeutic targets, but also implies that Piezo1 activators may benefit to prevent/treat UC and sepsis.
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Affiliation(s)
- Shaoya Rong
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Luyun Zhang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China; Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Jianxin Wang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China
| | - Hui Dong
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
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Gao D, Chen C, Wu Z, Li H, Tang B. Relationship between inflammatory bowel disease and erectile dysfunction: a 2-sample Mendelian randomization study. Sex Med 2023; 11:qfad067. [PMID: 38264202 PMCID: PMC10805346 DOI: 10.1093/sexmed/qfad067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/07/2023] [Accepted: 12/07/2023] [Indexed: 01/25/2024] Open
Abstract
Background Observational studies have indicated a high prevalence of erectile dysfunction (ED) among patients with inflammatory bowel disease (IBD), but a definitive causal relationship remains unestablished. Aim The primary aim of this study was to assess the potential causal relationship between IBD and ED using Mendelian randomization (MR) analysis. Methods We obtained statistical data for 2 subtypes of IBD, ulcerative colitis (UC) and Crohn's disease (CD), as well as for ED, from publicly available genome-wide association studies (GWASs). Subsequently, a 2-sample MR analysis was conducted using these datasets. The primary MR analysis utilized the inverse variance-weighted (IVW) method, complemented by secondary analyses employing MR-Egger and weighted median methods. Furthermore, we assessed heterogeneity using Cochran's Q test and evaluated pleiotropy with the MR-Egger intercept test. To identify potential influential single nucleotide polymorphisms, we employed a leave-one-out analysis. Additionally, outliers were identified using the MR-PRESSO method. Outcomes The study outcomes encompassed results from 3 MR analyses, namely IVW, MR-Egger, and weighted median, along with sensitivity analyses involving Cochran's Q test, the MR-Egger intercept test, leave-one-out analysis, and the MR-PRESSO method. Results There was no causal effect of UC and CD on ED in the MR analysis (IVW P > .05). Results of complementary methods were consistent with those of the IVW method. The results of sensitivity analyses supported our conclusion, and no directional pleiotropy was found. Clinical Implications Genetically, despite the absence of a causal link between IBD and ED according to MR analysis, we must emphasize the elevated ED prevalence among IBD patients in observational studies, with particular consideration for the influence of negative emotions on erectile function. Strengths & Limitations This study is the inaugural application of a 2-sample MR analysis using extensive GWAS datasets to evaluate the causal relationship between IBD and ED, effectively mitigating biases stemming from confounding factors and reverse causality often present in observational studies. Nevertheless, it is imperative to exercise caution when drawing conclusions due to inherent limitations in GWAS data, encompassing factors like samples overlap, gender categorization, population ancestry, and the persistent ambiguity surrounding the precise functionality of specific single nucleotide polymorphisms. Conclusions MR analysis did not provide genetic-level evidence supporting a direct causal relationship between IBD (UC and CD) and ED.
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Affiliation(s)
- Dawei Gao
- Clinical School of Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Cheng Chen
- Clinical School of Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
- Traditional Chinese Medicine Department, Chongqing General Hospital, Chongqing 401121, China
| | - Ziliang Wu
- Health Management Center, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Huakang Li
- Clinical School of Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Bo Tang
- Department of Urology, Chengdu Pidu District Hospital of Traditional Chinese Medicine, Chengdu 611730, China
- Department of Urology, No.3 Affiliated Hospital of Chengdu University of Traditional Chinese Medicine (West District), Chengdu 611730, China
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Akiya A, Takahashi K, Akimoto S, Hosono Y, Ifuku M, Iso T, Yazaki K, Shigemitsu S, Jimbo K, Kudo T, Ohtsuka Y, Shimizu T. Novel Findings of Early Cardiac Dysfunction in Patients With Childhood-Onset Inflammatory Bowel Disease Using Layer-Specific Strain Analysis. Inflamm Bowel Dis 2023; 29:1546-1554. [PMID: 36971087 DOI: 10.1093/ibd/izad031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Indexed: 06/18/2023]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) are at a higher risk of developing cardiovascular diseases than healthy individuals, owing to persistent chronic inflammation and treatment effects. This study aimed to assess left ventricular function in patients with childhood-onset IBD using layer-specific strain analysis and to identify early indicators of cardiac dysfunction in them. METHODS A total of 47 patients with childhood-onset ulcerative colitis (UC), 20 patients with Crohn's disease (CD), and 75 age- and sex-matched healthy control subjects were included in this study. Conventional echocardiographic measurements of layer-specific (ie, endocardium, midmyocardium, and epicardium) global longitudinal strain and global circumferential strain (GCS) were evaluated in these participants. RESULTS Layer-specific strain analysis showed that global longitudinal strain was lower in all layers for the UC (P < .001) and CD (P < .001) groups, regardless of the age at onset, but that GCS was only lower in the midmyocardial (P = .032) and epicardial (P = .018) layers in the CD group than in the control group. Although the mean left ventricular wall thickness was not significantly different among the groups, it was significantly correlated with the GCS of the endocardial layer in the CD group (ρ= -0.615; P = .004), suggesting that thickening of the left ventricular wall occurred as a compensatory mechanism to maintain the endocardial strain in the CD group layer. CONCLUSIONS Children and young adults with childhood-onset IBD displayed decreased midmyocardial deformation. Layer-specific strain could also be useful to identify indicators of cardiac dysfunction in patients with IBD.
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Affiliation(s)
- Azusa Akiya
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ken Takahashi
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Satoshi Akimoto
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yu Hosono
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Mayumi Ifuku
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Takeshi Iso
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kana Yazaki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Sachie Shigemitsu
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Keisuke Jimbo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Takahiro Kudo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yoshikazu Ohtsuka
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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16
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Grunz EA, Jones BW, Lateef OM, Sen S, Wilkinson K, Joshi T, Boerman EM. Adventitial macrophage accumulation impairs perivascular nerve function in mesenteric arteries with inflammatory bowel disease. Front Physiol 2023; 14:1198066. [PMID: 37342800 PMCID: PMC10278583 DOI: 10.3389/fphys.2023.1198066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
Introduction: Inflammatory bowel disease involves aberrant immune responses and is associated with both cardiovascular disease risk and altered intestinal blood flow. However, little is known about how inflammatory bowel disease affects regulation of perivascular nerves that mediate blood flow. Previous work found perivascular nerve function is impaired in mesenteric arteries with Inflammatory bowel disease. The purpose of this study was to determine the mechanism of impaired perivascular nerve function. Methods: RNA sequencing was performed on mesenteric arteries from IL10-/- mice treated with H. hepaticus to induce disease (inflammatory bowel disease) or left non-gavaged (Control). For all other studies, Control and Inflammatory bowel disease mice received either saline or clodronate liposome injections to study the effect of macrophage depletion. Perivascular nerve function was assessed using pressure myography and electrical field stimulation. Leukocyte populations, and perivascular nerves, and adventitial neurotransmitter receptors were labeled using fluorescent immunolabeling. Results: Inflammatory bowel disease was associated with increases in macrophage-associated gene expression, and immunolabeling showed accumulation of adventitial macrophages. Clodronate liposome injection eliminated adventitial macrophages, which reversed significant attenuation of sensory vasodilation, sympathetic vasoconstriction and sensory inhibition of sympathetic constriction in inflammatory bowel disease. Acetylcholine-mediated dilation was impaired in inflammatory bowel disease and restored after macrophage depletion, but sensory dilation remained nitric oxide independent regardless of disease and/or macrophage presence. Conclusion: Altered neuro-immune signaling between macrophages and perivascular nerves in the arterial adventitia contributes to impaired vasodilation, particularly via dilatory sensory nerves. Targeting the adventitial macrophage population may help preserve intestinal blood flow in Inflammatory bowel disease patients.
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Affiliation(s)
- Elizabeth A. Grunz
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States
| | - Benjamin W. Jones
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States
| | - Olubodun Michael Lateef
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States
| | - Sidharth Sen
- MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO, United States
| | - Katie Wilkinson
- MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO, United States
| | - Trupti Joshi
- MU Institute for Data Science and Informatics, University of Missouri, Columbia, MO, United States
- Department of Health Management and Informatics and Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, United States
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17
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Grunz EA, Jones BW, Sen S, Wilkenson K, Joshi T, Boerman EM. Adventitial macrophage accumulation impairs perivascular nerve function in mesenteric arteries with inflammatory bowel disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.04.535591. [PMID: 37066314 PMCID: PMC10104036 DOI: 10.1101/2023.04.04.535591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Introduction Inflammatory bowel disease (IBD) involves aberrant immune responses and is associated with both cardiovascular disease risk and altered intestinal blood flow. However, little is known about how IBD affects regulation of perivascular nerves that mediate blood flow. Previous work found perivascular nerve function is impaired in mesenteric arteries with IBD. The purpose of this study was to determine the mechanism of impaired perivascular nerve function. Methods RNA sequencing was performed on mesenteric arteries from IL10 -/- mice treated with H.hepaticus to induce disease (IBD) or left non-gavaged (Control). For all other studies, Control and IBD mice received either saline or clodronate liposome injections to study the effect of macrophage depletion. Perivascular nerve function was assessed using pressure myography and electrical field stimulation. Fluorescent immunolabeling was used to label leukocyte populations and perivascular nerves. Results IBD was associated with increased in macrophage-associated gene expression, and immunolabeling showed accumulation of adventitial macrophages. Clodronate liposome injection eliminated adventitial macrophages, which reversed significant attenuation of sensory vasodilation, sympathetic vasoconstriction and sensory inhibition of sympathetic constriction in IBD. Acetylcholine-mediated dilation was impaired in IBD and restored after macrophage depletion, but sensory dilation remained nitric oxide independent regardless of disease and/or macrophage presence. Conclusion Altered neuro-immune signaling between macrophages and perivascular nerves in the arterial adventitia contributes to impaired vasodilation, particularly via dilatory sensory nerves. Targeting the adventitial macrophage population may help preserve intestinal blood flow in IBD patients.
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Britzen-Laurent N, Weidinger C, Stürzl M. Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases. Int J Mol Sci 2023; 24:ijms24065517. [PMID: 36982601 PMCID: PMC10051397 DOI: 10.3390/ijms24065517] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD.
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Affiliation(s)
- Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Correspondence:
| | - Carl Weidinger
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Michael Stürzl
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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19
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Kuang R, O'Keefe SJD, Ramos Del Aguila de Rivers C, Koutroumpakis F, Binion DG. Is Salt at Fault? Dietary Salt Consumption and Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:140-150. [PMID: 35380668 DOI: 10.1093/ibd/izac058] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Indexed: 02/05/2023]
Abstract
Epidemiological trends have led to a growing consensus that diet plays a central role in the etiopathogenesis of inflammatory bowel diseases (IBD). A Western diet high in ultra-processed foods has been associated with an increased prevalence of IBD worldwide. Much attention has focused on components of the Western diet, including the high fat content, lack of fiber, added sugars, and use of additives, such as carrageenan and other emulsifiers. Less attention has been paid to the impact of high salt intake, an integral component of ultra-processed foods, which has increased dramatically in the US diet over the past 50 years. We review a growing body of literature linking the rise in dietary salt intake with the epidemiology of IBD, increased consumption of salt as a component of ultra-processed foods, high salt intake and imbalances in immune homeostasis, the effects of a high-salt diet on other inflammatory disorders, salt's impact on animal colitis models, salt as an underrecognized component in diet modification-induced remission of IBD, and directions for future investigation.
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Affiliation(s)
- Rebecca Kuang
- University of Toledo College of Medicine & Life Sciences, Toledo, OH, USA
| | - Stephen J D O'Keefe
- University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital, Pittsburgh, PA, USA
| | | | - Filippos Koutroumpakis
- University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital, Pittsburgh, PA, USA
| | - David G Binion
- University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital, Pittsburgh, PA, USA
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20
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Cirillo G, Negrete-Diaz F, Yucuma D, Virtuoso A, Korai SA, De Luca C, Kaniusas E, Papa M, Panetsos F. Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn's and Other Inflammatory Bowel Diseases. Cells 2022; 11:cells11244103. [PMID: 36552867 PMCID: PMC9776705 DOI: 10.3390/cells11244103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/03/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus nerve stimulation, and in particular, the transcutaneous stimulation of the auricular branch of the vagus nerve. Then, we expose the working hypotheses for the modulation of the molecular processes that are responsible for intestinal inflammation in autoimmune diseases and the way we could develop personalized neuroprosthetic therapeutic devices and procedures in favor of the patients.
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Affiliation(s)
- Giovanni Cirillo
- Division of Human Anatomy, Neuronal Morphology Networks & Systems Biology Lab, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli, 80138 Naples, Italy
| | - Flor Negrete-Diaz
- Neurocomputing & Neurorobotics Research Group, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias (IdISSC), Hospital Clinico San Carlos de Madrid, 28040 Madrid, Spain
| | - Daniela Yucuma
- Neurocomputing & Neurorobotics Research Group, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Andalusian School of Public Health, University of Granada, 18011 Granada, Spain
| | - Assunta Virtuoso
- Division of Human Anatomy, Neuronal Morphology Networks & Systems Biology Lab, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli, 80138 Naples, Italy
| | - Sohaib Ali Korai
- Division of Human Anatomy, Neuronal Morphology Networks & Systems Biology Lab, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli, 80138 Naples, Italy
| | - Ciro De Luca
- Division of Human Anatomy, Neuronal Morphology Networks & Systems Biology Lab, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli, 80138 Naples, Italy
| | | | - Michele Papa
- Division of Human Anatomy, Neuronal Morphology Networks & Systems Biology Lab, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli, 80138 Naples, Italy
- SYSBIO Centre of Systems Biology ISBE-IT, University of Milano-Bicocca, 20126 Milan, Italy
- Correspondence: (M.P.); (F.P.)
| | - Fivos Panetsos
- Neurocomputing & Neurorobotics Research Group, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias (IdISSC), Hospital Clinico San Carlos de Madrid, 28040 Madrid, Spain
- Silk Biomed SL, 28260 Madrid, Spain
- Correspondence: (M.P.); (F.P.)
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Wieder C, Lai RPJ, Ebbels TMD. Single sample pathway analysis in metabolomics: performance evaluation and application. BMC Bioinformatics 2022; 23:481. [PMID: 36376837 PMCID: PMC9664704 DOI: 10.1186/s12859-022-05005-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/25/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Single sample pathway analysis (ssPA) transforms molecular level omics data to the pathway level, enabling the discovery of patient-specific pathway signatures. Compared to conventional pathway analysis, ssPA overcomes the limitations by enabling multi-group comparisons, alongside facilitating numerous downstream analyses such as pathway-based machine learning. While in transcriptomics ssPA is a widely used technique, there is little literature evaluating its suitability for metabolomics. Here we provide a benchmark of established ssPA methods (ssGSEA, GSVA, SVD (PLAGE), and z-score) alongside the evaluation of two novel methods we propose: ssClustPA and kPCA, using semi-synthetic metabolomics data. We then demonstrate how ssPA can facilitate pathway-based interpretation of metabolomics data by performing a case-study on inflammatory bowel disease mass spectrometry data, using clustering to determine subtype-specific pathway signatures. RESULTS While GSEA-based and z-score methods outperformed the others in terms of recall, clustering/dimensionality reduction-based methods provided higher precision at moderate-to-high effect sizes. A case study applying ssPA to inflammatory bowel disease data demonstrates how these methods yield a much richer depth of interpretation than conventional approaches, for example by clustering pathway scores to visualise a pathway-based patient subtype-specific correlation network. We also developed the sspa python package (freely available at https://pypi.org/project/sspa/ ), providing implementations of all the methods benchmarked in this study. CONCLUSION This work underscores the value ssPA methods can add to metabolomic studies and provides a useful reference for those wishing to apply ssPA methods to metabolomics data.
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Affiliation(s)
- Cecilia Wieder
- Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion, and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Rachel P J Lai
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK
| | - Timothy M D Ebbels
- Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion, and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
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22
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Beydoun N, Feinstein MJ. Heart Failure in Chronic Infectious and Inflammatory Conditions: Mechanistic Insights from Clinical Heterogeneity. Curr Heart Fail Rep 2022; 19:267-278. [PMID: 35838874 PMCID: PMC9283814 DOI: 10.1007/s11897-022-00560-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 01/21/2023]
Abstract
PURPOSE OF REVIEW The balance between inflammation and its resolution plays an important and increasingly appreciated role in heart failure (HF) pathogenesis. In humans, different chronic inflammatory conditions and immune-inflammatory responses to infection can lead to diverse HF manifestations. Reviewing the phenotypic and mechanistic diversity of these HF presentations offers useful clinical and scientific insights. RECENT FINDINGS HF risk is increased in patients with chronic inflammatory and autoimmune disorders and relates to disease severity. Inflammatory condition-specific HF manifestations exist and underlying pathophysiologic causes may differ across conditions. Although inflammatory disease-specific presentations of HF differ, chronic excess in inflammation and auto-inflammation relative to resolution of this inflammation is a common underlying contributor to HF. Further studies are needed to phenotypically refine inflammatory condition-specific HF pathophysiologies and prognoses, as well as potential targets for intervention.
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Affiliation(s)
- Nour Beydoun
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Matthew J Feinstein
- Division of Cardiology, Department of Medicine, Northwestern University, Chicago, IL, USA.
- Department of Pathology, Northwestern University, Chicago, IL, USA.
- Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
- Northwestern University Feinberg School of Medicine, 300 E. Superior St, Tarry 3-703, Chicago, IL, 60611, USA.
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23
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Crohn's Disease and Female Infertility: Can Nutrition Play a Supporting Role? Nutrients 2022; 14:nu14122423. [PMID: 35745153 PMCID: PMC9230147 DOI: 10.3390/nu14122423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 02/04/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory disease (IBD) that can affect the entire gastrointestinal tract in a non-continuous mode. CD is generally diagnosed most commonly between 15 and 35 years of age and may affect female fertility. The role of diet in supporting wellbeing outcome and reproductive potential in women is well-known; however, no effective efforts have been made to improve women's awareness in CD. Our review aims to describe the burden of CD on women's fertility, reporting the most relevant nutrients that support reproductive function to ensure women diagnosed with IBD an adequate health-related quality of life.
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Circulating Exosomal miR-144-3p from Crohn’s Disease Patients Inhibits Human Umbilical Vein Endothelial Cell Function by Targeting FN1. DISEASE MARKERS 2022; 2022:8219557. [PMID: 35692876 PMCID: PMC9184168 DOI: 10.1155/2022/8219557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/20/2022] [Indexed: 11/20/2022]
Abstract
Background Crohn's disease (CD) is a chronic nonspecific inflammatory disease with unknown pathogenesis and vascular changes associated with the progression of CD. Many studies have shown that miRNAs participate in the development of CD. However, the effect of miRNAs in circulating exosomes on vascular endothelial cells in CD has not been investigated. Our study is aimed at identifying the differential miRNAs in circulating exosomes in CD and exploring their potential roles in human umbilical vein endothelial cells (HUVECs). Methods In our study, exosomes were extracted from circulating blood to identify differential miRNAs. After in vitro transfection of HUVECs with miR-144-3p mimics and inhibitors and the corresponding controls, cell counting kit-8, wound healing, Transwell migration, and tube formation assays were performed to study the viability, migration, and angiogenesis of HUVECs. Furthermore, bioinformatics analysis was used to predict miRNA targets. Western blotting was used to determine protein expression. In addition, exogenous supplementation with the fibronectin 1 (FN1) protein rescued the effects of miR-144-3p on changes in cell function in vitro. Results miR-144-3p was significantly increased in circulating exosomes of patients with CD compared with those in the control group. The promotion or inhibition of miR-144-3p correspondingly abolished or accelerated cell viability, migration, and angiogenesis. FN1 is a significant target of miR-144-3p, and exogenous FN1 administration improved the function of HUVECs in vitro. Conclusions Circulating exosomal miR-144-3p from patients with active CD contributes to vascular endothelial dysfunction by affecting the gene expression of FN1. These findings suggested that circulating exosomal miR-144-3p could be a potential biological marker for CD.
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de Voogd F, Bots S, Gecse K, Gilja OH, D’Haens G, Nylund K. Intestinal Ultrasound Early on in Treatment Follow-up Predicts Endoscopic Response to Anti-TNFα Treatment in Crohn's Disease. J Crohns Colitis 2022; 16:1598-1608. [PMID: 35639823 PMCID: PMC9624292 DOI: 10.1093/ecco-jcc/jjac072] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/02/2022] [Accepted: 05/26/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND To assess treatment response, objective measures are superior to clinical improvement in Crohn's disease [CD]. Intestinal ultrasound [IUS] is an attractive, non-invasive alternative to endoscopy, demonstrating early transmural changes after treatment initiation. Therefore, we investigated IUS and contrast-enhanced ultrasound [CEUS] to predict [early] endoscopic treatment response. METHODS Consecutive patients with endoscopically active CD, starting anti-TNFα therapy, were included. Clinical, biochemical, IUS, and CEUS parameters at baseline [T0], after 4-8 weeks [T1] and 12-34 weeks [T2] were collected. The most severely inflamed segment at endoscopy (highest segmental Simplified Endoscopic Score for Crohn's Disease [SES-CD]) and IUS (highest segmental bowel wall thickness [BWT]) was identified. At T2, endoscopic response [decrease in SES-CD ≥ 50%] and remission [SES-CD = 0] were scored. RESULTS A total of 40 patients were included: 14 reached endoscopic remission and 17 endoscopic response. At T1 (3.1 mm [1.9-4.2] vs 5.3 mm [3.8-6.9], p = 0.005) and T2 (2.0 mm [1.8-3.1] vs 5.1 [3.0-6.3] mm, p = 0.002) BWT was lower in patients with endoscopic remission. At T1 and T2, 18% (area under the receiver operating curve [AUROC]: 0.77; odds ratio [OR]: 10.80, p = 0.012) and 29% [AUROC: 0.833; OR: 37.50, p = 0.006] BWT decrease predicted endoscopic response, respectively. To determine endoscopic remission, BWT 3.2 mm was most accurate [AUROC: 0.94; OR: 39.42, p < 0.0001] at T2. In addition, absence of colour Doppler signal [OR: 13.76, p = 0.03] and the CEUS parameter wash-out rate [OR: 0.76, p = 0.019] improved the prediction model. CONCLUSIONS Reduction in BWT, already after 4-8 weeks of follow-up, predicted endoscopic response and remission. CEUS parameters were of limited value. Furthermore, we have provided accurate cut-offs for BWT reflecting endoscopic response and remission at different time points.
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Affiliation(s)
- F de Voogd
- Corresponding author: Floris de Voogd, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
| | | | - K Gecse
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - O H Gilja
- National Centre of Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - G D’Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - K Nylund
- National Centre of Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Zhang J, Nie J, Zou M, Zeng Q, Feng Y, Luo Z, Gan H. Prevalence and Associated Factors of Sexual Dysfunction in Patients With Inflammatory Bowel Disease. Front Endocrinol (Lausanne) 2022; 13:881485. [PMID: 35573991 PMCID: PMC9094619 DOI: 10.3389/fendo.2022.881485] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/16/2022] [Indexed: 12/14/2022] Open
Abstract
Background Sexual dysfunction (SD) in patients who suffer from inflammatory bowel disease (IBD) has not attracted widespread attention, and thus research studies are scarce. Objective This study aims to evaluate the rates of SD in IBD compared with healthy individuals and elucidate the associated factors. Methods In this cross-sectional study, the Female Sexual Function Index (FSFI) and the simplified version of the International Index of Erectile Function (IIEF-5) were filled by IBD patients, as well as healthy control individuals. Results A total of 208 IBD patients, including 133 with Crohn's disease (CD) and 75 with ulcerative colitis (UC), and 190 healthy individuals filled out the questionnaires. In women, SD rates were 61.9% in the patients with IBD vs. 24.4% in the healthy controls (p < 0.01). In men, the rates of erectile dysfunction (ED) were 43.5% in the patients with IBD vs. 12.5% in the healthy controls (p < 0.01). Anxiety (OR, 3.092; 95%CI: 1.033-9.252, p = 0.044) and active perianal disease (OR, 4.481; 95%CI: 1.055-19.029, p = 0.042) were independent risk factors for SD in female IBD patients. age (OR, 1.050; 95%CI: 1.007-1.095, p = 0.022), depression (OR, 5.763; 95%CI: 1.864-17.821, p = 0.002) and active perianal disease (OR, 7.117; 95%CI: 1.747-28.983, p = 0.006) were independent risk factors for ED in male patients. Conclusions In the IBD patients, 62% of women reported having SD, and 44% of men reported having ED. These higher rates, as compared to the healthy controls, are mostly driven by active perianal disease and psychological factors.
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Affiliation(s)
- Jinzhi Zhang
- Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jiao Nie
- Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zou
- Laboratory of Inflammatory Bowel Disease, The Center for Inflammatory Bowel Disease, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Qishan Zeng
- Laboratory of Inflammatory Bowel Disease, The Center for Inflammatory Bowel Disease, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yue Feng
- Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenyi Luo
- Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Huatian Gan
- Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, The Center for Inflammatory Bowel Disease, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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Wu H, Hu T, Zhang L, Xia X, Liu X, Zhu Q, Wang M, Sun Z, Hao H, Cui Y, Parrish AR, Li DP, Hill MA, Xu C, Liu Z. Abdominal Aortic Endothelial Dysfunction Occurs in Female Mice With Dextran Sodium Sulfate-Induced Chronic Colitis Independently of Reactive Oxygen Species Formation. Front Cardiovasc Med 2022; 9:871335. [PMID: 35463755 PMCID: PMC9021429 DOI: 10.3389/fcvm.2022.871335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/04/2022] [Indexed: 01/19/2023] Open
Abstract
Background and Objective Inflammatory bowel disease (IBD) produces significant local and systemic inflammation with increased reactive oxygen species (ROS) formation. IBD Patients are at an increased risk for developing endothelial dysfunction and cardiovascular diseases. The present study tested the hypothesis that IBD impairs aortic endothelial function via ROS formation and investigate potential sex-related differences. Methods and Results Acute and chronic colitis models were induced in male and female C57BL/6 mice with dextran sodium sulfate (DSS) treatment. Aortic wall stiffness, endothelial function, and ROS levels, as well as serum levels of pro-inflammatory cytokines were evaluated. Acetylcholine (Ach)-induced endothelium-dependent relaxation of abdominal aorta without perivascular adipose tissue (PVAT) was significantly reduced in female mice, not males, with chronic colitis without a change in nitroglycerin-induced endothelium-independent relaxation. PVAT effectively preserved Ach-induced relaxation in abdominal aorta of female mice with chronic colitis. Aortic peak velocity, maximal intraluminal diameters, pulse wave velocity, distensibility and radial strain were preserved in mice with both acute and chronic colitis. Although pro-inflammatory cytokines levels were increased in mice with acute and chronic colitis, aortic ROS levels were not increased. Conclusion The data demonstrate that abdominal aortic endothelial function was attenuated selectively in female mice with chronic colitis independent of ROS formation. Further, PVAT played an important role in preserving endothelial function in female mice with chronic colitis.
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Affiliation(s)
- Hao Wu
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Tingzi Hu
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Linfang Zhang
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Xiujuan Xia
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Xuanyou Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Qiang Zhu
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Meifang Wang
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Zhe Sun
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, United States
| | - Hong Hao
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Yuqi Cui
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Alan R. Parrish
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, United States
| | - De-Pei Li
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
| | - Michael A. Hill
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, United States
| | - Canxia Xu
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhenguo Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, United States
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Principi M, Scicchitano P, Carparelli S, Nitti R, Ruggieri R, Bellino MC, Cecere A, Manca F, DI Leo A, Ciccone MM. Influence of systemic manifestations of inflammatory bowel diseases on endothelial function and cardiovascular risk. Minerva Med 2022; 113:291-299. [PMID: 33913656 DOI: 10.23736/s0026-4806.21.06970-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) may be complicated by extraintestinal manifestations (EIM). Both conditions may be implicated in the overall increase of cardiovascular (CV) risk profile of the patients. The study aimed to assess CV risk in IBD patients with EIMs in relation to the stages of both diseases. METHODS A total of 70 (38 men, mean age 51.7±12.4 years) patients with IBD and 22 controls (12 men, mean age 49.2±13.6 years) were enrolled. All patients and controls were screened for extraintestinal manifestations and underwent physical and anthropometric examinations, standard laboratory investigations, ultrasound evaluation of carotid arteries and flow-mediated vasodilatation (FMD). Patients were divided into four groups in relation to their active or remission stage of disease: 1) IBD+ EIM+; 2) IBD+ EIM-; 3) IBD- EIM+; and 4) IBD- EIM-. RESULTS The groups were homogenous according to their clinical characteristics. Patients with both IBD and EIM in active phase showed significantly lower values in FMD than controls (P=0.024). Carotid intima-media thickness values (cIMT) were similar among groups. Patients with active phases of IBD and/or EIM showed statistically significant lower values in FMD measurements (P=0.0008 and P=0.0011, respectively). Multivariate regression did not reveal any independent predictors for FMD values. CONCLUSIONS The active phase of IBD or EIM or both may promote endothelial dysfunction in patients, thus increasing their CV risk profile. Patients in remission phase showed endothelial function similar at controls.
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Affiliation(s)
- Mariabeatrice Principi
- Unit of Gastroenterology, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Pietro Scicchitano
- Section of Cardiovascular Diseases, Ospedale della Murgia Fabio Perinei, Altamura, Bari, Italy -
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Sonia Carparelli
- Unit of Gastroenterology, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Rosa Nitti
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Roberta Ruggieri
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Maria C Bellino
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Annagrazia Cecere
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Fabio Manca
- Department of Science of Educational, Psychology, and Communication, University of Bari, Bari, Italy
| | - Alfredo DI Leo
- Unit of Gastroenterology, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Marco M Ciccone
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
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Polat E, Erolu E, Gerenli N, Ayyıldız Civan H. Is There Any Effect of Diagnostic Disease Activity Index on Current Myocardial Function in Pediatric Inflammatory Bowel Disease Patients? THE JOURNAL OF PEDIATRIC RESEARCH 2022; 9:19-25. [DOI: 10.4274/jpr.galenos.2021.46794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Pilz AC, Schielein MC, Schuster B, Heinrich L, Haufe E, Abraham S, Heratizadeh A, Harder I, Kleinheinz A, Wollenberg A, Wiemers F, Weisshaar E, Augustin M, von Kiedrowski R, Pawlak M, Schäkel K, Wildberger J, Hilgers M, Werfel T, Weidinger S, Schmitt J, Biedermann T, Zink A. Atopic Dermatitis: Disease Characteristics and Comorbidities in Smoking and Nonsmoking Patients from the TREATgermany Registry. J Eur Acad Dermatol Venereol 2021; 36:413-421. [PMID: 34743344 DOI: 10.1111/jdv.17789] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/15/2021] [Accepted: 10/22/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disease with a multifactorial genesis including genetic predispositions and environmental risk and trigger factors. One of the latter possibly is smoking, indicated by an increased prevalence of AD in adults and children that are actively or passively exposed to cigarette smoke. OBJECTIVES In this study AD characteristics and its atopic comorbidities are compared in smoking and nonsmoking AD patients. METHODS TREATgermany is a non-interventional clinical registry which includes patients with moderate to severe AD in Germany. Baseline data of patients included into TREATgermany from inception in June 2016 to April 2020 in 39 sites across Germany was analyzed comparing AD disease characteristics and comorbidities in smokers versus non-smokers. RESULTS Of 921 patients, 908 (male: 58.7%) with a mean age of 41.9 ± 14.4 reported their smoking status. The objective Scoring of Atopic Dermatitis (oSCORAD) did not differ between smokers (n=352; 38.8%) and nonsmokers, however lesions' intensity of oozing/crusts and excoriations as well as patient global assessment scores (PGA) of AD severity were higher in smoking as opposed to nonsmoking patients. Smokers reported a lower number of weeks with well-controlled AD and more severe pruritus than nonsmokers. Total IgE levels were more elevated in smokers and they displayed a younger age at initial diagnosis of bronchial asthma. After adjustment for potential confounders, the increased intensity of oozing/crusts, the reduced number of weeks with well-controlled AD and the greater pruritus remained different in smokers compared to nonsmokers. In addition, smoking patients with adult-onset AD showed a 2.5 times higher chance of involvement of the feet. CONCLUSIONS German registry data indicate that AD patients who smoke have a higher disease burden with a different distribution pattern of lesions in adult-onset AD.
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Affiliation(s)
- A C Pilz
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - M C Schielein
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - B Schuster
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - L Heinrich
- Center of Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden
| | - E Haufe
- Center of Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden
| | - S Abraham
- Department of Dermatology, University Allergy Center, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden
| | - A Heratizadeh
- Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover
| | - I Harder
- Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel
| | - A Kleinheinz
- Clinics for Dermatology, Elbe Klinikum Buxtehude
| | - A Wollenberg
- Clinics and Outpatient Clinics for Dermatology and Allergy, LMU Munich
| | - F Wiemers
- Practice Dr. med. Franca Wiemers, Leipzig
| | - E Weisshaar
- Occupational Dermatology, Department of Dermatology, University of Heidelberg
| | - M Augustin
- Institute for Health Services Research in Dermatology Hamburg, University Medical Center Hamburg Eppendorf
| | | | - M Pawlak
- Practice Dr. med, Anika Hünermund and Mario Pawlak, Heilbad Heiligenstadt
| | - K Schäkel
- Department of Dermatology, Ruprecht-Karls University Heidelberg
| | | | - M Hilgers
- Clinics for Dermatology and Allergy, University Hospital Aachen
| | - T Werfel
- Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover
| | - S Weidinger
- Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel
| | - J Schmitt
- Center of Evidence-Based Healthcare, University Hospital Carl Gustav Carus and Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden
| | - T Biedermann
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - A Zink
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
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Zhang L, Lu W, Lu C, Guo Y, Chen X, Chen J, Xu F, Wan H, Dong H. Beneficial effect of capsaicin via TRPV4/EDH signals on mesenteric arterioles of normal and colitis mice. J Adv Res 2021; 39:291-303. [PMID: 35777913 PMCID: PMC9263647 DOI: 10.1016/j.jare.2021.11.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 01/01/2023] Open
Abstract
Capsaicin induced vasorelaxation of human colonic submucosal arterioles in vitro and in vitro. Capsaicin induced an endothelium-dependent vasorelaxation of human submucosal arterioles. Capsaicin induced an endothelium-dependent vasorelaxation of mouse mesenteric arterioles. Capsaicin induced vasorelaxation minily by TRPV1-mediated endothelial nitric oxide release. Capsaicin induced vasorelaxation mainly by TRPV4/endothelium-dependent hyperpolarization. Capsaicin exerted anti-colitis action in wide-type mice, but not in TRPV4 knock-out mice. Capsaicin rescued the impaired endothelium-dependent vasorelaxation via TRPV4/EDH pathway. Introduction Although capsaicin has long been used as food additive and medication worldwide, its actions on gastrointestinal tract as its most delivery pathway have not been well addressed. Objectives In the present study, we aimed to study GI actions of capsaicin on mesenteric arterioles in normal and colitis mice and to elucidate the underlying mechanisms. Methods Vasorelaxation of human submucosal arterioles and the mesenteric arterioles from wide-type (WT) mice, TRPV1−/− and TRPV4−/− (KO) mice were measured. The expression and function of TRPV channels in endothelial cells were examined by q-PCR, immunostaining, Ca2+ imaging and membrane potential measurements. Results Capsaicin dose-dependently induced vasorelaxation of human submucosal arterioles and mouse mesenteric arterioles in vitro and in vivo through endothelium-dependent hyperpolarization (EDH), nitric oxide (NO), and prostacyclin (PGI2). Using TRPV1 and TRPV4 KO mice, we found that capsaicin-induced vasorelaxation was predominately through TRPV4/EDH, but marginally through TRPV1/NO/PGI2. Capsaicin induced hyperpolarization through activation of endothelial TRPV4 channels and intermediate-conductance of Ca2+-activated K+ channels to finally stimulate vasorelaxation. Importantly, capsaicin exerted anti-colitis action by rescuing the impaired ACh-induced vasorelaxation in WT colitis mice but not in TRPV4 KO colitis mice. Conclusions Capsaicin increases intestinal mucosal blood perfusion to potentially prevent/treat colitis through a novel TRPV4/EDH-dependent vasorelaxation of submucosal arterioles in health and colitis. This study further supports our previous notion that TRPV4/EDH in mesenteric circulation plays a critical role in the pathogenesis of colitis.
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32
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Pinto RV, Carvalho S, Antunes F, Pires J, Pinto ML. Emerging Nitric Oxide and Hydrogen Sulfide Releasing Carriers for Skin Wound Healing Therapy. ChemMedChem 2021; 17:e202100429. [PMID: 34714595 DOI: 10.1002/cmdc.202100429] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/26/2021] [Indexed: 12/19/2022]
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2 S) have been recognized as important signalling molecules involved in multiple physiological functions, including wound healing. Their exogenous delivery has been established as a new route for therapies, being the topical application the nearest to commercialization. Nevertheless, the gaseous nature of these therapeutic agents and their toxicity at high levels imply additional challenges in the design of effective delivery systems, including the tailoring of their morphology and surface chemistry to get controllable release kinetics and suitable lifetimes. This review highlights the increasing interest in the use of these gases in wound healing applications by presenting the various potential strategies in which NO and/or H2 S are the main therapeutic agents, with focus on their conceptual design, release behaviour and therapeutic performance. These strategies comprise the application of several types of nanoparticles, polymers, porous materials, and composites as new releasing carriers of NO and H2 S, with characteristics that will facilitate the application of these molecules in the clinical practice.
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Affiliation(s)
- Rosana V Pinto
- CERENA-Centro de Recursos Naturais e Ambiente, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal.,CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - Sílvia Carvalho
- CERENA-Centro de Recursos Naturais e Ambiente, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal.,CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - Fernando Antunes
- CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - João Pires
- CQE-Ciências-Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 16, 1749-016, Lisboa, Portugal
| | - Moisés L Pinto
- CERENA-Centro de Recursos Naturais e Ambiente, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001, Lisboa, Portugal
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33
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Sinh P, Cross R. Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1107-1115. [PMID: 32978937 DOI: 10.1093/ibd/izaa258] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Indexed: 12/12/2022]
Abstract
There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.
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Affiliation(s)
- Preetika Sinh
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Raymond Cross
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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34
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Norton CE, Grunz-Borgmann EA, Hart ML, Jones BW, Franklin CL, Boerman EM. Role of perivascular nerve and sensory neurotransmitter dysfunction in inflammatory bowel disease. Am J Physiol Heart Circ Physiol 2021; 320:H1887-H1902. [PMID: 33710922 PMCID: PMC8163646 DOI: 10.1152/ajpheart.00037.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/03/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) is associated with both impaired intestinal blood flow and increased risk of cardiovascular disease, but the functional role of perivascular nerves that control vasomotor function of mesenteric arteries (MAs) perfusing the intestine during IBD is unknown. Because perivascular sensory nerves and their transmitters calcitonin gene-related peptide (CGRP) and substance P (SP) are important mediators of both vasodilation and inflammatory responses, our objective was to identify IBD-related deficits in perivascular sensory nerve function and vascular neurotransmitter signaling. In MAs from an interleukin-10 knockout (IL-10-/-) mouse model, IBD significantly impairs electrical field stimulation (EFS)-mediated sensory vasodilation and inhibition of sympathetic vasoconstriction, despite decreased sympathetic nerve density and vasoconstriction. The MA content and EFS-mediated release of both CGRP and SP are decreased with IBD, but IBD has unique effects on each transmitter. CGRP nerve density, receptor expression, hyperpolarization, and vasodilation are preserved with IBD. In contrast, SP nerve density and receptor expression are increased, and SP hyperpolarization and vasodilation are impaired with IBD. A key finding is that blockade of SP receptors restores EFS-mediated sensory vasodilation and enhanced CGRP-mediated vasodilation in MAs from IBD but not Control mice. Together, these data suggest that an aberrant role for the perivascular sensory neurotransmitter SP and its downstream signaling in MAs underlies vascular dysfunction with IBD. We propose that with IBD, SP signaling impedes CGRP-mediated sensory vasodilation, contributing to impaired blood flow. Thus, substance P and NK1 receptors may represent an important target for treating vascular dysfunction in IBD.NEW & NOTEWORTHY Our study is the first to show that IBD causes profound impairment of sensory vasodilation and inhibition of sympathetic vasoconstriction in mesenteric arteries. This occurs alongside decreased SP-containing nerve density and increased expression of NK1 receptors for SP. In contrast, CGRP dilation, nerve density, and receptor expression are unchanged. Blocking NK1 receptors restores sensory vasodilation in MAs and increases CGRP-mediated vasodilation, indicating that SP interference with CGRP signaling may underlie impaired sensory vasodilation with IBD.
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Affiliation(s)
- Charles E Norton
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | | | - Marcia L Hart
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri
| | - Benjamin W Jones
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Craig L Franklin
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri
| | - Erika M Boerman
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
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35
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Kakuta K, Dohi K, Yamamoto T, Fujimoto N, Shimoyama T, Umegae S, Ito M. Coronary Microvascular Dysfunction Restored After Surgery in Inflammatory Bowel Disease: A Prospective Observational Study. J Am Heart Assoc 2021; 10:e019125. [PMID: 33899514 PMCID: PMC8200729 DOI: 10.1161/jaha.120.019125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background We aimed to investigate the presence and severity of coronary microvascular dysfunction (CMD) in inflammatory bowel disease (IBD) including Crohn disease and ulcerative colitis and to elucidate the influence of surgical resection of the diseased intestines on CMD by assessing coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography. Methods and Results Thirty‐seven patients with IBD (aged 44±15 years; 22 patients with Crohn disease and 15 patients with ulcerative colitis) and 30 controls (aged 46±12 years) were enrolled. For CFVR measurement, coronary flow velocity was recorded at rest and during hyperemia by ADP infusion using transthoracic Doppler echocardiography, and CFVR <2.5 defined CMD. CFVR measurement was repeated before and within 1 year after surgery. CFVR was similarly and significantly lower in patients with Crohn disease and those with ulcerative colitis than controls (Crohn disease: 2.92±1.03 [P<0.05 versus controls], ulcerative colitis: 2.99±0.65 [P<0.05 versus controls], and controls: 3.84±0.75). Multiple linear regression analysis showed that the presence of IBD and baseline hs‐CRP (high‐sensitivity C‐reactive protein) were independently associated with low CFVR among all study participants (β=−0.403 [P=0.001] and −0.237 [P=0.037], respectively). Hyperemic coronary flow velocity significantly improved after surgery only in patients with IBD who had CMD. CFVR significantly improved in patients with IBD who had both CMD and non‐CMD, and the extent of CFVR improvements were greater in patients with CMD than non‐CMD. Multiple linear regression analysis showed that the reduction of hs‐CRP was independently associated with improvement of hyperemic coronary flow velocity and CFVR among all patients with IBD (β=−0.481 [P=0.003] and β=−0.334 [P=0.043], respectively). Conclusions IBD is associated with CMD, which improved after surgical resection of diseased intestines.
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Affiliation(s)
- Kentaro Kakuta
- Department of Cardiology and Nephrology Mie University Graduate School of Medicine Tsu Japan.,Department of Cardiology Japan Community Health Care Organization Yokkaichi Hazu Medical Center Yokkaichi Japan
| | - Kaoru Dohi
- Department of Cardiology and Nephrology Mie University Graduate School of Medicine Tsu Japan
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Center Japan Community Health care Organization Yokkaichi Hazu Medical Center Yokkaichi Japan
| | - Naoki Fujimoto
- Department of Cardiology and Nephrology Mie University Graduate School of Medicine Tsu Japan
| | - Takahiro Shimoyama
- Inflammatory Bowel Disease Center Japan Community Health care Organization Yokkaichi Hazu Medical Center Yokkaichi Japan
| | - Satoru Umegae
- Inflammatory Bowel Disease Center Japan Community Health care Organization Yokkaichi Hazu Medical Center Yokkaichi Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology Mie University Graduate School of Medicine Tsu Japan
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36
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Zhang LY, Chen XY, Dong H, Xu F. Cyclopiazonic Acid-Induced Ca 2+ Store Depletion Initiates Endothelium-Dependent Hyperpolarization-Mediated Vasorelaxation of Mesenteric Arteries in Healthy and Colitis Mice. Front Physiol 2021; 12:639857. [PMID: 33767636 PMCID: PMC7985063 DOI: 10.3389/fphys.2021.639857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/09/2021] [Indexed: 12/20/2022] Open
Abstract
Purposes: Since the role of store-operated calcium entry (SOCE) in endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of mesenteric arteries in health and colitis is not fully understood, cyclopiazonic acid (CPA), a specific inhibitor of the sarco(endo) plasmic reticulum calcium-ATPases (SERCA), was used as a SOCE activator to investigate its role in normal mice and its alteration in colitis mice. Methods: The changes in Ca2+ signaling in vascular endothelial cells (VEC) were examined by single cell Ca2+ imaging and tension of mesenteric arteries in response to CPA were examined using Danish DMT520A microvascular measuring system. Results: CPA activated the SOCE through depletion of the endoplasmic reticulum (ER) Ca2+ in endothelial cells. CPA had a concentration-dependent vasorelaxing effect in endothelium-intact mesenteric arteries, which was lost after endothelial removal. Both nitric oxide (NO) and prostacyclin (PGI2) inhibitors did not affect CPA-induced vasorelaxation; however, after both NO and PGI2 were inhibited, KCa channel blocker [10 mM tetraethylammonium chloride (TEA)] inhibited CPA-induced vasorelaxation while KCa channel activator (0.3 μM SKA-31) promoted it. Two SOCE blockers [30 μM SKF96365 and 100 μM flufenamic acid (FFA)], and an Orai channel blocker (30 μM GSK-7975A) inhibited this vasorelaxation. The inhibition of both Na+/K+-ATPase (NKA) and Na+/Ca2+-exchange (NCX) also inhibited CPA-induced vasorelaxation. Finally, the CPA involved in EDH-induced vasorelaxation by the depletion of ER Ca2+ of mesenteric arteries was impaired in colitis mice. Conclusion: Depletion of ER Ca2+ by CPA induces a vasorelaxation of mesenteric arteries that is mediated through EDH mechanism and invokes the activation of SOCE. The CPA-induced endothelium-dependent dilation is impaired in colitis which may limit blood perfusion to the intestinal mucosa.
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Affiliation(s)
- Lu Yun Zhang
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiong Ying Chen
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Hui Dong
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.,Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Feng Xu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
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Zhong J, Yu R, Zhou Q, Liu P, Liu Z, Bian Y. Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways. Food Funct 2021; 12:2715-2725. [PMID: 33667286 DOI: 10.1039/d1fo00155h] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The microvasculature endothelium accurately regulates the passage of molecules across the gut-vascular barrier (GVB), which plays an essential role in intestinal immunity. Naringenin is reported to have therapeutic potential against several intestinal disorders. However, the effect of naringenin on GVB disruption has been rarely studied. This study aims to investigate the effect of naringenin on GVB function and the potential mechanism. In the present study, the in vitro GVB disruption of rat intestinal microvascular endothelial cells (RIMVEC) was induced by 50 ng mL-1 of tumor necrosis factor-α (TNF-α). The integrity of the in vitro GVB was determined by Evans blue (EB)-albumin efflux assay and trans-endothelial electrical resistance (TER). Meanwhile, the expression of tight junction proteins and the related NF-κB, MLCK/p-MLC and NLRP3 pathways were determined using enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunofluorescence. The results show that naringenin (100 μM) inhibits TNF-α-induced interleukin (IL)-6 hypersecretion, alleviates GVB disruption and mitigates the change in the tight junction protein expression pattern. Naringenin inhibits the GVB-disruption-associated activation of the MLCK/p-MLC system and TLR4/NF-κB/NLRP3 pathways. Furthermore, naringenin shows a similar effect to that of NF-κB inhibitor Bay 11-7082 in reducing the TNF-α-induced activation of NLRP3, p-MLC and secondary GVB disruption. The results suggest that naringenin evidently alleviates TNF-α-induced in vitro GVB disruption via the maintenance of a tight junction protein pattern, partly with the inhibition of the NF-κB-mediated MLCK/p-MLC and NLRP3 pathway activation.
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Affiliation(s)
- Jia Zhong
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
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38
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Wang X, Chen S, Xiang H, Liang Z, Lu H. Role of sphingosine-1-phosphate receptors in vascular injury of inflammatory bowel disease. J Cell Mol Med 2021; 25:2740-2749. [PMID: 33595873 PMCID: PMC7957208 DOI: 10.1111/jcmm.16333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/14/2022] Open
Abstract
Sphingosine‐1‐phosphate receptors (S1PRs) have an impact on the intestinal inflammation of inflammatory bowel disease (IBD) by regulating lymphocyte migration and differentiation. S1PR modulators as an emerging therapeutic approach are being investigated for the treatment of IBD. However, the role of S1PRs in intestinal vessels has not drawn much attention. Intestinal vascular damage is one of the major pathophysiological features of IBD, characterized by increased vascular density and impaired barrier function. S1PRs have pleiotropic effects on vascular endothelial cells, including proliferation, migration, angiogenesis and barrier homeostasis. Mounting evidence shows that S1PRs are abnormally expressed on intestinal vascular endothelial cells in IBD. Unexpectedly, S1PR modulators may damage intestinal vasculature, for example increase intestinal bleeding; therefore, S1PRs are thought to be involved in the regulation of intestinal vascular function in IBD. However, little is understood about how S1PRs regulate intestinal vascular function and participate in the initiation and progression of IBD. In this review, we summarize the pathogenic role of S1PRs in and the underlying mechanisms behind the intestinal vascular injury in IBD in order for improving IBD practice including S1PR‐targeted therapies.
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Affiliation(s)
- Xuewen Wang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China
| | - Hong Xiang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Ziwei Liang
- Department of Clinical laboratory, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, China
| | - Hongwei Lu
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
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Guo Y, Lu C, Zhang L, Wan H, Jiang E, Chen Y, Dong H. Nutrient-induced hyperosmosis evokes vasorelaxation via TRPV1 channel-mediated, endothelium-dependent, hyperpolarisation in healthy and colitis mice. Br J Pharmacol 2020; 178:689-708. [PMID: 33169358 DOI: 10.1111/bph.15322] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 10/12/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE In humans, blood flow in the mesenteric circulation is greatly increased after meals, but the mechanisms underlying postprandial mesenteric vasorelaxation induced by nutrients and whether this process is involved in the pathogenesis of colitis, are not well understood. Here we have studied the direct actions of nutrients on mesenteric arterial tone and the underlying molecular mechanisms in healthy and colitis mice. EXPERIMENTAL APPROACH Colitis in C57BL/6 mice was induced with dextran sodium sulphate. Nutrient-induced vasorelaxation of mesenteric arterioles from humans and mice was studied with wire myograph assays. Ca2+ and Na+ imaging were performed in human vascular endothelial cells and vascular smooth muscle cells, using selective pharmacological agents and shRNA knockdown of TRPV1 channels. KEY RESULTS Glucose, sodium and mannitol concentration-dependently induced endothelium-dependent relaxation of human and mouse mesenteric arterioles via hyperosmotic action,. Hyperosmosis-induced vasorelaxation was almost abolished by selective blockers for TRPV1, IKCa and SKCa channels. Glucose markedly stimulated Ca2+ influx through endothelial TRPV1 channels, an effect attenuated by selective blockers and shRNA knockdown of TRPV1 channels. Capsaicin synergised the glucose-induced vasorelaxation. Nutrient-induced hyperosmosis also activated Na+ /K+ -ATPase and the Na/Ca exchanger (NCX) to decrease [Ca2+ ]i in VSMCs. Glucose-induced vasorelaxation was impaired in mouse colitis. CONCLUSION AND IMPLICATIONS Nutrient-induced hyperosmosis evoked endothelium-dependent mesenteric vasorelaxation via the TRPV1/Ca2+ / endothelium-dependent hyperpolarisation pathway to increase normal mucosal perfusion, which is impaired in our model of colitis. The TRPV1/Ca2+ / endothelium-dependent hyperpolarisation pathway could provide novel drug targets for gastrointestinal diseases with hypoperfusion, such as chronic colitis and mesenteric ischaemia.
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Affiliation(s)
- Yanjun Guo
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Cheng Lu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Luyun Zhang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hanxing Wan
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Enlai Jiang
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yao Chen
- Department of Plastic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hui Dong
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, China.,Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA, USA
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40
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Kondreddy V, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis. Sci Rep 2020; 10:20569. [PMID: 33239717 PMCID: PMC7689504 DOI: 10.1038/s41598-020-77502-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 11/11/2020] [Indexed: 12/28/2022] Open
Abstract
Crohn’s disease and ulcerative colitis are the two forms of disorders of the human inflammatory bowel disease with unknown etiologies. Endothelial cell protein C receptor (EPCR) is a multifunctional and multiligand receptor, which is expressed on the endothelium and other cell types, including epithelial cells. Here, we report that EPCR is expressed in the colon epithelial cells, CD11c+, and CD21+/CD35+ myeloid cells surrounding the crypts in the colon mucosa. EPCR expression was markedly decreased in the colon mucosa during colitis. The loss of EPCR appeared to associate with increased disease index of the experimental colitis in mice. EPCR−/− mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, manifested by increased weight loss, macrophage infiltration, and inflammatory cytokines in the colon tissue. DSS treatment of EPCR−/− mice resulted in increased bleeding, bodyweight loss, anemia, fibrin deposition, and loss of colon epithelial and goblet cells. Administration of coagulant factor VIIa significantly attenuated the DSS-induced colon length shortening, rectal bleeding, bodyweight loss, and disease activity index in the wild-type mice but not EPCR−/− mice. In summary, our data provide direct evidence that EPCR plays a crucial role in regulating the inflammation in the colon during colitis.
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Affiliation(s)
- Vijay Kondreddy
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - Charles T Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Usha R Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - L Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA.
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Manivannan A, Lee ES, Han K, Lee HE, Kim DS. Versatile Nutraceutical Potentials of Watermelon-A Modest Fruit Loaded with Pharmaceutically Valuable Phytochemicals. Molecules 2020; 25:E5258. [PMID: 33187365 PMCID: PMC7698065 DOI: 10.3390/molecules25225258] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 11/16/2022] Open
Abstract
Watermelon (Citrulus lantus) is an important horticultural crop which belongs to the Curcubitaceae family. The nutraceutical potential of watermelon has been illustrated by several researchers, which makes it a better choice of functional food. Watermelon has been used to treat various ailments, such as cardio-vascular diseases, aging related ailments, obesity, diabetes, ulcers, and various types of cancers. The medicinal properties of watermelon are attributed by the presence of important phytochemicals with pharmaceutical values such as lycopene, citrulline, and other polyphenolic compounds. Watermelon acts as vital source of l-citrulline, a neutral-alpha amino acid which is the precursor of l-arginine, an essential amino acid necessary for protein synthesis. Supplementation of l-citrulline and lycopene displayed numerous health benefits in in vitro and in vivo studies. Similarly, the dietary intake of watermelon has proven benefits as functional food in humans for weight management. Apart from the fruits, the extracts prepared from the seeds, sprouts, and leaves also evidenced medicinal properties. The present review provides a comprehensive overview of benefits of watermelon for the treatment of various ailments.
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Affiliation(s)
| | | | | | | | - Do-Sun Kim
- Vegetable Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Jeonju 55365, Korea; (A.M.); (E.-S.L.); (K.H.); (H.-E.L.)
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42
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Baier J, Gänsbauer M, Giessler C, Arnold H, Muske M, Schleicher U, Lukassen S, Ekici A, Rauh M, Daniel C, Hartmann A, Schmid B, Tripal P, Dettmer K, Oefner PJ, Atreya R, Wirtz S, Bogdan C, Mattner J. Arginase impedes the resolution of colitis by altering the microbiome and metabolome. J Clin Invest 2020; 130:5703-5720. [PMID: 32721946 PMCID: PMC7598089 DOI: 10.1172/jci126923] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Arginase 1 (Arg1), which converts l-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1fl/fl) littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells, and an accumulation of intraluminal polyamines that promote epithelial healing. The proresolving effect of Arg1 deletion was reduced by an l-arginine-free diet, but rescued by simultaneous deletion of other l-arginine-metabolizing enzymes, such as Arg2 or Nos2, demonstrating that protection from colitis requires l-arginine. Fecal microbiota transfers from Tie2-Cre Arg1fl/fl mice into WT recipients ameliorated intestinal inflammation, while transfers from WT littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of l-arginine as well as altered intestinal microbiota and metabolic products accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, l-arginine metabolism may serve as a target for clinical intervention in IBD patients.
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Affiliation(s)
- Julia Baier
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | | | - Claudia Giessler
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | - Harald Arnold
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | - Mercedes Muske
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | - Ulrike Schleicher
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
| | | | | | | | | | - Arndt Hartmann
- Pathologisches Institut, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Benjamin Schmid
- Optical Imaging Centre Erlangen (OICE), FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Philipp Tripal
- Optical Imaging Centre Erlangen (OICE), FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Katja Dettmer
- Institut für Funktionelle Genomik, Universität Regensburg, Regensburg, Germany
| | - Peter J. Oefner
- Institut für Funktionelle Genomik, Universität Regensburg, Regensburg, Germany
| | - Raja Atreya
- Medizinische Klinik 1–Gastroenterologie, Pneumologie and Endokrinologie, Universitätsklinikum Erlangen and FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Stefan Wirtz
- Medizinische Klinik 1–Gastroenterologie, Pneumologie and Endokrinologie, Universitätsklinikum Erlangen and FAU Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Bogdan
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie und Hygiene
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
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43
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COVID-19 and Microvascular Disease: Pathophysiology of SARS-CoV-2 Infection With Focus on the Renin-Angiotensin System. Heart Lung Circ 2020; 29:1596-1602. [PMID: 32972810 PMCID: PMC7467122 DOI: 10.1016/j.hlc.2020.08.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/26/2020] [Accepted: 08/14/2020] [Indexed: 02/08/2023]
Abstract
The recently described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people, with thousands of fatalities. It has prompted global efforts in research, with focus on the pathophysiology of coronavirus disease-19 (COVID-19), and a rapid surge of publications. COVID-19 has been associated with a myriad of clinical manifestations, including the lungs, heart, kidneys, central nervous system, gastrointestinal system, skin, and blood coagulation abnormalities. The endothelium plays a key role in organ dysfunction associated with severe infection, and current data suggest that it is also involved in SARS-CoV-2-induced sepsis. This critical review aimed to address a possible unifying mechanism underlying the diverse complications of COVID-19: microvascular dysfunction, with emphasis on the renin-angiotensin system. In addition, research perspectives are suggested in order to expand understanding of the pathophysiology of the infection.
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44
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Koike Y, Li B, Ganji N, Zhu H, Miyake H, Chen Y, Lee C, Janssen Lok M, Zozaya C, Lau E, Lee D, Chusilp S, Zhang Z, Yamoto M, Wu RY, Inoue M, Uchida K, Kusunoki M, Delgado-Olguin P, Mertens L, Daneman A, Eaton S, Sherman PM, Pierro A. Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation. Nat Commun 2020; 11:4950. [PMID: 33009377 PMCID: PMC7532542 DOI: 10.1038/s41467-020-18750-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 09/09/2020] [Indexed: 02/07/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC. Necrotizing enterocolitis (NEC) is one of the most lethal gastrointestinal emergencies in neonates needing precision treatment. Here the authors show that remote ischemic conditioning is a non-invasive therapeutic method that enhances blood flow in the intestine, reduces damage, and improves NEC outcome.
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Affiliation(s)
- Yuhki Koike
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Bo Li
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Niloofar Ganji
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Haitao Zhu
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Hiromu Miyake
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yong Chen
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Carol Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Maarten Janssen Lok
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Carlos Zozaya
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Ethan Lau
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Dorothy Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Sinobol Chusilp
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Zhen Zhang
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Masaya Yamoto
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Richard Y Wu
- Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Mikihiro Inoue
- Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Keiichi Uchida
- Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Masato Kusunoki
- Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Paul Delgado-Olguin
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.,Heart & Stroke Richard Lewar Centre of Excellence, Toronto, ON, Canada
| | - Luc Mertens
- The Labatt Family Heart Center, Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Alan Daneman
- Department of Diagnostic Imaging, Division of Nuclear Medicine, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Simon Eaton
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Philip M Sherman
- Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada.,Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
| | - Agostino Pierro
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada. .,Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada. .,Department of Surgery, University of Toronto, Toronto, ON, Canada.
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Weissman S, Sinh P, Mehta TI, Thaker RK, Derman A, Heiberger C, Qureshi N, Amrutiya V, Atoot A, Dave M, Tabibian JH. Atherosclerotic cardiovascular disease in inflammatory bowel disease: The role of chronic inflammation. World J Gastrointest Pathophysiol 2020; 11:104-113. [PMID: 32832194 PMCID: PMC7403753 DOI: 10.4291/wjgp.v11.i5.104] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/24/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) causes systemic vascular inflammation. The increased risk of venous as well as arterial thromboembolic phenomena in IBD is well established. More recently, a relationship between IBD and atherosclerotic cardiovascular disease (ASCVD) has been postulated. Systemic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have well characterized cardiac pathologies and treatments that focus on prevention of disease associated ASCVD. The impact of chronic inflammation on ASCVD in IBD remains poorly characterized. This manuscript aims to review and summarize the current literature pertaining to IBD and ASCVD with respect to its pathophysiology and impact of medications in order to encourage further research that can improve understanding and help develop clinical recommendations for prevention and management of ASCVD in patients with IBD.
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Affiliation(s)
- Simcha Weissman
- Department of Medicine, Hackensack Meridian Health Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Preetika Sinh
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Tej I Mehta
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57108, United States
| | - Rishi K Thaker
- Department of Medicine, New York Presbyterian, Brooklyn, NY 11215, United States
| | - Abraham Derman
- Department of Medicine, Mount Sinai-Saint Luke’s Roosevelt, NY 10025, United States
| | - Caleb Heiberger
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57108, United States
| | - Nabeel Qureshi
- Department of Medicine, Hackensack Meridian Health Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Viralkumar Amrutiya
- Department of Medicine, Hackensack Meridian Health Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Adam Atoot
- Department of Medicine, Hackensack Meridian Health Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Maneesh Dave
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, CA 95817, United States
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States
- David Geffen School of Medicine at UCLA, Los Angeles, CA 90001, United States
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46
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Ferreira-Duarte M, Sousa JB, Diniz C, Sousa T, Duarte-Araújo M, Morato M. Experimental and Clinical Evidence of Endothelial Dysfunction in Inflammatory Bowel Disease. Curr Pharm Des 2020; 26:3733-3747. [PMID: 32611296 DOI: 10.2174/1381612826666200701212414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.
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Affiliation(s)
| | | | - Carmen Diniz
- LAQV@REQUIMTE, University of Porto, Porto, Portugal
| | - Teresa Sousa
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
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47
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Liu XM, Chen QH, Hu Q, Liu Z, Wu Q, Liang SS, Zhang HG, Zhang Q, Zhang XK. Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades. Exp Mol Pathol 2020; 115:104444. [PMID: 32335082 DOI: 10.1016/j.yexmp.2020.104444] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/15/2020] [Accepted: 04/21/2020] [Indexed: 12/15/2022]
Abstract
Intestinal ischemia-reperfusion (I/R) is a life-threatening condition associated with high morbidity and mortality. Dexmedetomidine (DEX), an agonist of α2-adrenoceptor with sedation and analgesia effect, has recently been identified with protective function against I/R injury in multiple organs. However, the mechanism underlying the beneficial effect of DEX on intestine after I/R injury remained poorly understood. In the present study, using in both in vitro and in vivo models, we found that intestinal I/R injury was associated with the activation of p38 MAPK cascade, while DEX was capable of deactivating p38 MAPK and thus protect intestinal cells from apoptosis by inhibiting p38 MAPK-mediated mitochondrial depolarization and cytochrome c (Cyto C) release. Moreover, through inhibiting p38 MAPK activity, the downstream production of pro-inflammatory cytokines-regulated by NF-κB was also suppressed by DEX treatment, leading to the resolution of I/R-induced inflammation in intestine. In general, our study provided evidence that DEX protected intestine from I/R injury by inhibiting p38 MAPK-mediated mitochondrial apoptosis and inflammatory response.
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Affiliation(s)
- Xiao-Ming Liu
- Department of Thoracic Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Qiu-Hong Chen
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Qian Hu
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Zhen Liu
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Qiong Wu
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Si-Si Liang
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Huai-Gen Zhang
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Qin Zhang
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xue-Kang Zhang
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
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48
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Piovani D, Danese S, Peyrin-Biroulet L, Bonovas S. Environmental, Nutritional, and Socioeconomic Determinants of IBD Incidence: A Global Ecological Study. J Crohns Colitis 2020; 14:323-331. [PMID: 31504350 DOI: 10.1093/ecco-jcc/jjz150] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS The wide variation in inflammatory bowel disease [IBD] incidence across countries entails an opportunity to recognise global disease determinants and hypothesise preventive policies. METHODS We fitted multivariable models to identify putative environmental, nutritional, and socioeconomic determinants associated with the incidence of IBD (i.e. ulcerative colitis [UC] and Crohn's disease [CD]). We used the latest available country-specific incidence rates, and aggregate data for 20 determinants, from over 50 countries accounting for more than half of the global population. We presented the associations with exponentiated beta coefficients (exp[β]) indicating the relative increase of disease incidence per unit increase in the predictor variables. RESULTS Country-specific incidence estimates demonstrate wide variability across the world, with a median of 4.8 new UC cases (interquartile range [IQR] 2.4-9.3), and 3.5 new CD cases [IQR 0.8-5.7] per 100 000 population per year. Latitude (exp[β] 1.05, 95% confidence interval [CI] 1.04‒1.06, per degree increase), prevalence of obesity [1.05, 1.02‒1.07, per 1% increase], and of tobacco smoking [0.97, 0.95‒0.99, per 1% increase] explained 71.5% of UC incidence variation across countries in the adjusted analysis. The model for CD included latitude [1.04, 1.02‒1.06], expenditure for health (1.03, 1.01‒1.05, per 100 purchasing power parity [PPP]/year per capita increase), and physical inactivity prevalence [1.03, 1.00‒1.06, per 1% increase], explaining 58.3% of incidence variation across countries. Besides expenditure for health, these associations were consistent in low/middle- and high-income countries. CONCLUSIONS Our analysis highlights factors able to explain a substantial portion of incidence variation across countries. Further high-quality research is warranted to develop global strategies for IBD prevention.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and INSERM U954, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
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49
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Zhang J, Yu WQ, Wei T, Zhang C, Wen L, Chen Q, Chen W, Qiu JY, Zhang Y, Liang TB. Effects of Short-Peptide-Based Enteral Nutrition on the Intestinal Microcirculation and Mucosal Barrier in Mice with Severe Acute Pancreatitis. Mol Nutr Food Res 2020; 64:e1901191. [PMID: 31965752 DOI: 10.1002/mnfr.201901191] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 12/28/2019] [Indexed: 01/08/2023]
Abstract
SCOPE Short-peptide-based enteral nutrition (SPEN) is absorbed more efficiently in patients with severe acute pancreatitis (SAP). More importantly, SPEN decreases SAP-induced enterogenous infection risk. This study aims to investigate whether SPEN alleviates intestinal bacterial translocation in mice with SAP, and the underlying mechanisms. METHODS AND RESULTS The SAP model is established after pre-treatment with SPEN or intact-protein-based enteral nutrition. Although there is no improvement in pancreas injury, as evaluated through Hematoxylin-Eosin staining or serum amylase, SPEN obviously attenuates intestinal bacterial translocation after SAP. To unveil the mechanisms, it is found that the intestinal mechanical barrier destroyed by SAP is significantly relieved by SPEN, which presents with recovered ZO-1 expression, mucus layer, and goblet cell function. Additionally, SPEN alleviates local CCR6/CCL20 induced CD11c+ dendritic cell infiltration, systemic immunosuppression, and inhibits the secretion of luminal secretory immunoglobulin A. Possibly responsible for SAP-induced mucosal dysfunctions, destroyed intestinal mucosal microcirculation and local hypoxia are largely improved in SAP+SPEN group. CONCLUSION SPEN can improve downregulated intestinal mucosal microcirculation secondary to SAP, which may be responsible for mucosal inflammation relief, maintenance of the mechanical barrier and mucosal immunity, the correction of systemic immunosuppression, and play a protective role in defending commensal bacterial translocation after SAP.
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Affiliation(s)
- Jian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Wen-Qiao Yu
- Department of Surgical Intensive Care Unit, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Tao Wei
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Cheng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Liang Wen
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Jun-Yu Qiu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Yun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
| | - Ting-Bo Liang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou, 310009, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310009, Zhejiang, China
- Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310009, Zhejiang, China
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deZoeten EF, Battista KD, Colson SB, Lovell MA, Kessler BE, Isfort RW, Fennimore BP, Onyiah JC, Kao DJ, Yeckes A, Keely S, Murray M, Hoffenberg EJ, Colgan SP, Gerich ME. Markers of Hypoxia Correlate with Histologic and Endoscopic Severity of Colitis in Inflammatory Bowel Disease. HYPOXIA (AUCKLAND, N.Z.) 2020; 8:1-12. [PMID: 32104717 PMCID: PMC7026141 DOI: 10.2147/hp.s219049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 10/16/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Inflammation results in significant shifts in tissue metabolism. Recent studies indicate that inflammation and hypoxia occur concomitantly. We examined whether circulating and tissue markers of hypoxia could serve as surrogate indicators of disease severity in adult and pediatric patients with inflammatory bowel disease (IBD). METHODS Serum and colonic biopsies were obtained from pediatric subjects with active IBD colitis and adult subjects with active and inactive ulcerative colitis, along with healthy non-colitis controls of all ages. Disease activity was evaluated by endoscopy and histopathology. Levels of serum hypoxia markers (macrophage inflammatory protein-3α [MIP-3α], vascular endothelial growth factor [VEGF], and erythropoietin [EPO]) were measured. RESULTS Children with active IBD colitis had higher levels of serum MIP-3α and VEGF compared to non-colitis controls (p<0.01 and p<0.05, respectively). In adult subjects with endoscopically active ulcerative colitis, serum MIP-3α and EPO were significantly elevated compared to non-colitis controls (both p<0.01). In parallel, analysis of colon tissue MIP-3α mRNA and protein in pediatric subjects revealed increased expression in those with IBD colitis compared to controls (p<0.05 and p<0.01 for mRNA and protein, respectively). Serum MIP-3α and VEGF significantly increased with histology grade. CONCLUSION Peripheral blood hypoxia markers may be useful indicators of disease activity for pediatric and adult IBD patients.
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Affiliation(s)
- Edwin F deZoeten
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Kayla D Battista
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Steven B Colson
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Mark A Lovell
- Department of Pathology, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Brittelle E Kessler
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Robert W Isfort
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Blair P Fennimore
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Joseph C Onyiah
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Daniel J Kao
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Alyson Yeckes
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Simon Keely
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
| | - Monica Murray
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Edward J Hoffenberg
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Sean P Colgan
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mark E Gerich
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
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