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Stakenborg N, Viola MF, Boeckxstaens G. Intestinal neuron-associated macrophages in health and disease. Nat Immunol 2025:10.1038/s41590-025-02150-6. [PMID: 40399608 DOI: 10.1038/s41590-025-02150-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/14/2025] [Indexed: 05/23/2025]
Abstract
Neuron-macrophage cross-talk in the intestine plays a crucial role in the maintenance of tissue homeostasis and the modulation of immune responses throughout life. Here, we describe how gut neuron-macrophage interactions shift macrophage phenotype and function from early development to adulthood and how this cross-talk modulates the macrophage function in response to infection and inflammation. We highlight how a neural microenvironment instructs a neuron-associated macrophage phenotype in the gut and show that their phenotype may resemble nerve-associated macrophages in other organs. Finally, we note that the loss of neuron-associated macrophages or a shift in their phenotype can contribute to enteric neurodegeneration in the gastrointestinal tract, causing gut motility disorders.
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Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Maria Francesca Viola
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Guy Boeckxstaens
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium.
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2
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Jing S, Chen H, Bao L, Lyu R, Xu B, Pu L, Bian X, Tao L, Wang M. Effects of perioperative ω-3 fish oil fat emulsion on postoperative gastric emptying function following Roux-en-Y reconstruction for gastric cancer. J Gastrointest Surg 2025; 29:102066. [PMID: 40268084 DOI: 10.1016/j.gassur.2025.102066] [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] [Received: 01/15/2025] [Revised: 04/12/2025] [Accepted: 04/14/2025] [Indexed: 04/25/2025]
Abstract
PURPOSE Despite standardized surgical techniques, delayed gastric emptying (DGE) remains a major complication after Roux-en-Y reconstruction in patients with gastric cancer. This study aimed to evaluate the efficacy of ω-3 fish oil fat emulsion in reducing DGE incidence and improving postoperative outcomes. METHODS In this retrospective cohort study, 210 patients undergoing radical gastrectomy with Roux-en-Y reconstruction (Nanjing Drum Tower Hospital, 2018-2020) were stratified into 2 groups: the intervention group (n = 139) received parenteral nutrition (PN) with ω-3 fish oil emulsion (0.2 g/kg/d), whereas controls (n = 71) received standard PN. DGE diagnosis required persistent symptoms (>72 h postoperatively) and objective evidence of impaired motility (computed tomography contrast retention ≥ 50% at 4 h or scintigraphic T½ > 90 min), excluding mechanical obstructions (luminal stenosis < 8 mm). RESULTS The ω-3 group exhibited significantly lower DGE incidence (4.3% vs 15.5%; P =.005) and shorter median postoperative hospital stay (10 vs 13 days; P <.001). Multivariate analysis identified ω-3 supplementation as an independent protective factor against DGE (odds ratio, 0.32; 95% CI, 0.11-0.96; P =.042). Symptom severity (Gastroparesis Cardinal Symptom Index) showed progressive improvement in the ω-3 cohort, with significant reductions in nausea and vomiting scores by week 4 (P <.05). CONCLUSION Perioperative ω-3 fish oil fat emulsion supplementation reduces DGE risk by 71%, accelerates recovery, and improves surgical outcomes in patients with gastric cancer undergoing Roux-en-Y reconstruction. These findings support its integration into enhanced recovery protocols, particularly in high-risk populations.
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Affiliation(s)
- Siqing Jing
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hao Chen
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Linsen Bao
- Department of Pediatric and Hernia Abdominal Wall Surgery, The Bozhou Hospital Affiliated to Anhui Medical University, Bozhou, Anhui Province, China
| | - Ruohan Lyu
- Department of Statistics, Beijing Forestry University, Beijing, China
| | - Boqi Xu
- Department of General Surgery, Suzhou Municipal Hospital, Suzhou, China
| | - Lingxiao Pu
- Department of General Surgery Ⅰ, Jiangyin People's Hospital, Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
| | - Xiaojie Bian
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Liang Tao
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Meng Wang
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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AlAsfoor S, Jessen E, Pullapantula SR, Voisin JR, Hsi LC, Pavelko KD, Farwana S, Patraw JA, Chai XY, Ji S, Strausbauch MA, Cipriani G, Wei L, Linden DR, Hou R, Myers R, Bhattarai Y, Wykosky J, Burns AJ, Dasari S, Farrugia G, Grover M. Mass cytometric analysis of circulating monocyte subsets in a murine model of diabetic gastroparesis. Am J Physiol Gastrointest Liver Physiol 2025; 328:G323-G341. [PMID: 39947648 DOI: 10.1152/ajpgi.00229.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/06/2024] [Accepted: 12/23/2024] [Indexed: 03/14/2025]
Abstract
Circulating monocytes (Mo) are precursors to a subset of gastric resident muscularis macrophages. Changes in muscularis macrophages (MMs) result in delayed gastric emptying (DGE) in diabetic gastroparesis. However, the dynamics of Mo in the development of DGE in an animal model are unknown. Using cytometry by time-of-flight and computational approaches, we show a high heterogeneity within the Mo population. In DGE mice, via unbiased clustering, we identified two reduced Mo clusters that exhibit migratory phenotype (Ly6ChiCCR2hi-intCD62LhiLy6GhiCD45RhiMERTKhiintLGALS3intCD14intCX3CR1lowSiglec-Hint-low) resembling classical Mo (CMo-like). All markers enriched in these clusters are known to regulate cell differentiation, proliferation, adhesion, and migration. Trajectory inference analysis predicted these Mo as precursors to subsequent Mo lineages. In gastric muscle tissue, we demonstrated an increase in the gene expression levels of chemokine receptor C-C chemokine receptor type 2 (Ccr2) and its C-C motif ligand 2 (Ccl2), suggesting increased trafficking of classical-Mo. These findings establish a link between two CMo-like clusters and the development of the DGE phenotype and contribute to a better understanding of the heterogenicity of the Mo population.NEW & NOTEWORTHY Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the Ccr2-Ccl2 axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the Ccr2-Ccl2 axis.
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Affiliation(s)
- Shefaa AlAsfoor
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Erik Jessen
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, United States
| | | | - Jennifer R Voisin
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
| | - Linda C Hsi
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Kevin D Pavelko
- Immune Monitoring Core, Office of Core Shared Services, Mayo Clinic, Rochester, Minnesota, United States
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States
| | - Samera Farwana
- Immune Monitoring Core, Office of Core Shared Services, Mayo Clinic, Rochester, Minnesota, United States
| | - Jack A Patraw
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
| | - Xin-Yi Chai
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Sihan Ji
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, People's Republic of China
| | - Michael A Strausbauch
- Immune Monitoring Core, Office of Core Shared Services, Mayo Clinic, Rochester, Minnesota, United States
| | - Gianluca Cipriani
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Lai Wei
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - David R Linden
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
| | - Ruixue Hou
- Gastrointestinal Drug Discovery Unit, Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
| | - Richard Myers
- Gastrointestinal Drug Discovery Unit, Takeda Development Center Americas, Inc., San Diego, California, United States
| | - Yogesh Bhattarai
- Gastrointestinal Drug Discovery Unit, Takeda Development Center Americas, Inc., San Diego, California, United States
| | - Jill Wykosky
- Gastrointestinal Drug Discovery Unit, Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
| | - Alan J Burns
- Gastrointestinal Drug Discovery Unit, Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States
| | - Surendra Dasari
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States
| | - Gianrico Farrugia
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
| | - Madhusudan Grover
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States
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Abstract
Gastroparesis is a neurogastrointestinal disorder of motility in which patients experience symptoms of nausea, vomiting, bloating, early satiety, postprandial fullness, upper abdominal discomfort or pain, and delayed gastric emptying of solids based on scintigraphy or stable isotope breath test when mechanical obstruction has been excluded. Symptoms of gastroparesis may result from diverse pathophysiological mechanisms, including antroduodenal hypomotility, pylorospasm, increased gastric accommodation, and visceral hypersensitivity. The most common etiologies of gastroparesis are idiopathic, diabetic, and postsurgical, and less frequent causes are neurodegenerative disorders (Parkinson's disease), myopathies (scleroderma, amyloidosis), medication-induced (glucagon-like peptide-1 agonists and opioid agents), and paraneoplastic syndrome. This review addresses pharmacologic management of gastroparesis including prokinetic and antiemetic agents, pharmacologic agents targeting the pylorus, and effects of neuromodulators. SIGNIFICANCE STATEMENT: Gastroparesis is a neurogastrointestinal motility disorder characterized by delayed gastric emptying without mechanical obstruction with numerous upper gastrointestinal symptoms, including nausea and vomiting. The management of gastroparesis involves nutritional support, medications, and procedures. The only Food and Drug Administration-approved medication for gastroparesis is metoclopramide. This article reviews the pharmacology and efficacy of all classes of antiemetics or prokinetic effects used in gastroparesis. There is still a considerable unmet need for efficacious medications specifically for the treatment of gastroparesis, especially in refractory cases.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Kara J Jencks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Zaher H, Quílez del Moral JF, Lemrabet S, Koutchala N, Bencharki B. In Vitro Antiviral Activity of a Silydianin-Rich Extract from Silybum marianum Seeds Against Four Strains of Enteroviruses: EV71, Coxsackievirus B2, Coxsackievirus A10, and Poliovirus SL-1 and Its Impact on Improving Delayed Gastric Emptying in Mice. Antibiotics (Basel) 2025; 14:196. [PMID: 40001439 PMCID: PMC11851915 DOI: 10.3390/antibiotics14020196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/16/2024] [Accepted: 09/19/2024] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Gastroparesis, a chronic digestive disorder characterized by delayed gastric emptying, often results from diabetes, post-surgical complications, autoimmune diseases, and neurological disorders. In approximately 50% of cases, the cause is idiopathic gastroparesis (IGD). Recent studies suggest a link between chronic enteroviral infection and persistent gastrointestinal symptoms, including delayed gastric emptying. This study investigates the effects of a silydianin-rich extract from Silybum marianum seeds on enteroviral infections in vitro and the mitigation of delayed gastric emptying in mice. Silydianin, a key bioactive compound known for its liver-protective and antioxidant properties, has not been extensively studied for its impact on enteroviral infections and gastroparesis. METHODS NMR spectroscopy (1H, 13C, DEPT 135 and 2D, and HSQC) and HRMS identified silydianin as the primary compound, with minor flavonolignans. This study assessed the cytotoxicity and antiviral activity of the extract at various stages of the viral life cycle, including virucidal activity, cell protection, and post-infection effects, using neutral red assays in RD cells, with results confirmed by real-time PCR. The viruses studied included coxsackievirus B2, coxsackievirus A10, poliovirus SL-1, and enterovirus EV71. The impact on delayed gastric emptying was evaluated in a mouse model using doses of 100 and 200 mg/kg compared to a control group receiving physiological saline. RESULTS The silydianin-rich extract showed consistent antiviral activity, with the highest selectivity index (SI) for EV71 (4.08) during virucidal activity. It provided moderate cell protection, with EC50 values ranging from 120.88 to 186.10 µg/mL and SI values from 2.20 to 3.39. Post-infection treatment showed varying efficacy, with coxsackie A10 demonstrating the highest SI (3.90). In vivo, the extract at 200 mg/kg significantly improved gastric emptying to 96.47% and slightly increased gastrointestinal transit from 50.33% to 61.46%. CONCLUSIONS These results suggest that silydianin may be effective for treating enteroviral infections and enhancing intestinal function, making it a promising candidate for gastroparesis treatment and warranting further research.
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Affiliation(s)
- Houda Zaher
- Laboratory of Agro-Alimentary and Health, Faculty of Sciences and Techniques, Hassan First University of Settat, Settat 26000, Morocco;
- Department of Organic Chemistry, Institute of Biotechnology, University of Granada, 18071 Granada, Spain;
- Virology Department, National Institute of Hygiene, Ministry of Health, Rabat 10020, Morocco;
| | | | - Sanae Lemrabet
- Virology Department, National Institute of Hygiene, Ministry of Health, Rabat 10020, Morocco;
| | - Neri Koutchala
- Department of Computer Science and Artificial Intelligence, Technical School of Computer Engineering and Telecommunications, University of Granada, 18071 Granada, Spain;
| | - Bouchaib Bencharki
- Laboratory of Agro-Alimentary and Health, Faculty of Sciences and Techniques, Hassan First University of Settat, Settat 26000, Morocco;
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6
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Lou M, Heuckeroth RO, Tjaden NEB. Neuroimmune Crossroads: The Interplay of the Enteric Nervous System and Intestinal Macrophages in Gut Homeostasis and Disease. Biomolecules 2024; 14:1103. [PMID: 39334870 PMCID: PMC11430413 DOI: 10.3390/biom14091103] [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: 07/31/2024] [Revised: 08/24/2024] [Accepted: 08/25/2024] [Indexed: 09/30/2024] Open
Abstract
A defining unique characteristic of the gut immune system is its ability to respond effectively to foreign pathogens while mitigating unnecessary inflammation. Intestinal macrophages serve as the cornerstone of this balancing act, acting uniquely as both the sword and shield in the gut microenvironment. The GI tract is densely innervated by the enteric nervous system (ENS), the intrinsic nervous system of the gut. Recent advances in sequencing technology have increasingly suggested neuroimmune crosstalk as a critical component for homeostasis both within the gut and in other tissues. Here, we systematically review the ENS-macrophage axis. We focus on the pertinent molecules produced by the ENS, spotlight the mechanistic contributions of intestinal macrophages to gut homeostasis and inflammation, and discuss both existing and potential strategies that intestinal macrophages use to integrate signals from the ENS. This review aims to elucidate the complex molecular basis governing ENS-macrophage signaling, highlighting their cooperative roles in sustaining intestinal health and immune equilibrium.
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Affiliation(s)
- Meng Lou
- Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Abramson Research Center and Department of Pediatrics, Pearlman School of Medicine at the University of Pennsylvania, 3615 Civic Center Blvd, Philadelphia, PA 19004, USA; (R.O.H.); (N.E.B.T.)
| | - Robert O. Heuckeroth
- Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Abramson Research Center and Department of Pediatrics, Pearlman School of Medicine at the University of Pennsylvania, 3615 Civic Center Blvd, Philadelphia, PA 19004, USA; (R.O.H.); (N.E.B.T.)
- Division of Gastroenterology, Nutrition and Hepatology, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19004, USA
| | - Naomi E. Butler Tjaden
- Department of Pediatrics, The Children’s Hospital of Philadelphia Research Institute, Abramson Research Center and Department of Pediatrics, Pearlman School of Medicine at the University of Pennsylvania, 3615 Civic Center Blvd, Philadelphia, PA 19004, USA; (R.O.H.); (N.E.B.T.)
- Division of Gastroenterology, Nutrition and Hepatology, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19004, USA
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Wang Z, Liu C, Hu K, Zuo M, Tian Z, Wei Y, Zhou Q, Li Q. Postoperative delayed gastric emptying: may gut microbiota play a role? Front Cell Infect Microbiol 2024; 14:1449530. [PMID: 39193506 PMCID: PMC11347441 DOI: 10.3389/fcimb.2024.1449530] [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: 06/15/2024] [Accepted: 07/22/2024] [Indexed: 08/29/2024] Open
Abstract
Postoperative delayed gastric emptying is a prevalent complication following surgical procedures, imposing heavy physical and financial burdens on patients. However, current treatment options remain suboptimal. In recent years, an increasing number of studies have highlighted that the gut microbiota and its metabolites are closely associated with postoperative complications. Various factors can disrupt the gut microbiome after surgery. This review discusses the potential mechanisms by which the gut microbiota and their metabolites may contribute to the pathogenesis of postoperative delayed gastric emptying. However, the current knowledge base is limited in terms of fully understanding the exact mechanisms involved. It is therefore evident that further research is required to fully elucidate the role of the gut microbiome in postoperative delayed gastric emptying, with the aim of uncovering new possibilities for preventive measures and therapeutic treatments.
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Affiliation(s)
- Zhiyi Wang
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
- Department of Oncology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chuanbo Liu
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Kaiwen Hu
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Minghuan Zuo
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Zhen Tian
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Yue Wei
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Qin Zhou
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
| | - Quanwang Li
- Graduate School of Beijing, University of Chinese Medicine, Beijing, China
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Akhmetova DR, Rogova A, Tishchenko YA, Mitusova KA, Postovalova AS, Dovbysh OV, Gavrilova NV, Epifanovskaya OS, Pyatiizbyantsev TA, Shakirova AI, Brodskaia AV, Shipilovskikh SA, Timin AS. An investigation of nano- and micron-sized carriers based on calcium carbonate and polylactic acid for oral administration of siRNA. Expert Opin Drug Deliv 2024; 21:1279-1295. [PMID: 39141571 DOI: 10.1080/17425247.2024.2393244] [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: 01/10/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND Oral delivery of small interfering RNAs (siRNAs) draws significant attention, but the gastrointestinal tract (GIT) has many biological barriers that limit the drugs' bioavailability. The aim of this work was to investigate the potential of micro- and nano-sized CaCO3 and PLA carriers for oral delivery of siRNA and reveal a relationship between the physicochemical features of these carriers and their biodistribution. RESEARCH DESIGN AND METHODS In vitro stability of carriers was investigated in simulated gastric and intestinal fluids. Toxicity and cellular uptake were investigated on Caco-2 cells. The biodistribution profiles of the developed CaCO3 and PLA carriers were examined using different visualization methods, including SPECT, fluorescence imaging, radiometry, and histological analysis. The delivery efficiency of siRNA loaded carriers was investigated both in vitro and in vivo. RESULTS Micro-sized carriers were accumulated in the stomach and later localized in the colon tissues. The nanoscale particles (100-250 nm) were distributed in the colon tissues. nPLA was also detected in small intestine. The developed carriers can prevent siRNA from premature degradation in GIT media. CONCLUSION Our results reveal how the physicochemical properties of the particles, including their size and material type can affect their biodistribution profile and oral delivery of siRNA.
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Affiliation(s)
- Darya R Akhmetova
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
- International Research and Education Centre for Physics of Nanostructures, ITMO University, St. Petersburg, Russia
| | - Anna Rogova
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
| | - Yulia A Tishchenko
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
| | - Ksenia A Mitusova
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
| | - Alisa S Postovalova
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
| | - Olesya V Dovbysh
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
| | - Nina V Gavrilova
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, St. Petersburg, Russia
| | - Olga S Epifanovskaya
- Laboratory of gene and cell therapy, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
| | - Timofey A Pyatiizbyantsev
- Laboratory of gene and cell therapy, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
| | - Alena I Shakirova
- Laboratory of gene and cell therapy, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
| | - Alexandra V Brodskaia
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
- Smorodintsev Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, St. Petersburg, Russia
| | - Sergei A Shipilovskikh
- International Research and Education Centre for Physics of Nanostructures, ITMO University, St. Petersburg, Russia
| | - Alexander S Timin
- Laboratory of nano- and microencapsulation of biologically active substances, Peter The Great St. Petersburg Polytechnic University, St. Petersburg, Russia
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Urias Rivera AC, Pizuorno Machado A, Shatila M, Triadafilopoulos G, McQuade JL, Altan M, Zhao D, Wang Y, Shafi MA. The Effect of Immune Checkpoint Inhibitor Therapy on Pre-Existing Gastroparesis and New Onset of Symptoms of Delayed Gastric Emptying. Cancers (Basel) 2024; 16:2658. [PMID: 39123385 PMCID: PMC11311627 DOI: 10.3390/cancers16152658] [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: 06/17/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) can cause myenteric plexopathy, which could result in delayed gastric emptying (GE) and possibly gastroparesis. We assessed the clinical outcomes of patients who had pre-existing gastroparesis or who developed symptoms of delayed GE following ICI therapy. We retrospectively identified adults with ICD-9 and ICD-10 codes for gastroparesis who received ICI therapy between 1 January 2020 and 31 December 2022 at a tertiary cancer center. Of 76 eligible patients, 37 had pre-existing gastroparesis; 39 (0.2% of the more than 18,000 screened) developed symptoms of delayed GE after ICI therapy, of which 27 (69%) patients had an alternative etiology for delayed GE. Four patients (11%) with pre-existing gastroparesis had a flare-up after ICI, and the median time to flare-up was 10.2 months (IQR, 0.7-28.6 months); for patients with new onset of suspected delayed GE after ICI, the median time to symptom onset was 12.8 months (IQR, 4.4-35.5 months). The clinical symptom duration of patients without an alternative etiology (74.5 days (IQR, 21.5-690 days)) and those with an alternative etiology (290 days (IQR, 147-387 days)) did not differ significantly (p = 1.00). Delayed GE after ICI therapy is a rare presentation but has a late onset and a prolonged symptom duration.
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Affiliation(s)
| | - Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.)
| | - George Triadafilopoulos
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.)
| | - Jennifer L. McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mehmet Altan
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Dan Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.)
| | - Mehnaz A. Shafi
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.)
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10
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McKay DM, Defaye M, Rajeev S, MacNaughton WK, Nasser Y, Sharkey KA. Neuroimmunophysiology of the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 2024; 326:G712-G725. [PMID: 38626403 PMCID: PMC11376980 DOI: 10.1152/ajpgi.00075.2024] [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: 03/07/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 04/18/2024]
Abstract
Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.
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Affiliation(s)
- Derek M McKay
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Manon Defaye
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sruthi Rajeev
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Wallace K MacNaughton
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Yasmin Nasser
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A Sharkey
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
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11
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Zhang YX, Zhang YJ, Li M, Tian JX, Tong XL. Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis. J Neurogastroenterol Motil 2024; 30:143-155. [PMID: 38576367 PMCID: PMC10999838 DOI: 10.5056/jnm23100] [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] [Received: 07/06/2023] [Revised: 10/29/2023] [Accepted: 11/06/2023] [Indexed: 04/06/2024] Open
Abstract
Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP.
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Affiliation(s)
- Yu-Xin Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yan-Jiao Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Li
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jia-Xing Tian
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiao-Lin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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12
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Goyal RK, Rattan S. Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders. Am J Physiol Gastrointest Liver Physiol 2024; 326:G398-G410. [PMID: 38290993 PMCID: PMC11213482 DOI: 10.1152/ajpgi.00258.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/15/2024] [Accepted: 01/29/2024] [Indexed: 02/01/2024]
Abstract
Major esophageal disorders involve obstructive transport of bolus to the stomach, causing symptoms of dysphagia and impaired clearing of the refluxed gastric contents. These may occur due to mechanical constriction of the esophageal lumen or loss of relaxation associated with deglutitive inhibition, as in achalasia-like disorders. Recently, immune inflammation has been identified as an important cause of esophageal strictures and the loss of inhibitory neurotransmission. These disorders are also associated with smooth muscle hypertrophy and hypercontractility, whose cause is unknown. This review investigated immune inflammation in the causation of smooth muscle changes in obstructive esophageal bolus transport. Findings suggest that smooth muscle hypertrophy occurs above the obstruction and is due to mechanical stress on the smooth muscles. The mechanostressed smooth muscles release cytokines and other molecules that may recruit and microlocalize mast cells to smooth muscle bundles, so that their products may have a close bidirectional effect on each other. Acting in a paracrine fashion, the inflammatory cytokines induce genetic and epigenetic changes in the smooth muscles, leading to smooth muscle hypercontractility, hypertrophy, and impaired relaxation. These changes may worsen difficulty in the esophageal transport. Immune processes differ in the first phase of obstructive bolus transport, and the second phase of muscle hypertrophy and hypercontractility. Moreover, changes in the type of mechanical stress may change immune response and effect on smooth muscles. Understanding immune signaling in causes of obstructive bolus transport, type of mechanical stress, and associated smooth muscle changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.NEW & NOTEWORTHY Esophageal disorders such as esophageal stricture or achalasia, and diffuse esophageal spasm are associated with smooth muscle hypertrophy and hypercontractility, above the obstruction, yet the cause of such changes is unknown. This review suggests that smooth muscle obstructive disorders may cause mechanical stress on smooth muscle, which then secretes chemicals that recruit, microlocalize, and activate mast cells to initiate immune inflammation, producing functional and structural changes in smooth muscles. Understanding the immune signaling in these changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.
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Affiliation(s)
- Raj K Goyal
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts, United States
- Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts, United States
| | - Satish Rattan
- Department of Medicine, Division of Gastroenterology and Hepatology, Sidney Kummel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, United States
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13
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Chikkamenahalli LL, Jessen E, Bernard CE, Ip WE, Breen-Lyles M, Cipriani G, Pullapantula SR, Li Y, AlAsfoor S, Wilson L, Koch KL, Kuo B, Shulman RJ, Chumpitazi BP, McKenzie TJ, Kellogg TA, Tonascia J, Hamilton FA, Sarosiek I, McCallum R, Parkman HP, Pasricha PJ, Abell TL, Farrugia G, Dasari S, Grover M, the NIDDK Gastroparesis Clinical Research Consortium (GpCRC). Single cell atlas of human gastric muscle immune cells and macrophage-driven changes in idiopathic gastroparesis. iScience 2024; 27:108991. [PMID: 38384852 PMCID: PMC10879712 DOI: 10.1016/j.isci.2024.108991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 11/17/2023] [Accepted: 01/17/2024] [Indexed: 02/23/2024] Open
Abstract
Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with the enteric nervous system and influence gastrointestinal motility. Here we determine the human gastric muscle immunome and its changes in patients with idiopathic gastroparesis (IG). Single cell sequencing was performed on 26,000 CD45+ cells obtained from the gastric tissue of 20 subjects. We demonstrate 11 immune cell clusters with T cells being most abundant followed by myeloid cells. The proportions of cells belonging to the 11 clusters were similar between IG and controls. However, 9/11 clusters showed 578-11,429 differentially expressed genes. In IG, MM had decreased expression of tissue-protective and microglial genes and increased the expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in the activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis were upregulated. Patients with IG had a greater abundance of monocyte-like cells. These data further link immune dysregulation to the pathophysiology of gastroparesis.
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Affiliation(s)
| | - Erik Jessen
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Cheryl E. Bernard
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - W.K. Eddie Ip
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Margaret Breen-Lyles
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Gianluca Cipriani
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Suraj R. Pullapantula
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Ying Li
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Shefaa AlAsfoor
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Laura Wilson
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | | | - Braden Kuo
- Massachusetts General Hospital, Boston, MA, USA
| | | | | | | | | | - James Tonascia
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Frank A. Hamilton
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Irene Sarosiek
- Texas Tech University Health Sciences Center, El Paso, TX, USA
| | | | | | | | | | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Surendra Dasari
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - the NIDDK Gastroparesis Clinical Research Consortium (GpCRC)
- Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
- Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
- Wake Forest University, Winston-Salem, NC, USA
- Massachusetts General Hospital, Boston, MA, USA
- Baylor College of Medicine, Houston, TX, USA
- Duke University, Durham, NC, USA
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
- Texas Tech University Health Sciences Center, El Paso, TX, USA
- Temple University, Philadelphia, PA, USA
- Mayo Clinic, Scottsdale, AZ, USA
- University of Louisville, Louisville, KY, USA
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14
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Kumar KP, Wilson JL, Nguyen H, McKay LD, Wen SW, Sepehrizadeh T, de Veer M, Rajasekhar P, Carbone SE, Hickey MJ, Poole DP, Wong CHY. Stroke Alters the Function of Enteric Neurons to Impair Smooth Muscle Relaxation and Dysregulates Gut Transit. J Am Heart Assoc 2024; 13:e033279. [PMID: 38258657 PMCID: PMC11056134 DOI: 10.1161/jaha.123.033279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/05/2023] [Indexed: 01/24/2024]
Abstract
BACKGROUND Gut dysmotility is common after ischemic stroke, but the mechanism underlying this response is unknown. Under homeostasis, gut motility is regulated by the neurons of the enteric nervous system that control contractile/relaxation activity of muscle cells in the gut wall. More recently, studies of gut inflammation revealed interactions of macrophages with enteric neurons are also involved in modulating gut motility. However, whether poststroke gut dysmotility is mediated by direct signaling to the enteric nervous system or indirectly via inflammatory macrophages is unknown. METHODS AND RESULTS We examined these hypotheses by using a clinically relevant permanent intraluminal midcerebral artery occlusion experimental model of stroke. At 24 hours after stroke, we performed in vivo and ex vivo gut motility assays, flow cytometry, immunofluorescence, and transcriptomic analysis. Stroke-induced gut dysmotility was associated with recruitment of muscularis macrophages into the gastrointestinal tract and redistribution of muscularis macrophages away from myenteric ganglia. The permanent intraluminal midcerebral artery occlusion model caused changes in gene expression in muscularis macrophages consistent with an altered phenotype. While the size of myenteric ganglia after stroke was not altered, myenteric neurons from post-permanent intraluminal midcerebral artery occlusion mice showed a reduction in neuronal nitric oxide synthase expression, and this response was associated with enhanced intestinal smooth muscle contraction ex vivo. Finally, chemical sympathectomy with 6-hydroxydopamine prevented the loss of myenteric neuronal nitric oxide synthase expression and stroke-induced slowed gut transit. CONCLUSIONS Our findings demonstrate that activation of the sympathetic nervous system after stroke is associated with reduced neuronal nitric oxide synthase expression in myenteric neurons, resulting in impaired smooth muscle relaxation and dysregulation of gut transit.
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Affiliation(s)
- Kathryn Prame Kumar
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
| | - Jenny L. Wilson
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
| | - Huynh Nguyen
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
| | - Liam D. McKay
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
| | - Shu Wen Wen
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
| | | | - Michael de Veer
- Monash Biomedical ImagingMonash UniversityClaytonVictoriaAustralia
| | - Pradeep Rajasekhar
- Centre for Dynamic ImagingWalter and Eliza Hall Institute of Medical ResearchParkvilleVictoriaAustralia
| | - Simona E. Carbone
- Drug Discovery Biology, Faculty of Pharmacy and Pharmaceutical SciencesMonash Institute of Pharmaceutical Sciences, Monash UniversityParkvilleVictoriaAustralia
| | - Michael J. Hickey
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
| | - Daniel P. Poole
- Drug Discovery Biology, Faculty of Pharmacy and Pharmaceutical SciencesMonash Institute of Pharmaceutical Sciences, Monash UniversityParkvilleVictoriaAustralia
| | - Connie H. Y. Wong
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical CentreMonash UniversityClaytonVictoriaAustralia
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15
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Wang Y, Kong Q, Zhang Q, Ma T, An Y, Zhou YJ, Zhang X, Cao B. BPI 23-Fcγ alleviates lethal multi-drug-resistant Acinetobacter baumannii infection by enhancing bactericidal activity and orchestrating neutrophil function. Int J Antimicrob Agents 2024; 63:107002. [PMID: 37838150 DOI: 10.1016/j.ijantimicag.2023.107002] [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: 03/16/2023] [Revised: 09/22/2023] [Accepted: 10/01/2023] [Indexed: 10/16/2023]
Abstract
Antibiotic resistance has become a major threat, contributing significantly to morbidity and mortality globally. Administering non-antibiotic therapy, such as antimicrobial peptides, is one potential strategy for effective treatment of multi-drug-resistant Gram-negative bacterial infections. Bactericidal/permeability-increasing protein (BPI) derived from neutrophils has bactericidal and endotoxin-neutralizing activity. However, the protective roles and mechanisms of BPI in multi-drug-resistant bacterial infections have not been fully elucidated. In this study, a chimeric BPI23-Fcγ recombined protein comprising the functional N terminus of BPI and Fcγ was constructed and expressed by adenovirus vector 5 (Ad5). Ad5-BPI23-Fcγ or recombinant BPI23-Fcγ protein significantly improved the survival of mice with pneumonia induced by a minimal lethal dose of multi-drug-resistant Acinetobacter baumannii or Klebsiella pneumoniae by ameliorating lung pathology and reducing pro-inflammatory cytokines. Transfection with Ad5-BPI23-Fcγ significantly decreased the bacterial load and endotoxaemia, which was associated with enhanced bactericidal ability and elevated the phagocytic activity of neutrophils in vitro and in vivo. In addition, Ad5-BPI23-Fcγ transfection significantly increased the recruitment of neutrophils to lung, increased the proportion and number of neutrophils in peripheral blood, and promoted the maturation of bone marrow (BM) neutrophils after drug-resistant A. baumannii infection. BPI23-Fcγ and neutrophils synergistically enhanced bactericidal activity and decreased pro-inflammatory cytokines. These results demonstrated that the chimeric BPI23-Fcγ protein protected mice from pneumonia induced by multi-drug-resistant A. baumannii infection by direct bactericidal effects and promotion of neutrophil recruitment, phagocytosis and maturation. Chimeric BPI23-Fcγ may be a promising candidate as a non-antibiotic biological agent for multi-drug-resistant A. baumannii infection.
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Affiliation(s)
- Yang Wang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Qingli Kong
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Qi Zhang
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Tianxiao Ma
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Yunqing An
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yu-Jie Zhou
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xulong Zhang
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
| | - Bin Cao
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China; Department of Pulmonary and Critical Care Medicine, Centre of Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Centre for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China; Tsinghua University School of Medicine, Beijing, China; Changping Laboratory, Beijing, China.
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16
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Gao F, Hayashi Y, Saravanaperumal SA, Gajdos GB, Syed SA, Bhagwate AV, Ye Z, Zhong J, Zhang Y, Choi EL, Kvasha SM, Kaur J, Paradise BD, Cheng L, Simone BW, Wright AM, Kellogg TA, Kendrick ML, McKenzie TJ, Sun Z, Yan H, Yu C, Bharucha AE, Linden DR, Lee JH, Ordog T. Hypoxia-Inducible Factor 1α Stabilization Restores Epigenetic Control of Nitric Oxide Synthase 1 Expression and Reverses Gastroparesis in Female Diabetic Mice. Gastroenterology 2023; 165:1458-1474. [PMID: 37597632 PMCID: PMC10840755 DOI: 10.1053/j.gastro.2023.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 07/18/2023] [Accepted: 08/09/2023] [Indexed: 08/21/2023]
Abstract
BACKGROUND & AIMS Although depletion of neuronal nitric oxide synthase (NOS1)-expressing neurons contributes to gastroparesis, stimulating nitrergic signaling is not an effective therapy. We investigated whether hypoxia-inducible factor 1α (HIF1A), which is activated by high O2 consumption in central neurons, is a Nos1 transcription factor in enteric neurons and whether stabilizing HIF1A reverses gastroparesis. METHODS Mice with streptozotocin-induced diabetes, human and mouse tissues, NOS1+ mouse neuroblastoma cells, and isolated nitrergic neurons were studied. Gastric emptying of solids and volumes were determined by breath test and single-photon emission computed tomography, respectively. Gene expression was analyzed by RNA-sequencing, microarrays, immunoblotting, and immunofluorescence. Epigenetic assays included chromatin immunoprecipitation sequencing (13 targets), chromosome conformation capture sequencing, and reporter assays. Mechanistic studies used Cre-mediated recombination, RNA interference, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated epigenome editing. RESULTS HIF1A signaling from physiological intracellular hypoxia was active in mouse and human NOS1+ myenteric neurons but reduced in diabetes. Deleting Hif1a in Nos1-expressing neurons reduced NOS1 protein by 50% to 92% and delayed gastric emptying of solids in female but not male mice. Stabilizing HIF1A with roxadustat (FG-4592), which is approved for human use, restored NOS1 and reversed gastroparesis in female diabetic mice. In nitrergic neurons, HIF1A up-regulated Nos1 transcription by binding and activating proximal and distal cis-regulatory elements, including newly discovered super-enhancers, facilitating RNA polymerase loading and pause-release, and by recruiting cohesin to loop anchors to alter chromosome topology. CONCLUSIONS Pharmacologic HIF1A stabilization is a novel, translatable approach to restoring nitrergic signaling and treating diabetic gastroparesis. The newly recognized effects of HIF1A on chromosome topology may provide insights into physioxia- and ischemia-related organ function.
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Affiliation(s)
- Fei Gao
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Department of Gastroenterology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Yujiro Hayashi
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Siva Arumugam Saravanaperumal
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Gabriella B Gajdos
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Sabriya A Syed
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Aditya V Bhagwate
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Zhenqing Ye
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Jian Zhong
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Yuebo Zhang
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Egan L Choi
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Sergiy M Kvasha
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Jagneet Kaur
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Brooke D Paradise
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Liang Cheng
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Brandon W Simone
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Alec M Wright
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Todd A Kellogg
- Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | | | | | - Zhifu Sun
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Huihuang Yan
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Chuanhe Yu
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Adil E Bharucha
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - David R Linden
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Jeong-Heon Lee
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota; Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Tamas Ordog
- Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
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17
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Zhou L, Lian H, Yin Y, Zheng YS, Han YX, Liu GQ, Wang ZY. New insights into muscularis macrophages in the gut: from their origin to therapeutic targeting. Immunol Res 2023; 71:785-799. [PMID: 37219708 DOI: 10.1007/s12026-023-09397-x] [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: 02/10/2023] [Accepted: 05/15/2023] [Indexed: 05/24/2023]
Abstract
Muscularis macrophages, as the most abundant immune cells in the intestinal muscularis externa, exhibit tissue protective phenotype in the steady state. Owing to tremendous advances in technology, we now know the fact that muscularis macrophages are a heterogeneous population of cells which could be divided into different functional subsets depending on their anatomic niches. There is emerging evidence showing that these subsets, through molecular interactions with their neighbours, take part in a wide range of physiological and pathophysiological processes in the gut. In this review, we summarize recent progress (particularly over the past 4 years) on distribution, morphology, origin and functions of muscularis macrophages and, where possible, the characteristics of specific subsets in response to the microenvironment they occupy, with particular emphasis on their role in muscular inflammation. Furthermore, we also integrate their role in inflammation-related gastrointestinal disorders, such as post-operative ileus and diabetic gastroparesis, in order to propose future therapeutic strategies.
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Affiliation(s)
- Li Zhou
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Hui Lian
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yue Yin
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yuan-Sheng Zheng
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yu-Xin Han
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Gao-Qi Liu
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Zhi-Yong Wang
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
- Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, 453003, China.
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Li M, Gao N, Wang S, Guo Y, Liu Z. A global bibliometric and visualized analysis of the status and trends of gastroparesis research. Eur J Med Res 2023; 28:543. [PMID: 38017518 PMCID: PMC10683151 DOI: 10.1186/s40001-023-01537-1] [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: 11/26/2022] [Accepted: 11/17/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Gastroparesis has a substantial impact on the quality of life but has limited treatment options, which makes it a public health concern. No bibliometric studies on gastroparesis have been published thus far. Thus, this article aims to summarize and analyze research hotspots to provide a reference for clinical researchers. MATERIALS AND METHODS Gastroparesis-related research articles were searched in the Web of Science Core Collection (WOSCC), and relevant information was extracted after screening. A total of 1033 documents were analyzed with the bibliometric method using Microsoft Excel, Citespace, and VOSviewer. RESULTS Overall, our search retrieved 1033 papers contributed by 966 research institutions from 53 countries. Since 1980, publications in this field have increased rapidly. United States (n = 645) and Temple University (n = 122) were the most productive country and institution, respectively. Parkman, with 96 publications, was the most prominent author. CONCLUSIONS Research hotspots in gastroparesis can be summarized into four domains: innovation in diagnostic modalities, change of oral therapeutic agents, choice of surgical interventions, and pathological mechanisms. Future research on gastroparesis should focus on the quality of life of patients, diagnostic techniques, pyloromyotomy, and transpyloric stent placement.
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Affiliation(s)
- Meng Li
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange St., Xicheng District, Beijing, 100053, China
| | - Ning Gao
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange St., Xicheng District, Beijing, 100053, China
| | - Shaoli Wang
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange St., Xicheng District, Beijing, 100053, China
| | - Yufeng Guo
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange St., Xicheng District, Beijing, 100053, China.
| | - Zhen Liu
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange St., Xicheng District, Beijing, 100053, China.
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19
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Li X, Ji S, Cipriani G, Hillestad ML, Eisenman ST, Barry MA, Nath KA, Linden DR, Wright A, AlAsfoor S, Grover M, Sha L, Hsi LC, Farrugia G. Adeno-associated virus-9 reverses delayed gastric emptying of solids in diabetic mice. Neurogastroenterol Motil 2023; 35:e14669. [PMID: 37702100 PMCID: PMC10841310 DOI: 10.1111/nmo.14669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 06/07/2023] [Accepted: 08/14/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Gastroparesis is defined by delayed gastric emptying (GE) without obstruction. Studies suggest targeting heme oxygenase-1 (HO1) may ameliorate diabetic gastroparesis. Upregulation of HO1 expression via interleukin-10 (IL-10) in the gastric muscularis propria is associated with reversal of delayed GE in diabetic NOD mice. IL-10 activates the M2 cytoprotective phenotype of macrophages and induces expression of HO1 protein. Here, we assess delivery of HO1 by recombinant adeno-associated viruses (AAVs) in diabetic mice with delayed GE. METHODS C57BL6 diabetic delayed GE mice were injected with 1 × 1012 vg scAAV9-cre, scAAV9-GFP, or scAAV9-HO1 particles. Changes to GE were assessed weekly utilizing our [13 C]-octanoic acid breath test. Stomach tissue was collected to assess the effect of scAAV9 treatment on Kit, NOS1, and HO1 expression. KEY RESULTS Delayed GE returned to normal within 2 weeks of treatment in 7/12 mice receiving scAAV9-cre and in 4/5 mice that received the scAAV9-GFP, whereas mice that received scAAV9-HO1 did not respond in the same manner and had GE that took significantly longer to return to normal (6/7 mice at 4-6 weeks). Kit, NOS1, and HO1 protein expression in scAAV9-GFP-treated mice with normal GE were not significantly different compared with diabetic mice with delayed GE. CONCLUSIONS AND INFERENCES Injection of scAAV9 into diabetic C57BL6 mice produced a biological response that resulted in acceleration of GE independently of the cargo delivered by the AAV9 vector. Further research is needed to determine whether use of AAV mediated gene transduction in the gastric muscularis propria is beneficial and warranted.
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Affiliation(s)
- Xiaojie Li
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Sihan Ji
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Gianluca Cipriani
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | | | - Seth T. Eisenman
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Michael A. Barry
- Department of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Mn, USA
| | - Karl A. Nath
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
- Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Mn, USA
| | - David R. Linden
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Alec Wright
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
| | - Shefaa AlAsfoor
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Madhusudan Grover
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Lei Sha
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Linda C. Hsi
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
| | - Gianrico Farrugia
- Department of Medicine, Division of Gastroenterology and Hepatology, Enteric Neuroscience Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Mn, USA
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20
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Edwards PT, Soni KG, Conner ME, Fowler SW, Foong JPP, Stavely R, Cheng LS, Preidis GA. Site-specific pathophysiology in a neonatal mouse model of gastroparesis. Neurogastroenterol Motil 2023; 35:e14676. [PMID: 37772676 PMCID: PMC11023621 DOI: 10.1111/nmo.14676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 07/30/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023]
Abstract
BACKGROUND Early-life events impact maturation of the gut microbiome, enteric nervous system, and gastrointestinal motility. We examined three regions of gastric tissue to determine how maternal separation and gut microbes influence the structure and motor function of specific regions of the neonatal mouse stomach. METHODS Germ-free and conventionally housed C57BL/6J mouse pups underwent timed maternal separation (TmSep) or nursed uninterrupted (controls) until 14 days of life. We assessed gastric emptying by quantifying the progression of gavaged fluorescein isothiocyanate (FITC)-dextran. With isolated rings of forestomach, corpus, and antrum, we measured tone and contractility by force transduction, gastric wall thickness by light microscopy, and myenteric plexus neurochemistry by whole-mount immunostaining. KEY RESULTS Regional gastric sampling revealed site-specific differences in contractile patterns and myenteric plexus structure. In neonatal mice, TmSep prolonged gastric emptying. In the forestomach, TmSep increased contractile responses to carbachol, decreased muscularis externa and mucosa thickness, and increased the relative proportion of myenteric plexus nNOS+ neurons. Germ-free conditions did not appreciably alter the structure or function of the neonatal mouse stomach and did not impact the changes caused by TmSep. CONCLUSIONS AND INFERENCES A regional sampling approach facilitates site-specific investigations of murine gastric motor physiology and histology to identify site-specific alterations that may impact gastrointestinal function. Delayed gastric emptying in TmSep is associated with a thinner muscle wall, exaggerated cholinergic contractile responses, and increased proportions of inhibitory myenteric plexus nNOS+ neurons in the forestomach. Gut microbes do not profoundly affect the development of the neonatal mouse stomach or the gastric pathophysiology that results from TmSep.
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Affiliation(s)
- Price T. Edwards
- Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
| | - Krishnakant G. Soni
- Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
| | - Margaret E. Conner
- Molecular Virology and Microbiology, Department of Education, Innovation and Technology, Baylor College of Medicine, Houston, TX, USA
| | - Stephanie W. Fowler
- Molecular Virology and Microbiology, Department of Education, Innovation and Technology, Baylor College of Medicine, Houston, TX, USA
| | - Jaime P. P. Foong
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, Vic., Australia
| | - Rhian Stavely
- Department of Pediatric Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lily S. Cheng
- Michael E. DeBakey Department of Surgery, Division of Pediatric Surgery, Texas Children’s Surgical Oncology Program, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
| | - Geoffrey A. Preidis
- Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
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21
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Xu S, Liang S, Pei Y, Wang R, Zhang Y, Xu Y, Huang B, Li H, Li J, Tan B, Cao H, Guo S. TRPV1 Dysfunction Impairs Gastric Nitrergic Neuromuscular Relaxation in High-Fat Diet-Induced Diabetic Gastroparesis Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:548-557. [PMID: 36740184 DOI: 10.1016/j.ajpath.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/30/2022] [Accepted: 01/06/2023] [Indexed: 02/05/2023]
Abstract
Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food. Nitrergic neuron-mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in DGP. Transient receptor potential vanilloid 1 (TRPV1) ion channels are expressed in gastrointestinal vagal afferent nerves and have a potential role in relevant gastrointestinal disorders. In this study, mice with high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM), associated with gastroparesis, were used to determine the role of TRPV1 in DGP. After feeding with HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic neuron-mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was attenuated. Interestingly, activating or suppressing TRPV1 facilitated or inhibited gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increased or reduced NO release. TRPV1 was specifically localized with neuronal NOS in the gastric fundus. These data suggest that TRPV1 activation facilitates gastric fundus relaxation by regulating neuronal NOS and promoting NO release. However, these effects and mechanisms disappeared in mice with DGP induced by HFD diet. TRPV1 expression was only marginally decreased in the fundus of DGP mice. TRPV1 dysfunction may be a potential mechanism underlying the dysfunction of DGP gastric nitrergic neuromuscular relaxation.
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Affiliation(s)
- Siyuan Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Shaochan Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Pei
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yifei Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bin Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Haiwen Li
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Juanjuan Li
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bo Tan
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongying Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Shaoju Guo
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China.
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22
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Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev 2023; 103:1487-1564. [PMID: 36521049 PMCID: PMC9970663 DOI: 10.1152/physrev.00018.2022] [Citation(s) in RCA: 138] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gary M Mawe
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
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23
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Zhou B, Mo Z, Lai G, Chen X, Li R, Wu R, Zhu J, Zheng F. Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-𝜅B-IL-6 axis of tumor-associated macrophages. J Exp Clin Cancer Res 2023; 42:48. [PMID: 36797769 PMCID: PMC9936722 DOI: 10.1186/s13046-023-02620-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 02/09/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have important regulatory functions in cancer, but the role of circRNAs in the tumor microenvironment (TME) remains unclear. Moreover, we also explore the effects of si-circRNAs loaded in nanoparticles as therapeutic agent for anti-tumor in vivo. METHODS We conducted bioinformatics analysis, qRT-PCR, EdU assays, Transwell assays, co-culture system and multiple orthotopic xenograft models to investigate the expression and function of circRNAs. Additionally, PLGA-based nanoparticles loaded with si-circRNAs were used to evaluate the potential of nanotherapeutic strategy in anti-tumor response. RESULTS We identified oncogene SERPINE2 derived circRNA, named as cSERPINE2, which was notably elevated in breast cancer and was closely related to poor clinical outcome. Functionally, tumor exosomal cSERPINE2 was shuttled to tumor associated macrophages (TAMs) and enhanced the secretion of Interleukin-6 (IL-6), leading to increased proliferation and invasion of breast cancer cells. Furthermore, IL-6 in turn increased the EIF4A3 and CCL2 levels within tumor cells in a positive feedback mechanism, further enhancing tumor cSERPINE2 biogenesis and promoting the recruitment of TAMs. More importantly, we developed a PLGA-based nanoparticle loaded with si-cSERPINE2, which effectively attenuated breast cancer progression in vivo. CONCLUSIONS Our study illustrates a novel mechanism that tumor exosomal cSERPINE2 mediates a positive feedback loop between tumor cells and TAMs to promote cancer progression, which may serve as a promising nanotherapeutic strategy for the treatment of breast cancer.
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Affiliation(s)
- Boxuan Zhou
- grid.452437.3Department of Breast Surgery, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000 China ,grid.412536.70000 0004 1791 7851Medical Research Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China
| | - Zhaohong Mo
- grid.412558.f0000 0004 1762 1794Department of Hepatobiliary Surgery, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630 China
| | - Guie Lai
- grid.452437.3Department of Breast Surgery, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000 China
| | - Xiaohong Chen
- grid.452437.3Department of Laboratory, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000 China
| | - Ruixi Li
- grid.12981.330000 0001 2360 039XDepartment of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033 China
| | - Runxin Wu
- grid.12981.330000 0001 2360 039XZhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080 China
| | - Jia Zhu
- Department of Breast Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
| | - Fang Zheng
- Medical Research Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
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24
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Chavero-Pieres M, Viola MF, Appeltans I, Abdurahiman S, Gsell W, Matteoli G, Himmelreich U, Boeckxstaens G. Magnetic resonance imaging as a non-invasive tool to assess gastric emptying in mice. Neurogastroenterol Motil 2023; 35:e14490. [PMID: 36371706 PMCID: PMC10078537 DOI: 10.1111/nmo.14490] [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] [Received: 07/19/2022] [Revised: 10/04/2022] [Accepted: 10/18/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Methods to study gastric emptying in rodents are time consuming or terminal, preventing repetitive assessment in the same animal. Magnetic resonance imaging (MRI) is a non-invasive technique increasingly used to investigate gastrointestinal function devoid of these shortcomings. Here, we evaluated MRI to measure gastric emptying in control animals and in two different models of gastroparesis. METHODS Mice were scanned using a 9.4 Tesla MR scanner. Gastric volume was measured by delineating the stomach lumen area. Control mice were scanned every 30 min after ingestion of a 0.2 g meal and stomach volume was quantified. The ability of MRI to detect delayed gastric emptying was evaluated in models of morphine-induced gastroparesis and streptozotocin-induced diabetes. KEY RESULTS Magnetic resonance imaging reproducibly detected increased gastric volume following ingestion of a standard meal and progressively decreased with a half emptying time of 59 ± 5 min. Morphine significantly increased gastric volume measured at t = 120 min (saline: 20 ± 2 vs morphine: 34 ± 5 mm3 ; n = 8-10; p < 0.001) and increased half emptying time using the breath test (saline: 85 ± 22 vs morphine: 161 ± 46 min; n = 10; p < 0.001). In diabetic mice, gastric volume assessed by MRI at t = 60 min (control: 23 ± 2 mm3 ; n = 14 vs diabetic: 26 ± 5 mm3 ; n = 18; p = 0.014) but not at t = 120 min (control: 21 ± 3 mm3 ; n = 13 vs diabetic: 18 ± 5 mm3 ; n = 18; p = 0.115) was significantly increased compared to nondiabetic mice. CONCLUSIONS AND INFERENCES Our data indicate that MRI is a reliable and reproducible tool to assess gastric emptying in mice and represents a useful technique to study gastroparesis in disease models or for evaluation of pharmacological compounds.
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Affiliation(s)
- Marta Chavero-Pieres
- Laboratory for Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium
| | - Maria Francesca Viola
- Laboratory for Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium
| | - Iris Appeltans
- Laboratory for Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium
| | - Saeed Abdurahiman
- Laboratory for Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium
| | - Willy Gsell
- Biomedical MRI Unit, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Laboratory for Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium
| | - Uwe Himmelreich
- Biomedical MRI Unit, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Laboratory for Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium
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25
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Hou Y, Meng X, Sun K, Zhao M, Liu X, Yang T, Zhang Z, Su R. Anti-cancer effects of ginsenoside CK on acute myeloid leukemia in vitro and in vivo. Heliyon 2022; 8:e12106. [PMID: 36544827 PMCID: PMC9761710 DOI: 10.1016/j.heliyon.2022.e12106] [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: 08/01/2022] [Revised: 10/17/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Objectives Acute myeloid leukemia (AML) is a malignant disease characterized by clonal proliferation of myeloid cells, and its treatment continues to be a challenge due to high morbidity and mortality. Ginsenoside compound K, a major active metabolite of the protopanaxadiol-type ginsenosides, exhibits biological activities in various cancer cells and animal models. Here, we investigated the role of CK in anticancer potential in AML both in vitro and in vivo. Materials and methods To investigate the inhibitory effects of CK in AML cells, in vitro experiments, including cell viability assays, colony forming assays, and cell cycle and apoptosis assays were performed. AML animal experiment was established and quantitative analysis of lung tumor growth nodules and spleen weight and H&E staining were carried out to further determine the effects of CK on AML. In addition, the potential key genes induced and influenced by CK during treatment was identification by RNA-seq and qRT-PCR. Results CK suppressed AML cell activity and induced apoptosis and G1 cell cycle arrest based on the experiment results. Moreover, significantly down-regulated expression genes of BCL2, KIT, DNMT3A, MYC and CSF-1 and up-regulated expression gene of TET2 in CK treatment AML cells were discovered. Conclusion Our results demonstrated that CK could be used as an anti-AML drug with significant therapeutic efficacy and good biosafety.
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Affiliation(s)
- Yuzhu Hou
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Xiangru Meng
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Kaiju Sun
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Mingyue Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Xin Liu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Tongtong Yang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
| | - Zhe Zhang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
- Corresponding author.
| | - Rui Su
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130017, China
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130012, China
- Corresponding author.
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26
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Bishop ES, Namkoong H, Aurelian L, McCarthy M, Nallagatla P, Zhou W, Neshatian L, Gurland B, Habtezion A, Becker L. Age-dependent Microglial Disease Phenotype Results in Functional Decline in Gut Macrophages. GASTRO HEP ADVANCES 2022; 2:261-276. [PMID: 36908772 PMCID: PMC10003669 DOI: 10.1016/j.gastha.2022.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/15/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND AND AIMS Muscularis macrophages (MMs) are tissue-resident macrophages in the gut muscularis externa which play a supportive role to the enteric nervous system. We have previously shown that age-dependent MM alterations drive low-grade enteric nervous system inflammation, resulting in neuronal loss and disruption of gut motility. The current studies were designed to identify the MM genetic signature involved in these changes, with particular emphasis on comparison to genes in microglia, the central nervous system macrophage population involved in age-dependent cognitive decline. METHODS Young (3 months) and old (16-24 months) C57BL/6 mice and human tissue were studied. Immune cells from mouse small intestine, colon, and spinal cord and human colon were dissociated, immunophenotyped by flow cytometry, and examined for gene expression by single-cell RNA sequencing and quantitative real-time PCR. Phagocytosis was assessed by in vivo injections of pHrodo beads (Invitrogen). Macrophage counts were performed by immunostaining of muscularis whole mounts. RESULTS MMs from young and old mice express homeostatic microglial genes, including Gpr34, C1qc, Trem2, and P2ry12. An MM subpopulation that becomes more abundant with age assumes a geriatric state (GS) phenotype characterized by increased expression of disease-associated microglia genes including Cd9, Clec7a, Itgax (CD11c), Bhlhe40, Lgals3, IL-1β, and Trem2 and diminished phagocytic activity. Acquisition of the GS phenotype is associated with clearance of α-synuclein aggregates. Human MMs demonstrate a similar age-dependent acquisition of the GS phenotype associated with intracellular α-synuclein accumulation. CONCLUSION MMs demonstrate age-dependent genetic changes that mirror the microglial disease-associated microglia phenotype and result in functional decline.
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Affiliation(s)
- Estelle Spear Bishop
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California
| | - Hong Namkoong
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California
| | - Laure Aurelian
- Stanford University School of Medicine OFDD, Stanford, California
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Madison McCarthy
- Department of Surgery, Stanford University, Stanford, California
| | - Pratima Nallagatla
- Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California
| | - Wenyu Zhou
- Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California
- Department of Genetics, Stanford University, Stanford, California
| | - Leila Neshatian
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California
| | - Brooke Gurland
- Department of Surgery, Stanford University, Stanford, California
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California
| | - Laren Becker
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, California
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27
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Delfini M, Stakenborg N, Viola MF, Boeckxstaens G. Macrophages in the gut: Masters in multitasking. Immunity 2022; 55:1530-1548. [PMID: 36103851 DOI: 10.1016/j.immuni.2022.08.005] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/17/2022] [Accepted: 08/09/2022] [Indexed: 11/05/2022]
Abstract
The gastrointestinal tract has the important task of absorbing nutrients, a complex process that requires an intact barrier allowing the passage of nutrients but that simultaneously protects the host against invading microorganisms. To maintain and regulate intestinal homeostasis, the gut is equipped with one of the largest populations of macrophages in the body. Here, we will discuss our current understanding of intestinal macrophage heterogeneity and describe their main functions in the different anatomical niches of the gut during steady state. In addition, their role in inflammatory conditions such as infection, inflammatory bowel disease, and postoperative ileus are discussed, highlighting the roles of macrophages in immune defense. To conclude, we describe the interaction between macrophages and the enteric nervous system during development and adulthood and highlight their contribution to neurodegeneration in the context of aging and diabetes.
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Affiliation(s)
- Marcello Delfini
- Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Maria Francesca Viola
- Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium.
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28
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Nguyen VTT, Taheri N, Chandra A, Hayashi Y. Aging of enteric neuromuscular systems in gastrointestinal tract. Neurogastroenterol Motil 2022; 34:e14352. [PMID: 35279912 PMCID: PMC9308104 DOI: 10.1111/nmo.14352] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 01/12/2022] [Accepted: 02/09/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Aging is a complex biological process and associated with a progressive decline in functions of most organs including the gastrointestinal (GI) tract. Age-related GI motor disorders/dysfunctions include esophageal reflux, dysphagia, constipation, fecal incontinence, reduced compliance, and accommodation. Although the incidence and severity of these diseases and conditions increase with age, they are often underestimated due in part to nonspecific and variable symptoms and lack of sufficient medical attention. They negatively affect quality of life and predispose the elderly to other diseases, sarcopenia, and frailty. The mechanisms underlying aging-associated GI dysfunctions remain unclear, and there is limited data examining the effect of aging on GI motor functions. Many studies on aging-associated changes to cells within the tunica muscularis including enteric neurons, smooth muscles, and interstitial cells have proposed that cell loss and/or molecular changes may be involved in the pathogenesis of age-related GI motor disorders/dysfunctions. There is also evidence that the aging contributes to phenotypic changes in innate immune cells, which are physically and functionally linked to other cells in the tunica muscularis and can alter GI (patho) physiology. However, various patterns of changes have been reported, some of which are contradictory, indicating a need for additional work in this area. PURPOSE Although GI infection due to intestinal bacterial overgrowth, bleeding, and cancers are also important and common problems in the elderly patients, this mini-review focuses on data obtained from enteric neuromuscular aging research with the goal of better understanding the cellular and molecular mechanisms of enteric neuromuscular aging to enhance future therapy.
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Affiliation(s)
- Vy Truong Thuy Nguyen
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, USA,Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Negar Taheri
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, USA,Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Abhishek Chandra
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Yujiro Hayashi
- Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, USA,Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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29
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Mercado-Perez A, Beyder A. Gut feelings: mechanosensing in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2022; 19:283-296. [PMID: 35022607 PMCID: PMC9059832 DOI: 10.1038/s41575-021-00561-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/22/2021] [Indexed: 12/11/2022]
Abstract
The primary function of the gut is to procure nutrients. Synchronized mechanical activities underlie nearly all its endeavours. Coordination of mechanical activities depends on sensing of the mechanical forces, in a process called mechanosensation. The gut has a range of mechanosensory cells. They function either as specialized mechanoreceptors, which convert mechanical stimuli into coordinated physiological responses at the organ level, or as non-specialized mechanosensory cells that adjust their function based on the mechanical state of their environment. All major cell types in the gastrointestinal tract contain subpopulations that act as specialized mechanoreceptors: epithelia, smooth muscle, neurons, immune cells, and others. These cells are tuned to the physical properties of the surrounding tissue, so they can discriminate mechanical stimuli from the baseline mechanical state. The importance of gastrointestinal mechanosensation has long been recognized, but the latest discoveries of molecular identities of mechanosensors and technical advances that resolve the relevant circuitry have poised the field to make important intellectual leaps. This Review describes the mechanical factors relevant for normal function, as well as the molecules, cells and circuits involved in gastrointestinal mechanosensing. It concludes by outlining important unanswered questions in gastrointestinal mechanosensing.
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Affiliation(s)
- Arnaldo Mercado-Perez
- Enteric NeuroScience Program (ENSP), Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
- Medical Scientist Training Program (MSTP), Mayo Clinic, Rochester, MN, USA
| | - Arthur Beyder
- Enteric NeuroScience Program (ENSP), Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA.
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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30
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Mischopoulou M, D'Ambrosio M, Bigagli E, Luceri C, Farrugia G, Cipriani G. Role of Macrophages and Mast Cells as Key Players in the Maintenance of Gastrointestinal Smooth Muscle Homeostasis and Disease. Cell Mol Gastroenterol Hepatol 2022; 13:1849-1862. [PMID: 35245688 PMCID: PMC9123576 DOI: 10.1016/j.jcmgh.2022.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/18/2022]
Abstract
The gut contains the largest macrophage pool in the body, with populations of macrophages residing in the mucosa and muscularis propria of the gastrointestinal (GI) tract. Muscularis macrophages (MMs), which are located within the muscularis propria, interact with cells essential for GI function, such as interstitial cells of Cajal, enteric neurons, smooth muscle cells, enteric glia, and fibroblast-like cells, suggesting that these immune cells contribute to several aspects of GI function. This review focuses on the latest insights on the factors contributing to MM heterogeneity and the functional interaction of MMs with other cell types essential for GI function. This review integrates the latest findings on macrophages in other organs with increasing knowledge of MMs to better understand their role in a healthy and diseased gut. We describe the factors that contribute to (muscularis macrophage) MM heterogeneity, and the nature of MM interactions with cells regulating GI function. Finally, we also describe the increasing evidence suggesting a critical role of another immune cell type, the mast cell, in normal and diseased GI physiology.
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Affiliation(s)
| | - Mario D'Ambrosio
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Elisabetta Bigagli
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Cristina Luceri
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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31
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Carbone SE. Neurons, Macrophages, and Glia: The Role of Intercellular Communication in the Enteric Nervous System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:251-258. [PMID: 36587164 DOI: 10.1007/978-3-031-05843-1_24] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Neurons of the enteric nervous system (ENS) are the primary controllers of gastrointestinal functions. Although the ENS has been the central focus of research areas such as motility, this has now expanded to include the modulatory roles that non-neuronal cells have on neuronal function. This review discusses how enteric glia (EGC) and resident muscularis macrophages (mMacs) influence ENS communication. It highlights how the understanding of neuroglia interactions has extended beyond EGCs responding to exogenously applied neurotransmitters. Proposed mechanisms for neuron-EGC and glio-glia communication are discussed. The significance of these interactions is evidenced by gut functions that rely on these processes. mMacs are commonly known for their roles as immune cells which sample and respond to changes in the tissue environment. However, a more recent theory suggests that mMacs and enteric neurons are mutually dependent for their maintenance and function. This review summarizes the supportive and contradictory evidence for this theory, including potential mechanisms for mMac-neuron interaction. The need for a more thorough classification scheme to define how the "state" of mMacs relates to neuron loss or impaired function in disease is discussed. Despite the growing literature suggesting EGCs and mMacs have supportive or modulatory roles in ENS communication and gut function, conflicting evidence from different groups suggests more investigation is required. A broader understanding of why enteric neurons may need assistance from EGCs and mMacs in neurotransmission is still missing.
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Affiliation(s)
- Simona Elisa Carbone
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
- Monash University, Parkville, VIC, Australia.
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32
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Li Z, Jia Y, Zhu H, Xing X, Pang F, Shan F, Li S, Wang D, Zhao F, Ma T, Wang S, Ji J. Tumor mutation burden is correlated with response and prognosis in microsatellite-stable (MSS) gastric cancer patients undergoing neoadjuvant chemotherapy. Gastric Cancer 2021; 24:1342-1354. [PMID: 34406546 DOI: 10.1007/s10120-021-01207-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. METHODS We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. RESULTS High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). CONCLUSION The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated with better DFS, and can be evaluated at the time of diagnosis.
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Affiliation(s)
- Ziyu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Yongning Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Honglin Zhu
- Genetron Health (Beijing) Technology, Co. Ltd, Beijing, 102206, China
| | - Xiaofang Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Center for Molecular Diagnostics, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Fei Pang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Fei Shan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Shuangxi Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Danhua Wang
- Genetron Health (Beijing) Technology, Co. Ltd, Beijing, 102206, China
| | - Fangping Zhao
- Genetron Health (Beijing) Technology, Co. Ltd, Beijing, 102206, China
| | - Tonghui Ma
- Genetron Health (Beijing) Technology, Co. Ltd, Beijing, 102206, China
| | - Sizhen Wang
- Genetron Health (Beijing) Technology, Co. Ltd, Beijing, 102206, China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
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Li Y, Jiang MY, Chen JY, Xu ZW, Zhang JW, Li T, Zhang LL, Wei W. CP-25 exerts therapeutic effects in mice with dextran sodium sulfate-induced colitis by inhibiting GRK2 translocation to downregulate the TLR4-NF-κB-NLRP3 inflammasome signaling pathway in macrophages. IUBMB Life 2021; 73:1406-1422. [PMID: 34590407 DOI: 10.1002/iub.2564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/26/2022]
Abstract
Deficiency of G protein-coupled receptor kinase 2 (GRK2) was found to protect mice from dextran sulfate sodium (DSS)-induced colitis. Paeoniflorin-6'-O-benzene sulfonate (CP-25) has been shown to exert anti-inflammatory immune regulatory effects in animal models of inflammatory autoimmune disease. This study aimed to investigate the of GRK2 in the pathogenesis of ulcerative colitis (UC) and its effects on macrophage polarization, macrophage subtype regulation of intestinal barrier function, and therapeutic effects of CP-25 in mice with DSS-induced colitis. We found imbalanced macrophage polarization, intestinal barrier dysfunction, and abnormal activation of GRK2 and TLR4-NF-κB-NLRP3 inflammasome signaling pathway in the colonic mucosa of patients with UC. CP-25, restored the damaged intestinal barrier function by inhibiting the transmembrane region of GRK2 in macrophages stimulated by lipopolysaccharides. CP-25 exerted therapeutic effects by ameliorating clinical manifestation, regulating macrophage polarization, and restoring abnormally activated TLR4-NF-κB-NLRP3 inflammasome signaling pathway by inhibiting GRK2. These data suggest the pathogenesis of UC may be related to the imbalance of macrophage polarization, which leads to abnormal activation of TLR4-NF-κB-NLRP3 inflammasome signaling pathway mediated by GRK2 and destruction of the intestinal mucosal barrier. CP-25 confers therapeutic effects on colitis by inhibiting GRK2 translocation to induce the downregulation of TLR4-NF-κB-NLRP3 inflammasome signaling in macrophages.
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Affiliation(s)
- Ying Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China
| | - Meng-Ya Jiang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China
| | - Jing-Yu Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China
| | - Zhou-Wei Xu
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jia-Wei Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China.,Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tao Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China.,Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ling-Ling Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicines, Hefei, China
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Nitric Oxide: From Gastric Motility to Gastric Dysmotility. Int J Mol Sci 2021; 22:ijms22189990. [PMID: 34576155 PMCID: PMC8470306 DOI: 10.3390/ijms22189990] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/11/2021] [Accepted: 09/13/2021] [Indexed: 12/27/2022] Open
Abstract
It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better understanding of their involvement in gastric pathophysiological conditions of hypo- or hyper-motility states and for future therapeutic approaches. A possible role of substances which, by interfering with NO production, could prove useful in managing such motor disorders has been advanced.
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35
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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.
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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.
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36
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Hou W, Li J, Cao Z, Lin S, Pan C, Pang Y, Liu J. Decorating Bacteria with a Therapeutic Nanocoating for Synergistically Enhanced Biotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101810. [PMID: 34365713 DOI: 10.1002/smll.202101810] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 06/09/2021] [Indexed: 06/13/2023]
Abstract
Disorders in the gut microbiota have been implicated in various diseases, such as inflammatory bowel diseases, diabetes, and cancers. Oral microecologics are of great importance due to their ability to directly intervene the gut microbiome as well as their noninvasiveness and low side effects, while have suffered from low bioavailability and a single therapeutic effect. Here, probiotics are coated with a therapeutic nanocoating for synergistically enhanced biotherapy, a method inspired by the robust protective and therapeutic effectiveness of silkworm cocoon. With its transition from a random coil to β-sheet conformation, silk fibroin can self-assemble onto the surface of bacteria. By a simple layer-by-layer procedure, an entire nanocoating can be formed along with a near quantitative coating ratio and almost uninfluenced bacterial viability. Thanks to its protective barrier role and innate pharmaceutical activity, silk fibroin nanocoating endows the coated bacteria with a markedly improved survival against gastric insults and a synergistically enhanced therapeutic effect in a murine model of intestinal mucositis. This work demonstrates how therapeutic elements can be combined with probiotics via a simple coating strategy and proposes an alternative to enhance bioavailability and treatment efficacy of oral microecologics.
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Affiliation(s)
- Weiliang Hou
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Juanjuan Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Zhenping Cao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Sisi Lin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Chao Pan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Yan Pang
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China
| | - Jinyao Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
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Camilleri M, Atieh J. New Developments in Prokinetic Therapy for Gastric Motility Disorders. Front Pharmacol 2021; 12:711500. [PMID: 34504426 PMCID: PMC8421525 DOI: 10.3389/fphar.2021.711500] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/10/2021] [Indexed: 12/13/2022] Open
Abstract
Prokinetic agents amplify and coordinate the gastrointestinal muscular contractions to facilitate the transit of intra-luminal content. Following the institution of dietary recommendations, prokinetics are the first medications whose goal is to improve gastric emptying and relieve symptoms of gastroparesis. The recommended use of metoclopramide, the only currently approved medication for gastroparesis in the United States, is for a duration of less than 3 months, due to the risk of reversible or irreversible extrapyramidal tremors. Domperidone, a dopamine D2 receptor antagonist, is available for prescription through the FDA's program for Expanded Access to Investigational Drugs. Macrolides are used off label and are associated with tachyphylaxis and variable duration of efficacy. Aprepitant relieves some symptoms of gastroparesis. There are newer agents in the pipeline targeting diverse gastric (fundic, antral and pyloric) motor functions, including novel serotonergic 5-HT4 agonists, dopaminergic D2/3 antagonists, neurokinin NK1 antagonists, and ghrelin agonist. Novel targets with potential to improve gastric motor functions include the pylorus, macrophage/inflammatory function, oxidative stress, and neurogenesis. In the current review, we discuss the use of pharmacological approaches with potential to enhance motor functions in the management of gastroparesis.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
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Viola MF, Boeckxstaens G. Niche-specific functional heterogeneity of intestinal resident macrophages. Gut 2021; 70:1383-1395. [PMID: 33384336 PMCID: PMC8223647 DOI: 10.1136/gutjnl-2020-323121] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 12/22/2022]
Abstract
Intestinal resident macrophages are at the front line of host defence at the mucosal barrier within the gastrointestinal tract and have long been known to play a crucial role in the response to food antigens and bacteria that are able to penetrate the mucosal barrier. However, recent advances in single-cell RNA sequencing technology have revealed that resident macrophages throughout the gut are functionally specialised to carry out specific roles in the niche they occupy, leading to an unprecedented understanding of the heterogeneity and potential biological functions of these cells. This review aims to integrate these novel findings with long-standing knowledge, to provide an updated overview on our understanding of macrophage function in the gastrointestinal tract and to speculate on the role of specialised subsets in the context of homoeostasis and disease.
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Affiliation(s)
- Maria Francesca Viola
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (Chrometa), KU Leuven, Leuven, Flanders, Belgium
| | - Guy Boeckxstaens
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (Chrometa), KU Leuven, Leuven, Flanders, Belgium
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Song S, An J, Liu S. Electroacupuncture accelerates the delayed intestinal transit in POI by suppressing M1 like muscularis macrophages and IL6 secretion. Neurogastroenterol Motil 2021; 33:e14066. [PMID: 33483984 DOI: 10.1111/nmo.14066] [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] [Received: 08/10/2020] [Revised: 10/22/2020] [Accepted: 11/19/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Electroacupuncture (EA) at ST-36 could accelerate the delayed gastrointestinal (GI) motility in many GI motility dysfunction models, but the definite effect and mechanisms are unclear. In this study, we intended to investigate the effects of EA on intestinal manipulation (IM) mice model and involved mechanisms. METHODS Male C57BL/6 mice were randomized into five groups: normal control, intestinal manipulation (IM), IM with sham EA (SEA), IM with high-frequency EA (HEA), and IM with low-frequency EA (LEA). The GI transit was evaluated. The infiltration of muscularis macrophages (MMφ) and its phenotype were analyzed with flow cytometry. Magnetic-activated cell sorting was applied to isolate MMφ, and the relationship between the MMφ and interstitial cells of Cajal (ICCs) was further investigated. RESULTS (1) Compared with the IM group, HEA and LEA attenuated the delayed intestinal transit. (2) Both the HEA and LEA obviously reduced the MMφ and suppressed the M1 activation of the MMφ in the ileum. (3) EA restored the disrupted ICC networks through inhibiting the release of IL6 by the MMφ. CONCLUSION (1) Electroacupuncture at acupoint ST-36 could accelerate the delayed intestinal transit in the IM murine model by restoring the ICC networks. (2) EA protected the ICCs through reducing the MMφ, inhibiting its M1 polarization and its IL6 secretion.
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Affiliation(s)
- Shuangning Song
- Division of Gastroenterology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing An
- Division of Gastroenterology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shi Liu
- Division of Gastroenterology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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40
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Abstract
Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aim was to ascertain whether epigenetic alterations in whole blood discriminate among patients with DM with normal, delayed, and rapid gastric emptying (GE).
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Chen Q, Jiang Z, Zhang J, Cao L, Chen Z. Arecoline hydrobromide enhances jejunum smooth muscle contractility via voltage-dependent potassium channels in W/Wv mice. Physiol Res 2021; 70:437-446. [PMID: 33982580 DOI: 10.33549/physiolres.934557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Gastrointestinal motility was disturbed in W/Wv, which were lacking of interstitial cells of Cajal (ICC). In this study, we have investigated the role of arecoline hydrobromide (AH) on smooth muscle motility in the jejunum of W/Wv and wild-type (WT) mice. The jejunum tension was recorded by an isometric force transducer. Intracellular recording was used to identify whether AH affects slow wave and resting membrane potential (RMP) in vitro. The whole-cell patch clamp technique was used to explore the effects of AH on voltage-dependent potassium channels for jejunum smooth muscle cells. AH enhanced W/Wv and WT jejunum contractility in a dose-dependent manner. Atropine and nicardipine completely blocked the excitatory effect of AH in both W/Wv and WT. TEA did not reduce the effect of AH in WT, but was sufficient to block the excitatory effect of AH in W/Wv. AH significantly depolarized the RMP of jejunum cells in W/Wv and WT. After pretreatment with TEA, the RMP of jejunum cells indicated depolarization in W/Wv and WT, but subsequently perfused AH had no additional effect on RMP. AH inhibited the voltage-dependent K+ currents of acutely isolated mouse jejunum smooth muscle cells. Our study demonstrate that AH enhances the contraction activity of jejunum smooth muscle, an effect which is mediated by voltage-dependent potassium channels that acts to enhance the excitability of jejunum smooth muscle cells in mice.
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Affiliation(s)
- Q Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.
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Affiliation(s)
- Raj K Goyal
- From the Division of Gastroenterology, Department of Medicine, Veterans Affairs Boston Healthcare System, West Roxbury, and the Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston - both in Massachusetts
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Campbell NJ, Malpartida JC, Davis MG. Trying to stomach multiple myeloma: A case report. J Family Med Prim Care 2021; 10:1785-1788. [PMID: 34123929 PMCID: PMC8144781 DOI: 10.4103/jfmpc.jfmpc_2201_20] [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: 10/24/2020] [Revised: 12/05/2020] [Accepted: 12/18/2020] [Indexed: 11/16/2022] Open
Abstract
We report a case of a 51-year-old male with minimal past medical history who presented to his primary care provider with nausea, vomiting and constipation in the outpatient setting. Concomitantly, he was found to have a renal injury, anemia and lytic lesions which were confirmed to be due to multiple myeloma. After further investigation of the gastrointestinal symptoms, he was diagnosed with gastroparesis. This case represents an unusual presentation of gastroparesis, diagnosed at the same time as multiple myeloma, for which there has yet to be a published association. Here we detail the case, review gastric emptying physiology, the diagnostic criteria for gastroparesis and hypothesize the connection if it might have with multiple myeloma.
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Affiliation(s)
- Nicholas J Campbell
- College of Medicine Chattanooga, The University of Tennessee Health Science Center, Chattanooga, TN 37403, USA
| | - Juan C Malpartida
- College of Medicine Chattanooga, The University of Tennessee Health Science Center, Chattanooga, TN 37403, USA
| | - Michael G Davis
- College of Medicine Chattanooga, The University of Tennessee Health Science Center, Chattanooga, TN 37403, USA
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Ji S, Traini C, Mischopoulou M, Gibbons SJ, Ligresti G, Faussone-Pellegrini MS, Sha L, Farrugia G, Vannucchi MG, Cipriani G. Muscularis macrophages establish cell-to-cell contacts with telocytes/PDGFRα-positive cells and smooth muscle cells in the human and mouse gastrointestinal tract. Neurogastroenterol Motil 2021; 33:e13993. [PMID: 33020982 PMCID: PMC7902307 DOI: 10.1111/nmo.13993] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 07/22/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Muscularis macrophages (MMs) not only mediate the innate immunity, but also functionally interact with cells important for gastrointestinal motility. The aim of this study was to determine the spatial relationship and types of contacts between the MMs and neighboring cells in the muscularis propria of human and mouse stomach, small intestine, and large intestine. METHODS The distribution and morphology of MMs and their contacts with other cells were investigated by immunohistochemistry and transmission electron microscopy. KEY RESULTS Immunohistochemistry showed variable shape and number of MMs according to their location in different portions of the muscle coat. By double labeling, a close association between MMs and neighboring cells, that is, neurons, smooth muscle cells, interstitial cells of Cajal (ICCs), telocytes (TCs)/PDGFRα-positive cells, was seen. Electron microscopy demonstrated that in the muscle layers of both animal species, MMs have similar ultrastructural features and have specialized cell-to-cell contacts with smooth muscle cells and TCs/PDGFRα-positive cells but not with ICCs and enteric neurons. CONCLUSION & INFERENCES This study describes varying patterns of distribution of MMs between different regions of the gut, and reports the presence of distinct and extended cell-to-cell contacts between MMs and smooth muscle cells and between MMs and TCs/PDGFRα-positive cells. In contrast, MMs, although close to ICCs and nerve elements, did not make contact with them. These findings indicate specialized and variable roles for MMs in the modulation of gastrointestinal motility whose significance should be more closely investigated in normal and pathological conditions.
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Affiliation(s)
- Sihan Ji
- Enteric NeuroScience Program, Mayo Clinic, Rochester, Minnesota, USA,Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Chiara Traini
- Department of Experimental and Clinical Medicine, Research Unit of Histology and Embryology, University of Florence, Italy
| | | | - Simon J. Gibbons
- Enteric NeuroScience Program, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Lei Sha
- Department of Neuroendocrine Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China,Corresponding authors: Gianluca Cipriani, PhD, Mayo Clinic, Enteric NeuroScience Program, 200 First Street SW, Rochester, MN 55905, 507-210-6402, ; Maria Giuliana Vannucchi MD, PhD, Research Unit of Histology and Embryology, Dept of Experimental and Clinical Medicine, Viale G. Pieraccini,6, 50139 Florence, Italy, ; Lei Sha, MD, China Medical University, Department of Neuroendocrine Pharmacology, School of Pharmacy, Shenyang, Liaoning, China, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning province, P. R. China,110122, 18900911003,
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Mayo Clinic, Rochester, Minnesota, USA
| | - Maria Giuliana Vannucchi
- Department of Experimental and Clinical Medicine, Research Unit of Histology and Embryology, University of Florence, Italy,Corresponding authors: Gianluca Cipriani, PhD, Mayo Clinic, Enteric NeuroScience Program, 200 First Street SW, Rochester, MN 55905, 507-210-6402, ; Maria Giuliana Vannucchi MD, PhD, Research Unit of Histology and Embryology, Dept of Experimental and Clinical Medicine, Viale G. Pieraccini,6, 50139 Florence, Italy, ; Lei Sha, MD, China Medical University, Department of Neuroendocrine Pharmacology, School of Pharmacy, Shenyang, Liaoning, China, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning province, P. R. China,110122, 18900911003,
| | - Gianluca Cipriani
- Enteric NeuroScience Program, Mayo Clinic, Rochester, Minnesota, USA,Corresponding authors: Gianluca Cipriani, PhD, Mayo Clinic, Enteric NeuroScience Program, 200 First Street SW, Rochester, MN 55905, 507-210-6402, ; Maria Giuliana Vannucchi MD, PhD, Research Unit of Histology and Embryology, Dept of Experimental and Clinical Medicine, Viale G. Pieraccini,6, 50139 Florence, Italy, ; Lei Sha, MD, China Medical University, Department of Neuroendocrine Pharmacology, School of Pharmacy, Shenyang, Liaoning, China, 77 Pu He Road, Shenbei New District, Shenyang, Liaoning province, P. R. China,110122, 18900911003,
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Wang H, Zhao K, Ba Y, Gao T, Shi N, Niu Q, Liu C, Chen Y. Gastric Electrical Pacing Reduces Apoptosis of Interstitial Cells of Cajal via Antioxidative Stress Effect Attributing to Phenotypic Polarization of M2 Macrophages in Diabetic Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1298657. [PMID: 33728017 PMCID: PMC7937455 DOI: 10.1155/2021/1298657] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 02/08/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Gastric electrical pacing (GEP) could restore interstitial cells of Cajal in diabetic rats. M2 macrophages contribute to the repair of interstitial cells of Cajal injury though secreting heme oxygenase-1 (HO-1). The aim of the study is to investigate the effects and mechanisms of gastric electrical pacing on M2 macrophages in diabetic models. METHODS Sixty male Sprague-Dawley rats were randomized into control, diabetic (DM), diabetic with the sham GEP (DM+SGEP), diabetic with GEP1 (5.5 cpm, 100 ms, 4 mA) (DM+GEP1), diabetic with GEP2 (5.5 cpm, 300 ms, 4 mA) (DM+GEP2), and diabetic with GEP3 (5.5 cpm, 550 ms, 4 mA) (DM+GEP3) groups. The apoptosis of interstitial cells of Cajal and the expression of macrophages were detected by immunofluorescence technique. The expression levels of the Nrf2/HO-1 and NF-κB pathway were evaluated using western blot analysis or immunohistochemical method. Malonaldehyde, superoxide dismutase, and reactive oxygen species were tested to reflect the level of oxidative stress. RESULTS Apoptosis of interstitial cells of Cajal was increased in the DM group but significantly decreased in the DM+GEP groups. The total number of macrophages was almost the same in each group. In the DM group, M1 macrophages were increased and M2 macrophages were decreased. However, M2 macrophages were dramatically increased and M1 macrophages were reduced in the DM+GEP groups. Gastric electrical pacing improved the Nrf2/HO-1 pathway and downregulated the phosphorylation of NF-κB. In the DM group, the levels of malonaldehyde and reactive oxygen species were elevated and superoxide dismutase was lowered, while gastric electrical pacing reduced the levels of malonaldehyde and reactive oxygen species and improved superoxide dismutase. CONCLUSION Gastric electrical pacing reduces apoptosis of interstitial cells of Cajal though promoting M2 macrophages polarization to play an antioxidative stress effect in diabetic rats, which associates with the activated Nrf2/HO-1 pathway and the phosphorylation of NF-κB pathway.
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Affiliation(s)
- Hongcai Wang
- Department of Neurology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Kaile Zhao
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Ying Ba
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Tao Gao
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Ning Shi
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Qiong Niu
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Chengxia Liu
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
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Pontikos A, Jayakumar P, Rios Perez C, Barker H, Hughes M, Yang X, Fraig M, Stocker A, McElmurray L, Pinkston C, Thomas A. Gastric Electrical Stimulation Has an Effect on Gastric Interstitial cells of Cajal (ICC) That is Associated With Mast Cells. Cureus 2020; 12:e11458. [PMID: 33329956 PMCID: PMC7733771 DOI: 10.7759/cureus.11458] [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] [Indexed: 11/21/2022] Open
Abstract
Introduction Gastric electrical stimulation (GES) is an emerging therapy for gastric motility disorders, showing improvement of gastroparesis related symptoms in previous studies. Interstitial cells of Cajal (ICC) and mast cells have been shown to have a relevant role in gastroparesis pathogenesis. However, the exact effects of GES in those cells is relatively unknown. Methods Full thickness biopsies (FTBx) of 20 patients with refractory gastroparesis were obtained at the time of GES placement and repeated when the device was exchanged (mean of 22.5 months between biopsies). A patient-reported outcomes survey was obtained during each office visit during this period. All biopsies were stained with cluster of differentiation 117 (CD117), S100, and mast cell tryptase antibodies and were analyzed. Results Half of the patients had a significant increase of ICC during the repeated biopsy compared with baseline (p=0.01) and the other half had significant decrease in ICC levels (p=0.006) but there was no noticeable difference in mast cells counts at baseline between groups. Mast cells analysis was performed in two different groups depending on ICC change from the baseline biopsy (CD117 increase vs CD117 decrease). There was only a significant increase of mast cells count within the CD117 worsened ICC group (p=0.007). Conclusion No significant increase in the number of mast cells count seen in patients who received a GES may indicate an improvement in overall inflammation in patients with refractory gastroparesis after GES placement.
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Affiliation(s)
- Alex Pontikos
- Gastroenterology, University of Louisville, Louisville, USA
| | | | | | - Heather Barker
- Gastroenterology, University of Louisville, Louisville, USA
| | - Michael Hughes
- Gastroenterology, University of Louisville, Louisville, USA
| | - Xiu Yang
- Gastroenterology, University of Louisville, Louisville, USA
| | - Mostafa Fraig
- Gastroenterology, University of Louisville, Louisville, USA
| | | | | | | | - Abell Thomas
- Gastroenterology, University of Louisville, Louisville, USA
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Chikkamenahalli LL, Pasricha PJ, Farrugia G, Grover M. Gastric Biopsies in Gastroparesis: Insights into Gastric Neuromuscular Disorders to Aid Treatment. Gastroenterol Clin North Am 2020; 49:557-570. [PMID: 32718570 PMCID: PMC7387746 DOI: 10.1016/j.gtc.2020.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The cellular and molecular understanding of human gastroparesis has markedly improved due to studies on full-thickness gastric biopsies. A decrease in the number of interstitial cells of Cajal (ICC) and functional changes in ICC constitutes the hallmark cellular feature of gastroparesis. More recently, in animal models, macrophages have also been identified to play a central role in development of delayed gastric emptying. Activation of macrophages leads to loss of ICC. In human gastroparesis, loss of anti-inflammatory macrophages in gastric muscle has been shown. Deeper molecular characterization using transcriptomics and proteomics has identified macrophage-based immune dysregulation in human gastroparesis.
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Affiliation(s)
- Lakshmikanth L. Chikkamenahalli
- Enteric NeuroScience Program, Mayo clinic, Division of Gastroenterology & Hepatology, Physiology & Biomedical Engineering Mayo Clinic, 200 1 Street SW, Rochester, MN 55905, Tel: +1 507-538-0337
| | - Pankaj J. Pasricha
- Center for Neurogastroenterology, Division of Gastroenterology & Hepatology Johns Hopkins School of Medicine, Ross 958, 720 Rutland Avenue, Baltimore, MD 21205, Tel: +1 443-613-8152
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Division of Gastroenterology & Hepatology, Physiology & Biomedical Engineering Mayo Clinic, 200 1 Street SW, Rochester, MN 55905, Tel: +1 507-284-4695
| | - Madhusudan Grover
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA; Division of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA.
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Kim TH. Toward an Improved Treatment for Gastroparesis. J Neurogastroenterol Motil 2020; 26:297-298. [PMID: 32606252 PMCID: PMC7329150 DOI: 10.5056/jnm20129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/12/2020] [Indexed: 11/20/2022] Open
Affiliation(s)
- Tae-Han Kim
- Department of Surgery, Gyeongsang National University School of Medicine, Changwon, Gyeongsangnam-do, Korea
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49
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Wu X, Yang Z, Li Z, Yang L, Wang X, Wang C, Gu J. Increased expression of hypoxia inducible factor-1 alpha and vascular endothelial growth factor is associated with diabetic gastroparesis. BMC Gastroenterol 2020; 20:216. [PMID: 32650726 PMCID: PMC7350597 DOI: 10.1186/s12876-020-01368-y] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/02/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Gastroparesis is a recognized complication of diabetes but its pathogenic mechanism incompletely understood. Our aim was to determine whether HIF-1α and VEGF are secreted from gastric tissue is a fundamental factor that drives diabetic gastroparesis. METHODS Diabetes was induced in Sprague-Dawley by a single intraperitoneal injection of 65 mg/kg streptozotocin. After 4 and 12 weeks, rats were euthanized for assaying body weight, blood glucose, gastric acid secretion and gastric emptying. Morphologic changes in gastric mucosa were observed by the light microscope. Expression of HIF-1α and VEGF were assessed using immunohistochemistry, RT-PCR and Western blot analyses. RESULTS Compared with control group, blood glucose were significantly increased and body weight were markedly decreased in streptozotocin-induced diabetes. Gastric emptying was significantly decreased in diabetic rats compared to the control group at different times. The number of parietal cells was obviously decreased, and vacuolated degeneration in diabetic rats. Gastric acid secretion in diabetic group was significantly decreased, and expression of HIF-1α and VEGF were significantly increased in the diabetic group. CONCLUSION These results indicated that overexpression of HIF-1α and VEGF in the gastric mucosa and played a pivotal role in the progression of diabetic gastroparesis.
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Affiliation(s)
- Xueping Wu
- Department of Anatomy, Histology and Embryology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
| | - Zhifang Yang
- Department of Physiology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
| | - Zhihong Li
- Department of Anatomy, Histology and Embryology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
| | - Ling Yang
- Department of Anatomy, Histology and Embryology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
| | - Xinyan Wang
- Department of Anatomy, Histology and Embryology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
| | - Congrong Wang
- Department of Anatomy, Histology and Embryology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
| | - Jun Gu
- Department of Anatomy, Histology and Embryology, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New District, Shanghai, China
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50
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Liu W, Jin Y, Wilde PJ, Hou Y, Wang Y, Han J. Mechanisms, physiology, and recent research progress of gastric emptying. Crit Rev Food Sci Nutr 2020; 61:2742-2755. [DOI: 10.1080/10408398.2020.1784841] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Weilin Liu
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Yangyi Jin
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Peter J. Wilde
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
- Food Innovation and Health Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich, UK
| | - Yingying Hou
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Yanping Wang
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Jianzhong Han
- School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
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