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Yu Z, Guo Y, Chen H, Wan W, Hu M, Li Y, Wei T, Chen Q. A phloem-limited unculturable bacterium induces mild xenophagy in insect vectors for persistent infection. Microbiol Res 2025; 297:128186. [PMID: 40262357 DOI: 10.1016/j.micres.2025.128186] [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: 01/17/2025] [Revised: 04/04/2025] [Accepted: 04/14/2025] [Indexed: 04/24/2025]
Abstract
Xenophagy is an important antibacterial defense mechanism that many organisms use to engulf intracellular pathogens. However, the mechanisms of xenophagy triggered by insect-borne plant bacteria are not well understood. Candidatus Liberibacter asiaticus (CLas) causes Huanglongbing, which poses a serious threat to citrus production. CLas is a phloem-limited unculturable bacterium that is transmitted by the Asian citrus psyllid in a persistent and propagative manner in nature. Here, we found that CLas infection in the gut of psyllids triggered a mild and anti-bacterial xenophagy. Xenophagy limited excessive propagation of CLas to maintain psyllid survival, because overload of CLas was detrimental to psyllid life. Furthermore, the outer membrane β-barrel protein (OMBB) of CLas is the key secreted protein that induces xenophagy in psyllids by interacting with ATG8 and ATG14. OMBB can independently induce autophagy in psyllid and non-host cells. Together, these results revealed that an insect-borne plant bacterium activates mild xenophagy to control its propagation, thereby achieving persistent infection in insect vectors.
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Affiliation(s)
- Zhongkai Yu
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China
| | - Yuxin Guo
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China
| | - Hongyan Chen
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China
| | - Wenqiang Wan
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China
| | - Mengting Hu
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China
| | - You Li
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China
| | - Taiyun Wei
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China.
| | - Qian Chen
- State Key Laboratory of Agricultural and Forestry Biosecurity, Fujian Agriculture and Forestry University, Fujian, Fuzhou, China.
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Zhang X, Wang L, Huang L, Cao G, Huang C, Duan Y, Lyu W. Potential mechanisms by which Jiawei Lianpu Yin inhibits Helicobacter pylori colonization and alleviates gastric mucosal inflammation and damage: Integrated transcriptomics, network pharmacology, and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119793. [PMID: 40239879 DOI: 10.1016/j.jep.2025.119793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 04/18/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Helicobacter pylori (H. pylori) infection is a primary cause of gastric mucosal damage and inflammation, and its persistent presence is recognized as a major risk factor for the development of gastric cancer. Despite available treatments, eradication of H. pylori remains a significant clinical challenge, highlighting the urgent need for new therapeutic agents that can disrupt bacterial colonization and facilitate its elimination. Jiawei Lianpu Yin (JWLPY), a traditional herbal formula composed of natural medicinal substances, has been used to treat gastric disorders related to H. pylori infection. However, the precise mechanisms underlying its therapeutic effects have not yet been fully elucidated. AIM OF THE STUDY The aim of this study was to investigate whether JWLPY can inhibit H. pylori colonization, alleviate gastric mucosal inflammation and damage, and to explore its underlying mechanisms of action. MATERIALS AND METHODS The effects of JWLPY on H. pylori and gastric mucosal injury were evaluated both in vitro and in vivo, using a rat model of H. pylori induced gastritis and an in vitro model of H. pylori induced damage in human gastric mucosal epithelial cells. The mechanisms of action of JWLPY were further investigated through transcriptomic analysis, network pharmacology, and bioinformatics approaches. RESULTS JWLPY inhibited the aggregation of inflammatory cells and preserved the integrity of the mucosal barrier, while reducing autophagy and apoptosis in gastric mucosal epithelial cells. Network pharmacology and transcriptomic analyses revealed that JWLPY promotes the assembly and synthesis of MUC5AC in the endoplasmic reticulum by activating the IRE1 XBP1 signaling pathway. This activation enhances protein folding and assembly processes within the endoplasmic reticulum, thereby inhibiting H. pylori colonization in the gastric mucosa. CONCLUSION This study is the first to demonstrate that JWLPY inhibits H. pylori colonization in the gastric mucosa, alleviates gastric inflammation and tissue damage, and holds potential as a therapeutic agent for the treatment of H. pylori related gastritis.
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Affiliation(s)
- Xinyue Zhang
- The Affiliated Hospital of Wuhan Sports University, Wuhan, 430079, China.
| | - Lingyan Wang
- The Affiliated Hospital of Wuhan Sports University, Wuhan, 430079, China
| | - Lei Huang
- The Affiliated Hospital of Wuhan Sports University, Wuhan, 430079, China
| | - Guojun Cao
- The Affiliated Hospital of Wuhan Sports University, Wuhan, 430079, China
| | - Chaoqun Huang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Chinese Medicine, Hubei, Wuhan, 430061, China; Hubei Shizhen Laboratory, Hubei, Wuhan, 430061, China
| | - Yanjun Duan
- Hubei University of Chinese Medicine, Wuhan, 430060, China
| | - Wenliang Lyu
- Hubei University of Chinese Medicine, Wuhan, 430060, China; Hubei Shizhen Laboratory, Hubei, Wuhan, 430061, China.
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Duan Y, Xu Y, Dou Y, Xu D. Helicobacter pylori and gastric cancer: mechanisms and new perspectives. J Hematol Oncol 2025; 18:10. [PMID: 39849657 PMCID: PMC11756206 DOI: 10.1186/s13045-024-01654-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Gastric cancer remains a significant global health challenge, with Helicobacter pylori (H. pylori) recognized as a major etiological agent, affecting an estimated 50% of the world's population. There has been a rapidly expanding knowledge of the molecular and pathogenetic mechanisms of H. pylori over the decades. This review summarizes the latest research advances to elucidate the molecular mechanisms underlying the H. pylori infection in gastric carcinogenesis. Our investigation of the molecular mechanisms reveals a complex network involving STAT3, NF-κB, Hippo, and Wnt/β-catenin pathways, which are dysregulated in gastric cancer caused by H. pylori. Furthermore, we highlight the role of H. pylori in inducing oxidative stress, DNA damage, chronic inflammation, and cell apoptosis-key cellular events that pave the way for carcinogenesis. Emerging evidence also suggests the effect of H. pylori on the tumor microenvironment and its possible implications for cancer immunotherapy. This review synthesizes the current knowledge and identifies gaps that warrant further investigation. Despite the progress in our previous knowledge of the development in H. pylori-induced gastric cancer, a comprehensive investigation of H. pylori's role in gastric cancer is crucial for the advancement of prevention and treatment strategies. By elucidating these mechanisms, we aim to provide a more in-depth insights for the study and prevention of H. pylori-related gastric cancer.
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Affiliation(s)
- Yantao Duan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yonghu Xu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi Dou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dazhi Xu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Yan Z, Liu Y, Yuan Y. The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer. Cell Death Discov 2024; 10:512. [PMID: 39719478 DOI: 10.1038/s41420-024-02275-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity. In this paper, based on the review of the characteristics of normal differentiation of gastric epithelial cells and their markers, the four main phenotypes of gastric epithelial cell remodeling and their relationship with gastric cancer (GC) are drawn. Furthermore, we summarize the regulatory factors and mechanisms that affect gastric epithelial cell plasticity and outline the current status of research and future prospection for the treatment targeting gastric epithelial cell plasticity. This study has important theoretical reference value for the in-depth exploration of epithelial cell plasticity and the tumor heterogeneity caused by it, as well as for the precise treatment of GC.
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Affiliation(s)
- Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
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Lin Y, Liu K, Lu F, Zhai C, Cheng F. Programmed cell death in Helicobacter pylori infection and related gastric cancer. Front Cell Infect Microbiol 2024; 14:1416819. [PMID: 39145306 PMCID: PMC11322058 DOI: 10.3389/fcimb.2024.1416819] [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: 04/13/2024] [Accepted: 07/08/2024] [Indexed: 08/16/2024] Open
Abstract
Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.
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Affiliation(s)
- Yukun Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Kunjing Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fang Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Changming Zhai
- Department of Rheumatism, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
| | - Fafeng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Ma S, Xu Y, Qin X, Tao M, Gu X, Shen L, Chen Y, Zheng M, Qin S, Wu G, Ju S. RUNX1, FUS, and ELAVL1-induced circPTPN22 promote gastric cancer cell proliferation, migration, and invasion through miR-6788-5p/PAK1 axis-mediated autophagy. Cell Mol Biol Lett 2024; 29:95. [PMID: 38956466 PMCID: PMC11218243 DOI: 10.1186/s11658-024-00610-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/14/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND An increasing number of studies have demonstrated the association of circular RNAs (circRNAs) with the pathological processes of various diseases and their involvement in the onset and progression of multiple cancers. Nevertheless, the functional roles and underlying mechanisms of circRNAs in the autophagy regulation of gastric cancer (GC) have not been fully elucidated. METHODS We used transmission electron microscopy and the mRFP-GFP-LC3 dual fluorescent autophagy indicator to investigate autophagy regulation. The cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, Transwell assay, and Western blot assay were conducted to confirm circPTPN22's influence on GC progression. Dual luciferase reporter assays validated the binding between circPTPN22 and miR-6788-5p, as well as miR-6788-5p and p21-activated kinase-1 (PAK1). Functional rescue experiments assessed whether circPTPN22 modulates PAK1 expression by competitively binding miR-6788-5p, affecting autophagy and other biological processes in GC cells. We investigated the impact of circPTPN22 on in vivo GC tumors using a nude mouse xenograft model. Bioinformatics tools predicted upstream regulatory transcription factors and binding proteins of circPTPN22, while chromatin immunoprecipitation and ribonucleoprotein immunoprecipitation assays confirmed the binding status. RESULTS Upregulation of circPTPN22 in GC has been shown to inhibit autophagy and promote cell proliferation, migration, and invasion. Mechanistically, circPTPN22 directly binds to miR-6788-5p, subsequently regulating the expression of PAK1, which activates protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) phosphorylation. This modulation ultimately affects autophagy levels in GC cells. Additionally, runt-related transcription factor 1 (RUNX1) negatively regulates circPTPN22 expression, while RNA-binding proteins such as FUS (fused in sarcoma) and ELAVL1 (recombinant ELAV-like protein 1) positively regulate its expression. Inhibition of the autophagy pathway can increase FUS expression, further upregulating circPTPN22 in GC cells, thereby exacerbating the progression of GC. CONCLUSION Under the regulation of the transcription factor RUNX1 and RNA-binding proteins FUS and ELAVL1, circPTPN22 activates the phosphorylation of Akt and Erk through the miR-6788-5p/PAK1 axis, thereby modulating autophagy in GC cells. Inhibition of autophagy increases FUS, which in turn upregulates circPTPN22, forming a positive feedback loop that ultimately accelerates the progression of GC.
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Affiliation(s)
- Shuo Ma
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China
- Diagnostics Department, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yanhua Xu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Xinyue Qin
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
| | - Mei Tao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
| | - Xinliang Gu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
| | - Lei Shen
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
| | - Yinhao Chen
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Bonn, Germany
| | - Ming Zheng
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
| | - Shiyi Qin
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China
| | - Guoqiu Wu
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China.
- Diagnostics Department, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China.
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, NO.20, Nantong, 226001, Jiangsu, China.
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Kumar S, Dhiman M. Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation. Cell Immunol 2024; 399-400:104811. [PMID: 38518686 DOI: 10.1016/j.cellimm.2024.104811] [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: 07/12/2023] [Revised: 01/09/2024] [Accepted: 01/15/2024] [Indexed: 03/24/2024]
Abstract
Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91phox (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91phox expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS. This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.
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Affiliation(s)
- Sandeep Kumar
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Bathinda, 151 401 Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Bathinda, 151 401 Punjab, India.
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Sadeghloo Z, Saffarian P, Hakemi-Vala M, Sadeghi A, Yadegar A. The modulatory effect of Lactobacillus gasseri ATCC 33323 on autophagy induced by extracellular vesicles of Helicobacter pylori in gastric epithelial cells in vitro. Microb Pathog 2024; 188:106559. [PMID: 38272328 DOI: 10.1016/j.micpath.2024.106559] [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: 10/30/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Helicobacter pylori has been recognized as a true pathogen, which is associated with various gastroduodenal diseases, and gastric adenocarcinoma. The crosstalk between H. pylori virulence factors and host autophagy remains challenging. H. pylori can produce extracellular vesicles (EVs) that contribute to gastric inflammation and malignancy. Some probiotic strains have been documented to modulate cell autophagy process. This study was aimed to investigate the modulatory effect of cell-free supernatant (CFS) obtained from Lactobacillus gasseri ATCC 33323 on autophagy induced by H. pylori-derived EVs. EVs were isolated from two clinical H. pylori strains (BY-1 and OC824), and characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). The viability of AGS cells was assessed after exposure to different concentrations of H. pylori EVs, and L. gasseri CFS. Based on MTT assay and Annexin V-FITC/PI staining, 50 μg/ml of H. pylori EVs and 10 % v/v of L. gasseri CFS were used for further cell treatment experiments. Autophagy was examined using acridin orange (AO) staining, RT-qPCR analysis for autophagy mediators (LC3B, ATG5, ATG12, ATG16L1, BECN1, MTOR, and NOD1), and western blotting for LC3B expression. H. pylori EVs were detected to range in size from 50 to 200 nm. EVs of both H. pylori strains and L. gasseri CFS showed no significant effect on cell viability as compared to untreated cells. H. pylori EVs promoted the development of acidic vesicular organelles and the expression of autophagy-related genes (LC3B, ATG5, ATG12, ATG16L1, BECN1, and NOD1), and decreased the expression of MTOR in AGS cells at 12 and 24 h time periods. In addition, the production of LC3B was increased following 12 h of treatment in AGS cells. In contrast, L. gasseri CFS effectively inhibited EVs-induced autophagy, as evidenced by reduced acidic vesicular organelle formation and modulation of autophagy markers. Our study indicated that L. gasseri CFS can effectively suppress H. pylori EV-induced autophagy in AGS cells. Further investigations are required to decipher the mechanism of action L. gasseri CFS and its metabolites on autophagy inhibition induced by H. pylori.
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Affiliation(s)
- Zahra Sadeghloo
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parvaneh Saffarian
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mojdeh Hakemi-Vala
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Yang S, Hao S, Ye H, Zhang X. Cross-talk between Helicobacter pylori and gastric cancer: a scientometric analysis. Front Cell Infect Microbiol 2024; 14:1353094. [PMID: 38357448 PMCID: PMC10864449 DOI: 10.3389/fcimb.2024.1353094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 01/17/2024] [Indexed: 02/16/2024] Open
Abstract
Background Helicobacter pylori (HP) is considered a leading risk factor for gastric cancer (GC). The aim of this article is to conduct bibliometric and visual analysis to assess scientific output, identify highly cited papers, summarize current knowledge, and explore recent hotspots and trends in HP/GC research. Methods A bibliographic search was conducted on October 24, 2023, to retrieve relevant studies on HP/GC research between 2003 and 2022. The search terms were attached to HP and GC. The main data were from the Web of Science Core Collection (WoSCC). Data visualization was performed using Biblioshiny, VOSviewer, and Microsoft Excel. Results In HP/GC research, 1970 papers were retrieved. The total number of papers (Np) in HP/GC was growing from 2003 to 2022. China and Japan were in the leading position and made the most contributions to HP/GC. Vanderbilt University and the US Department of Veterans Affairs had the highest Np. The most productive authors were Peek Jr Richard M. and Piazuelo M Blanca. Helicobacter received the most Np, while Gastroenterology had the most total citations (TC). High-cited publications and keyword clustering were used to identify the current status and trends in HP/GC research, while historical citation analysis provided insight into the evolution of HP/GC research. The hot topics included the effect of HP on gastric tumorigenesis and progression, the pathogenesis of HP-induced GC (HP factors), and the mechanisms by which HP affects GC (host factors). Research in the coming years could focus on topics such as autophagy, gut microbiota, immunotherapy, exosomes, epithelial-mesenchymal transition (EMT), and gamma-glutamyl transpeptidase (GGT). Conclusion This study evaluated the global scientific output in HP/GC research and its quantitative characteristics, identified the essential works, and collected information on the current status, main focuses and emerging trends in HP/GC research to provide academics with guidance for future paths.
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Affiliation(s)
- Shanshan Yang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
| | - Shaodong Hao
- Spleen-Stomach Department, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Ye
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
| | - Xuezhi Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
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10
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Liu J, Wu Y, Meng S, Xu P, Li S, Li Y, Hu X, Ouyang L, Wang G. Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives. Mol Cancer 2024; 23:22. [PMID: 38262996 PMCID: PMC10807193 DOI: 10.1186/s12943-024-01934-y] [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: 12/01/2023] [Accepted: 01/05/2024] [Indexed: 01/25/2024] Open
Abstract
Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future.
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Affiliation(s)
- Jiaxi Liu
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Yongya Wu
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Sha Meng
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Ping Xu
- Emergency Department, Zigong Fourth People's Hospital, Zigong, 643000, China
| | - Shutong Li
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Yong Li
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China
| | - Xiuying Hu
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China.
| | - Liang Ouyang
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China.
| | - Guan Wang
- Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China.
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11
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Peng YL, Wang ZY, Zhong RW, Mei SQ, Liu JQ, Tang LB, Guo Z, Ren ZR, Wu L, Deng Y, Chen ZH, Zhou Q, Xu CR. Association of COVID-19 and Lung Cancer: Short-Term and Long-Term Interactions. Cancers (Basel) 2024; 16:304. [PMID: 38254793 PMCID: PMC10813989 DOI: 10.3390/cancers16020304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Background: COVID-19 has been ravaging the globe for more than three years. Due to systemic immunosuppression of anti-tumor therapy, application of chemotherapy and adverse effects of surgery, the short- and long-term prognosis of cancer patients to COVID-19 are of significant concern. Method: This research included three parts of data. The first part of the data came from the public database that covered Veneto residents. The second part of the data included participants in Guangzhou. The third part of the data was used for MR analysis. We assessed the associations by logistic, linear or Cox regression when appropriate. Result: Lung cancer patients with COVID-19 had shorter progression-free survival (PFS) after COVID-19 (Model II: HR: 3.28, 95% CI: 1.6~6.72; Model III: HR: 3.39, 95% CI: 1.45~7.95), compared with lung cancer patients without COVID-19. Targeted therapy patients recovered from SARS-CoV-2 infection more quickly (Model I: β: -0.58, 95% CI: -0.75~-0.41; Model II: β: -0.59, 95% CI: -0.76~-0.41; Model III: β: -0.57; 95% CI: -0.75~-0.40). Conclusions: PFS in lung cancer patients is shortened by COVID-19. The outcome of COVID-19 in lung cancer patients was not significantly different from that of the healthy population. In lung cancer patients, targeted therapy patients had a better outcome of COVID-19, while chemotherapy patients had the worst.
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Affiliation(s)
- Ying-Long Peng
- School of Medicine, South China University of Technology, Guangzhou 510006, China (R.-W.Z.)
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Zi-Yan Wang
- The First Clinical School, Guangzhou Medical University, Guangzhou 510120, China
| | - Ri-Wei Zhong
- School of Medicine, South China University of Technology, Guangzhou 510006, China (R.-W.Z.)
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Shi-Qi Mei
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Jia-Qi Liu
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Li-Bo Tang
- School of Medicine, South China University of Technology, Guangzhou 510006, China (R.-W.Z.)
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Zhi Guo
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Zi-Rui Ren
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Lv Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Yu Deng
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Qing Zhou
- School of Medicine, South China University of Technology, Guangzhou 510006, China (R.-W.Z.)
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
| | - Chong-Rui Xu
- School of Medicine, South China University of Technology, Guangzhou 510006, China (R.-W.Z.)
- Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510180, China (J.-Q.L.); (Z.G.)
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12
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Seeger AY, Zaidi F, Alhayek S, Jones RM, Zohair H, Holland RL, Kim IJ, Blanke SR. Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells. mBio 2023; 14:e0211723. [PMID: 37815365 PMCID: PMC10653863 DOI: 10.1128/mbio.02117-23] [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] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 10/11/2023] Open
Abstract
IMPORTANCE Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.
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Affiliation(s)
- Ami Y. Seeger
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Faisal Zaidi
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Sammy Alhayek
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Rachel M. Jones
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Huzaifa Zohair
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Robin L. Holland
- Department of Pathobiology, University of Illinois, Urbana, Illinois, USA
| | - Ik-Jung Kim
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
- Buck Institute for Research on Aging, Novato, California, USA
| | - Steven R. Blanke
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
- Department of Pathobiology, University of Illinois, Urbana, Illinois, USA
- Department of Biomedical and Translational Medicine, University of Illinois, Urbana, Illinois, USA
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13
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Nabavi-Rad A, Yadegar A, Sadeghi A, Aghdaei HA, Zali MR, Klionsky DJ, Yamaoka Y. The interaction between autophagy, Helicobacter pylori, and gut microbiota in gastric carcinogenesis. Trends Microbiol 2023; 31:1024-1043. [PMID: 37120362 PMCID: PMC10523907 DOI: 10.1016/j.tim.2023.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 05/01/2023]
Abstract
Chronic infection with Helicobacter pylori is the primary risk factor for the development of gastric cancer. Hindering our ability to comprehend the precise role of autophagy during H. pylori infection is the complexity of context-dependent autophagy signaling pathways. Recent and ongoing progress in understanding H. pylori virulence allows new frontiers of research for the crosstalk between autophagy and H. pylori. Novel approaches toward discovering autophagy signaling networks have further revealed their critical influence on the structure of gut microbiota and the metabolome. Here we intend to present a holistic view of the perplexing role of autophagy in H. pylori pathogenesis and carcinogenesis. We also discuss the intermediate role of autophagy in H. pylori-mediated modification of gut inflammatory responses and microbiota structure.
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Affiliation(s)
- Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Daniel J Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan; Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA; Research Center for Global and Local Infectious Diseases, Oita University, Oita, Japan.
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14
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Li B, Lv X, Xu Z, He J, Liu S, Zhang X, Tong X, Li J, Zhang Y. Helicobacter pylori infection induces autophagy via ILK regulation of NOXs-ROS-Nrf2/HO-1-ROS loop. World J Microbiol Biotechnol 2023; 39:284. [PMID: 37599292 DOI: 10.1007/s11274-023-03710-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 07/21/2023] [Indexed: 08/22/2023]
Abstract
Reactive oxygen species (ROS) can regulate the occurrence of autophagy, and effective control of the balance between ROS and autophagy may be an important strategy for Helicobacter pylori induced gastric-related diseases. In this study, infection with H. pylori led to a lower level of ILK phosphorylation and increased ROS generation. Knockdown of ILK enhanced total ROS generation, and upregulated NADPH oxidase (NOX) subunit p22-phox levels. Inhibition of NOXs affected total ROS generation. The inhibition of NOX and ROS generation reduced Nrf2 and HO-1 levels, and knockdown of ILK significantly enhanced Nrf2 levels in H. pylori-infected GES-1 cells. Activation of Nrf2 by DMF decreased ROS levels. Therefore, NOX-dependent ROS production regulated by ILK was essential for activation of Nrf2/HO-1 signaling pathways in H. pylori-infected GES-1 cells. Beclin1, ATG5 and LC3B-II levels were higher both in H. pylori-infected and ILK-knockdown GES-1 cells. In NAC-pretreated GES-1 cells infected with H. pylori, the LC3B-II level was decreased compared to that in cells after H. pylori infection alone. Stable low expression of ILK with further knockdown of Beclin1 or ATG5 significantly reduced LC3B-II levels in GES-1 cells, while with the addition of the autophagy inhibitor chloroquine (CQ), LC3B-II and p62 protein levels were both remarkably upregulated. H. pylori accelerated the accumulation of ROS and further led to the induction of ROS-mediated autophagy by inhibiting ILK levels. Together, these results indicate that H. pylori infection manipulates the NOX-ROS-Nrf2/HO-1-ROS loop to control intracellular oxygen stress and further induced ROS-mediated autophagy by inhibiting ILK levels.
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Affiliation(s)
- Boqing Li
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Xin Lv
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Zheng Xu
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Jing He
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - SiSi Liu
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Xiaolin Zhang
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Xiaohan Tong
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Jing Li
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China
| | - Ying Zhang
- School of Basic Medical Sciences, Binzhou Medical University, 346# Guanhai Road, Yantai, 264003, China.
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15
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The Effect of Quadruple Therapy with Polaprezinc or Bismuth on Gut Microbiota after Helicobacter pylori Eradication: A Randomized Controlled Trial. J Clin Med 2022; 11:jcm11237050. [PMID: 36498624 PMCID: PMC9739995 DOI: 10.3390/jcm11237050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/05/2022] Open
Abstract
Background: Quadruple therapy with polaprezinc provided an alternative to Helicobacter pylori eradication; however, the effect on gut microbiota remains uncertain. This study aims to identify whether polaprezinc-containing quadruple therapy causes adverse microbiota effects among asymptomatic adults, compared with bismuth therapy. Methods: This was a randomized control trial. One hundred asymptomatic H. pylori-infected adults were randomly (1:1) assigned to two treatment groups (polaprezinc-containing therapy, PQT; or bismuth-containing therapy, BQT). Fecal samples were collected from subjects before and 4−8 weeks after therapy. Samples were sequenced for the V4 regions of the 16S rRNA gene. Results: The relative abundance of the three dominant bacterial phyla (Bacteroidota, Firmicutes, and Proteobacteria) accounted for more than 95% of each treatment group. The alpha diversity between eradications that succeeded and those that failed had no significant difference (p > 0.05). After successful eradication, the alpha diversity in the BQT group decreased in comparison with the baseline (p < 0.05). Subjects who were successfully eradicated by BQT showed considerably lower alpha diversity indices than those of the PQT at follow-up (p < 0.05). The abundance of Parasutterella in subjects who were successfully eradicated by PQT was four times greater than that of BQT (q < 0.05). Conclusion: A 14-day PQT may be superior to BQT in maintaining short-term gut microbiota homeostasis after H. pylori treatment. Our findings preliminarily provide evidence of the short-term impacts of the gut microbiota after PQT treatment of H. pylori infection.
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16
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Host Cell Antimicrobial Responses against Helicobacter pylori Infection: From Biological Aspects to Therapeutic Strategies. Int J Mol Sci 2022; 23:ijms231810941. [PMID: 36142852 PMCID: PMC9504325 DOI: 10.3390/ijms231810941] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 02/07/2023] Open
Abstract
The colonization of Helicobacter pylori (H. pylori) in human gastric mucosa is highly associated with the occurrence of gastritis, peptic ulcer, and gastric cancer. Antibiotics, including amoxicillin, clarithromycin, furazolidone, levofloxacin, metronidazole, and tetracycline, are commonly used and considered the major treatment regimens for H. pylori eradication, which is, however, becoming less effective by the increasing prevalence of H pylori resistance. Thus, it is urgent to understand the molecular mechanisms of H. pylori pathogenesis and develop alternative therapeutic strategies. In this review, we focus on the virulence factors for H. pylori colonization and survival within host gastric mucosa and the host antimicrobial responses against H. pylori infection. Moreover, we describe the current treatments for H. pylori eradication and provide some insights into new therapeutic strategies for H. pylori infection.
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17
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Wang L, Yi J, Yin XY, Hou JX, Chen J, Xie B, Chen G, Wang QF, Wang LN, Wang XY, Sun J, Huo LM, Che TJ, Wei HL. Vacuolating Cytotoxin A Triggers Mitophagy in Helicobacter pylori-Infected Human Gastric Epithelium Cells. Front Oncol 2022; 12:881829. [PMID: 35912184 PMCID: PMC9329568 DOI: 10.3389/fonc.2022.881829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/20/2022] [Indexed: 11/30/2022] Open
Abstract
Helicobacter pylori (H. pylori)-derived vacuolating cytotoxin A (VacA) causes damage to various organelles, including mitochondria, and induces autophagy and cell death. However, it is unknown whether VacA-induced mitochondrial damage can develop into mitophagy. In this study, we found that H. pylori, H. pylori culture filtrate (HPCF), and VacA could activate autophagy in a gastric epithelial cell line (GES-1). VacA-caused mitochondrial depolarization retards the import of PINK1 into the damaged mitochondria and evokes mitophagy. And, among mass spectrometry (LC-MS/MS) identified 25 mitochondrial proteins bound with VacA, Tom20, Tom40, and Tom70, TOM complexes responsible for PINK1 import, were further identified as having the ability to bind VacA in vitro using pull-down assay, co-immunoprecipitation, and protein–protein docking. Additionally, we found that the cell membrane protein STOM and the mitochondrial inner membrane protein PGAM5 also interacted with VacA. These findings suggest that VacA captured by STOM forms endosomes to enter cells and target mitochondria. Then, VacA is transported into the mitochondrial membrane space through the TOM complexes, and PGAM5 aids in inserting VacA into the inner mitochondrial membrane to destroy the membrane potential, which promotes PINK1 accumulation and Parkin recruitment to induce mitophagy. This study helps us understand VacA entering mitochondria to induce the mitophagy process.
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Affiliation(s)
- Li Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Juan Yi
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Xiao-Yang Yin
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jin-Xia Hou
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jing Chen
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Bei Xie
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Gang Chen
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Qun-Feng Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Li-Na Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Xiao-Yuan Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jing Sun
- Geriatrics Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Lei-Ming Huo
- Neurosurgery Department, The First Hospital of Lanzhou University, Lanzhou, China
| | - Tuan-Jie Che
- Key Laboratory of Functional Genomics and Molecular Diagnosis of Gansu Province, Lanzhou Baiyuan Gene Technology Co., Ltd, Lanzhou, China
- *Correspondence: Tuan-Jie Che, ; Hu-Lai Wei,
| | - Hu-Lai Wei
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Key Laboratory of Functional Genomics and Molecular Diagnosis of Gansu Province, Lanzhou Baiyuan Gene Technology Co., Ltd, Lanzhou, China
- *Correspondence: Tuan-Jie Che, ; Hu-Lai Wei,
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18
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Zheng L, Wei F, Li G. The crosstalk between bacteria and host autophagy: host defense or bacteria offense. J Microbiol 2022; 60:451-460. [DOI: 10.1007/s12275-022-2009-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/18/2022] [Accepted: 03/29/2022] [Indexed: 12/26/2022]
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19
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Yang Y, Shu X, Xie C. An Overview of Autophagy in Helicobacter pylori Infection and Related Gastric Cancer. Front Cell Infect Microbiol 2022; 12:847716. [PMID: 35463631 PMCID: PMC9033262 DOI: 10.3389/fcimb.2022.847716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/16/2022] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection is considered a class I carcinogen in the pathogenesis of gastric cancer. In recent years, the interaction relationship between H. pylori infection and autophagy has attracted increasing attention. Most investigators believe that the pathogenesis of gastric cancer is closely related to the formation of an autophagosome-mediated downstream signaling pathway by H. pylori infection-induced cells. Autophagy is involved in H. pylori infection and affects the occurrence and development of gastric cancer. In this paper, the possible mechanism by which H. pylori infection affects autophagy and the progression of related gastric cancer signaling pathways are reviewed.
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Affiliation(s)
| | - Xu Shu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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20
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Aziz F, Khan I, Shukla S, Dey DK, Yan Q, Chakraborty A, Yoshitomi H, Hwang SK, Sonwal S, Lee H, Haldorai Y, Xiao J, Huh YS, Bajpai VK, Han YK. Partners in crime: The Lewis Y antigen and fucosyltransferase IV in Helicobacter pylori-induced gastric cancer. Pharmacol Ther 2022; 232:107994. [PMID: 34571111 DOI: 10.1016/j.pharmthera.2021.107994] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 02/05/2023]
Abstract
Helicobacter pylori (H. pylori) is a major causative agent of chronic gastritis, gastric ulcer and gastric carcinoma. H. pylori cytotoxin associated antigen A (CagA) plays a crucial role in the development of gastric cancer. Gastric cancer is associated with glycosylation alterations in glycoproteins and glycolipids on the cell surface. H. pylori cytotoxin associated antigen A (CagA) plays a significant role in the progression of gastric cancer through post-translation modification of fucosylation to develop gastric cancer. The involvement of a variety of sugar antigens in the progression and development of gastric cancer has been investigated, including type II blood group antigens. Lewis Y (LeY) is overexpressed on the tumor cell surface either as a glycoprotein or glycolipid. LeY is a difucosylated oligosaccharide, which is catalyzed by fucosyltransferases such as FUT4 (α1,3). FUT4/LeY overexpression may serve as potential correlative biomarkers for the prognosis of gastric cancer. We discuss the various aspects of H. pylori in relation to fucosyltransferases (FUT1-FUT9) and its fucosylated Lewis antigens (LeY, LeX, LeA, and LeB) and gastric cancer. In this review, we summarize the carcinogenic effect of H. pylori CagA in association with LeY and its synthesis enzyme FUT4 in the development of gastric cancer as well as discuss its importance in the prognosis and its inhibition by combination therapy of anti-LeY antibody and celecoxib through MAPK signaling pathway preventing gastric carcinogenesis.
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Affiliation(s)
- Faisal Aziz
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA; Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, PR China.
| | - Imran Khan
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA
| | - Shruti Shukla
- TERI-Deakin Nanobiotechnology Centre, The Energy and Resources Institute, Gwal Pahari, Gurugram, Haryana 122003, India
| | - Debasish Kumar Dey
- Department of Biotechnology, College of Engineering, Daegu University, Gyeongsan 38453, Republic of Korea
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian 116044, PR China
| | | | - Hisae Yoshitomi
- The Hormel Institute-University of Minnesota, Austin, MN 55912, USA
| | - Seung-Kyu Hwang
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Sonam Sonwal
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Hoomin Lee
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea
| | - Yuvaraj Haldorai
- Department of Nanoscience and Technology, Bharathiar University, Coimbatore, Tamilnadu 641046, India
| | - Jianbo Xiao
- Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China; University of Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, E32004 Ourense, Spain.
| | - Yun Suk Huh
- Department of Biological Engineering, NanoBio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Nam-gu, Incheon 22212, Republic of Korea.
| | - Vivek K Bajpai
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea.
| | - Young-Kyu Han
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea.
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21
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miR-30c Increases the Intracellular Survival of Helicobacter pylori by Inhibiting Autophagy. Cell Microbiol 2022. [DOI: 10.1155/2022/4536450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Persistent Helicobacter pylori infection causes a variety of gastrointestinal diseases and even gastric cancer. H. pylori invades gastric epithelial cells to survive and proliferate, which is one of the key factors in persistent colonization. A Published study has confirmed that cells can eliminate intracellular H. pylori through xenophagy to maintain intracellular balance. However, a growing body of evidences indicate that H. pylori can inhibit xenophagy by miRNA through regulating the expression of key autophagy-related genes. Through western blot analysis, mRFP-GFP-LC3 transfection assay, and transmission electron microscopy, we found that H. pylori infection obstructed autophagy flux degradation stage in GES-1 cell lines. Gentamicin protection assay confirmed that inhibit xenophagy is benefit for intracellular H. pylori survive. miR-30c-1-3p and miR-30c-5p were upregulated in GES-1 cell lines after infecting with H. pylori, resulting in the negative regulation on xenophagy. Further studies through bioinformatics analysis and dual-luciferase reporter assays confirmed that ATG14 and ULK1 were the target genes of miR-30c-1-3p and that ATG12 was the target gene of miR-30c-5p. The overexpression of miR-30c-1-3p and miR-30c-5p reduces the expression of ATG14, ULK1, and ATG12 at mRNA level and also decreased intracellular H. pylori elimination in GES-1 cells. The above results suggested that the inhibition on xenophagy by miR-30c-1-3p and miR-30c-5p through ATG14, ULK1, and ATG12 targeting benefitted intracellular H. pylori in the evasion of xenophagy clearance.
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22
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Shao Y, Wang Z, Chen K, Li D, Lv Z, Zhang C, Zhang W, Li C. Xenophagy of invasive bacteria is differentially activated and modulated via a TLR-TRAF6-Beclin1 axis in echinoderms. J Biol Chem 2022; 298:101667. [PMID: 35120925 PMCID: PMC8902612 DOI: 10.1016/j.jbc.2022.101667] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/13/2022] [Accepted: 01/18/2022] [Indexed: 11/16/2022] Open
Abstract
In marine environments, organisms are confronted with numerous microbial challenges, although the differential regulation of xenophagy in response to different pathogenic bacterial species remains relatively unknown. Here, we addressed this issue using Apostichopus japonicus as a model. We identified 39 conserved autophagy-related genes by genome-wide screening, which provided a molecular basis for autophagy regulation in sea cucumbers. Furthermore, xenophagy of two Gram-negative bacteria, Vibrio splendidus and Escherichia coli, but not a Gram-positive bacteria, Micrococcus luteus, was observed in different autophagy assays. Surprisingly, a significantly higher autophagy capacity was found in the E. coli–challenged group than in the V. splendidus–challenged group. To confirm these findings, two different lipopolysaccharides, LPSV. splendidus and LPSE. coli, were isolated; we found that these LPS species differentially activated coelomocyte xenophagy. To explore the molecular mechanism mediating differential levels of xenophagy, we used an siRNA knockdown assay and confirmed that LPSV. splendidus-mediated xenophagy was dependent on an AjTLR3-mediated pathway, whereas LPSE. coli-mediated xenophagy was dependent on AjToll. Moreover, the activation of different AjTLRs resulted in AjTRAF6 ubiquitination and subsequent activation of K63-linked ubiquitination of AjBeclin1. Inversely, the LPSV. splendidus-induced AjTLR3 pathway simultaneously activated the expression of AjA20, which reduced the extent of K63-linked ubiquitination of AjBeclin1 and impaired the induction of autophagy; however, this finding was no t evident with LPSE. coli. Our present results provide the first evidence showing that xenophagy could be differentially induced by different bacterial species to yield differential autophagy levels in echinoderms.
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Affiliation(s)
- Yina Shao
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Zhenhui Wang
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Kaiyu Chen
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Dongdong Li
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Zhimeng Lv
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Chundan Zhang
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Weiwei Zhang
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China
| | - Chenghua Li
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, PR China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, PR China; State-Province Joint Laboratory of Marine Biotechnology and Engineering, Ningbo University, Ningbo 315211, China.
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23
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Sekar R, Preethi M, Mohammed J. Quantification of Helicobacter pylori and its oncoproteins in oral cavity. A cross sectional study. Oral Dis 2022; 29:1868-1874. [PMID: 35092112 DOI: 10.1111/odi.14141] [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: 03/21/2021] [Revised: 12/30/2021] [Accepted: 01/20/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To identify Helicobacter pylori (H.pylori) and related oncogenic and virulent proteins (CagA and VacA) in patients with gingivitis, periodontitis, oral cancer and gastric cancer. METHODS Subgingival plaque samples were collected from 90 individuals with either gingivitis/ periodontitis (group A, n=30), oral cancer (group B, n=30) and gastric cancer (group C, n=30). H.pylori was identified by real time- polymerase chain reaction (RT-PCR). The virulent organisms were detected by identification of proteins CagA and VacA through Enzyme Linked Immuno Sorbent Assay (ELISA). RESULTS We identified the presence of H.pylori in subgingival plaque samples among a large majority (76/90) of our study cohort. The proportions of CagA and VacA identified among H.pylori individuals with periodontal inflammation and oral cancer were lower than those diagnosed with gastric cancer. Furthermore, the relative risk of oral cancer based on the presence of the organism was no different to those with gingivitis/periodontitis. CONCLUSION The findings of our study does not indicate significant association between the organism and oral cancer but preludes that the oral cavity could act as a potential niche for H.pylori. The possibility for CagA and VacA proteins to be pathogenic in oral cavity is highly possible and to be researched extensively.
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Affiliation(s)
- Ramya Sekar
- Department of Oral and Maxillofacial Pathology, Meenakshi Ammal Dental College and Hospital, Maduravoyal, Chennai, 600 095, India
| | - Murali Preethi
- Department of Oral and Maxillofacial Pathology, Meenakshi Ammal Dental College and Hospital, Maduravoyal, Chennai, 600 095, India
| | - Junaid Mohammed
- School of Population and Global Health, University of Western Australia, Clifton Street Building, Clifton street, Nedlands, 6009, Western Australia, Australia.,Telethon Kids Institute, University of Western Australia, Nedlands, 6009, Western Australia, Australia
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24
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Qin Y, Lao YH, Wang H, Zhang J, Yi K, Chen Z, Han J, Song W, Tao Y, Li M. Combatting Helicobacter pylori with oral nanomedicines. J Mater Chem B 2021; 9:9826-9838. [PMID: 34854456 DOI: 10.1039/d1tb02038b] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori (H. pylori) infection is considered to be the main cause of most digestive diseases,such as chronic active gastritis, gastroduodenal ulcers, or even gastric cancer. Oral medication is a transformative approach to treat H. pylori-induced infections. However, unlike intravenous administration, orally administrated drugs have to overcome various barriers before reaching the infected sites, which significantly limits the therapeutic efficacy. These challenges may be addressed by emerging nanomedicine that is equipped with nanotechnology approaches to enable efficient and effective targeted delivery of drugs. Herein, in this review, we first discuss the conventional therapy for the eradication of H. pylori. Through the introduction of the critical barriers of oral administration, the benefits of nanomedicine are highlighted. Recently-published examples of nanocarriers for combating H. pylori in terms of design, preparation, and antimicrobial mechanisms are then presented, followed by our perspective on potential future research directions of oral nanomedicines.
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Affiliation(s)
- Yuan Qin
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Yeh-Hsing Lao
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Ke Yi
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Zhuanggui Chen
- Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Han
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wantong Song
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, China
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25
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Prashar A, Capurro MI, Jones NL. Under the Radar: Strategies Used by Helicobacter pylori to Evade Host Responses. Annu Rev Physiol 2021; 84:485-506. [PMID: 34672717 DOI: 10.1146/annurev-physiol-061121-035930] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The body depends on its physical barriers and innate and adaptive immune responses to defend against the constant assault of potentially harmful microbes. In turn, successful pathogens have evolved unique mechanisms to adapt to the host environment and manipulate host defenses. Helicobacter pylori (Hp), a human gastric pathogen that is acquired in childhood and persists throughout life, is an example of a bacterium that is very successful at remodeling the host-pathogen interface to promote a long-term persistent infection. Using a combination of secreted virulence factors, immune subversion, and manipulation of cellular mechanisms, Hp can colonize and persist in the hostile environment of the human stomach. Here, we review the most recent and relevant information regarding how this successful pathogen overcomes gastric epithelial host defense responses to facilitate its own survival and establish a chronic infection. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Akriti Prashar
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Mariana I Capurro
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Nicola L Jones
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada; .,Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.,Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada
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26
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Autophagy induced by H. pylori VacA regulated the survival mechanism of the SGC7901 human gastric cancer cell line. Genes Genomics 2021; 43:1223-1230. [PMID: 34398448 PMCID: PMC8429402 DOI: 10.1007/s13258-021-01151-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 08/06/2021] [Indexed: 11/08/2022]
Abstract
Background Vacuolating cytotoxin (VacA) is an important virulence factor of Helicobacter pylori (H. pylori). It was previously believed that VacA can trigger the cascade of apoptosis on mitochondria to lead to cell apoptosis. Recently, it was found that VacA can induce autophagy. However, the molecular mechanism by which VacA induces autophagy is largely unknown. Objective We aimed to explore the molecular mechanism of autophagy induced by H. pylori in gastric cancer cells and the effect of autophagy on the survival of gastric cancer cells. Methods The autophagy of human gastric cancer cell line SGC7901 was detected by Western blot and RT-PCR in the treatment of VacA protein of H. pylori. The relationship between autophagy and reactive oxygen species (ROS) in the proliferation of gastric cancer cells were studied by gene expression silences (siRNA) and CM-H2DCFDA (DCF) staining. Results The results showed that VacA protein secreted by H. pylori in the supernatant stimulated autophagy in SGC7901 cells. After VacA protein treatment, the mRNA expressions of BECN1, ATG7 and PIK3C3, were up-regulated. ATG7 silencing by siRNA inhibited VacA-induced autophagy. Furthermore, our data demonstrated that VacA protein increased ROS levels. Addition of the antioxidant N-acetyl-l-cysteine (NAC) suppressed the levels of ROS, leading to inhibition of autophagy. Conclusions H. pylori VacA is a key toxin that induces autophagy by increased ROS levels. And our findings demonstrated that VacA significantly inhibited proliferation in SGC7901 cells.
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27
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Lin TY, Lan WH, Chiu YF, Feng CL, Chiu CH, Kuo CJ, Lai CH. Statins' Regulation of the Virulence Factors of Helicobacter pylori and the Production of ROS May Inhibit the Development of Gastric Cancer. Antioxidants (Basel) 2021; 10:1293. [PMID: 34439541 PMCID: PMC8389206 DOI: 10.3390/antiox10081293] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Conventionally, statins are used to treat high cholesterol levels. They exhibit pleiotropic effects, such as the prevention of cardiovascular disease and decreased cancer mortality. Gastric cancer (GC) is one of the most common cancers, ranking as the third leading global cause of cancer-related deaths, and is mainly attributed to chronic Helicobacter pylori infection. During their co-evolution with hosts, H. pylori has developed the ability to use the cellular components of the host to evade the immune system and multiply in intracellular niches. Certain H. pylori virulence factors, including cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and cholesterol-α-glucosyltransferase (CGT), have been shown to exploit host cholesterol during pathogenesis. Therefore, using statins to antagonize cholesterol synthesis might prove to be an ideal strategy for reducing the occurrence of H. pylori-related GC. This review discusses the current understanding of the interplay of H. pylori virulence factors with cholesterol and reactive oxygen species (ROS) production, which may prove to be novel therapeutic targets for the development of effective treatment strategies against H. pylori-associated GC. We also summarize the findings of several clinical studies on the association between statin therapy and the development of GC, especially in terms of cancer risk and mortality.
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Affiliation(s)
- Ting-Yu Lin
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Wen-Hsi Lan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
| | - Ya-Fang Chiu
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Medical Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chun-Lung Feng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hsinchu Hospital, Hsinchu 30272, Taiwan;
- Department of Internal Medicine, Department of Medical Research, School of Medicine, China Medical University and Hospital, Taichung 40447, Taiwan
| | - Cheng-Hsun Chiu
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Chang Gung Microbiota Therapy Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chia-Jung Kuo
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (T.-Y.L.); (W.-H.L.); (Y.-F.C.); (C.-H.C.)
- Chang Gung Microbiota Therapy Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
| | - Chih-Ho Lai
- Research Center for Emerging Viral, Infections Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Internal Medicine, Department of Medical Research, School of Medicine, China Medical University and Hospital, Taichung 40447, Taiwan
- Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Department of Nursing, Asia University, Taichung 41354, Taiwan
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28
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Thein W, Po WW, Choi WS, Sohn UD. Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches. Biomol Ther (Seoul) 2021; 29:353-364. [PMID: 34127572 PMCID: PMC8255139 DOI: 10.4062/biomolther.2021.086] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/11/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.
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Affiliation(s)
- Wynn Thein
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Wah Wah Po
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Won Seok Choi
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Uy Dong Sohn
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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29
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Helicobacter pylori regulates ILK to influence autophagy through Rac1 and RhoA signaling pathways in gastric epithelial cells. Microb Pathog 2021; 158:105054. [PMID: 34146643 DOI: 10.1016/j.micpath.2021.105054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 05/27/2021] [Accepted: 06/09/2021] [Indexed: 11/22/2022]
Abstract
The ability of Helicobacter pylori to manipulate host autophagy is an important pathogenic mechanism. We found an inverse correlation between the expression of ILK and the autophagy marker protein LC3B in H. pylori-positive human samples, H. pylori-infected mice models and H. pylori-infected GES-1 cell lines. When the ILK-knockdown GES-1 cells were infected by H. pylori, CagA were significantly degraded, autophagosomes accumulation and autolysosomes formation were significantly increased, and LC3B protein levels and ratio of LC3BII to LC3BI were also remarkably upregulated. And chloroquine treatment increased LC3B levels in ILK-knockdown GES-1 cells. The expression levels of both Rac1 and RhoA were downregulated in GES-1 cells after H. pylori infection and were decreased in ILK-knockdown GES-1 cells. The mRNA and protein levels of PAK1, MLC, and LIMK were significantly decreased and cofilin mRNA and protein levels were significantly increased in GES-1 cells treated with the Rac1 inhibitor NSC 23766. The mRNA and protein levels of ROCK1, ROCK2, MLC, and LIMK1 were significantly reduced and cofilin mRNA and protein levels were significantly increased in GES-1 cells treated with the RhoA inhibitor CCG-1423. F-actin was significantly reduced in Rac1- or RhoA-inhibited GES-1 cells. F-actin depolymerization induced autophagosomes accumulation, autolysosomes formation, and the increase of LC3B levels in GES-1 cells. Therefore, these findings revealed that ILK could serve as a novel regulator to affect Rac1/PAK1 and RhoA/ROCKs signaling pathways, thereby influencing H. pylori-induced autophagy.
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30
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Xu Y, Deng Q, Zhong Y, Jing L, Li H, Li J, Yu H, Pan H, Guo S, Cao H, Huang P, Huang B. Clinical Strains of Helicobacter pylori With Strong Cell Invasiveness and the Protective Effect of Patchouli Alcohol by Improving miR-30b/C Mediated Xenophagy. Front Pharmacol 2021; 12:666903. [PMID: 33995095 PMCID: PMC8120110 DOI: 10.3389/fphar.2021.666903] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/19/2021] [Indexed: 11/13/2022] Open
Abstract
Helicobacter pylori was classified by the World Health Organization as a class 1 carcinogen. The development of drug-resistant strains of this pathogen poses a serious threat to human health worldwide. The cell invasion of H. pylori activates xenophagy in gastric epithelial cells by mediating miR-30b/c, and the emergence of autophagosomes provides a niche that enables the survival of intracellular H. pylori and promotes its drug resistance. This study revealed that some clinical drug-resistant H. pylori strains present much stronger invasive ability than standard strains. Patchouli alcohol (PA), a tricyclic sesquiterpene from Pogostemon cablin (Blanco) Benth (Labiatae), showed reliable activity against intracellular H. pylori. The mechanisms appeared to involve the downregulation of miR-30c-3p/5p and miR-30b-5p, thereby upregulating xenophagy-related gene expression (ULK1, ATG5, ATG12, and ATG14) and enhancing xenophagy. PA also inhibited the nuclear transfection of miR-30b-5p induced by H. pylori, thereby enhancing transcription factor EB function and increasing lysosome activity. The finding of strongly invasive intracellular H. pylori has great implications for clinical treatment, and PA can act against invasive H. pylori based on the improvement of miR-30b/c mediated xenophagy. Taken together, the results demonstrate that PA have potential use as a candidate medication for intracellular drug-resistant H. pylori.
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Affiliation(s)
- Yifei Xu
- Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiuhua Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuanzun Zhong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li Jing
- School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Haiwen Li
- Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jingwei Li
- Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Huimin Yu
- School of Medicine, Shenzhen University, Shenzhen, China
| | - Huafeng Pan
- Science and Technology Innovation Center, 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
| | - Hongying Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ping Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Huang
- Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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Riahi Rad Z, Riahi Rad Z, Goudarzi H, Goudarzi M, Mahmoudi M, Yasbolaghi Sharahi J, Hashemi A. MicroRNAs in the interaction between host-bacterial pathogens: A new perspective. J Cell Physiol 2021; 236:6249-6270. [PMID: 33599300 DOI: 10.1002/jcp.30333] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/17/2022]
Abstract
Gene expression regulation plays a critical role in host-pathogen interactions, and RNAs function is essential in this process. miRNAs are small noncoding, endogenous RNA fragments that affect stability and/or translation of mRNAs, act as major posttranscriptional regulators of gene expression. miRNA is involved in regulating many biological or pathological processes through targeting specific mRNAs, including development, differentiation, apoptosis, cell cycle, cytoskeleton organization, and autophagy. Deregulated microRNA expression is associated with many types of diseases, including cancers, immune disturbances, and infection. miRNAs are a vital section of the host immune response to bacterial-made infection. Bacterial pathogens suppress host miRNA expression for their benefit, promoting survival, replication, and persistence. The role played through miRNAs in interaction with host-bacterial pathogen has been extensively studied in the past 10 years, and knowledge about these staggering molecules' function can clarify the complicated and ambiguous interactions of the host-bacterial pathogen. Here, we review how pathogens prevent the host miRNA expression. We briefly discuss emerging themes in this field, including their role as biomarkers in identifying bacterial infections, as part of the gut microbiota, on host miRNA expression.
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Affiliation(s)
- Zohreh Riahi Rad
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Riahi Rad
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahmoudi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Javad Yasbolaghi Sharahi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Hashemi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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32
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Courtois S, Haykal M, Bodineau C, Sifré E, Azzi-Martin L, Ménard A, Mégraud F, Lehours P, Durán RV, Varon C, Bessède E. Autophagy induced by Helicobacter pylori infection is necessary for gastric cancer stem cell emergence. Gastric Cancer 2021; 24:133-144. [PMID: 32940810 DOI: 10.1007/s10120-020-01118-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The main cause of gastric cancer is the infection by the bacterium Helicobacter pylori which induces a chronic inflammation and an epithelial-to-mesenchymal transition (EMT) leading to the emergence of cells with cancer stem cell (CSC) properties. However, the underlying mechanisms have not been fully characterized. Moreover, H. pylori modulates the host cell autophagic process, but a few studies have investigated the role of this process in tumoral transformation. The aim of this study was to determine whether H. pylori-induced autophagy has a role in CSC emergence. METHODS Autophagic flux in response to H. pylori infection was characterized in AGS cell line expressing the tandem-tagged mCherry-GFP-LC3 protein and using a ratiometric flow cytometry analysis. Then, AGS and MKN45 cell lines were treated with bafilomycin or chloroquine, two pharmaceutical well-known inhibitors of autophagy, and different EMT and CSC characteristics were analyzed. RESULTS First, a co-expression of the gastric CSC marker CD44 and the autophagic marker LC3 in mice and human stomach tissues infected with H. pylori was observed. Then, we demonstrated in vitro that H. pylori was able to activate the autophagy process with a reduced autophagic flux. Finally, infected cells were treated with autophagy inhibitors, which reduced (i) appearance of mesenchymal phenotypes and migration ability related to EMT and (ii) CD44 expression as well as tumorsphere formation capacities reflecting CSC properties. CONCLUSION In conclusion, all these data show that H. pylori-induced autophagy is implicated in gastric CSC emergence and could represent an interesting therapeutic target.
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Affiliation(s)
- Sarah Courtois
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
| | - Maria Haykal
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
| | - Clément Bodineau
- Centro Andaluz de Biología Molecular Y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Américo Vespucio 24, 41092, Sevilla, Spain.,Institut Européen de Chimie et Biologie, INSERM U1218, University of Bordeaux, Pessac, France
| | - Elodie Sifré
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
| | | | - Armelle Ménard
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
| | - Francis Mégraud
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France.,French National Reference Center for Campylobacters and Helicobacters (CNRCH), University Hospital of Bordeaux, Place Amelie Raba Leon, 33076, Bordeaux, France
| | - Philippe Lehours
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France.,French National Reference Center for Campylobacters and Helicobacters (CNRCH), University Hospital of Bordeaux, Place Amelie Raba Leon, 33076, Bordeaux, France
| | - Raúl V Durán
- Centro Andaluz de Biología Molecular Y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Américo Vespucio 24, 41092, Sevilla, Spain
| | - Christine Varon
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
| | - Emilie Bessède
- Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France. .,French National Reference Center for Campylobacters and Helicobacters (CNRCH), University Hospital of Bordeaux, Place Amelie Raba Leon, 33076, Bordeaux, France.
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Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev 2020; 39:1179-1203. [PMID: 32894370 PMCID: PMC7680370 DOI: 10.1007/s10555-020-09925-3] [Citation(s) in RCA: 435] [Impact Index Per Article: 87.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
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Affiliation(s)
- Rachel E Sexton
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Maria Diab
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA.
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Xie C, Li N, Wang H, He C, Hu Y, Peng C, Ouyang Y, Wang D, Xie Y, Chen J, Shu X, Zhu Y, Lu N. Inhibition of autophagy aggravates DNA damage response and gastric tumorigenesis via Rad51 ubiquitination in response to H. pylori infection. Gut Microbes 2020; 11:1567-1589. [PMID: 32588736 PMCID: PMC7524160 DOI: 10.1080/19490976.2020.1774311] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is the strongest known risk factor for the development of gastric cancer. DNA damage response (DDR) and autophagy play key roles in tumorigenic transformation. However, it remains unclear how H. pylori modulate DDR and autophagy in gastric carcinogenesis. Here we report that H. pylori infection promotes DNA damage via suppression of Rad51 expression through inhibition of autophagy and accumulation of p62 in gastric carcinogenesis. We find that H. pylori activated DNA damage pathway in concert with downregulation of repair protein Rad51 in gastric cells, C57BL/6 mice and Mongolian gerbils. In addition, autophagy was increased early and then decreased gradually during the duration of H. pylori infection in vitro in a CagA-dependent manner. Moreover, loss of autophagy led to promotion of DNA damage in H. pylori-infected cells. Furthermore, knockdown of autophagic substrate p62 upregulated Rad51 expression, and p62 promoted Rad51 ubiquitination via the direct interaction of its UBA domain. Finally, H. pylori infection was associated with elevated levels of p62 in gastric intestinal metaplasia and decreased levels of Rad51 in dysplasia compared to their H. pylori- counterparts. Our findings provide a novel mechanism into the linkage of H. pylori infection, autophagy, DNA damage and gastric tumorigenesis.
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Affiliation(s)
- Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Nianshuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Huan Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Cong He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Chao Peng
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yaobin Ouyang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Dejie Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yong Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Xu Shu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,CONTACT NongHua Lu Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province330006, China
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He Y, Wang C, Zhang X, Lu X, Xing J, Lv J, Guo M, Huo X, Liu X, Lu J, Du X, Li C, Chen Z. Sustained Exposure to Helicobacter pylori Lysate Inhibits Apoptosis and Autophagy of Gastric Epithelial Cells. Front Oncol 2020; 10:581364. [PMID: 33194715 PMCID: PMC7658535 DOI: 10.3389/fonc.2020.581364] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori is designated as a class I carcinogen of human gastric cancer following long-term infection. During this process, H. pylori bacteria persist in proliferation and death, and release bacterial components that come into contact with gastric epithelial cells and regulate host cell function. However, the impact of long-term exposure to H. pylori lysate on the pathological changes of gastric cells is not clear. In this study, we aimed to investigate the regulation and mechanisms involved in gastric cell dysfunction following continuous exposure to H. pylori lysate. We co-cultured gastric cell lines GES-1 and MKN-45 with H. pylori lysate for 30 generations, and we found that sustained exposure to H. pylori lysate inhibited GES-1 cell invasion, migration, autophagy, and apoptosis, while it did not inhibit MKN-45 cell invasion or migration. Furthermore, Mongolian gerbils infected with H. pylori ATCC 43504 strains for 90 weeks confirmed the in vitro results. The clinical and in vitro data indicated that sustained exposure to H. pylori lysate inhibited cell apoptosis and autophagy through the Nod1-NF-κB/MAPK-ERK/FOXO4 signaling pathway. In conclusion, sustained exposure to H. pylori lysate promoted proliferation of gastric epithelial cells and inhibited autophagy and apoptosis via Nod1-NF-κB/MAPK-ERK/FOXO4 signaling pathway. In the process of H. pylori-induced gastric lesions, H. pylori lysate plays as an "accomplice" to carcinogenesis.
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Affiliation(s)
- Yang He
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Cunlong Wang
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xiulin Zhang
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xuancheng Lu
- Laboratory Animal Center, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jin Xing
- Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, China
| | - Jianyi Lv
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Meng Guo
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xin Liu
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Jing Lu
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
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Piao JY, Kim SJ, Kim DH, Park JH, Park SA, Han HJ, Na HK, Yoon K, Lee HN, Kim N, Hahm KB, Surh YJ. Helicobacter pylori infection induces STAT3 phosphorylation on Ser727 and autophagy in human gastric epithelial cells and mouse stomach. Sci Rep 2020; 10:15711. [PMID: 32973302 PMCID: PMC7519032 DOI: 10.1038/s41598-020-72594-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 08/31/2020] [Indexed: 01/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is considered as one of the principal risk factors of gastric cancer. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated gastric carcinogenesis. In the canonical STAT3 pathway, phosphorylation of STAT3 on Tyr705 is a major event of STAT3 activation. However, recent studies have demonstrated that STAT3 phosphorylated on Ser727 has an independent function in mitochondria. In the present study, we found that human gastric epithelial AGS cells infected with H. pylori resulted in localization of STAT3 phosphorylated on Ser727 (P-STAT3Ser727), predominantly in the mitochondria. Notably, H. pylori-infected AGS cells exhibited the loss of mitochondrial integrity and increased expression of the microtubule-associated protein light chain 3 (LC3), the autophagosomal membrane-associated protein. Treatment of AGS cells with a mitophagy inducer, carbonyl cyanide 3-chlorophenylhydrazone (CCCP), resulted in accumulation of P-STAT3Ser727 in mitochondria. In addition, the elevated expression and mitochondrial localization of LC3 induced by H. pylori infection were attenuated in AGS cells harboring STAT3 mutation defective in Ser727 phosphorylation (S727A). We also observed that both P-STAT3Ser727 expression and LC3 accumulation were increased in the mitochondria of H. pylori-inoculated mouse stomach.
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Affiliation(s)
- Juan-Yu Piao
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea
| | - Su-Jung Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do, 16227, South Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Sin-Aye Park
- Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan, 31538, South Korea
| | - Hyeong-Jun Han
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, 01133, South Korea
| | - Kichul Yoon
- Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University Sanbon Hospital, Gunpo, Gyeonggi-do, 15865, South Korea
| | - Ha-Na Lee
- Laboratory of Immunology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Nayoung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Ki Baik Hahm
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Gyunggi-do, 13496, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea. .,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
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Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A Streptococcus To Initiate Autophagy during Infection. mBio 2020; 11:mBio.00771-20. [PMID: 32518187 PMCID: PMC7371361 DOI: 10.1128/mbio.00771-20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Autophagy is generally considered a strategy used by the innate immune system to eliminate invasive pathogens through capturing and transferring them to lysosomes. Currently, researchers pay more attention to how virulence factors secreted by GAS regulate the autophagic process. Here, we provide the first evidence that the structural protein FbaA of M1 GAS strain SF370 is a potent inducer of autophagy in epithelial cells. Furthermore, we demonstrate that integrin α5β1 in epithelial cells in vitro and in vivo acts as a receptor to initiate the signaling for inducing autophagy by binding to FbaA of M1 GAS strain SF370 via Fn. Our study reveals the underlying mechanisms by which pathogens induce Fn-integrin α5β1 to trigger autophagy in a conserved pattern in epithelial cells. Group A Streptococcus (GAS), one of the most common extracellular pathogens, has been reported to invade epithelial and endothelial cells. Our results reveal that M1 GAS strain SF370 can be effectively eliminated by respiratory epithelial cells. Emerging evidence indicates that autophagy is an important strategy for nonphagocytes to eliminate intracellular bacteria. Upon pathogen recognition, cell surface receptors can directly trigger autophagy, which is a critical step in controlling infection. However, the mechanisms of how cells sense invading bacteria and use this information specifically to trigger autophagy remain unclear. In this study, we stimulated cells and infected mice with M and FbaA mutants of M1 GAS strain SF370 or with purified M and FbaA proteins (two critical surface structural proteins of GAS), and found that only FbaA protein was involved in autophagy induction. Furthermore, the FbaA protein induced autophagy independent of common pattern recognition receptors (such as Toll-like receptors); rather, it relies on binding to integrin α5β1 expressed on the cell surface, which is mediated by extracellular matrix protein fibronectin (Fn). The FbaA-Fn-integrin α5β1 complex activates Beclin-1 through the mTOR-ULK1–Beclin-1 pathway, which enables the Beclin-1/Vps34 complex to recruit Rab7 and, ultimately, to promote the formation of autophagosomes. By knocking down integrin α5β1, Fn, Atg5, Beclin-1, and ULK1 in Hep2 cells and deleting Atg5 or integrin α5β1 in mice, we reveal a novel role for integrin α5β1 in inducing autophagy. Our study demonstrates that integrin α5β1, through interacting with pathogen components, initiates effective host innate immunity against invading intracellular pathogens.
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Silwal P, Kim YS, Basu J, Jo EK. The roles of microRNAs in regulation of autophagy during bacterial infection. Semin Cell Dev Biol 2020; 101:51-58. [DOI: 10.1016/j.semcdb.2019.07.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/30/2019] [Accepted: 07/15/2019] [Indexed: 02/07/2023]
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Ammanathan V, Vats S, Abraham IM, Manjithaya R. Xenophagy in cancer. Semin Cancer Biol 2020; 66:163-170. [PMID: 32126260 DOI: 10.1016/j.semcancer.2020.02.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/24/2022]
Abstract
Macroautophagy (herein autophagy) is an intracellular pathway in which cytoplasmic components are captured by double-membrane vesicles (autophagosomes) that eventually fuse with lysosomes to degrade the cargo. Basal levels of autophagy in all eukaryotic cells maintain cellular homeostasis and under conditions of stress, organelles and proteins not essential for survival are degraded. Apart from these functions, cargoes like aggregated proteins, damaged organelles and intracellular pathogens, which are otherwise harmful to cells, are also selectively captured by autophagy and are destined for degradation. In terms of infectious diseases, pathogens are cleared by a specific form of autophagy known as xenophagy. This lysosomal mediated degradation of pathogens also increases the antigen presentation of cells thereby inducing a further immune response. The process of xenophagy provides a broad spectrum of defense mechanism to capture bacterial, viral and protozoan pathogens. However, pathogens have developed ingenious mechanisms to modulate xenophagy to enhance their intracellular survival. Meanwhile, certain pathogens also induce deleterious effects such as chronic inflammation and overexpression of oncogenes in the host system. This over time can increase the susceptibility of the host for tumorigenesis. Hence targeting tumor through anti-microbial mechanisms like xenophagy could be a novel strategy for combinatorial anti-cancer therapy. The recent developments in understanding the role of xenophagy in combating cancer causing pathogens will be discussed in this review.
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Affiliation(s)
- Veena Ammanathan
- Jawaharlal Nehru Centre for Advanced Scientific Research, 560064, Bangalore, India
| | - Somya Vats
- Jawaharlal Nehru Centre for Advanced Scientific Research, 560064, Bangalore, India
| | - Irine Maria Abraham
- Jawaharlal Nehru Centre for Advanced Scientific Research, 560064, Bangalore, India
| | - Ravi Manjithaya
- Jawaharlal Nehru Centre for Advanced Scientific Research, 560064, Bangalore, India
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40
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Eslami M, Yousefi B, Kokhaei P, Arabkari V, Ghasemian A. Current information on the association of Helicobacter pylori with autophagy and gastric cancer. J Cell Physiol 2019; 234:14800-14811. [PMID: 30784066 DOI: 10.1002/jcp.28279] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/23/2018] [Accepted: 11/30/2018] [Indexed: 01/24/2023]
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative bacterium and causative agent of gastric cancer. H. pylori induce defective autophagy or inhibit it by means of CagA and vacuolating cytotoxin A (VacA) toxins leading to the gastric cancer induction. Impaired or defective autophagy leads to the accumulation of cytotoxic materials, such as ROS and P62 that lead to increased mutations in the DNA, genome instability, and risk of cancer formation. H. pylori CagA may inhibit autophagy through the c-Met-PI3k/Akt-mTOR signaling pathway. However, VacA induces autophagy by some signaling pathways. In the gastric epithelial cells, VacA is a necessary and sufficient factor for the creation of autophagy. While CagA is a negative regulator of this phenomenon, the elimination of this gene from H. pylori has increased autophagy and the production of inflammatory cytokines is reduced. In gastrointestinal cancers, some of the microRNAs (miRNAs) act as tumor suppressors and some other are oncogenes by regulating various genes expression. H. pylori can also modify autophagy through a mechanism that includes the function of miRNAs. In autophagy, oncogenic miRNAs inhibit activation of some tumor suppressor signaling pathways (e.g., ULK1 complex, Beclin-1 function, and Atg4 messaging), whereas tumor suppressor miRNAs can block the activation of oncogenic signaling pathways. For instance, Beclin-1 is negatively regulated by miRNA-376b (oncogenic miRNA) and miRNA-30a (tumor suppressor miRNA). Similarly, Atg4 by miRNA-376b (oncogenic miRNA) and miRNA-101 (tumor suppressor miRNA). So, this apparent paradox can be explained as that both Beclin-1 and Atg4 play different roles in a particular cell or tissue.
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Affiliation(s)
- Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Parviz Kokhaei
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Immune and Gene Therapy Lab, Cancer Centre Karolinska, Karolinska University Hospital, Stockholm, Sweden
| | - Vahid Arabkari
- Discipline of Pathology, Lambe Institute for Translational Research, Clinical Science Institute, School of Medicine, National University of Ireland, Galway, Ireland
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Rapid Characterization of Virulence Determinants in Helicobacter pylori Isolated from Non-Atrophic Gastritis Patients by Next-Generation Sequencing. J Clin Med 2019; 8:jcm8071030. [PMID: 31336977 PMCID: PMC6678415 DOI: 10.3390/jcm8071030] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 07/09/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is a major human pathogen that causes a wide range of gastrointestinal pathology. Progression of H. pylori induced gastritis to more severe disease has been found to highly correlate with the array of virulence factors expressed by the pathogen. The objective of this study was twofold: first, to characterize the genetic diversity of H. pylori strains isolated from 41 non-atrophic gastritis patients in Switzerland, an issue that has not been investigated to date. And second, to assess the prevalence and sequence variation of H. pylori virulence factors (cagA, vacA, iceA and dupA) and genes encoding outer membrane proteins (OMPs; babA, babB, sabA, sabB, hopZ, hopQ and oipA) by whole genome sequencing (WGS) using an Illumina MiSeq platform. WGS identified high genetic diversity in the analyzed H. pylori strains. Most H. pylori isolates were assigned to hpEurope (95.0%, 39/41), and the remaining ones (5.0%, 2/41) to hpEastAsia, subpopulation hspEAsia. Analysis of virulence factors revealed that 43.9% of the strains were cagA-positive, and the vacA s1 allele was detected in 56.0% of the isolates. The presence of cagA was found to be significantly associated (P < 0.001) with the presence of vacA s1, babA2 and hopQ allele 1 as well as expression of oipA. Moreover, we found an association between the grade of gastritis and H. pylori abundance in the gastric mucosa, respectively and the presence of cagA, vacA s1 and hopQ allele 1. Among our 41 gastritis patients, we identified seven patients infected with H. pylori strains that carried a specific combination of virulence factors (i.e., cagA, vacA s1 allele and babA2 allele), recently implicated in the development of more severe gastrointestinal pathology, like peptic ulcer disease and even gastric cancer. To this end, WGS can be employed for rapid and detailed characterization of virulence determinants in H. pylori, providing valuable insights into the pathogenic capacity of the bacterium. This could ultimately lead to a higher level of personalized treatment and management of patients suffering from H. pylori associated infections.
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Bravo J, Díaz P, Corvalán AH, Quest AFG. A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells. Cancers (Basel) 2019; 11:cancers11060801. [PMID: 31185677 PMCID: PMC6627848 DOI: 10.3390/cancers11060801] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/23/2019] [Accepted: 04/26/2019] [Indexed: 12/12/2022] Open
Abstract
The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular bacterium, several reports indicate that it internalizes, possibly to avoid exposure to antibiotics. Mechanisms by which H. pylori manipulates host cell autophagic processes remain unclear and, importantly, none of the available studies consider a role for the secreted H. pylori virulence factor gamma-glutamyltranspeptidase (HpGGT) in this context. Here, we identify HpGGT as a novel autophagy inhibitor in gastric cells. Our experiments revealed that deletion of HpGGT increased autophagic flux following H. pylori infection of AGS and GES-1 gastric cells. In AGS cells, HpGGT disrupted the late stages of autophagy by preventing degradation in lysosomes without affecting lysosomal acidification. Specifically, HpGGT impaired autophagic flux by disrupting lysosomal membrane integrity, which leads to a decrease in lysosomal cathepsin B activity. Moreover, HpGGT was necessary for efficient internalization of the bacteria into gastric cells. This important role of HpGGT in internalization together with the ability to inhibit autophagy posits HpGGT as a key virulence factor in the development of gastric cancer.
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Affiliation(s)
- Jimena Bravo
- Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Program in Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
| | - Paula Díaz
- Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Program in Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
| | - Alejandro H Corvalán
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
- Laboratory of Oncology, Department of Hematology and Oncology, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile.
| | - Andrew F G Quest
- Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Program in Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380492, Chile.
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Differential Helicobacter pylori Plasticity in the Gastric Niche of Subjects at Increased Gastric Cancer Risk. Pathogens 2019; 8:pathogens8020065. [PMID: 31109082 PMCID: PMC6630233 DOI: 10.3390/pathogens8020065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/09/2019] [Accepted: 05/15/2019] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) represents an independent risk factor for Gastric Cancer (GC). First Degree Relatives (FDR) of GC subjects and Autoimmune Gastritis (AG) patients are both at increased risk for GC. H. pylori genetic heterogeneity within the gastric niche of FDR and AG individuals has been little explored. To understand whether they exploit an increased H. pylori stability and virulence, 14 AG, 25 FDR, 39 GC and 13 dyspeptic patients (D) were investigated by a cultural PCR-based approach characterizing single colonies-forming-units. We chose three loci within the Cytotoxin-associated gene-A Pathogenicity Island (CagPAI) (cagA,cagE,virB11), vacA, homA and homB as markers of virulence with reported association to GC. Inflammatory/precancerous lesions were staged according to Sydney System. When compared to D, FDR, similarly to GC patients, were associated to higher atrophy (OR = 6.29; 95% CI:1.23-31.96 in FDR; OR = 7.50; 95% CI:1.67-33.72 in GC) and a lower frequency of mixed infections (OR = 0.16; 95% CI:0.03-0.81 in FDR; OR = 0.10; 95% CI:0.02-0.48 in GC). FDR presented also an increased neutrophil infiltration (OR = 7.19; 95% CI:1.16-44.65). Both FDR and GC carried a higher proportion of CagPAI+vacAs1i1mx+homB+ profiles (OR = 2.71; 95% CI: 1.66-4.41 and OR = 3.43; 95% CI: 2.16-5.44, respectively). Conversely, AG patients presented a lower frequency of subtypes carrying a stable CagPAI and vacAs1i1mx. These results underline different H. pylori plasticity in FDR and AG individuals, and thus, a different host-bacterium interaction capacity that should be considered in the context of eradication therapies.
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Cao Y, Luo Y, Zou J, Ouyang J, Cai Z, Zeng X, Ling H, Zeng T. Autophagy and its role in gastric cancer. Clin Chim Acta 2018; 489:10-20. [PMID: 30472237 DOI: 10.1016/j.cca.2018.11.028] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/17/2018] [Accepted: 11/20/2018] [Indexed: 02/08/2023]
Abstract
Autophagy, which is tightly regulated by a series of autophagy-related genes (ATGs), is a vital intracellular homeostatic process through which defective proteins and organelles are degraded and recycled under starvation, hypoxia or other specific cellular stress conditions. For both normal cells and tumour cells, autophagy not only sustains cell survival but can also promote cell death. Autophagy-related signalling pathways include mTOR-dependent pathways, such as the AMPK/mTOR and PI3K/Akt/mTOR pathways, and non-mTOR dependent pathways, such as the P53 pathway. Additionally, autophagy plays a dual role in gastric carcinoma (GC), including a tumour-suppressor role and a tumour-promoter role. Long-term Helicobacter pylori infection can impair autophagy, which may eventually promote tumourigenesis of the gastric mucosa. Moreover, Beclin1, LC3 and P62/SQSTM1 are regarded as autophagy-related markers with GC prognostic value. Autophagy inhibitors and autophagy inducers show promise for GC treatment. This review describes research progress regarding autophagy and its significant role in gastric cancer.
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Affiliation(s)
- Yijing Cao
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Yichen Luo
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Juan Zou
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Jun Ouyang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Zhihong Cai
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Xi Zeng
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China
| | - Hui Ling
- Key Laboratory of Tumor Cellular & Molecular Pathology (University of South China), College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, PR China; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China.
| | - Tiebing Zeng
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study [Hunan Provincial Education Department document (Approval number: 2014-405)], Hengyang, Hunan 421001, PR China; Institute of Pathogenic Biology, Key Laboratory of Special Pathogen Prevention and Control of Hunan Province, University of South China, Hengyang, Hunan 421001, PR China.
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45
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Lai CH, Huang JC, Cheng HH, Wu MC, Huang MZ, Hsu HY, Chen YA, Hsu CY, Pan YJ, Chu YT, Chen TJ, Wu YF, Sit WY, Liu JS, Chiu YF, Wang HJ, Wang WC. Helicobacter pylori cholesterol glucosylation modulates autophagy for increasing intracellular survival in macrophages. Cell Microbiol 2018; 20:e12947. [PMID: 30151951 DOI: 10.1111/cmi.12947] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 08/11/2018] [Accepted: 08/13/2018] [Indexed: 12/17/2022]
Abstract
Cholesterol-α-glucosyltransferase (CGT) encoded by the type 1 capsular polysaccharide biosynthesis protein J (capJ) gene of Helicobacter pylori converts cellular cholesterol into cholesteryl glucosides. H. pylori infection induces autophagy that may increase bacterial survival in epithelial cells. However, the role of H. pylori CGT that exploits lipid rafts in interfering with autophagy for bacterial survival in macrophages has not been investigated. Here, we show that wild-type H. pylori carrying CGT modulates cholesterol to trigger autophagy and restrain autophagosome fusion with lysosomes, permitting a significantly higher bacterial burden in macrophages than that in a capJ-knockout (∆CapJ) mutant. Knockdown of autophagy-related protein 12 impairs autophagosome maturation and decreases the survival of internalised H. pylori in macrophages. These results demonstrate that CGT plays a crucial role in the manipulation of the autophagy process to impair macrophage clearance of H. pylori.
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Affiliation(s)
- Chih-Ho Lai
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.,Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkuo, Taiwan.,Graduate Institute of Biomedical Sciences, School of Medicine, Department of Laboratory Medicine, China Medical University and Hospital, Taichung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan
| | - Ju-Chun Huang
- Graduate Institute of Biomedical Sciences, School of Medicine, Department of Laboratory Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Hsin-Hung Cheng
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Meng-Chen Wu
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Mei-Zi Huang
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Hui-Ying Hsu
- Graduate Institute of Biomedical Sciences, School of Medicine, Department of Laboratory Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Yu-An Chen
- Graduate Institute of Biomedical Sciences, School of Medicine, Department of Laboratory Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Chung-Yao Hsu
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Jiun Pan
- Graduate Institute of Biomedical Sciences, School of Medicine, Department of Laboratory Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Yen-Ting Chu
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Tsan-Jan Chen
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-Fang Wu
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Wei Yang Sit
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Jai-Shin Liu
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Ya-Fang Chiu
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.,Molecular Infectious Disease Research Center, Department of Pediatrics, Chang Gung Memorial Hospital, Linkuo, Taiwan
| | - Hung-Jung Wang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Wen-Ching Wang
- Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan.,Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
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Yang L, Li C, Jia Y. MicroRNA-99b promotes Helicobacter pylori-induced autophagyand suppresses carcinogenesis by targeting mTOR. Oncol Lett 2018; 16:5355-5360. [PMID: 30250606 DOI: 10.3892/ol.2018.9269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 05/27/2017] [Indexed: 12/14/2022] Open
Abstract
The regulatory mechanism of Helicobacter pylori-induced gastric carcinogenesis remains unclear. Autophagy has previously been identified as an effective method of regulating carcinogenesis. In the present study, microRNA (miR)-99b levels increased in H. pylori-infected gastric cancer tissues and the BGC-823 gastric cancer cell line. Overexpression of miR-99b significantly enhanced autophagy, decreased intracellular bacterial loads and blocked cell proliferation. The effect on autophagy was demonstrated to be triggered by mammalian target of rapamycin inhibition. These results indicate that miR-99b expression serves a key role in preventing H. pylori-associated gastric cancer formation and this may provide potential targets for the future treatment of H. pylori-associated diseases.
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Affiliation(s)
- Liu Yang
- Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Cong Li
- Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yujie Jia
- Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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47
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Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:257-273. [PMID: 29463907 PMCID: PMC6016373 DOI: 10.1038/nrgastro.2018.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.
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Affiliation(s)
- José B. Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
| | - Jason C. Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
- Department of Developmental Biology, Washington University School of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine
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48
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Huang Y, Deng X, Lang J, Liang X. Modulation of quantum dots and clearance of Helicobacter pylori with synergy of cell autophagy. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 14:849-861. [PMID: 29309908 DOI: 10.1016/j.nano.2017.12.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 12/18/2017] [Accepted: 12/23/2017] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori (Hp) is one type of Gram-negative pathogenic bacterium that colonizes and causes a wide range of gastric diseases. Once Hp penetrates into cells, the currently recognized triple or quadruple therapy often loses effectiveness. Recent evidence suggests that autophagy is closely associated with Hp infection, and can play an important role in the eradication of Hp. More importantly, certain types of quantum dots (QDs) can induce and modulate cellular autophagy, and can be developed into conjugates making QDs potential candidates as new anti-Hp agents.
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Affiliation(s)
- Yu Huang
- Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, PR China
| | - Xin Deng
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, PR China.
| | - Jian Lang
- Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, PR China
| | - Xingqiu Liang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, PR China
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49
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Mao K, Klionsky DJ. Xenophagy: A battlefield between host and microbe, and a possible avenue for cancer treatment. Autophagy 2017; 13:223-224. [PMID: 28026986 DOI: 10.1080/15548627.2016.1267075] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
In eukaryotes, xenophagy is defined as a type of selective macroautophagy/autophagy that is used for eliminating invading pathogens. In contrast to other types of selective autophagy, such as mitophagy, pexophagy and ribophagy, xenophagy is used by eukaryotes for targeting microbes-hence the prefix "xeno" meaning "other" or "foreign"-that have infected a host cell, leading to their lysosomal degradation. This unique characteristic links xenophagy to antibacterial and antiviral defenses, as well as the immune response. Furthermore, recent studies suggest a complicated role of xenophagy in cancer, through either suppressing tumorigenesis or promoting survival of established tumors. In this issue, Sui et al. summarize previous and current studies of xenophagy and consider them in the context of anticancer treatment.
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Affiliation(s)
- Kai Mao
- a Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology , University of Michigan , Ann Arbor , MI , USA.,b Present address: Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics , Harvard Medical School , Boston , MA , USA
| | - Daniel J Klionsky
- a Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology , University of Michigan , Ann Arbor , MI , USA
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50
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Olivera-Severo D, Uberti AF, Marques MS, Pinto MT, Gomez-Lazaro M, Figueiredo C, Leite M, Carlini CR. A New Role for Helicobacter pylori Urease: Contributions to Angiogenesis. Front Microbiol 2017; 8:1883. [PMID: 29021786 PMCID: PMC5623709 DOI: 10.3389/fmicb.2017.01883] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/14/2017] [Indexed: 12/29/2022] Open
Abstract
Helicobacter pylori is a pathogen involved in gastric diseases such as ulcers and carcinomas. H. pylori's urease is an important virulence factor produced in large amounts by this bacterium. In previous studies, we have shown that this protein is able to activate several cell types like neutrophils, monocytes, platelets, endothelial cells, and gastric epithelial cells. Angiogenesis is a physiological process implicated in growth, invasion and metastization of tumors. Here, we have analyzed the angiogenic potential of H. pylori urease (HPU) in gastric epithelial cells. No cytotoxicity was observed in AGS, Kato-III, and MKN28 gastric cell lines treated with 300 nM HPU, as evaluated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. As we previously reported in neutrophils, treatment with 300 nM HPU also had an anti-apoptotic effect in gastric epithelial cells leading to a 2.2-fold increase in the levels of Bcl-XL after 6 h, and a decrease of 80% in the content of BAD, after 48 h, two mitochondrial proteins involved in regulation of apoptosis. Within 10 min of exposure, HPU is rapidly internalized by gastric epithelial cells. Treatment of the gastric cells with methyl-β-cyclodextrin abolished HPU internalization suggesting a cholesterol-dependent process. HPU induces the expression of pro-angiogenic factors and the decrease of expression of anti-angiogenic factors by AGS cells. The angiogenic activity of HPU was analyzed using in vitro and in vivo models. HPU induced formation of tube-like structures by human umbilical vascular endothelial cells in a 9 h experiment. In the chicken embryo chorioallantoic membrane model, HPU induced intense neo-vascularization after 3 days. In conclusion, our results indicate that besides allowing bacterial colonization of the gastric mucosa, H. pylori's urease triggers processes that initiate pro-angiogenic responses in different cellular models. Thus, this bacterial urease, a major virulence factor, may also play a role in gastric carcinoma development.
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Affiliation(s)
- Deiber Olivera-Severo
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil.,Biology Department, Universidade Regional Integrada do Alto Uruguai e das Missões, São Luiz Gonzaga, Brazil
| | - Augusto F Uberti
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil.,Institute of Biology, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Miguel S Marques
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Marta T Pinto
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Maria Gomez-Lazaro
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,INEB - Instituto Nacional de Engenharia Biomédica, University of Porto, Porto, Portugal
| | - Céu Figueiredo
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Marina Leite
- i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Célia R Carlini
- Center of Biotechnology, Universidade Federal Rio Grande do Sul, Porto Alegre, Brazil.,Brain Institute (BRAINS-InsCer), Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil
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