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Zhao SQ, Zheng HL, Zhong XT, Wang ZY, Su Y, Shi YY. Effects and mechanisms of Helicobacter pylori infection on the occurrence of extra-gastric tumors. World J Gastroenterol 2024; 30:4090-4103. [DOI: 10.3748/wjg.v30.i37.4090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/23/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024] Open
Abstract
Helicobacter pylori (H. pylori) colonizes the human stomach and many studies have discussed the mechanisms of H. pylori infection leading to gastric diseases, including gastric cancer. Additionally, increasing data have shown that the infection of H. pylori may contribute to the development of extra-gastric diseases and tumors. Inflammation, systemic immune responses, microbiome disorders, and hypergastrinemia caused by H. pylori infection are associated with many extra-gastric malignancies. This review highlights recent discoveries; discusses the relationship between H. pylori and various extra-gastric tumors, such as colorectal cancer, lung cancer, cholangiocarcinoma, and gallbladder carcinoma; and explores the mechanisms of extra-gastric carcinogenesis by H. pylori. Overall, these findings refine our understanding of the pathogenic processes of H. pylori, provide guidance for the clinical treatment and management of H. pylori-related extra-gastric tumors, and help improve prognosis.
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Affiliation(s)
- Shi-Qing Zhao
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Hui-Ling Zheng
- Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China
| | - Xiao-Tian Zhong
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Zi-Ye Wang
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Yi Su
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Yan-Yan Shi
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
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Liu Y, Yang DQ, Jiang JN, Jiao Y. Relationship between Helicobacter pylori infection and colorectal polyp/colorectal cancer. World J Gastrointest Surg 2024; 16:1008-1016. [PMID: 38690050 PMCID: PMC11056658 DOI: 10.4240/wjgs.v16.i4.1008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/01/2024] [Accepted: 03/13/2024] [Indexed: 04/22/2024] Open
Abstract
Helicobacter pylori (H. pylori) plays an important role in the development of gastric cancer, although its association to colorectal polyp (CP) or colorectal cancer (CRC) is unknown. In this issue of World Journal of Gastrointestinal Surgery, Zhang et al investigated the risk factors for H. pylori infection after colon polyp resection. Importantly, the researchers used R software to create a prediction model for H. pylori infection based on their findings. This editorial gives an overview of the association between H. pylori and CP/CRC, including the clinical significance of H. pylori as an independent risk factor for CP/CRC, the underlying processes of H. pylori-associated carcinogenesis, and the possible risk factors and identification of H. pylori.
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Affiliation(s)
- Ying Liu
- Department of General Surgery, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun 130021, Jilin Province, China
| | - Ding-Quan Yang
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Jun-Nan Jiang
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Fioretzaki R, Sarantis P, Charalampakis N, Christofidis K, Mylonakis A, Koustas E, Karamouzis MV, Sakellariou S, Schizas D. Progastrin: An Overview of Its Crucial Role in the Tumorigenesis of Gastrointestinal Cancers. Biomedicines 2024; 12:885. [PMID: 38672239 PMCID: PMC11047876 DOI: 10.3390/biomedicines12040885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/09/2024] [Accepted: 04/14/2024] [Indexed: 04/28/2024] Open
Abstract
Defining predictive biomarkers for targeted therapies and optimizing anti-tumor immune response is a main challenge in ongoing investigations. Progastrin has been studied as a potential biomarker for detecting and diagnosing various malignancies, and its secretion has been associated with cell proliferation in the gastrointestinal tract that may promote tumorigenesis. Progastrin is a precursor molecule of gastrin, synthesized as pre-progastrin, converted to progastrin after cleavage, and transformed into amidated gastrin via biosynthetic intermediates. In cancer, progastrin does not maturate in gastrin and becomes a circulating and detectable protein (hPG80). The development of cancer is thought to be dependent on the progressive dysregulation of normal signaling pathways involved in cell proliferation, thus conferring a growth advantage to the cells. Understanding the interaction between progastrin and the immune system is essential for developing future cancer strategies. To that end, the present review will approach the interlink between gastrointestinal cancers and progastrin by exploring the underlying molecular steps involved in the initiation, evolution, and progression of gastrointestinal cancers. Finally, this review will focus on the clinical applications of progastrin and investigate its possible use as a diagnostic and prognostic tumor circulating biomarker for disease progression and treatment effectiveness, as well as its potential role as an innovative cancer target.
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Affiliation(s)
- Rodanthi Fioretzaki
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (R.F.); (A.M.); (D.S.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, 18537 Piraeus, Greece;
| | - Konstantinos Christofidis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.C.); (S.S.)
| | - Adam Mylonakis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (R.F.); (A.M.); (D.S.)
| | - Evangelos Koustas
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Stratigoula Sakellariou
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.C.); (S.S.)
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (R.F.); (A.M.); (D.S.)
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Zhuang Q, Liao A, He Q, Liu C, Zheng C, Li X, Liu Y, Wang B, Liu S, Zhang Y, Lin R, Chen H, Deng M, Tang Y, He C, Dai W, Tang H, Gong L, Li L, Xu B, Yang C, Zhou B, Su D, Guo Q, Li B, Zhou Y, Wang X, Fei S, Wu H, Wei S, Peng Z, Wang J, Li Y, Wang H, Deng T, Ding S, Li F, Chen M, Xiao Y. The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study. J Gastroenterol Hepatol 2024; 39:658-666. [PMID: 38251791 DOI: 10.1111/jgh.16471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/22/2023] [Accepted: 12/18/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND AND AIM Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.
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Affiliation(s)
- Qianjun Zhuang
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Aijun Liao
- Department of Gastroenterology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Qingling He
- Department of Gastroenterology, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Chengxia Liu
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Changqing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xing Li
- Department of Gastroenterology, Pingxiang People's Hospital, Pingxiang, Jiangxi, China
| | - Youli Liu
- Department of Gastroenterology, Xuancheng People's Hospital, Xuancheng, Anhui, China
| | - Bangmao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
| | - Side Liu
- Department of Gastroenterology, Nanfang Hospital, Guangzhou, Guangdong, China
| | - Yan Zhang
- Department of Gastroenterology, Zigong Fourth People's Hospital, Zigong, Sichuan, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huixin Chen
- Department of Gastroenterology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, China
| | - Min Deng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yanping Tang
- Department of Gastroenterology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chiyi He
- Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Weijie Dai
- Department of Gastroenterology, Huai'an First People's Hospital, Huai'an, Jiangsu, China
| | - Haitao Tang
- Department of Gastroenterology, Lu'an People's Hospital, Lu'an, Anhui, China
| | - Lei Gong
- Department of Gastroenterology, Wuxi Second People's Hospital, Wuxi, Jiangsu, China
| | - Liangping Li
- Department of Gastroenterology, Sichuan Province People's Hospital, Chengdu, Sichuan, China
| | - Baohong Xu
- Department of Gastroenterology, Beijing Luhe Hospital Capital Medical University, Beijing, China
| | - Changqing Yang
- Department of Gastroenterology, Tongji Hospital of Tongji University, Shanghai, China
| | - Bingxi Zhou
- Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Dongxing Su
- Department of Gastroenterology, The Second Nanning People's Hospital, Nanning, Guangxi, China
| | - Qinghong Guo
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Bin Li
- Department of Gastroenterology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yongjian Zhou
- Department of Gastroenterology, Guangzhou First People's Hospital, Guangzhou, Guangdong, China
| | - Xiaoyang Wang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Sujuan Fei
- Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Huili Wu
- Department of Gastroenterology, Zhengzhou Central Hospital, Zhengzhou, Henan, China
| | - Sichen Wei
- Department of Gastroenterology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Zhihong Peng
- Department of Gastroenterology, The Southwest Hospital of Army Medical University, Chongqing, China
| | - Jianning Wang
- Department of Gastroenterology, Nanjing Jiangning Hospital, Nanjing, Jiangsu, China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Hong Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Tianwei Deng
- Department of Gastroenterology, Chongqing University Three Gorges Hospital, Chongqing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Fangfang Li
- Department of Gastroenterology, Chenzhou First People's Hospital, Chenzhou, Hunan, China
| | - Minhu Chen
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yinglian Xiao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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He Y, Koido M, Sutoh Y, Shi M, Otsuka-Yamasaki Y, Munter HM, Morisaki T, Nagai A, Murakami Y, Tanikawa C, Hachiya T, Matsuda K, Shimizu A, Kamatani Y. East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease. Nat Genet 2023; 55:2129-2138. [PMID: 38036781 PMCID: PMC10703676 DOI: 10.1038/s41588-023-01569-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 10/12/2023] [Indexed: 12/02/2023]
Abstract
Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.
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Affiliation(s)
- Yunye He
- Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Masaru Koido
- Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoichi Sutoh
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Mingyang Shi
- Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | | | - Hans Markus Munter
- Victor Phillip Dahdaleh Institute of Genomic Medicine and Department of Human Genetics, McGill University, Montreal, Québec, Canada
| | - Takayuki Morisaki
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Akiko Nagai
- Department of Public Policy, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Chizu Tanikawa
- Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Tsuyoshi Hachiya
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Atsushi Shimizu
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Yoichiro Kamatani
- Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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Waldum H, Mjønes P. The central role of gastrin in gastric cancer. Front Oncol 2023; 13:1176673. [PMID: 37941554 PMCID: PMC10628637 DOI: 10.3389/fonc.2023.1176673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 09/19/2023] [Indexed: 11/10/2023] Open
Abstract
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid-Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and in situ hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, Helicobacter pylori, is thought to be its main cause. H. pylori predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single H. pylori factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to H. pylori, autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by H. pylori eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term H. pylori infection and those with autoimmune gastritis.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pathology, St. Olav’s Hospital – Trondheim University Hospital, Trondheim, Norway
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Saki F, Shams M, Dastghaib S, Koohpeyma F. Pantoprazole-Induced Bone Loss through Gastrin Secretion: A Stereological Study. BIOMED RESEARCH INTERNATIONAL 2023; 2023:2594664. [PMID: 37711876 PMCID: PMC10499535 DOI: 10.1155/2023/2594664] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/20/2023] [Accepted: 07/11/2023] [Indexed: 09/16/2023]
Abstract
Background Recent researches have failed to uncover a clear explanation for proton pump inhibitors' bone-loss effects. In light of pantoprazole's effects on gastrin secretion, the goal of this study was to see if it caused bone loss through gastrin secretion. Methods Forty male rats were divided into control, octreotide (Oct), pantoprazole (Pan), and pantoprazole plus octreotide (Pan+Oct) groups. Serum calcium, phosphorous, alkaline phosphatase, parathyroid hormone, and gastrin were measured before and three months after the treatment, and bone densitometry was examined. The rats' femoral bones were examined stereologically at the end of the investigation. Results The Pan group had considerably greater levels of serum alkaline phosphatase, parathyroid hormone (PTH), and gastrin, but this was prevented in the presence of Oct, a gastrin secretion inhibitor. All parameters of femoral bone densitometry in the Pan group were significantly lower than the control after treatment which was considerably inhibited in the presence of Oct. Furthermore, when compared to the control and Oct groups, the rats in the Pan group had a lower trabecular volume, femur bone weight, and volume, as well lower number of osteocytes. The amount of osteoclasts, on the other hand, was much higher in the Pan group than in the other groups. Conclusion Overall findings revealed that pantoprazole caused bone loss, which could be prevented by adding octreotide. Because these detrimental effects were not detected in rats given both Oct and Pan, it was suggested that the effect of Pan on bone was produced by a hypergastrinemic condition.
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Affiliation(s)
- Forough Saki
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mesbah Shams
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farhad Koohpeyma
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Richman CM, Leiman DA. Can We StoP Worrying about Long-term PPIs and Gastric Cancer Risk? Cancer Epidemiol Biomarkers Prev 2023; 32:1127-1129. [PMID: 37655427 DOI: 10.1158/1055-9965.epi-23-0809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 09/02/2023] Open
Abstract
Proton pump inhibitors (PPI) are a cornerstone of management for many digestive diseases. While chronic PPI use induces physiologic changes including gastric acid suppression and hypergastrinemia, existing data are conflicting on whether this impacts the risk of gastric cancer among PPI users. Sassano and colleagues utilized pooled case-control data from five studies in the Stomach cancer Pooling (StoP) Project to investigate the association between PPI use and histologically confirmed gastric cancer. Short-term PPI use (6 months) was associated with increased risk of gastric cancer, but no association was found between long-term PPI use (3 years or more) and gastric cancer. Although the authors relied on patient-reported PPI use data, and data related to Helicobacter pylori infection and eradication rates were missing, no histologic gastric cancer subtypes in this international case-control study were associated with any PPI use. Currently reported findings provide patients and clinicians with reassuring observations that long-term PPI use does not significantly increase gastric cancer risk. The relationship identified among short-term PPI users may reflect reverse causality. Our understanding will be furthered by additional assessment of potential confounders, including comorbid conditions, PPI metabolism, and social determinants of health. See related article by Sassano et al., p. 1174.
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Affiliation(s)
- Courtney M Richman
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
| | - David A Leiman
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Duke Clinical Research Institute, Durham, North Carolina
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9
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Massironi S, Gallo C, Elvevi A, Stegagnini M, Coltro LA, Invernizzi P. Incidence and prevalence of gastric neuroendocrine tumors in patients with chronic atrophic autoimmune gastritis. World J Gastrointest Oncol 2023; 15:1451-1460. [PMID: 37663936 PMCID: PMC10473929 DOI: 10.4251/wjgo.v15.i8.1451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 06/23/2023] [Accepted: 07/07/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND The incidence of type I gastric neuroendocrine neoplasms (gNENs) has increased significantly over the past 50 years. Although autoimmune gastritis (AIG) increases the likelihood of developing gNENs, the exact incidence and prevalence of this association remain unclear. AIM To evaluate the incidence and prevalence of type I gNENs in a cohort of patients with a histological diagnosis of AIG. METHODS Patients with a histological diagnosis of AIG were enrolled between October 2020 and May 2022. Circulating levels of CgA and gastrin were assessed at enrollment. Included patients underwent regular endoscopic follow-up to detect gastric neoplastic lesions, enterochromaffin-like (ECL) cell hyperplasia, and the development of gNEN. RESULTS We included 176 patients [142 women (80.7%), median age 64 years, interquartile range (IQR) 53-71 years] diagnosed with AIG between January 1990 and June 2022. At enrollment. One hundred and sixteen patients (65.9%) had ECL hyperplasia, of whom, 29.5% had simple/linear, 30.7% had micronodular, and 5.7% had macronodular type. The median follow-up time was 5 (3-7.5) years. After 1032 person-years, 33 patients developed a total of 50 type I gNENs, with an incidence rate of 0.057 person-years, corresponding to an annual cumulative incidence of 5.7%. Circulating CgA levels did not significantly differ between AIG patients who developed gNENs and those who did not. Conversely, gastrin levels were significantly higher in AIG patients who developed gNENs [median 992 pg/mL IQR = 449-1500 vs 688 pg/mL IQR = 423-1200, P = 0.03]. Calculated gastrin sensitivity and specificity were 90.9% and 1.4%, respectively, with an overall diagnostic accuracy of 30% and a calculated area under the gastrin receiver operating characteristic curve (AUROC or AUC) of 0.53. CONCLUSION Type I gNENs are a significant complication in AIG. Gastrin's low diagnostic accuracy prevents it from serving as a marker for early diagnosis. Effective strategies for early detection and treatment are needed.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, School of Medicine, Monza 20900, Italy
| | - Camilla Gallo
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, School of Medicine, Monza 20900, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, School of Medicine, Monza 20900, Italy
| | - Marta Stegagnini
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, School of Medicine, Monza 20900, Italy
| | - Lorenzo Andrea Coltro
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, School of Medicine, Monza 20900, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, School of Medicine, Monza 20900, Italy
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Liu FS, Wang S, Guo XS, Ye ZX, Zhang HY, Li Z. State of art on the mechanisms of laparoscopic sleeve gastrectomy in treating type 2 diabetes mellitus. World J Diabetes 2023; 14:632-655. [PMID: 37383590 PMCID: PMC10294061 DOI: 10.4239/wjd.v14.i6.632] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Obesity and type-2 diabetes mellitus (T2DM) are metabolic disorders. Obesity increases the risk of T2DM, and as obesity is becoming increasingly common, more individuals suffer from T2DM, which poses a considerable burden on health systems. Traditionally, pharmaceutical therapy together with lifestyle changes is used to treat obesity and T2DM to decrease the incidence of comorbidities and all-cause mortality and to increase life expectancy. Bariatric surgery is increasingly replacing other forms of treatment of morbid obesity, especially in patients with refractory obesity, owing to its many benefits including good long-term outcomes and almost no weight regain. The bariatric surgery options have markedly changed recently, and laparoscopic sleeve gastrectomy (LSG) is gradually gaining popularity. LSG has become an effective and safe treatment for type-2 diabetes and morbid obesity, with a high cost-benefit ratio. Here, we review the me-chanism associated with LSG treatment of T2DM, and we discuss clinical studies and animal experiments with regard to gastrointestinal hormones, gut microbiota, bile acids, and adipokines to clarify current treatment modalities for patients with obesity and T2DM.
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Affiliation(s)
- Fa-Shun Liu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Song Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xian-Shan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Zhen-Xiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hong-Ya Zhang
- Central Laboratory, Yangpu District Control and Prevention Center, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
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11
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Zhou N, Wang Y, Zhang Z, Feng W, Liu T, Cao Y, Zhang J, Zhang B, Zheng X, Li K. Characterizing the specific mechanism of series processed Coptidis Rhizoma by multi-organ metabolomics combined with network pharmacology and molecular docking. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154804. [PMID: 37031638 DOI: 10.1016/j.phymed.2023.154804] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 03/20/2023] [Accepted: 04/02/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND After being processed with different excipients, the clinical application of Coptidis Rhizoma (CR) is differentially investigated. However, the underlying mechanism and material basis are not clear, and there is a lack of attention to the collaborative working mode of herbal medicine during exploration. PURPOSE To characterize the specific mechanism of wine/zingiberis rhizoma recens/euodiae fructus processed CR (wCR/zCR/eCR) and to investigate the role of excipients during processing. METHODS The multi-organ metabolomics approach was employed to explore the target organs of wCR/zCR/eCR and multiple pathways being triggered in each organ. The tissue distribution of CR and wCR/zCR/eCR components was compared to indicate the material basis of efficacy change after processing. Further, the network pharmacology study coupled with experimental validation was conducted to support metabolomic research and predicted active ingredients and core targets, and the molecular docking coupled with binding test was performed to identify the binding between active ingredient and core target. RESULTS The multi-organ metabolomics and network pharmacology study elucidated the intervening effect of wCR on heart/lung, zCR on stomach/colon, and eCR on liver/colon/stomach. Combined with molecular docking, binding test and tissue distribution studies, the specific mechanism was as follows: the wine made iso-quinoline alkaloids in CR more likely to accumulate in heart/lung, thus triggering the core targets of PTGS2, NOS2, ESR1 and SLC6A4 in heart/lung, and thereby highlighting the detoxifying and cardiopulmonary protective effect of wCR. The zingiberis rhizoma recens and euodiae fructus made organic acids in CR more likely to accumulate in stomach/colon and liver/colon/stomach respectively, thus triggering the core targets of ACTB, TNF and PRKCA in stomach/colon, the core targets of ACTB, TNF, PRKCA and GPT in stomach/colon/liver, and thereby highlighting the improving effect of zCR/eCR on digestive function. CONCLUSION Iso-quinoline alkaloids were the material basis of CR for anti-inflammation, and organic acids were mainly responsible for regulating gastrointestinal function. Due to the influence of excipients on the accumulation tendency of CR components, the differentially highlighted application of wCR/zCR/eCR was achieved. These findings propose a novel strategy for processing mechanism research.
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Affiliation(s)
- Ning Zhou
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Zhengzhou 450046, People's Republic of China
| | - Yongxiang Wang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, People's Republic of China
| | - Zhenkai Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, People's Republic of China
| | - Weisheng Feng
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Zhengzhou 450046, People's Republic of China
| | - Tong Liu
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China
| | - Yumin Cao
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China
| | - Jinying Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China
| | - Bingxian Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China
| | - Xiaoke Zheng
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Zhengzhou 450046, People's Republic of China
| | - Kai Li
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, People's Republic of China; Henan Research Center for Special Processing Technology of Chinese Medicine, Zhengzhou 450046, People's Republic of China
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Mahdi AL-Musawi NR, Al-Gazally ME, AL-Saffar YR. Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus. BIONATURA 2023. [DOI: 10.21931/rb/2023.08.01.68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023] Open
Abstract
Diabetes mellitus (DM) is a central public health problem impacting more than 400 million humhttp://wsx5customurl.comans worldwide. This metabolic disorder progressively drives chronic microvascular, macrovascular and neuropathic life-threatening problems. DM is happened because of a decrease in insulin secretion, harm to pancreatic β cells or insulin resistance connected to the nonuse of insulin. Type – I DM The immune system, by mistake, will attack the β cells of the pancreas, where genes play a vital role. The work was designed to determine the levels of anthropometric variables (age and BMI), immunological parameters (IL-27, IL-27 gene SNP), CCKBR and other biochemical parameters (HbA1C, cholesterol, triglyceride, HDL, LDL, VLDL, urea and creatinine) in sera of T1DM patients. The study contains 180 subjects who are split into two groups; the two groups are the healthy control group and the T1DM patients' group. The result recorded in this research showed a non-significant (p>0.05) difference between the control and patients in age, BMI, CCKBR, TRI, HDL, LDL, and VLDL. A very high significant elevation (P<0.001) has been observed in the level of IL-27, HbA1C, urea and creatinine; there is a highly significant increase (p<0.05) in cholesterol, the gene SNP study shows a significant association of IL27 rs153109 with T1DM was observed under the allele model (OR=2.124, 95% CI (1.349–3.345), P=0.00105), and genotype model in the dominant model (OR=1.00, 95% CI, P=0.0016), recessive model (OR=0.35, 95% CI ( 0.12–1.02), P=0.043) and homozygous model (OR=1.00, 95%, P=0.0037). The study it is cleared that T1DM affects the SNP gene used as a promoter to the excretion of IL-27 and increases its excretion. Lipid profile shows an effect on the level of glucose in the blood, and a high level of cholesterol may cause a severe problem if it is combined with T1DM. The elevated glucose level happens because T1DM affects the renal and causes extreme conditions like renal failure and other renal dysfunction diseases.
Keywords: T1DM, CCKBR, genetic disease, IL-27, IL-27.
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Gašenko E, Bogdanova I, Sjomina O, Aleksandraviča I, Kiršners A, Ancāns G, Rudzīte D, Vangravs R, Sīviņš A, Škapars R, Tzivian L, Polaka I, Folkmanis V, Leja M. Assessing the utility of pepsinogens and gastrin-17 in gastric cancer detection. Eur J Cancer Prev 2023:00008469-990000000-00046. [PMID: 36912185 DOI: 10.1097/cej.0000000000000791] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
OBJECTIVES The aim of the study was to determine the proportion of gastric cancer patients with decreased levels of pepsinogen and gastrin-17 in plasma, with the goal of providing indirect evidence of the sensitivity of these biomarkers when applied in a cancer screening setting. METHODS The levels of pepsinogens I and II, gastrin-17, and Helicobacter pylori immunoglobulin antibodies in plasma samples of gastric cancer patients were evaluated using the GastroPanel test system (Biohit Oyj, Helsinki, Finland). A decreased level of the pepsinogen I/II ratio was defined as less than three, while a decrease in gastrin-17 was defined as less than 1 pmol/L. Univariate analysis using non-parametric tests was used to investigate differences between normal and low concentrations of biomarkers. RESULTS In total, 481 plasma samples from patients (59.9% male) with a median age of 64 years (ranging from 27 to 88 years) were analyzed. Out of the 400 cases of gastric cancer (83.2% of the total), 182 were categorized as the intestinal type, 141 as the diffuse type, 60 as the mixed type, and 17 as indeterminate according to the Lauren classification system. The H. pylori immunoglobulin test was positive in 74.0% of the patients. Pepsinogen I/II ratio was decreased in 32.4% (36.8% of the intestinal type); gastrin-17 in 12.3% (10.1% of the antral region) of all cases. CONCLUSION The majority of gastric cancer patients had normal levels of pepsinogen and gastrin-17, suggesting that these biomarkers have limited application as screening tools in the Caucasian population.
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Affiliation(s)
| | | | - Olga Sjomina
- Department of Internal Medicine, Riga East University Hospital
| | - Ilona Aleksandraviča
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Arnis Kiršners
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Guntis Ancāns
- Department of Surgery, Jēkabpils Regional Hospital, Jēkabpils
| | | | - Reinis Vangravs
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Armands Sīviņš
- Department of Abdominal and Soft Tissue Surgery, Clinic of Oncological Surgery
| | - Roberts Škapars
- Department of Abdominal and Soft Tissue Surgery, Clinic of Oncological Surgery
| | - Lilian Tzivian
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Inese Polaka
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Valdis Folkmanis
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Mārcis Leja
- Department of Research, Riga East University Hospital, Riga, Latvia
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Laine L, DeVault K, Katz P, Mitev S, Lowe J, Hunt B, Spechler S. Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial. Gastroenterology 2023; 164:61-71. [PMID: 36228734 DOI: 10.1053/j.gastro.2022.09.041] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/11/2022] [Accepted: 09/23/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND & AIMS For decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited. METHODS Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks. Patients with healing were rerandomized to once-daily vonoprazan, 10 mg, vonoprazan, 20 mg, or lansoprazole, 15 mg, for 24 weeks. Primary end points, percentage with healing by week 8 endoscopy, and maintenance of healing at week 24 endoscopy, were assessed in noninferiority comparisons (noninferiority margins, 10%), with superiority analyses prespecified if noninferiority was demonstrated. Analyses of primary and secondary end points were performed using fixed-sequence testing procedures. RESULTS Among 1024 patients in the healing phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the exploratory analysis of healing (92.9 vs 84.6%; difference, 8.3%; 95% confidence interval [CI], 4.5%-12.2%). Secondary analyses showed vonoprazan was noninferior in heartburn-free days (difference, 2.7%; 95% CI, -1.6% to 7.0%), and superior in healing Los Angeles Classification Grade C/D esophagitis at week 2 (difference, 17.6%; 95% CI, 7.4%-27.4%). Among 878 patients in the maintenance phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the secondary analysis of maintenance of healing (20 mg vs lansoprazole: difference, 8.7%; 95% CI, 1.8%-15.5%; 10 mg vs lansoprazole: difference, 7.2%; 95% CI, 0.2%-14.1%) and secondary analysis of maintenance of healing Grade C/D esophagitis (20 mg vs lansoprazole: difference, 15.7%; 95% CI, 2.5%-28.4%; 10 mg vs lansoprazole: difference, 13.3%; 95% CI, 0.02%-26.1%). CONCLUSIONS Vonoprazan was noninferior and superior to the PPI lansoprazole in healing and maintenance of healing of erosive esophagitis. This benefit was seen predominantly in more severe erosive esophagitis. (ClinicalTrials.gov: NCT04124926).
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Affiliation(s)
- Loren Laine
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; Section of Digestive Diseases, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
| | - Kenneth DeVault
- Division of Gastroenterology & Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Philip Katz
- Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, New York
| | - Stefan Mitev
- Clinic of Gastroenterology, University Hospital Sv Ivan Rilski, Sofia, Bulgaria
| | - John Lowe
- Advanced Research Institute, Ogden, Utah
| | - Barbara Hunt
- Phathom Pharmaceuticals, Buffalo Grove, Illinois
| | - Stuart Spechler
- Center for Esophageal Diseases, Baylor University Medical Center at Dallas and Baylor Scott & White Health, Dallas Texas
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DDS Profile: Juanita L. Merchant, MD, PhD. Dig Dis Sci 2023; 68:16-20. [PMID: 36301448 PMCID: PMC9610307 DOI: 10.1007/s10620-022-07725-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/12/2022] [Indexed: 02/01/2023]
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16
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Duan S, Sawyer TW, Sontz RA, Wieland BA, Diaz AF, Merchant JL. GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming. Cell Mol Gastroenterol Hepatol 2022; 14:1025-1051. [PMID: 35835391 PMCID: PMC9490044 DOI: 10.1016/j.jcmgh.2022.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/16/2022] [Accepted: 06/28/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis. METHODS Transgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel. RESULTS GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1. CONCLUSIONS GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.
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Affiliation(s)
- Suzann Duan
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Travis W. Sawyer
- Wyant College of Optical Sciences, University of Arizona, Tucson, Arizona
| | - Ricky A. Sontz
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Bradley A. Wieland
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Andres F. Diaz
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Juanita L. Merchant
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona,Correspondence Address correspondence to: Dr Juanita L. Merchant, University of Arizona, 1515 N. Campbell Ave, Tucson, AZ 85724; tel: (520) 626-7897; fax: (520) 626-1291.
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Almasi M, Goodarzi N. Microanalysis of the stomach of southern white-breasted hedgehog (Erinaceus concolor): Histological, histochemical, immunohistochemical, and scanning electron microscopic studies. Microsc Res Tech 2022; 85:2714-2728. [PMID: 35522535 DOI: 10.1002/jemt.24137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/26/2022] [Accepted: 04/18/2022] [Indexed: 11/06/2022]
Abstract
This study was designed to provide more detailed knowledge on the stomach histochemistry and immunohistochemistry in the southern white-breasted hedgehog (Erinaceus concolor). Two animals were used in the present work. Periodic acid Schiff's (PAS) and Alcian blue were used for histochemical purposes. SOX9, gastrin, serotonin, and glucagon markers were traced immunohistochemically. The mucosa was extremely folded in the fundus with numerous opening of glands. The body and pylorus mucosa were almost smooth and equipped with gastric gland openings. A simple columnar epithelium covered the stomach entirely. Cardiac glands region was mucus secreting with both positive and negative reactions to PAS. Fundic mucosa was contained cardiac glands near to the cardia, and toward the body it was divided into the light and dark zones. These zones and body contained proper gastric gland, which constituted of parietal, chief, and mucous neck cells. These glands contained PAS-positive cells on their basal portions. The pyloric glands were mucus secreting but negative for PAS. All gastric glands were Alcian blue-negative, but epithelium showed moderate reaction especially in the pylorus. SOX and gastrin were express highly in the body and fundus. The expression of serotonin and glucagon was rare. Comparatively, some similarities between the stomach of hedgehog and dog can be assumed. The present findings provide additional information concerning the histochemical characteristics and endocrine cells distribution in the stomach of the southern white-breasted hedgehog (Erinaceus concolor). Further detailed studies are required to enhance the current knowledge on histophysiology of the digestive system in this species as a pet and exotic animal.
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Affiliation(s)
- Maryam Almasi
- Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Nader Goodarzi
- Department of Basic Sciences and Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
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