|
1
|
Na HK, Li AA, Gottfried-Blackmore A, Podboy AJ, Esquivel MM, Joseph AA, Nguyen L, Hwang JH. Pyloric Dysfunction: A Review of the Mechanisms, Diagnosis, and Treatment. Gut Liver 2025; 19:327-345. [PMID: 40058793 PMCID: PMC12070220 DOI: 10.5009/gnl240421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/04/2024] [Accepted: 11/06/2024] [Indexed: 05/14/2025] Open
Abstract
Pyloric dysfunction is defined as hypertonia or spasm of the pyloric sphincter. The pylorus plays a key role in gastric emptying, but its function remains incompletely understood. Most studies have focused on gastroparesis regardless of the underlying pathophysiology. Few studies have reported pyloric dysfunction in patients with gastroparesis, and the diagnostic and treatment modalities for pyloric dysfunction are not well established. Recently developed diagnostic modalities assessing pyloric function, such as high-resolution antroduodenal manometry and endoluminal functional lumen imaging, are currently being evaluated. A variety of therapeutic interventions targeting the pylorus, including pharmacologic agents, intrapyloric botulinum injection, endoscopic balloon dilation, stent insertion, surgical pyloroplasty, and gastric peroral endoscopic pyloromyotomy, have been proposed. Among these, gastric peroral endoscopic pyloromyotomy has emerged as a novel, minimally invasive therapy with demonstrated efficacy and safety for refractory gastroparesis. This article reviews the pathophysiology of pyloric dysfunction and the potential diagnostic and therapeutic modalities based on the latest literature.
Collapse
Affiliation(s)
- Hee Kyong Na
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Andrew A. Li
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Andres Gottfried-Blackmore
- Department of Pharmacology and Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Alexander J. Podboy
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA
| | - Micaela M. Esquivel
- Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Abel A. Joseph
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Linda Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joo Ha Hwang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
2
|
Ohishi K, Rahman AA, Ohkura T, Burns AJ, Goldstein AM, Hotta R. Effects of aged garlic extract on aging?related changes in gastrointestinal function and enteric nervous system cells. Exp Ther Med 2025; 29:103. [PMID: 40171138 PMCID: PMC11959352 DOI: 10.3892/etm.2025.12853] [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: 11/26/2024] [Accepted: 02/05/2025] [Indexed: 04/03/2025] Open
Abstract
Dysmotility of the gastrointestinal (GI) tract is commonly seen in elderly individuals, where it causes significant morbidity and can lead to more severe conditions, including sarcopenia and frailty. Although the precise mechanisms underlying aging-related GI dysmotility are not fully understood, neuronal loss or degeneration in the enteric nervous system (ENS) may be involved. Aged garlic extract (AGE) has been shown to have several beneficial effects in the GI tract; however, it is not known whether AGE can improve GI motility in older animals. The aim of the present study was to examine the effects of AGE on the ENS and gut motility in older mice and elucidate potential mechanisms of action. An AGE-formulated diet was given to 18-month-old female mice for 2 weeks. Organ bath studies and cell culture demonstrated that AGE: i) Altered gut contractile activity; ii) enhanced viability of ENS cells; and iii) exhibited neuroprotective effects on the ENS via reduction in oxidative stress. These findings suggest that AGE could be used to develop novel dietary therapeutics for aging-related GI dysmotility by targeting the associated loss and damage of the ENS.
Collapse
Affiliation(s)
- Kensuke Ohishi
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Hiroshima 739-1195, Japan
| | - Ahmed A. Rahman
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Takahiro Ohkura
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Alan J. Burns
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Allan M. Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| |
Collapse
|
|
3
|
Cable TG, Funnell MP, Reynolds KM, Hudson EF, Macrae HZ, Johnson DA, Taylor L, Heaney LM, Mears SA, Bailey SJ, James LJ. 7 days of L-citrulline supplementation does not improve running performance in the heat whilst in a hypohydrated state. Eur J Appl Physiol 2025; 125:1411-1421. [PMID: 39699639 PMCID: PMC12055621 DOI: 10.1007/s00421-024-05671-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024]
Abstract
PURPOSE 7 days L-citrulline supplementation has been reported to improve blood pressure, V . O2 kinetics, gastrointestinal (GI) perfusion and endurance cycling performance through increasing arterial blood flow. In situations where blood volume is compromised (e.g., hyperthermia/hypohydration), L-citrulline may improve thermoregulation and exercise performance by redistributing blood flow to aid heat loss and/or muscle function. This study assessed 7 days L-citrulline supplementation on running performance in the heat, whilst mildly hypohydrated. METHODS 13 endurance runners (2 female, 31 ± 8 y, V . O2peak 60 ± 6 mL/kg/min) participated in a randomised crossover study with 7 days L-citrulline (CIT; 6 g/d) or placebo (maltodextrin powder; PLA) supplementation. Participants completed a 50 min running 'preload' at 65% V . O2peak (32 °C, 50% relative humidity) to induce hyperthermia and hypohydration before a 3 km running time trial (TT). Body mass and blood samples were collected at baseline, pre-preload, post-preload and post-TT, whilst core and skin temperature, heart rate and perceptual responses were collected periodically throughout. RESULTS TT performance was not different between trials (CIT 865 ± 142 s; PLA 892 ± 154 s; P = 0.437). Core and skin temperature and heart rate (P ≥ 0.270), hydration (sweat rate, plasma volume, osmolality) indices (P ≥ 0.216), GI damage (P ≥ 0.260) and perceptual responses (P ≥ 0.610) were not different between trials during the preload and TT. CONCLUSIONS 7 days of L-citrulline supplementation had no effect on 3 km running performance in the heat or any effects on thermoregulation or GI damage in trained runners in a hypohydrated state.
Collapse
Affiliation(s)
- Thomas G Cable
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Mark P Funnell
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
- NIHR Applied Research Collaboration East Midlands, Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Kirsty M Reynolds
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | | | - Heather Z Macrae
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Drusus A Johnson
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Lee Taylor
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
- University of Technology Sydney, Sydney, NSW, Australia
| | - Liam M Heaney
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Stephen A Mears
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Stephen J Bailey
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Lewis J James
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester, UK.
| |
Collapse
|
|
4
|
Liu H, Yao K, Hu M, Li S, Yang S, Zhao A. On-Chip Electrochemical Sensor Based on 3D Graphene Assembly Decorated Ultrafine RuCu Alloy Nanocatalyst for In Situ Detection of NO in Living Cells. NANOMATERIALS (BASEL, SWITZERLAND) 2025; 15:417. [PMID: 40137592 PMCID: PMC11946219 DOI: 10.3390/nano15060417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/28/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025]
Abstract
In this work, we developed 3D ionic liquid (IL) functionalized graphene assemblies (GAs) decorated by ultrafine RuCu alloy nanoparticles (RuCu-ANPs) via a one-step synthesis process, and integrated it into a microfluidic sensor chip for in situ electrochemical detection of NO released from living cells. Our findings have demonstrated that RuCu-ANPs on 3D IL-GA exhibit high density, uniform distribution, lattice-shaped arrangement of atoms, and extremely ultrafine size, and possess high electrocatalytic activity to NO oxidation on the electrode. Meanwhile, the 3D IL-GA with hierarchical porous structures can facilitate the efficient electron/mass transfer at the electrode/electrolyte interface and the cell culture. Moreover, the graft of IL molecules on GA endows it with high hydrophilicity for facile and well-controllable printing on the electrode. Consequently, the resultant electrochemical microfluidic sensor demonstrated excellent sensing performances including fast response time, high sensitivity, good anti-interference ability, high reproducibility, long-term stability, as well as good biocompatibility, which can be used as an on-chip sensing system for cell culture and real-time in situ electrochemical detection of NO released from living cells with accurate and stable characteristics in physiological conditions.
Collapse
Affiliation(s)
- Haibo Liu
- Technology Inspection Center of ShengLi Oil Filed, China Petrochemical Corporation, Dongying 257000, China;
| | - Kaiyuan Yao
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471003, China;
| | - Min Hu
- Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan 430074, China (S.L.); (S.Y.)
| | - Shanting Li
- Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan 430074, China (S.L.); (S.Y.)
| | - Shengxiong Yang
- Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan 430074, China (S.L.); (S.Y.)
| | - Anshun Zhao
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471003, China;
| |
Collapse
|
|
5
|
Bakshi J, Mishra KP. Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells. Cell Immunol 2025; 408:104912. [PMID: 39729961 DOI: 10.1016/j.cellimm.2024.104912] [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: 09/17/2024] [Revised: 12/13/2024] [Accepted: 12/20/2024] [Indexed: 12/29/2024]
Abstract
The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.
Collapse
Affiliation(s)
- Jyotsana Bakshi
- Defence Institute of Physiology and Allied Sciences, Delhi 110054, India
| | - K P Mishra
- Defence Institute of Physiology and Allied Sciences, Delhi 110054, India.
| |
Collapse
|
|
6
|
Birmann PT, Sinott A, Zugno GP, Rodrigues RR, Conceição FR, Sousa FSS, Collares T, Seixas FK, Savegnago L. The antidepressant effect of Komagataella pastoris KM 71 H in maternal separation mice model mediated by the microbiota-gut-brain axis. Behav Brain Res 2025; 476:115287. [PMID: 39393682 DOI: 10.1016/j.bbr.2024.115287] [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: 06/06/2024] [Revised: 09/16/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024]
Abstract
BACKGROUND The intestinal microbiota plays a fundamental role in maintaining host health, especially during childhood, a critical period for its establishment. Early life stress can lead to shifts in gut microbiota composition, thus increasing the risk of major depressive disorder (MDD) in adulthood. The supplementation with probiotics restores intestinal permeability and the health of gut microbial communities, therefore being potential study targets for the treatment of MDD. In this sense, the yeast Komagataella pastoris was reported as a promising probiotic with antidepressant effect. METHODS Hence, the present study aims to investigate this effect in mice submitted to maternal separation (MS) 3 h per day from PND2 to PND14. Adult mice and mothers were treated with K. pastoris KM71H (8 log UFC.g-1/per animal, i.g.) or PBS (500 µl, i.g.) for 14 days. After behavioral tests, the animals were euthanized, followed by hippocampi and intestines removal for biochemical analysis. RESULTS On behavioral tests, K. pastoris KM71H treatment reduced the immobility time in TST of adult mice and increased the grooming activity in splash test of adult mice and mothers induced by MS. The probiotic treatment restored plasma corticosterone levels and glucocorticoid receptor expression in hippocampi, alongside nitrate/nitrite levels and superoxide dismutase activity in intestine, in addition to reducing reactive species levels in both structures. Moreover, it also normalized the fecal pH and water content of feces. CONCLUSION Thus, we conclude that K. pastoris KM71H is a promising therapeutic strategy for the treatment of MDD.
Collapse
Affiliation(s)
- Paloma T Birmann
- Neurobiotechnology Research Group, Postgraduate Program in Biotechnology, Technologic Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Airton Sinott
- Neurobiotechnology Research Group, Postgraduate Program in Biotechnology, Technologic Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Giuliana P Zugno
- Neurobiotechnology Research Group, Postgraduate Program in Biotechnology, Technologic Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Rafael R Rodrigues
- Applied Immunology Laboratory, Postgraduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Fabricio R Conceição
- Applied Immunology Laboratory, Postgraduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Fernanda S S Sousa
- Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Postgraduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Tiago Collares
- Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Postgraduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Fabiana K Seixas
- Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Postgraduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Lucielli Savegnago
- Neurobiotechnology Research Group, Postgraduate Program in Biotechnology, Technologic Development Center, Federal University of Pelotas, Pelotas, RS, Brazil.
| |
Collapse
|
|
7
|
Scull CE, Hu Y, Jennings S, Wang G. Normalization of Cystic Fibrosis Immune System Reverses Intestinal Neutrophilic Inflammation and Significantly Improves the Survival of Cystic Fibrosis Mice. Cell Mol Gastroenterol Hepatol 2024; 19:101424. [PMID: 39510500 PMCID: PMC11720009 DOI: 10.1016/j.jcmgh.2024.101424] [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: 03/19/2024] [Revised: 10/24/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND & AIMS Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis. METHODS CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction. RESULTS Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice. CONCLUSIONS CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.
Collapse
Affiliation(s)
- Callie E Scull
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Yawen Hu
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Scott Jennings
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Guoshun Wang
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
| |
Collapse
|
|
8
|
Haynes J, Palaniappan B, Crutchley JM, Sundaram U. Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers. Cells 2024; 13:1623. [PMID: 39404387 PMCID: PMC11482628 DOI: 10.3390/cells13191623] [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: 08/26/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/19/2024] Open
Abstract
In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, whether NHE3 and SGLT1 regulate one another in normal human enterocytes is unknown, mainly due to a lack of appropriate experimental models. To investigate this, we generated 2D enterocyte monolayers from human jejunal 3D organoids and used small interfering RNAs (siRNAs) to knock down NHE3 or SGLT1. Molecular and uptake studies were performed to determine the effects on NHE3 and SGLT1 expression and activity. Knockdown of NHE3 by siRNA in enterocyte monolayers was verified by qPCR and Western blot analysis and resulted in reduced NHE3 activity. However, in NHE3 siRNA-transfected cells, SGLT1 activity was significantly increased. siRNA knockdown of SGLT1 was confirmed by qPCR and Western blot analysis and resulted in reduced SGLT1 activity. However, in SGLT1 siRNA-transfected cells, NHE3 activity was significantly increased. These results demonstrate for the first time the functionality of siRNA in patient-derived organoid monolayers. Furthermore, they show that the two primary Na absorptive pathways in human enterocytes reciprocally regulate one another.
Collapse
Affiliation(s)
| | | | | | - Uma Sundaram
- Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA
| |
Collapse
|
|
9
|
Kerstens R, Ng YZ, Pettersson S, Jayaraman A. Balancing the Oral-Gut-Brain Axis with Diet. Nutrients 2024; 16:3206. [PMID: 39339804 PMCID: PMC11435118 DOI: 10.3390/nu16183206] [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: 08/04/2024] [Revised: 09/14/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Background: The oral microbiota is the second largest microbial community in humans. It contributes considerably to microbial diversity and health effects, much like the gut microbiota. Despite physical and chemical barriers separating the oral cavity from the gastrointestinal tract, bidirectional microbial transmission occurs between the two regions, influencing overall host health. Method: This review explores the intricate interplay of the oral-gut-brain axis, highlighting the pivotal role of the oral microbiota in systemic health and ageing, and how it can be influenced by diet. Results: Recent research suggests a relationship between oral diseases, such as periodontitis, and gastrointestinal problems, highlighting the broader significance of the oral-gut axis in systemic diseases, as well as the oral-gut-brain axis in neurological disorders and mental health. Diet influences microbial diversity in the oral cavity and the gut. While certain diets/dietary components improve both gut and oral health, others, such as fermentable carbohydrates, can promote oral pathogens while boosting gut health. Conclusions: Understanding these dynamics is key for promoting a healthy oral-gut-brain axis through dietary interventions that support microbial diversity and mitigate age-related health risks.
Collapse
Affiliation(s)
- Rebecca Kerstens
- ASEAN Microbiome Nutrition Centre, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
| | - Yong Zhi Ng
- ASEAN Microbiome Nutrition Centre, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
- Duke-NUS Medical School, 8 College Rd., Singapore 169857, Singapore
| | - Sven Pettersson
- ASEAN Microbiome Nutrition Centre, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
- Faculty of Medical Sciences, Sunway University, Subang Jaya 47500, Selangor, Malaysia
- Department of Microbiology and Immunology, National University Singapore, Singapore 117545, Singapore
| | - Anusha Jayaraman
- ASEAN Microbiome Nutrition Centre, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
| |
Collapse
|
|
10
|
Flores JA, Antonio JM, Suntornsaratoon P, Meadows V, Bandyopadhyay S, Han J, Singh R, Balasubramanian I, Upadhyay R, Liu Y, Bonder EM, Kiela P, Su X, Ferraris R, Gao N. The arginine and nitric oxide metabolic pathway regulate the gut colonization and expansion of Ruminococcous gnavus. J Biol Chem 2024; 300:107614. [PMID: 39089585 PMCID: PMC11387683 DOI: 10.1016/j.jbc.2024.107614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 08/04/2024] Open
Abstract
Ruminococcus gnavus is a mucolytic commensal bacterium whose increased gut colonization has been associated with chronic inflammatory and metabolic diseases in humans. Whether R. gnavus metabolites can modulate host intestinal physiology remains largely understudied. We performed untargeted metabolomic and bulk RNA-seq analyses using R. gnavus monocolonization in germ-free mice. Based on transcriptome-metabolome correlations, we tested the impact of specific arginine metabolites on intestinal epithelial production of nitric oxide (NO) and examined the effect of NO on the growth of various strains of R. gnavus in vitro and in nitric oxide synthase 2 (Nos2)-deficient mice. R. gnavus produces specific arginine, tryptophan, and tyrosine metabolites, some of which are regulated by the environmental richness of sialic acid and mucin. R. gnavus colonization promotes expression of amino acid transporters and enzymes involved in metabolic flux of arginine and associated metabolites into NO. R. gnavus induced elevated levels of NOS2, while Nos2 ablation resulted in R. gnavus expansion in vivo. The growth of various R. gnavus strains can be inhibited by NO. Specific R. gnavus metabolites modulate intestinal epithelial cell NOS2 abundance and reduce epithelial barrier function at higher concentrations. Intestinal colonization and interaction with R. gnavus are partially regulated by an arginine-NO metabolic pathway, whereby a balanced control by the gut epithelium may restrain R. gnavus growth in healthy individuals. Disruption in this arginine metabolic regulation will contribute to the expansion and blooming of R. gnavus.
Collapse
Affiliation(s)
- Juan A Flores
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | - Jayson M Antonio
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Panan Suntornsaratoon
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Vik Meadows
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA; Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | | | - Jiangmeng Han
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA; Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Rajbir Singh
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | | | - Ravij Upadhyay
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
| | - Yue Liu
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | - Edward M Bonder
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA
| | - Pawel Kiela
- Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children's Research Center, Department of Pediatrics, University of Arizona, Tucson, Arizona, USA
| | - Xiaoyang Su
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
| | - Ronaldo Ferraris
- Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA; Department of Pharmacology, Physiology and Neurosciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
| |
Collapse
|
|
11
|
Ran Q, Li A, Tan Y, Zhang Y, Zhang Y, Chen H. Action and therapeutic targets of myosin light chain kinase, an important cardiovascular signaling mechanism. Pharmacol Res 2024; 206:107276. [PMID: 38944220 DOI: 10.1016/j.phrs.2024.107276] [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: 05/18/2024] [Accepted: 06/19/2024] [Indexed: 07/01/2024]
Abstract
The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.
Collapse
Affiliation(s)
- Qingzhi Ran
- Guang'anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing 100070, China
| | - Aoshuang Li
- Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100053, China
| | - Yuqing Tan
- Guang'anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing 100070, China
| | - Yue Zhang
- Guang'anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing 100070, China.
| | - Yongkang Zhang
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
| | - Hengwen Chen
- Guang'anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing 100070, China.
| |
Collapse
|
|
12
|
Apte A, Bardill JR, Canchis J, Skopp SM, Fauser T, Lyttle B, Vaughn AE, Seal S, Jackson DM, Liechty KW, Zgheib C. Targeting Inflammation and Oxidative Stress to Improve Outcomes in a TNBS Murine Crohn's Colitis Model. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:894. [PMID: 38786849 PMCID: PMC11124096 DOI: 10.3390/nano14100894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/15/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024]
Abstract
Inflammation and oxidative stress are implicated in the pathogenesis of Crohn's disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn's disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn's colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.
Collapse
Affiliation(s)
- Anisha Apte
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, Tucson, AZ 85721, USA (K.W.L.)
| | - James R. Bardill
- Department of Surgery, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA; (J.R.B.)
| | - Jimena Canchis
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, Tucson, AZ 85721, USA (K.W.L.)
| | - Stacy M. Skopp
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, Tucson, AZ 85721, USA (K.W.L.)
| | - Tobias Fauser
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, Tucson, AZ 85721, USA (K.W.L.)
| | - Bailey Lyttle
- Department of Surgery, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA; (J.R.B.)
| | - Alyssa E. Vaughn
- Department of Surgery, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA; (J.R.B.)
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center, University of Central Florida, Orlando, FL 32827, USA
| | | | - Kenneth W. Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, Tucson, AZ 85721, USA (K.W.L.)
- Ceria Therapeutics, Inc., Tucson, AZ 85721, USA
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, Tucson, AZ 85721, USA (K.W.L.)
- Ceria Therapeutics, Inc., Tucson, AZ 85721, USA
| |
Collapse
|
|
13
|
Behmanesh MA, Rasekhian A, Kiani F, Dehghandoost M, Dezfuli DA, Ghorbanzadeh B. The nitric oxide-cyclic GMP-K ATP channels pathway contributes to the effects of montelukast against gastric damage induced by ethanol. Alcohol 2023; 113:33-40. [PMID: 37295565 DOI: 10.1016/j.alcohol.2023.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 03/12/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023]
Abstract
The leukotrienes, lipid mediators, have a role in gastric damage induced by ethanol. Here, the gastroprotective effect of montelukast, an antagonist of the leukotriene receptor, and the involvement of the NO-cGMP-KATP channel pathway, were evaluated in gastric damage induced by ethanol in rats. For this, l-arginine, l-NAME, methylene blue (guanylate cyclase inhibitor), sildenafil, diazoxide, or glibenclamide (ATP-sensitive potassium channel blocker) were administered 30 min before montelukast (0.1, 1, 10, and 20 mg/kg, by mouth [p.o.]). After 1 h, to induce gastric damage, the rats received absolute ethanol (4 mL/kg, p.o.), and then microscopic, macroscopic, and pro-inflammatory parameters (TNF-α and IL-1β) were assessed. Results obtained here revealed that montelukast significantly attenuated the macroscopic and microscopic lesions induced by ethanol. Montelukast also reduced IL-1β and TNF-α levels. It was also observed that NOS inhibitor (l-NAME), methylene blue, and glibenclamide inhibited the effects of montelukast in the stomach. Moreover, the NO precursor (l-arginine), the PDE-5 inhibitor (sildenafil), and a potassium channel opener (diazoxide) before montelukast produced gastroprotective effects. In conclusion, the effect of montelukast against gastric lesions induced by ethanol is mediated, at least in part, through the pathway of the NO-cGMP-KATP channel.
Collapse
Affiliation(s)
- Mohammad Amin Behmanesh
- Department of Histology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Amin Rasekhian
- Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Forutan Kiani
- Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Mostafa Dehghandoost
- Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | | | - Behnam Ghorbanzadeh
- Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran.
| |
Collapse
|
|
14
|
Bulc M, Całka J, Palus K. Changes in the Phenotype of Intramural Inhibitory Neurons of the Porcine Descending Colon Resulting from Glyphosate Administration. Int J Mol Sci 2023; 24:16998. [PMID: 38069321 PMCID: PMC10707063 DOI: 10.3390/ijms242316998] [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: 11/08/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Environmental contamination and the resulting food contamination represent a serious problem and pose a major threat to animal and human health. The gastrointestinal tract is directly exposed to a variety of substances. One is glyphosate, whose presence in the soil is commonly observed. This study demonstrates the effects of low and high glyphosate doses on the populations of intramural neurons of the porcine descending colon. An analysis was performed on neurons ex-pressing the vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, a neuronal isoform of nitrogen oxide synthase, and galanin. Even a low dose of glyphosate increased the number of neurons immunoreactive against the studied substances. However, the changes depended on both the plexus analysed and the substance tested. Meanwhile, a high glyphosate dose resulted in quantitative changes (an increase in the number) within neurons immunoreactive against all the studied neuropeptides/enzymes in the myenteric plexus and both submucosal plexuses. The response of the enteric nervous system in the form of an increase in the number of neurons immunoreactive against neuroprotective substances may suggest that glyphosate has a toxic effect on enteric neurons which attempt to increase their survivability through the released neuroprotective substances.
Collapse
Affiliation(s)
- Michał Bulc
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowski Str. 13, 10-718 Olsztyn, Poland; (J.C.); (K.P.)
| | | | | |
Collapse
|
|
15
|
Madka V, Patlolla JMR, Venkatachalam K, Zhang Y, Pathuri G, Stratton N, Lightfoot S, Janakiram NB, Mohammed A, Rao CV. Chemoprevention of Colon Cancer by DFMO, Sulindac, and NO-Sulindac Administered Individually or in Combinations in F344 Rats. Cancers (Basel) 2023; 15:4001. [PMID: 37568816 PMCID: PMC10417047 DOI: 10.3390/cancers15154001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs' associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% (p < 0.0001) and 51% (p < 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%, p = 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%, p < 0.0001; 50% p < 0.0004), and multiplicity (81%, p < 0.0001; 62%, p < 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and β-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone.
Collapse
Affiliation(s)
- Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Jagan M. R. Patlolla
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Karthikkumar Venkatachalam
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Yuting Zhang
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Gopal Pathuri
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Nicole Stratton
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Stanley Lightfoot
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
| | - Naveena B. Janakiram
- Translational Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA
| | - Altaf Mohammed
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20850, USA
| | - Chinthalapally V. Rao
- Center for Cancer Prevention and Drug Development, Department of Internal Medicine, Hem-Onc Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (V.M.)
- VA Medical Center, Oklahoma City, OK 73104, USA
| |
Collapse
|
|
16
|
Lu J, Shi T, Shi C, Chen F, Yang C, Xie X, Wang Z, Shen H, Xu J, Leong KW, Shao D. Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis. RESEARCH (WASHINGTON, D.C.) 2023; 6:0204. [PMID: 37533463 PMCID: PMC10393581 DOI: 10.34133/research.0204] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/11/2023] [Indexed: 08/04/2023]
Abstract
The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.
Collapse
Affiliation(s)
- Junna Lu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangdong 510006, China
| | - Tongfei Shi
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangdong 510006, China
| | - Chengxin Shi
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital of Zhejiang University, Hangzhou 310000, China
| | - Fangman Chen
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
| | - Chao Yang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Xiaochun Xie
- School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Zheng Wang
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and NanoBionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - He Shen
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and NanoBionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Jiaqi Xu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Kam W Leong
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Dan Shao
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangdong 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangdong 510006, China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China
| |
Collapse
|
|
17
|
Pitrone P, Cattafi A, Magnani F, Carerj ML, Bellone IG, Nirta G, Monsù E, Bonanno D, Trimarchi R, La Face A, Marino MA, Sofia C. Erratum: Spontaneous transverse colon volvulus in a patient with Duchenne muscular dystrophy: An unreported complication. Radiol Case Rep 2023; 18:2318-2322. [PMID: 37153484 PMCID: PMC10159818 DOI: 10.1016/j.radcr.2023.03.027] [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] [Indexed: 05/09/2023] Open
Abstract
[This corrects the article DOI: 10.1016/j.radcr.2022.12.062.][This corrects the article DOI: 10.1016/j.radcr.2023.03.026.].
Collapse
Affiliation(s)
- Pietro Pitrone
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
- Corresponding author.
| | - Antonino Cattafi
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Francesca Magnani
- Department of Radiodiagnostic, Oncologic Radiotherapy and Ematology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go A. F.Vito 1 Gemelli 8, 00168, Rome, Italy
| | - Maria Ludovica Carerj
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Italo Giuseppe Bellone
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Giuseppe Nirta
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Enrico Monsù
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Dora Bonanno
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Renato Trimarchi
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Alessandro La Face
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Maria Adele Marino
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| | - Carmelo Sofia
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy
| |
Collapse
|
|
18
|
Palus K, Bulc M, Całka J. Glyphosate affects the neurochemical phenotype of the intramural neurons in the duodenum in the pig. Neurogastroenterol Motil 2023; 35:e14507. [PMID: 36502523 DOI: 10.1111/nmo.14507] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 10/26/2022] [Accepted: 11/23/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Glyphosate-based herbicides have been one of the most intensively used pollutants worldwide and food products containing glyphosate are an essential component of human and animal diet. The aim of present study was to determine the effect of glyphosate intoxication on the neurochemical properties of the enteric nervous system (ENS) neurons located in the wall of the porcine duodenum. METHODS Fifteen sexually immature gilts divided into 3 groups were used: control-animals receiving empty gelatin capsules; G1-animals receiving a low dose of glyphosate-corresponding to the theoretical maximum daily intake (TMDI) - 0.05 mg/kg bw/day; G2-animals receiving a higher dose of glyphosate-corresponding to the acceptable daily intake (ADI)-0.5 mg/kg/day in gelatin capsules orally for 28 days. After this time, the animals were euthanized and small intestine samples were collected. Frozen sections were then subjected to the procedure of double immunofluorescent staining. KEY RESULTS Glyphosate supplementation led to alterations in the neurochemical code of the ENS neurons in the porcine duodenum. Generally, increased population of neurons immunoreactive to PACAP, CGRP, CART, nNOS, and a decreased number of VAChT-like immunoreactive neurons were noted. CONCLUSIONS AND INFERENCES It may be a first preclinical symptom of digestive tract dysfunction in the course of glyphosate intoxication and further studies are needed to assess the toxicity and risks of glyphosate to humans.
Collapse
Affiliation(s)
- Katarzyna Palus
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Michał Bulc
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Jarosław Całka
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| |
Collapse
|
|
19
|
Li T, Morselli M, Su T, Million M, Larauche M, Pellegrini M, Taché Y, Yuan PQ. Comparative transcriptomics reveals highly conserved regional programs between porcine and human colonic enteric nervous system. Commun Biol 2023; 6:98. [PMID: 36693960 PMCID: PMC9872754 DOI: 10.1038/s42003-023-04478-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023] Open
Abstract
The porcine gut is increasingly regarded as a useful translational model. The enteric nervous system in the colon coordinates diverse functions. However, knowledge of the molecular profiling of porcine enteric nerve system and its similarity to that of human is still lacking. We identified the distinct transcriptional programs associated with functional characteristics between inner submucosal and myenteric ganglia in porcine proximal and distal colon using bulk RNA and single-cell RNA sequencing. Comparative transcriptomics of myenteric ganglia in corresponding colonic regions of pig and human revealed highly conserved programs in porcine proximal and distal colon, which explained >96% of their transcriptomic responses to vagal nerve stimulation, suggesting that porcine proximal and distal colon could serve as predictors in translational studies. The conserved programs specific for inflammatory modulation were displayed in pigs with vagal nerve stimulation. This study provides a valuable transcriptomic resource for understanding of human colonic functions and neuromodulation using porcine model.
Collapse
Affiliation(s)
- Tao Li
- CURE/Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, USA
| | - Marco Morselli
- Department of Molecular, Cell, & Developmental Biology, UCLA, Los Angeles, USA
| | - Trent Su
- Department of Biological Chemistry, UCLA, Los Angeles, USA
| | - Mulugeta Million
- CURE/Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, USA
| | - Muriel Larauche
- CURE/Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell, & Developmental Biology, UCLA, Los Angeles, USA
| | - Yvette Taché
- CURE/Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, USA
| | - Pu-Qing Yuan
- CURE/Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, USA.
- VA Greater Los Angeles Healthcare System, Los Angeles, USA.
| |
Collapse
|
|
20
|
Pitrone P, Cattafi A, Magnani F, Carerj ML, Bellone IG, Nirta G, Monsù E, Bonanno D, Trimarchi R, La Face A, Marino MA, Sofia C. Spontaneous transverse colon volvulus in a patient with Duchenne muscular dystrophy: An unreported complication. Radiol Case Rep 2023; 18:1306-1310. [PMID: 36698720 PMCID: PMC9868232 DOI: 10.1016/j.radcr.2022.12.062] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/19/2023] Open
Abstract
A 22-year-old male patient with Duchenne muscular dystrophy (DMD) and chronic constipation presents to the emergency room with severe abdominal pain and hive closed to feces and gas. Contrast-enhanced computed tomography of the abdomen demonstrates mechanical ileus due to volvulus of the transverse colon: torsion of the transverse mesocolon is confirmed and subtotaly colectomy is performed, revealing multiple ischemic areas with focal perforations. DMD is frequently associated with gastrointestinal motility disorders, including chronic constipation and life-threatening conditions like intestinal pseudo-obstruction and sigmoid volvulus. To date, transverse colic localization of volvolus represents an unreported condition among patients with DMD.
Collapse
Affiliation(s)
- Pietro Pitrone
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy,Corresponding author.
| | - Antonino Cattafi
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Francesca Magnani
- Department of Radiodiagnostic, Oncologic Radiotherapy and Ematology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go A. F.Vito 1 Gemelli 8, 00168, Rome, Italy
| | - Maria Ludovica Carerj
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Italo Giuseppe Bellone
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Giuseppe Nirta
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Enrico Monsù
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Dora Bonanno
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Renato Trimarchi
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Alessandro La Face
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Maria Adele Marino
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| | - Carmelo Sofia
- Section of Radiological Sciences, Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico ``G. Martino'' Via Consolare Valeria 1, 98100, Messina, Italy
| |
Collapse
|
|
21
|
Makowska K, Całka J, Gonkowski S. Effects of the long-term influence of bisphenol A and bisphenol S on the population of nitrergic neurons in the enteric nervous system of the mouse stomach. Sci Rep 2023; 13:331. [PMID: 36609592 PMCID: PMC9822927 DOI: 10.1038/s41598-023-27511-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Bisphenol A (BPA) is an endocrine disruptor commonly used in the production of plastics. Due to its relatively well-known harmful effects on living organisms, BPA is often replaced by its various analogues. One of them is bisphenol S (BPS), widely used in the plastics industry. Until recently, BPS was considered completely safe, but currently, it is known that it is not safe for various internal organs. However, knowledge about the influence of BPS on the nervous system is scarce. Therefore, the aim of this study was to investigate the influence of two doses of BPA and BPS on the enteric nitrergic neurons in the CD1 strain mouse stomach using the double-immunofluorescence technique. The study found that both substances studied increased the number of nitrergic neurons, although changes under the impact of BPS were less visible than those induced by BPA. Therefore, the obtained results, for the first time, clearly indicate that BPS is not safe for the innervation of the gastrointestinal tract.
Collapse
Affiliation(s)
- Krystyna Makowska
- Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-957, Olsztyn, Poland.
| | - Jarosław Całka
- grid.412607.60000 0001 2149 6795Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland
| | - Sławomir Gonkowski
- grid.412607.60000 0001 2149 6795Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland
| |
Collapse
|
|
22
|
Sakiani S, Heller T, Koh C. Current and investigational drugs in early clinical development for portal hypertension. Front Med (Lausanne) 2022; 9:974182. [PMID: 36300180 PMCID: PMC9589453 DOI: 10.3389/fmed.2022.974182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients. Areas covered Multiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field. Methodology Published studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including "portal hypertension" as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included. Conclusion Many ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.
Collapse
Affiliation(s)
- Sasan Sakiani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Baltimore, MD, United States
| | - Theo Heller
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Koh
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
|
23
|
Regulation of nutrient and electrolyte absorption in human organoid-derived intestinal epithelial cell monolayers. Transl Res 2022; 248:22-35. [PMID: 35513245 DOI: 10.1016/j.trsl.2022.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/29/2022] [Accepted: 04/26/2022] [Indexed: 11/23/2022]
Abstract
Recently developed human intestinal epithelial 3D organoid cultures are a useful cell culture model to study intestinal transport physiology. From these, 2D monolayer cultures can be generated in which apical transporters are exposed to the medium, thereby better facilitating in vitro investigation of intestinal absorption processes. However, whether nutrient and electrolyte absorption can be physiologically regulated in human organoid-derived monolayers has not been determined. Constitutive nitric oxide (cNO) is known to regulate multiple gastrointestinal physiological functions. Previous studies using in vivo and in vitro mammalian animal models indicate that enhanced intracellular cNO differentially regulates the two primary apical Na transporters in small intestinal epithelial cells. Here, we generated human jejunal organoid-derived monolayers to determine whether apical nutrient and electrolyte transporter function is regulated by cNO in human enterocytes. Western blot analysis and immunocytochemical staining showed that organoid-derived 2D cultures express markers of enterocyte differentiation and form intact monolayers of apical-basal polarized epithelial cells. Uptake studies demonstrated that jejunal monolayers exhibit functional activity of Na-glucose cotransporter 1 (SGLT1; SLC5A1) and Na-H exchanger 3 (NHE3; SLC9A3). In response to physiological increases in cNO, the two primary apical Na transporters were differentially regulated in human intestinal organoid-derived monolayers, across multiple human specimens. An increase in cNO stimulated SGLT1, while NHE3 was inhibited. These results are similar to what is seen in vivo and in vitro in different animal intestinal models. Thus, human jejunal organoid-derived monolayers are an ideal in vitro model to better understand how intestinal nutrient absorption is regulated.
Collapse
|
|
24
|
Sui C, Tao L, Bai C, Shao L, Miao J, Chen K, Wang M, Hu Q, Wang F. Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types. Front Pharmacol 2022; 13:929901. [PMID: 35991871 PMCID: PMC9385171 DOI: 10.3389/fphar.2022.929901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
Postoperative ileus (POI) is a well-known complication following gut manipulation or surgical trauma, leading to an impaired gut motility and prolonged postoperative recovery time. Few current therapeutic strategies can prevent POI, and this disorder remains to be a major clinical challenge for patients undergoing surgery. Comprehensive understanding of cellular and molecular mechanisms related to the pathogenesis of POI stimulates the discovery of more promising targets for treatment. POI is closely associated with a series of inflammatory events within the bowel wall, and as key components of inflammatory mechanisms, different types of immune cells, including macrophages, dendritic cells, and T lymphocytes, play significant roles during the development of POI. A variety of immune cells are recruited into the manipulation sites after surgery, contributing to early inflammatory events or impaired gut motility. Our review intends to summarize the specific relationship between different immune cells and POI, mainly focusing on the relevant mechanisms underlying this disorder.
Collapse
Affiliation(s)
- Chao Sui
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Liang Tao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chunhua Bai
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Lihua Shao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ji Miao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Kai Chen
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Meng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Qiongyuan Hu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Feng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| |
Collapse
|
|
25
|
Xu J, Wang L, Chen X, Le W. New Understanding on the Pathophysiology and Treatment of Constipation in Parkinson’s Disease. Front Aging Neurosci 2022; 14:917499. [PMID: 35813960 PMCID: PMC9257174 DOI: 10.3389/fnagi.2022.917499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/27/2022] [Indexed: 11/13/2022] Open
Abstract
Constipation, one of the most common prodromal non-motor symptoms of Parkinson’s disease (PD), usually occurs several years earlier than the onset of motor symptoms. Previous studies have shown that constipation occurrence increases as the disease progresses. However, the mechanism underlying this pathologic disorder is not clear yet. Moreover, chronic constipation causes slowness in gastric emptying and, therefore, may lead to a delay in the absorption of medications for PD, including levodopa and dopamine agonists. Accordingly, it is necessary to understand how the pathophysiological factors contribute to constipation during PD as well as pursue precise and effective treatment strategies. In this review, we encapsulate the molecular mechanism of constipation underlying PD and update the progress in the treatments of PD-associated constipation.
Collapse
Affiliation(s)
- Jianli Xu
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lei Wang
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Xi Chen
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Xi Chen Weidong Le
| | - Weidong Le
- Institute of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Xi Chen Weidong Le
| |
Collapse
|
|
26
|
Fan YY, Zhang Y, Fan RF, Wang T, Yu X, Zheng LF, Zhu JX. Impaired nitrergic relaxation in pyloric sphincter of the 6-OHDA Parkinson's disease rat. Am J Physiol Gastrointest Liver Physiol 2022; 322:G553-G560. [PMID: 35380456 DOI: 10.1152/ajpgi.00363.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Patients with Parkinson's disease (PD) often suffer from delayed gastric emptying, but the underlying mechanism remains unclear. We have shown previously that a PD rat model comprising bilateral substantia nigra destruction by 6-hydroxydopamine (6-OHDA rats) exhibits gastroparesis with alteration of neural nitric oxide synthase (nNOS) and acetylcholine in gastric corpus. However, changes in pyloric motility in the 6-OHDA rats have not been characterized. Solid gastric emptying test, immunofluorescence, Western blot, and in vitro pyloric motility recordings were used to assess pyloric motor function in the 6-OHDA rats. The 6-OHDA-treated rats displayed delayed solid gastric emptying and a lower basal pyloric motility index. In the 6-OHDA rats, high K+-induced transient contractions were weaker in pyloric sphincters. Electric field stimulation (EFS)-induced pyloric sphincter relaxation was lower in the 6-OHDA rats. NG-nitro-l-arginine methyl ester (l-NAME), a nonselective inhibitor of NOS, markedly inhibited the EFS-induced relaxation in both control and 6-OHDA rats. Pretreatment of tetrodotoxin abolished the effect of EFS on the pyloric motility. In addition, nNOS-positive neurons were extensively distributed in the pyloric myenteric plexus, whereas the number of nNOS-immunoreactive neurons and the protein expression of nNOS were significantly decreased in the pyloric muscularis of 6-OHDA rats. However, sodium nitroprusside-induced pyloric relaxations were similar between the control and 6-OHDA rats. These results indicate that the pyloric sphincters of 6-OHDA rats exhibit both weakened contraction and relaxation. The latter may be due to reduced nNOS in the pyloric myenteric plexus. The dysfunction of the pyloric sphincter might be involved in the delayed gastric emptying.NEW & NOTEWORTHY Reduced nitrergic neurons in pyloric myenteric plexus potently contributed to the attenuated relaxation in 6-hydroxydopamine (6-OHDA) rats, subsequently affecting gastric emptying. SNP could well improve the relaxation of pylori in 6-OHDA rats. The present study provides new insight into the diagnosis and treatment of delayed gastric emptying in patients with PD.
Collapse
Affiliation(s)
- Yan-Yan Fan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| | - Yue Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| | - Rui-Fang Fan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| | - Tao Wang
- Department of Physiology, Xingtai Medical College, Xingtai, People's Republic of China
| | - Xiao Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| | - Li-Fei Zheng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| | - Jin-Xia Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| |
Collapse
|
|
27
|
Abstract
Due to recent advances, the mortality due to short bowel syndrome (SBS) has significantly decreased, but the morbidities are still high. Morbidities arising specifically due to dysmotility in SBS include feeding intolerance, prolonged dependence on parenteral nutrition, and associated complications such as intestinal failure associated liver disease, and bloodstream infections. The understanding of the pathogenesis of dysmotility in SBS has improved vastly. However, the tools to diagnose dysmotility in SBS in infants are restrictive, and the medical therapies to treat dysmotility are limited. Surgical techniques available for the treatment after failure of conservative management of dysmotility offer hope but carry their associated risks. The evidence to support either the medical therapies or the surgical techniques to treat dysmotility in SBS in children is scarce and weak. Development of newer therapies and efforts to build evidence to support currently available treatments in treating dysmotility in SBS is needed.
Collapse
Affiliation(s)
- Muralidhar H Premkumar
- Associate Professor, Division of Neonatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin, Suite 6104, Houston, TX 77030, USA.
| |
Collapse
|
|
28
|
Effect of Chemically-Induced Diabetes Mellitus on Phenotypic Variability of the Enteric Neurons in the Descending Colon in the Pig. ANNALS OF ANIMAL SCIENCE 2021. [DOI: 10.2478/aoas-2020-0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Abstract
Gastrointestinal neuropathy in diabetes is one of numerous diseases resulting in abnormal functioning of the gastrointestinal tract (GIT), and it may affect any section of the GIT, including the descending colon. In the gastrointestinal system, the neurons are arranged in an interconnecting network defined as the enteric nervous system (ENS) which includes the myenteric plexus and the submucosal plexuses: inner and outer. Regular functioning of the ENS is determined by normal synthesis of the neurotransmitters and neuromodulators. This paper demonstrates the effect of hyperglycaemia on the number of enteric neurons which are immunoreactive to: neural isoform of nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP), galanin (GAL), calcitonin generelated peptide (CGRP) and cocaine amphetamine-regulated transcript (CART) in the porcine descending colon. It was demonstrated that there was a statistically significant increase in the number of neurons within the myenteric plexus immunoreactive to all investigated substances. In the outer submucosal plexus, the CART-positive neurons were the only ones not to change, whereas no changes were recorded for nNOS or CART in the inner submucosal plexus. This study is the first study to discuss quantitative changes in the neurons immunoreactive to nNOS, VIP, GAL, CGRP and CART in the descending colon in diabetic pigs.
Collapse
|
|
29
|
Jalleh RJ, Marathe CS, Jones KL, Horowitz M, Rayner CK. Digesting the pathogenesis of diabetic gastroparesis. J Diabetes Complications 2021; 35:107992. [PMID: 34389236 DOI: 10.1016/j.jdiacomp.2021.107992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023]
|
|
30
|
Takahashi K, Khwaja IG, Schreyer JR, Bulmer D, Peiris M, Terai S, Aziz Q. Post-inflammatory Abdominal Pain in Patients with Inflammatory Bowel Disease During Remission: A Comprehensive Review. CROHN'S & COLITIS 360 2021; 3:otab073. [PMID: 36777266 PMCID: PMC9802269 DOI: 10.1093/crocol/otab073] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Indexed: 11/13/2022] Open
Abstract
Patients with inflammatory bowel disease often experience ongoing pain even after achieving mucosal healing (i.e., post-inflammatory pain). Factors related to the brain-gut axis, such as peripheral and central sensitization, altered sympatho-vagal balance, hypothalamic-pituitary-adrenal axis activation, and psychosocial factors, play a significant role in the development of post-inflammatory pain. A comprehensive study investigating the interaction between multiple predisposing factors, including clinical psycho-physiological phenotypes, molecular mechanisms, and multi-omics data, is still needed to fully understand the complex mechanism of post-inflammatory pain. Furthermore, current treatment options are limited and new treatments consistent with the underlying pathophysiology are needed to improve clinical outcomes.
Collapse
Affiliation(s)
- Kazuya Takahashi
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Iman Geelani Khwaja
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jocelyn Rachel Schreyer
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Madusha Peiris
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| |
Collapse
|
|
31
|
Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int J Mol Sci 2021; 22:10372. [PMID: 34638713 PMCID: PMC8508925 DOI: 10.3390/ijms221910372] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/10/2023] Open
Abstract
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.
Collapse
Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Markus Grosse Perdekamp
- Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
| |
Collapse
|
|
32
|
Yip JL, Balasuriya GK, Spencer SJ, Hill-Yardin EL. The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease. Cell Mol Gastroenterol Hepatol 2021; 12:1701-1718. [PMID: 34506953 PMCID: PMC8551786 DOI: 10.1016/j.jcmgh.2021.08.021] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022]
Abstract
Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. Their ability to keep the gut from chronic inflammation despite constantly facing foreign antigens has been an important focus in gastrointestinal research. However, the heterogeneity of intestinal macrophages has impeded our understanding of their specific roles. It is now becoming clear that subsets of intestinal macrophages play diverse roles in various gastrointestinal diseases. This occurs through a complex interplay between cytokine production and enteric nervous system activation that differs for each pathologic condition. Key diseases and disorders in which intestinal macrophages play a role include postoperative ileus, inflammatory bowel disease, necrotizing enterocolitis, as well as gastrointestinal disorders associated with human immunodeficiency virus and Parkinson's disease. Here, we review the identification of intestinal macrophage subsets based on their origins and functions, how specific subsets regulate gut physiology, and the potential for these heterogeneous subpopulations to contribute to disease states. Furthermore, we outline the potential for these subpopulations to provide unique targets for the development of novel therapies for these disorders.
Collapse
Affiliation(s)
| | | | - Sarah J. Spencer
- School of Health and Biomedical Sciences,Australian Research Council Centre of Excellence for Nanoscale Biophotonics, Royal Melbourne Instutite of Technology, Melbourne, Victoria, Australia
| | - Elisa L. Hill-Yardin
- School of Health and Biomedical Sciences,Correspondence Address correspondence to: Elisa L. Hill-Yardin, PhD, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
| |
Collapse
|
|
33
|
Bartsch B, Then CK, Harriss E, Kartsonaki C, Kiltie AE. The role of dietary supplements, including biotics, glutamine, polyunsaturated fatty acids and polyphenols, in reducing gastrointestinal side effects in patients undergoing pelvic radiotherapy: A systematic review and meta-analysis. Clin Transl Radiat Oncol 2021; 29:11-19. [PMID: 34027139 PMCID: PMC8134489 DOI: 10.1016/j.ctro.2021.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Pelvic radiotherapy (RT) often results in gastrointestinal toxicity and clinical trials have demonstrated a potential benefit of dietary supplements in alleviating acute effects. However, no prophylactic agents have been approved to date for relief of gastrointestinal side-effects caused by pelvic radiation. In this systematic review, we evaluated the efficacy of dietary supplements in preventing or alleviating symptoms of gastrointestinal toxicity in patients undergoing pelvic RT. MATERIALS AND METHODS CENTRAL, MEDLINE, EMBASE, and ClinicalTrials.gov were searched up to June 2020 for randomised controlled trials. Interventions included four supplement categories: biotics, glutamine, poly-unsaturated fatty acids and polyphenols. Efficacy was determined with reference to outcomes based on symptoms of acute gastrointestinal toxicity, including diarrhoea, nausea, vomiting, flatulence/bloating, bowel movement frequency, tenesmus and rectal bleeding. RESULTS Twenty-three randomised controlled trials (1919 patients) were identified in this review. Compared with placebo, probiotics (RR = 0.71; 95% CI: 0.52 to 0.99), synbiotics (RR = 0.45; 95% CI: 0.28 to 0.73) and polyphenols (RR = 0.30; 95% CI: 0.13 to 0.70) were significantly associated with a lower risk of diarrhoea. Biotic supplements also reduced the risk of moderate to severe diarrhoea (RR = 0.49; 95% CI: 0.36 to 0.67) and the need for anti-diarrhoeal medication (RR = 0.64; 95%CI: 0.44 to 0.92). In contrast, glutamine had no effect on acute symptoms (RR = 1.05; 95% CI: 0.86 to 1.29). There was a non-significant trend for reduction in nausea and mean bowel movements per day using dietary supplements. CONCLUSIONS Biotic supplements, especially probiotics and synbiotics, reduce acute symptoms of gastrointestinal toxicity in patients undergoing pelvic radiotherapy.
Collapse
Affiliation(s)
- Benjamin Bartsch
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Chee Kin Then
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Elinor Harriss
- Bodleian Health Care Libraries, University of Oxford, Oxford, UK
| | - Christiana Kartsonaki
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Medical Research Council Population Health Research Unit (MRC PHRU) at the University of Oxford, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Anne E. Kiltie
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| |
Collapse
|
|
34
|
Short-term Results of Platelet-Rich Plasma in the Treatment of Chronic Anal Fissure: Randomized Controlled Clinical Study. Dis Colon Rectum 2021; 64:714-723. [PMID: 33399410 DOI: 10.1097/dcr.0000000000001903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Anal fissure is one of the most common benign anal disorders, and medical treatments play an important role in its management. OBJECTIVE The purpose of this study was to investigate the short-term effects and success of platelet-rich plasma in the treatment of chronic anal fissure. DESIGN The study is a 2 parallel group, randomized, controlled clinical trial. SETTINGS The study was performed in 2 tertiary university hospitals. PATIENTS Forty-four patients with chronic anal fissure were randomly assigned to platelet-rich plasma treatment or control group. Presenting symptoms and pain scores were recorded on enrollment. The control patient self-administered topical glyceryl trinitrate. Platelet-rich plasma was injected locally in the intervention group followed by self-administered glyceryl trinitrate. MAIN OUTCOME MEASURES The primary outcome measure is a reduction in pain scores. RESULTS On day 10 and 1 month after treatment, the mean pain score was significantly lower in the patients treated with platelet-rich plasma than in the controls (p = 0.005 and p < 0.005). By 1 month after treatment, the mean pain score declined by 5.7 points in the platelet-rich plasma-treated group compared with a 4.1 mean pain score decline in the control group (mean difference:1.6 points (95% CI, 0.3-2.9)). According to the repeated-measures analyses, pain scores decreased in both groups, but the decrease in the treatment group was statistically higher than in the control group (p < 0.001). Complete epithelialization and recovery rates were significantly higher in the platelet-rich plasma group than in controls at all follow-up times, with p values ranging from 0.034 to <0.001. The observed difference in complete epithelialization after 2 months of treatment between the platelet-rich plasma group and the control group was 56.2% with a 95% CI of 14.03% to 98.4%. LIMITATIONS This study was limited by its small sample size, and long-term follow-up of the patients was not presented. CONCLUSIONS Platelet-rich plasma reduced concerns and accelerated epithelialization and healing in patients with chronic anal fissures. See Video Abstract at http://links.lww.com/DCR/B461.RESULTADOS A CORTO PLAZO DEL PLASMA RICO EN PLAQUETAS EN EL TRATAMIENTO DE LA FISURA ANAL CRÓNICA: ESTUDIO CLÍNICO CONTROLADO ALEATORIZADO. ANTECEDENTES La fisura anal es uno de los trastornos anales benignos más comunes y los tratamientos médicos juegan un papel importante en su manejo. OBJETIVO El propósito de este estudio fue investigar los efectos a corto plazo y el éxito del plasma rico en plaquetas en el tratamiento de la fisura an33al crónica. DISEO El estudio es un ensayo clínico controlado, aleatorizado y de dos grupos paralelos. ESCENARIO El estudio se llevó a cabo en dos hospitales universitarios terciarios. PACIENTES Cuarenta y cuatro pacientes con fisura anal crónica fueron asignados aleatoriamente al grupo de tratamiento con plasma rico en plaquetas o al grupo control. Los síntomas de presentación y las puntuaciones de dolor se registraron en la inscripción. Los pacientes de control se autoadministraron trinitrato de glicerilo tópico. El plasma rico en plaquetas se inyectó localmente en el grupo de intervención seguido de trinitrato de glicerilo autoadministrado. PRINCIPALES MEDIDAS DE RESULTADO La principal medida de resultado es una reducción en las puntuaciones de dolor. RESULTADOS El día 10 y un mes después del tratamiento, la puntuación media de dolor fue significativamente menor en los pacientes con plasma rico en plaquetas que en los controles (p = 0.005 y p <0.005, respectivamente). Un mes después del tratamiento, la puntuación media de dolor disminuyó 5.7 puntos en el grupo tratado con plasma rico en plaquetas en comparación con una disminución de la puntuación media de dolor de 4.1 en el grupo de control (diferencia media: 1.6 puntos [intervalo de confianza del 95%; 0.3-2.9] Según los análisis de medidas repetidas, las puntuaciones de dolor disminuyeron en ambos grupos, pero la disminución en el grupo de tratamiento fue estadísticamente mayor que en el grupo de control (p <0.001). Las tasas de epitelización completa y recuperación fueron significativamente más altas en los pacientes con plasma rico en plaquetas que en los controles en todos los tiempos de seguimiento, con valores de p que van desde 0.034 a <0.001. La diferencia observada en la epitelización completa después de dos meses de tratamiento entre el grupo de plasma rico en plaquetas y el grupo de control fue del 56.2% con un intervalo de confianza del 95% del 14.03% al 98.4%. LIMITACIONES Este estudio estuvo limitado por el pequeño tamaño de la muestra y porque no se proporcionó un seguimiento a largo plazo de los pacientes. CONCLUSIONES El plasma rico en plaquetas redujo las molestias y aceleró la epitelización y la curación en pacientes con fisuras anales crónicas. Consulte Video Resumen en http://links.lww.com/DCR/B461. (Traducción-Dr. Jorge Silva Velazco).
Collapse
|
|
35
|
Teixeira DF, Santos AM, Oliveira AMS, Nascimento Júnior JAC, Frank LA, Santana Souza MTD, Camargo EA, Serafini MR. Pharmaceuticals agents for preventing NSAID-induced gastric ulcers: a patent review. Expert Rev Clin Pharmacol 2021; 14:677-686. [PMID: 33843400 DOI: 10.1080/17512433.2021.1909475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs widely used due to their pharmacological potential, demonstrating anti-inflammatory, analgesic, or antipyretic activity. However, prolonged use of these medications can lead to the development of gastric ulcers in patients. This review aimed to find patents for drugs with an anti-inflammatory and gastroprotective character to treat NSAID-induced gastric ulcers. AREAS COVERED For the treatment of NSAID-induced gastric ulcers, formulations with different action mechanisms were found, including donors of nitric oxide, heterocyclic compounds, and natural products. EXPERT OPINION Many of the structures found have already been used in clinic settings and others, and according to the results found, they are promising for the treatment of gastric ulcers.
Collapse
Affiliation(s)
| | | | | | | | - Luiza Abrahão Frank
- College of Pharmacy, Department of Pharmacy, Federal University of Rio Grande Do Sul, Porto Alegre, Rio Grande Do Sul, Brazil.,Escola De Saúde E Bem Estar UniRitter; Faculdade De Farmácia Laureate International Universities; Porto Alegre; Brazil
| | | | | | - Mairim Russo Serafini
- Federal University of Sergipe, Department of Pharmacy, São Cristovão, Sergipe, Brazil
| |
Collapse
|
|
36
|
Livzan MA, Krolevets TS, Mozgovoy SI, Nikolaev NA, Nelidova AV. [Features of intestinal microbiota disorders in the development of metabolic disorders in non-alcoholic fatty liver disease]. TERAPEVT ARKH 2021; 93:222-227. [PMID: 36286641 DOI: 10.26442/00403660.2021.02.200614] [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: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 11/22/2022]
Abstract
We discussed about the term intestinal permeability like as the mucosal barrier a single structural and functional conception that includes the layer of mucus, the indigenous microbiota and the epithelium of the mucosa in this publication. Information was presented about the role of the microbiota, the composition of intestinal mucus, epithelial cells and proteins of tight junctions which lead to various metabolic diseases. The complex pathogenetic interactions are formed between the intestinal mucosal barrier, metabolic disorders such as non-alcoholic fatty liver disease and cardiovascular diseases. The complex researches and modification of this interactions will allow to create personalized approaches and to prevent of these diseases.
Collapse
|
|
37
|
Naïli I, Gardette M, Garrivier A, Daniel J, Desvaux M, Pizza M, Gobert A, Marchal T, Loukiadis E, Jubelin G. Interplay between enterohaemorrhagic Escherichia coli and nitric oxide during the infectious process. Emerg Microbes Infect 2021; 9:1065-1076. [PMID: 32459575 PMCID: PMC7336997 DOI: 10.1080/22221751.2020.1768804] [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] [Indexed: 01/25/2023]
Abstract
Enterohaemorrhagic Escherichia coli (EHEC) are bacterial pathogens responsible for life-threatening diseases in humans such as bloody diarrhoea and the hemolytic and uremic syndrome. To date, no specific therapy is available and treatments remain essentially symptomatic. In recent years, we demonstrated in vitro that nitric oxide (NO), a major mediator of the intestinal immune response, strongly represses the synthesis of the two cardinal virulence factors in EHEC, namely Shiga toxins (Stx) and the type III secretion system, suggesting NO has a great potential to protect against EHEC infection. In this study, we investigated the interplay between NO and EHEC in vivo using mouse models of infection. Using a NO-sensing reporter strain, we determined that EHEC sense NO in the gut of infected mice. Treatment of infected mice with a specific NOS inhibitor increased EHEC adhesion to the colonic mucosa but unexpectedly decreased Stx activity in the gastrointestinal tract, protecting mice from renal failure. Taken together, our data indicate that NO can have both beneficial and detrimental consequences on the outcome of an EHEC infection, and underline the importance of in vivo studies to increase our knowledge in host–pathogen interactions.
Collapse
Affiliation(s)
- Ilham Naïli
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France.,GSK, Siena, Italy
| | - Marion Gardette
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France.,Université de Lyon, CNRS, INRAE, Université Claude Bernard Lyon 1, VetAgro Sup, Laboratoire d'Ecologie Microbienne, F-63280 Marcy l'Etoile, France
| | - Annie Garrivier
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France
| | - Julien Daniel
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France
| | - Mickaël Desvaux
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France
| | | | - Alain Gobert
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France
| | - Thierry Marchal
- VetAgro Sup, Laboratoire vétérinaire d'histopathologie, F-63280 Marcy-l'Etoile, France
| | - Estelle Loukiadis
- Université de Lyon, CNRS, INRAE, Université Claude Bernard Lyon 1, VetAgro Sup, Laboratoire d'Ecologie Microbienne, F-63280 Marcy l'Etoile, France.,VetAgro Sup, Laboratoire national de référence des E. coli, F-63280 Marcy-l'Etoile, France
| | - Grégory Jubelin
- Université Clermont Auvergne, INRAE, MEDiS, F-63000 Clermont-Ferrand, France
| |
Collapse
|
|
38
|
Blanco-Rivero J, Xavier FE. Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases. Curr Pharm Des 2021; 26:3633-3651. [PMID: 32242780 DOI: 10.2174/1381612826666200403172736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/08/2020] [Indexed: 02/08/2023]
Abstract
Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.
Collapse
Affiliation(s)
- Javier Blanco-Rivero
- Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain
| | - Fabiano E Xavier
- Departamento de Fisiologia e Farmacologia, Centro de Biociencias, Universidade Federal de Pernambuco, Recife, Brazil
| |
Collapse
|
|
39
|
Ray A, Gulati K, Henke P. Stress Gastric Ulcers and Cytoprotective Strategies: Perspectives and Trends. Curr Pharm Des 2021; 26:2982-2990. [PMID: 32436823 DOI: 10.2174/1381612826666200521143203] [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: 03/24/2020] [Accepted: 05/11/2020] [Indexed: 11/22/2022]
Abstract
Stress gastric ulceration is a clinical condition leading to morbidity/mortality and complex etiopathological factors are involved. Pharmacotherapy of such gastric mucosal lesions is not consistent and novel strategies are being explored. Targeting gastrointestinal factors have showed equivocal results and there is a possibility of involvement of extra-gastrointestinal factors. Stress is a highly interactive biological response in which the brain plays a key role. The involvement of brain substrates like the limbic system (amygdala, cortex, hippocampus) and behavioral traits has been investigated and research data has shown that the limbic brain-gut axis may be involved in the regulation of gastric mucosal integrity during stressful situations. The amygdaloid complex, its connections with other limbic structures and their neural networks act in tandem to contribute to both stress ulceration and gastroprotection. Complex neurotransmitter interactions in these areas involving biogenic amines and neuropeptides have been shown to modulate stress ulcerogenesis in experimental models. The immune system and brain-immune interactions also appear to play a decisive role in the genesis of such stress gastric lesions and the possibility of a brain-gut-immune axis has been proposed during stress gastric lesions. More recent studies have shown the involvement of oxidative stress and nitric oxide as well as their interactions during such stress gastric pathology, indicating the possible role of antioxidants and NO modulators as gastroprotective agents for stress ulceration. In view of the complex pathophysiology, multiple targets and lack of consistent therapeutic modalities, newer/alternative hypotheses are constantly emerging, which could be explored for effective treatment strategies aimed at gastric cytoprotection. Herbal agents with adaptogenic properties could be worth exploring in this regard as some of these phytopharmaceutical agents used in traditional medicine have been shown to exhibit gastric cytoprotection as part of their anti-stress profile. Further, their interactions with brain neurotransmitters and immune mechanisms and their relative safety could make them prospective leads for stress ulcer prophylaxis and treatment.
Collapse
Affiliation(s)
- Arunabha Ray
- Department of Pharmacology, Hamdard Institute of Medical Sciences and Research (HIMSR), Hamdard University, New Delhi, India
| | - Kavita Gulati
- Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
| | - Peter Henke
- St. Francis Xavier University, Antigonish, Nova Scotia, B2G 2W5, Canada
| |
Collapse
|
|
40
|
Effect of Acrylamide Supplementation on the Population of Vasoactive Intestinal Peptide (VIP)-Like Immunoreactive Neurons in the Porcine Small Intestine. Int J Mol Sci 2020; 21:ijms21249691. [PMID: 33353157 PMCID: PMC7765847 DOI: 10.3390/ijms21249691] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/08/2020] [Accepted: 12/16/2020] [Indexed: 12/14/2022] Open
Abstract
Acrylamide is one of the harmful substances present in food. The present study aimed to establish the effect of acrylamide supplementation in tolerable daily intake (TDI) dose (0.5 µg/kg b.w./day) and a dose ten times higher than TDI (5 µg/kg b.w./day) on the population of vasoactive intestinal peptide-like immunoreactive (VIP-LI) neurons in the porcine small intestine and the degree of the co-localization of VIP with other neuroactive substances (neuronal nitric oxide synthase (nNOS), substance P (SP), and cocaine- and amphetamine-regulated transcript peptide (CART)). In our work, 15 Danish landrace gilts (5 in each experimental group) received capsules (empty or with low or high doses of acrylamide) for a period of 28 days with their morning feeding. Using double immunofluorescence staining, we established that acrylamide supplementation increased the number of neurons showing immunoreactivity towards VIP in all types of enteric nervous system (ENS) plexuses and fragments of the small intestine studied. Moreover, both doses of acrylamide led to changes in the degree of co-localization of VIP with nNOS, SP, and CART in intramural neurons. The observed changes may be the adaptation of neurons to local inflammation, oxidative stress, or the direct toxic effects of acrylamide on intestinal neurons, also referred to as neuronal plasticity.
Collapse
|
|
41
|
Truse R, Nolten I, Schulz J, Herminghaus A, Holtmanns T, Gördes L, Raupach A, Bauer I, Picker O, Vollmer C. Topical Melatonin Improves Gastric Microcirculatory Oxygenation During Hemorrhagic Shock in Dogs but Does Not Alter Barrier Integrity of Caco-2 Monolayers. Front Med (Lausanne) 2020; 7:510. [PMID: 32984383 PMCID: PMC7484810 DOI: 10.3389/fmed.2020.00510] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/23/2020] [Indexed: 12/21/2022] Open
Abstract
Systemic administration of melatonin exerts tissue protective effects in the context of hemorrhagic shock. Intravenous application of melatonin prior to hemorrhage improves gastric microcirculatory perfusion and maintains intestinal barrier function in dogs. The aim of the present study was to analyze the effects of a topical mucosal melatonin application on gastric microcirculation during hemorrhagic shock in vivo and on mucosal barrier function in vitro. In a randomized cross-over study, six anesthetized female foxhounds received 3.3 mg melatonin or the vehicle as a bolus to the gastric and oral mucosa during physiological and hemorrhagic (-20% blood volume) conditions. Microcirculation was analyzed with reflectance spectrometry and laser doppler flowmetry. Systemic hemodynamic variables were measured with transpulmonary thermodilution. For analysis of intestinal mucosal barrier function in vitro Caco-2 monolayers were used. The transepithelial electrical resistance (TEER) and the passage of Lucifer Yellow (LY) from the apical to the basolateral compartment of Transwell chambers were measured. Potential barrier protective effects of melatonin against oxidative stress were investigated in the presence of the oxidant H2O2. During physiologic conditions topical application of melatonin had no effect on gastric and oral microcirculation in vivo. During hemorrhagic shock, gastric microcirculatory oxygenation (μHbO2) was decreased from 81 ± 8% to 50 ± 15%. Topical treatment with melatonin led to a significant increase in μHbO2 to 60 ± 13%. Topical melatonin treatment had no effect on gastric microcirculatory perfusion, oral microcirculation or systemic hemodynamics. Incubation of H2O2 stressed Caco-2 monolayers with melatonin did neither influence transepithelial electrical resistance nor LY translocation. Topical treatment of the gastric mucosa with melatonin attenuates the shock induced decrease in microcirculatory oxygenation. As no effects on local microcirculatory and systemic perfusion were recorded, the improved μHbO2 is most likely caused by a modulation of local oxygen consumption. In vitro melatonin treatment did not improve intestinal barrier integrity in the context of oxidative stress. These results extend the current knowledge on melatonin's protective effects during hemorrhage in vivo. Topical application of melatonin exerts differential effects on local microcirculation compared to systemic pretreatment and might be suitable as an adjunct for resuscitation of hemorrhagic shock.
Collapse
Affiliation(s)
- Richard Truse
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Inga Nolten
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Jan Schulz
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Anna Herminghaus
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Tobias Holtmanns
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Lukas Gördes
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Annika Raupach
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Inge Bauer
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Olaf Picker
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Christian Vollmer
- Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
| |
Collapse
|
|
42
|
Duangjai A, Parseatsook K, Sajjapong W, Saokaew S. Assessment of Polygonum odoratum Lour. Leaf Extract on Rat's Ileum Contraction and the Mechanisms Involved. J Med Food 2020; 23:1169-1175. [PMID: 32976072 DOI: 10.1089/jmf.2020.4769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vietnamese coriander (Polygonum odoratum Lour.) is a plant native to northern Thailand. The biological activities of P. odoratum Lour. extract (POE) include antibacterial, antiviral, and expectorant. However, the effect of POE on intestinal smooth muscle motility is unclear. The aim of this study was to evaluate the relaxant effects of POE on isolated rat ileum. Propranolol (1 μM), calcium chloride (1-20 mM), and Nω-nitro-l-arginine methylester (l-NAME, 100 μM) were used to investigate the mechanisms of action. The results showed that POE (0.01-5 mg/mL) reduced KCl-induced contraction. In addition, POE (1 mg/mL) reduced the contraction by propranolol and l-NAME and attenuated CaCl2-induced contractions. Our results indicate that the relaxation effect of POE on ileum contractions seems to involve nitric oxide and β-adrenergic pathways, and blockade of calcium influx. These findings provide a pharmacological basis for the traditional use of POE to treat gastrointestinal disorders such as irritable bowel syndrome or diarrhea.
Collapse
Affiliation(s)
- Acharaporn Duangjai
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Kwanchanok Parseatsook
- Department of Nutrition, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Wittawas Sajjapong
- Department of Nutrition, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Surasak Saokaew
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
- Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
- Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
- Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
- Biofunctional Molecule Exploratory Research Group, Biomedicine Research Advancement Centre, School of Pharmacy, Monash University Malaysia, Subang Jaya, Malaysia
- Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
| |
Collapse
|
|
43
|
Jochems PGM, Garssen J, Rietveld PCS, Govers C, Tomassen MMM, Wichers HJ, van Bergenhenegouwen J, Masereeuw R. Novel Dietary Proteins Selectively Affect Intestinal Health In Vitro after Clostridium difficile-Secreted Toxin A Exposure. Nutrients 2020; 12:E2782. [PMID: 32932980 PMCID: PMC7551268 DOI: 10.3390/nu12092782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/01/2020] [Accepted: 09/10/2020] [Indexed: 12/25/2022] Open
Abstract
Bacterial gastroenteritis forms a burden on a global scale, both socially and economically. The Gram-positive bacterium Clostridium difficile is an inducer of gastrointestinal bacterial infections, often triggered following disruption of the microbiota by broad-spectrum antibiotics to treat other conditions. The clinical manifestatiaons, e.g., diarrhea, are driven by its toxins secretion, toxin A (TcdA) and toxin B (TcdB). Current therapies are focused on discontinuing patient medication, including antibiotics. However, relapse rates upon therapy are high (20-25%). Here, eighteen dietary proteins were evaluated for their capacity to restore gut health upon C. difficile-derived TcdA exposure. We used bioengineered intestinal tubules to assess proteins for their beneficial effects by examining the epithelial barrier, cell viability, brush-border enzyme activity, IL-6 secretion, IL-8 secretion and nitric oxide (NO) levels upon TcdA challenge. TcdA effectively disrupted the epithelial barrier, increased mitochondrial activity, but did not affect alkaline phosphatase activity, IL-6, IL-8 and NO levels. Intervention with dietary proteins did not show a protective effect on epithelial barrier integrity or mitochondrial activity. However, bovine plasma and potato protein increased alkaline phosphatase activity, egg-white protein increased IL-6 and IL-8 release and wheat, lesser mealworm and yeast protein increased NO levels after TcdA exposure. Hence, dietary proteins can influence parameters involved in intestinal physiology and immune activation suggesting that supplementation with specific dietary proteins may be of benefit during C. difficile infections.
Collapse
Affiliation(s)
- Paulus G. M. Jochems
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; (P.G.M.J.); (J.G.); (P.C.S.R.); (J.v.B.)
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; (P.G.M.J.); (J.G.); (P.C.S.R.); (J.v.B.)
- Nutricia Research, Global Center of Excellence Immunology, 3584 CT Utrecht, The Netherlands
| | - Pascale C. S. Rietveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; (P.G.M.J.); (J.G.); (P.C.S.R.); (J.v.B.)
| | - Coen Govers
- Food & Biobased Research, Wageningen University & Research, 6708 WE Wageningen, The Netherlands; (C.G.); (M.M.M.T.); (H.J.W.)
| | - Monic M. M. Tomassen
- Food & Biobased Research, Wageningen University & Research, 6708 WE Wageningen, The Netherlands; (C.G.); (M.M.M.T.); (H.J.W.)
| | - Harry J. Wichers
- Food & Biobased Research, Wageningen University & Research, 6708 WE Wageningen, The Netherlands; (C.G.); (M.M.M.T.); (H.J.W.)
| | - Jeroen van Bergenhenegouwen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; (P.G.M.J.); (J.G.); (P.C.S.R.); (J.v.B.)
- Nutricia Research, Global Center of Excellence Immunology, 3584 CT Utrecht, The Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; (P.G.M.J.); (J.G.); (P.C.S.R.); (J.v.B.)
| |
Collapse
|
|
44
|
Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
Collapse
Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| |
Collapse
|
|
45
|
Rychlik A, Gonkowski S, Kaczmar E, Obremski K, Calka J, Makowska K. The T2 Toxin Produced by Fusarium spp. Impacts Porcine Duodenal Nitric Oxide Synthase (nNOS)-Positive Nervous Structures-The Preliminary Study. Int J Mol Sci 2020; 21:ijms21145118. [PMID: 32698434 PMCID: PMC7404315 DOI: 10.3390/ijms21145118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/05/2020] [Accepted: 07/15/2020] [Indexed: 01/12/2023] Open
Abstract
T2 toxin synthetized by Fusarium spp. negatively affects various internal organs and systems, including the digestive tract and the immune, endocrine, and nervous systems. However, knowledge about the effects of T2 on the enteric nervous system (ENS) is still incomplete. Therefore, during the present experiment, the influence of T2 toxin with a dose of 12 µg/kg body weight (b.w.)/per day on the number of enteric nervous structures immunoreactive to neuronal isoform nitric oxide synthase (nNOS—used here as a marker of nitrergic neurons) in the porcine duodenum was studied using the double immunofluorescence method. Under physiological conditions, nNOS-positive neurons amounted to 38.28 ± 1.147%, 38.39 ± 1.244%, and 35.34 ± 1.151 of all enteric neurons in the myenteric (MP), outer submucous (OSP), and inner submucous (ISP) plexuses, respectively. After administration of T2 toxin, an increase in the number of these neurons was observed in all types of the enteric plexuses and nNOS-positive cells reached 46.20 ± 1.453% in the MP, 45.39 ± 0.488% in the OSP, and 44.07 ± 0.308% in the ISP. However, in the present study, the influence of T2 toxin on the intramucosal and intramuscular nNOS-positive nerves was not observed. The results obtained in the present study indicate that even low doses of T2 toxin are not neutral for living organisms because they may change the neurochemical characterization of the enteric neurons.
Collapse
Affiliation(s)
- Andrzej Rychlik
- Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-957 Olsztyn, Poland; (A.R.); (E.K.)
| | - Slawomir Gonkowski
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland; (S.G.); (J.C.)
| | - Ewa Kaczmar
- Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-957 Olsztyn, Poland; (A.R.); (E.K.)
| | - Kazimierz Obremski
- Department of Veterinary Prevention and Feed Hygiene, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-718 Olsztyn, Poland;
| | - Jaroslaw Calka
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland; (S.G.); (J.C.)
| | - Krystyna Makowska
- Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-957 Olsztyn, Poland; (A.R.); (E.K.)
- Correspondence: ; Fax: +48-95234460
| |
Collapse
|
|
46
|
Singhal R, Shah YM. Oxygen battle in the gut: Hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine. J Biol Chem 2020; 295:10493-10505. [PMID: 32503843 DOI: 10.1074/jbc.rev120.011188] [Citation(s) in RCA: 210] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/04/2020] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal tract is a highly proliferative and regenerative tissue. The intestine also harbors a large and diverse microbial population collectively called the gut microbiome (microbiota). The microbiome-intestine cross-talk includes a dynamic exchange of gaseous signaling mediators generated by bacterial and intestinal metabolisms. Moreover, the microbiome initiates and maintains the hypoxic environment of the intestine that is critical for nutrient absorption, intestinal barrier function, and innate and adaptive immune responses in the mucosal cells of the intestine. The response to hypoxia is mediated by hypoxia-inducible factors (HIFs). In hypoxic conditions, the HIF activation regulates the expression of a cohort of genes that promote adaptation to hypoxia. Physiologically, HIF-dependent genes contribute to the aforementioned maintenance of epithelial barrier function, nutrient absorption, and immune regulation. However, chronic HIF activation exacerbates disease conditions, leading to intestinal injury, inflammation, and colorectal cancer. In this review, we aim to outline the major roles of physiological and pathological hypoxic conditions in the maintenance of intestinal homeostasis and in the onset and progression of disease with a major focus on understanding the complex pathophysiology of the intestine.
Collapse
Affiliation(s)
- Rashi Singhal
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA .,Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.,Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA
| |
Collapse
|
|
47
|
Dadhich P, Bitar KN. Functional restoration of ex vivo model of pylorus: Co-injection of neural progenitor cells and interstitial cells of Cajal. Stem Cells Transl Med 2020; 9:713-723. [PMID: 32181603 PMCID: PMC7214644 DOI: 10.1002/sctm.19-0316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/28/2020] [Indexed: 12/12/2022] Open
Abstract
Transplantation of neural stem cells is a promising approach in treatment of intestinal dysfunctionality. The interstitial cells of Cajal (ICCs) are also critical in conditions such as pyloric dysfunctionality and gastroparesis. The objective of this study was to replenish neurons and ICCs in a dysfunctional pylorus as cell-based therapy to restore functionality. ICCs and enteric neural progenitor cells (NPCs) were isolated from rat duodenum and transduced with fluorescent proteins. Rat pylorus was harvested, and an ex-vivo neuromuscular dysfunctional model was developed by selective ablation of neurons and ICCs via chemical treatments. Cellular repopulation and restoration of motility were assessed by immunohistochemistry, qPCR, and functional analysis after delivery of fluorescently tagged cells. Chemical treatment of pylorus resulted in significant depletion of ICCs (67%, P = .0024; n = 3) and neural cells (83%, P = .0012; n = 3). Delivered ICCs and NPCs survived and integrated with host muscle layers. Co-injection of ICCs with NPCs exhibited 34.4% (P = .0004; n = 3) and 61.0% (P = .0003; n = 3) upregulation of ANO1 and βIII tubulin, respectively. This regeneration resulted in the restoration of agonist-induced excitatory contraction (82%) and neuron evoked relaxation (83%). The functional studies with specific neuronal nitric oxide (NO) synthase blocker confirmed that restoration of relaxation was NO mediated and neuronally derived. The simultaneous delivery of ICCs observed 35.7% higher neuronal differentiation and functional restoration compared with injection of NPCs alone. Injected NPCs and ICCs integrated into the dysfunctional ex vivo pylorus tissues and restored neuromuscular functionality. The co-transplantation of NPCs and ICCs can be used to treat neurodegenerative disorders of the pylorus.
Collapse
Affiliation(s)
- Prabhash Dadhich
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of MedicineWinston‐SalemNorth Carolina
- Program in Neuro‐Gastroenterology and Motility, Wake Forest School of MedicineWinston‐SalemNorth Carolina
| | - Khalil N. Bitar
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of MedicineWinston‐SalemNorth Carolina
- Program in Neuro‐Gastroenterology and Motility, Wake Forest School of MedicineWinston‐SalemNorth Carolina
- Section on Gastroenterology, Wake Forest School of MedicineWinston‐SalemNorth Carolina
- Virginia Tech‐Wake Forest School of Biomedical Engineering and Sciences, Wake Forest School of MedicineWinston‐SalemNorth Carolina
| |
Collapse
|
|
48
|
Xing M, Fu R, Liu Y, Wang P, Ma P, Zhu C, Fan D. Human-like collagen promotes the healing of acetic acid-induced gastric ulcers in rats by regulating NOS and growth factors. Food Funct 2020; 11:4123-4137. [PMID: 32347870 DOI: 10.1039/d0fo00288g] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Human-like collagen (HLC), the collagen produced using fermentation technology, has been demonstrated previously to promote wound healing. However, the healing property of HLC in gastric ulcers remains to be verified. In this study, we investigated the healing efficacy and healing mechanisms of HLC on gastric ulcers. To investigate whether HLC still has healing activity on gastric ulcers after gastric digestion, we simulated gastric digestion in vitro to obtain a human-like collagen digestion product (HLCP) and used it as the control drug. A chronic gastric ulcer model induced by 60% acetic acid in rats was used to evaluate the healing effect of gastric ulcers in this study. The results showed that oral administration of HLC or HLCP for 4 or 7 days promoted ulcer healing, which can be directly observed by significant reductions in ulcer area. The oral administration of HLC and HLCP significantly increased the protein expression of growth factors (EGF, HGF, VEGF, bFGF and TGF-β1) and the HGF receptor (HGFr), promoted collagen deposition, regulated the activity of NOS, and decreased pro-inflammatory cytokines (TNF-a, il-6, il-10) and endothelin-1 (ET-1) levels in gastric tissue. Moreover, cell experiments showed that the effects of HLC on cell proliferation and migration are mainly caused by its digestion products. These findings indicate that HLC may be used as a nutritional supplement or therapeutic drug to promote the healing of gastric ulcers.
Collapse
Affiliation(s)
- Mimi Xing
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China.
| | | | | | | | | | | | | |
Collapse
|
|
49
|
Hanrahan JP, Seferovic JP, Wakefield JD, Wilson PJ, Chickering JG, Jung J, Carlson KE, Zimmer DP, Frelinger AL, Michelson AD, Morrow L, Hall M, Currie MG, Milne GT, Profy AT. An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension. Diabetologia 2020; 63:733-743. [PMID: 31858186 PMCID: PMC7054374 DOI: 10.1007/s00125-019-05062-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 10/31/2019] [Indexed: 12/17/2022]
Abstract
AIMS/HYPOTHESIS Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension. METHODS This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1-14 (n = 10), or praliciguat 20 mg twice daily for days 1-7 then 40 mg once daily for days 8-14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment. RESULTS Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of -0.7 (-1.8, 0.4) mmol/l for fasting plasma glucose, -0.7 (-1.1, -0.2) mmol/l for total cholesterol, -0.5 (-1.0, -0.1) mmol/l for LDL-cholesterol, -23 (-56, 9) for HOMA-IR in those not being treated with insulin, and -5 (-10, 1) mmHg and 3 (-1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients. CONCLUSIONS/INTERPRETATION In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat. TRIAL REGISTRATION ClinicalTrials.gov NCT03091920. FUNDING This trial was funded by Cyclerion Therapeutics.
Collapse
Affiliation(s)
- John P Hanrahan
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA.
| | - Jelena P Seferovic
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - James D Wakefield
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - Phebe J Wilson
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | | | - Joon Jung
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - Kenneth E Carlson
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - Daniel P Zimmer
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - Andrew L Frelinger
- Center for Platelet Research Studies, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
| | - Alan D Michelson
- Center for Platelet Research Studies, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
| | | | - Michael Hall
- Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Mark G Currie
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - G Todd Milne
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| | - Albert T Profy
- Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA
| |
Collapse
|
|
50
|
Mu J, Zhao X, Zalan Z, Hegyi F, Takács K, Du M. Lactobacillus plantarum KFY02 enhances the relieving effect of gardenoside on montmorillonite induced constipation in mice. RSC Adv 2020; 10:10368-10381. [PMID: 35498605 PMCID: PMC9050385 DOI: 10.1039/c9ra10446a] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/12/2020] [Indexed: 12/19/2022] Open
Abstract
Lactobacillus plantarum KFY02 (KFY02), isolated from naturally fermented milk yoghurt in Korla, Xinjiang, Northwest of China, showed gardenoside action for the intestinal regulation of constipated mice. Comparatively, the effects of KFY02 (0.5 × 108 CFU kg-1, by body weight (BW)), gardenoside (50 mg kg-1, BW), and KFY02 (0.5 × 108 CFU kg-1, BW) + gardenoside (50 mg kg-1, BW) on intestinal regulation in mice with montmorillonite-induced constipation were also studied. Enzyme linked immunoassay, hemotoxylin and eosin (H&E) staining, quantitative polymerase chain reaction (qPCR) assay and high performance liquid chromatography (HPLC) analysis were used for the study. Compared with the model group, KFY02 + genipin (combined group) increased the propelling rate of activated carbon in the small intestines of mice and accelerated the discharge of the first black stool in mice. At the same time, the combination group reduced the levels of motilin (MTL), substance P (SP) and endothelin-1 (ET-1) in the serum, and increased the somatostatin (SS), vasoactive intestinal peptide (VIP), acetylcholinesterase (AchE) and gastrin (Gastrin) levels in the serum, which made these parameters close to those of the normal group. Using qPCR analysis, it was observed that the combined group up-regulated the mRNA expression of endothelial nitric oxide synthase (eNOS), stem cell factor (SCF), stem cell factor receptor (c-Kit), glutathione (GSH), catalase and manganese-superoxide dismutase (Mn-SOD) and down-regulated the expression of inducible nitric oxide synthase (iNOS) and transient receptor potential vanilloid receptor 1 (TRPV1). The combination increased the Bacteroides and Akkermansia abundances and decreased the Firmicutes abundance in the feces of the constipated mice and decreased the Firmicutes/Bacteroides ratio. The expression of the above genes was similar to that of the normal group. The results indicate that KFY02 produced β-glucosidase to hydrolyze the gardenoside glycosidic bond to produce genipin and can effectively promote the regulation of gastrointestinal hormones and intestinal peristalsis and reduce oxidative tissue damage in constipated mice. This study also confirmed that KFY02 has similar relieving effects to gardenoside for constipation in mice.
Collapse
Affiliation(s)
- Jianfei Mu
- College of Food Science, Southwest University Chongqing 400715 China +86-23-68250478
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 China
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 China
| | - Zsolt Zalan
- National Agricultural Research and Innovation Center, Food Science Research Institute Budapest H-1022 Hungary
| | - Ferenc Hegyi
- National Agricultural Research and Innovation Center, Food Science Research Institute Budapest H-1022 Hungary
| | - Krisztina Takács
- National Agricultural Research and Innovation Center, Food Science Research Institute Budapest H-1022 Hungary
| | - Muying Du
- College of Food Science, Southwest University Chongqing 400715 China +86-23-68250478
- Chinese-Hungarian Cooperative Research Centre for Food Science, Southwest University Chongqing 400715 China
| |
Collapse
|