<i>Helicobacter pylori</i> and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

Zhao, Jiang; Shen, Liangfang; Zhou, Meiling; Luo, Juhua; Yu, Zujiang; Qu, Can; Lei, Ridan; Lei, Mingjun; Huang, Ruixue

doi:10.1021/acschemneuro.2c00082

Cited by 12 publications

(5 citation statements)

References 85 publications

(137 reference statements)

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“…Furthermore, HPCFS triggered a mild inflammatory response in gut epithelial and brain endothelial cells via the inducible nitric oxide synthase (iNOS) signaling pathway (Figure 2e), which is consistent with previous studies on inflammatory role of H. pylori, particularly VacA toxin, in vascular barrier [45,46]. Another study also showed the correlation between H. pylori infection and Alzheimer's diseases in mice model through activation of TLR4/MYD88 inflammation pathway, which causes metabolic dysfunction in the gastrointestinal tract [47]. Collectively, these data indicated that HPCFS can cross the gut-blood-brain barrier by disrupting the tight junctions of the gut epithelium and brain endothelium with or without LRP1 binding.…”

Section: Resultssupporting

confidence: 90%

Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Tran,

Etemadi,

Tran

et al. 2023

Preprint

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Background Several epidemiological research have recommended a potential link between Helicobacter pylori infection and neurodegeneration, including Alzheimer’s and Parkinson’s diseases. However, the current research could not fully provide a comprehensive understanding of this association due to the absence of suitable model systems for studying multi-organ interactions and multiplex effects upon Helicobacter pylori infection. Results Here, we recapitulated a human stomach-brain axis by treating human in vitro cellular models with Helicobacter pylori’s cell-free supernatant (HPCFS). We first confirmed that HPCFS disrupted the tightness of gut and brain barriers via Vacuolating cytotoxin A (VacA) binding to Low-density Lipoprotein receptor 1 (LRP1) receptor, leading to reduced tight junction proteins and transmembrane electrical resistance. Blood-brain barrier-penetrating VacA toxin in HPCFS activated central innate immune cells, evidenced by the increased expression of inflammatory markers, oxidative stress, the release of neurotoxic factors, and inflammatory soluble markers, such as NO, IL-8, IL-18 from microglia as well as H2O2, IL-6, and IL-16 from astrocytes. VacA toxin hindered microglial amyloid-beta phagocytosis of amyloid-beta by microglia through by blocking LRP1, a receptor for amyloid-beta. We found that VacA in HPCFS led to neurodegeneration, evidenced by the presence of phosphorylated tau, phosphorylated alpha-synuclein, synaptic impairment, and neuronal loss. Notably, microglia stimulated with VacA exacerbated neurodegeneration compared to direct HPCFS stimulation. Furthermore, we demonstrated that VacA-mediated neuroinflammation and neurodegeneration were mitigated by LRP1 antagonist or VacA immunodepletion. Conclusions This study demonstrates the efficacy of our human stomach-brain axis model that allows us to untangle the complex association between Helicobacter pylori infection and neurological diseases and discover the mechanism of neurotoxic neuroinflammation systematically and this paves the way for future research and therapeutic interventions. Graphical Abstract

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Section: Resultssupporting

confidence: 90%

Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Tran,

Etemadi,

Tran

et al. 2023

Preprint

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“…Radiation-induced pneumonitis in patients with lung cancer treated with radiotherapy is associated with dysregulation of p53 signaling by p53 and ATM polymorphisms [ 102 ], which is consistent with the association between miRNAs and p53 signaling during whole-thorax lung irradiation in mice [ 103 ]. In patients with Alzheimer’s disease treated with low doses of radiation, Helicobacter pylori increased the intestinal permeability through p53-dependent activation of the TLR4/Myd88 inflammatory pathway, causing metabolic dysfunction [ 104 ].…”

Section: P53 and Inflammation Induced By Radiationmentioning

confidence: 99%

Role of p53 in Regulating Radiation Responses

Okazaki

2022

Life

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p53 is known as the guardian of the genome and plays various roles in DNA damage and cancer suppression. The p53 gene was found to express multiple p53 splice variants (isoforms) in a physiological, tissue-dependent manner. The various genes that up- and down-regulated p53 are involved in cell viability, senescence, inflammation, and carcinogenesis. Moreover, p53 affects the radioadaptive response. Given that several studies have already been published on p53, this review presents its role in the response to gamma irradiation by interacting with MDM2, NF-κB, and miRNA, as well as in the inflammation processes, senescence, carcinogenesis, and radiation adaptive responses. Finally, the potential of p53 as a biomarker is discussed.

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“…Furthermore, the deficiency of p53 results in reduced bile acid concentrations, ultimately leading to enhanced colonisation of H. pylori . These findings collectively highlight the significant role of H. pylori in promoting metabolic dysfunction associated with AD-induced metabolic dysfunction [ 131 ].…”

Section: Gut Microbiota–brain Axis and Neurodegenerative Diseasesmentioning

confidence: 89%

Emerging Paradigms in Inflammatory Disease Management: Exploring Bioactive Compounds and the Gut Microbiota

Benameur,

Porro,

Twfieg

et al. 2023

Brain Sciences

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The human gut microbiota is a complex ecosystem of mutualistic microorganisms that play a critical role in maintaining human health through their individual interactions and with the host. The normal gastrointestinal microbiota plays a specific physiological function in host immunomodulation, nutrient metabolism, vitamin synthesis, xenobiotic and drug metabolism, maintenance of structural and functional integrity of the gut mucosal barrier, and protection against various pathogens. Inflammation is the innate immune response of living tissues to injury and damage caused by infections, physical and chemical trauma, immunological factors, and genetic derangements. Most diseases are associated with an underlying inflammatory process, with inflammation mediated through the contribution of active immune cells. Current strategies to control inflammatory pathways include pharmaceutical drugs, lifestyle, and dietary changes. However, this remains insufficient. Bioactive compounds (BCs) are nutritional constituents found in small quantities in food and plant extracts that provide numerous health benefits beyond their nutritional value. BCs are known for their antioxidant, antimicrobial, anticarcinogenic, anti-metabolic syndrome, and anti-inflammatory properties. Bioactive compounds have been shown to reduce the destructive effect of inflammation on tissues by inhibiting or modulating the effects of inflammatory mediators, offering hope for patients suffering from chronic inflammatory disorders like atherosclerosis, arthritis, inflammatory bowel diseases, and neurodegenerative diseases. The aim of the present review is to summarise the role of natural bioactive compounds in modulating inflammation and protecting human health, for their safety to preserve gut microbiota and improve their physiology and behaviour.

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Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

Cited by 12 publications

References 85 publications

Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Role of p53 in Regulating Radiation Responses

Emerging Paradigms in Inflammatory Disease Management: Exploring Bioactive Compounds and the Gut Microbiota

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