scholarly journals Mechanisms of Action of Probiotics in Intestinal Diseases

2007 ◽  
Vol 7 ◽  
pp. 31-46 ◽  
Author(s):  
Ann M. O'Hara ◽  
Fergus Shanahan
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Clinical Medicine ◽  
Mechanisms Of Action ◽  
Host Cells ◽  
Positive Health ◽  
Beneficial Effects ◽  
Potential Therapeutic Role ◽  
Conditioning Effect ◽  
Clinical Conditions

Intestinal microbiota is a positive health asset that exerts a conditioning effect on intestinal homeostasis. Resident bacteria deliver regulatory signals to the epithelium and instruct mucosal immune responses. Recent research has revealed a potential therapeutic role for the manipulation of the microbiota and exploitation of host-microbial signalling pathways in the maintenance of human health and treatment of various mucosal disorders. A variety of pharmabiotic strategies, such as the use of specific members of the microbiota, their surface components, or metabolites, as well as genetically modified commensal bacteria, are being investigated for their ability to enhance the beneficial components of the microbiota. It is clear that engagement with host cells is central to pharmabiotic action, and several strain-specific mechanisms of action have been elucidated. However, the molecular details underpinning these mechanisms remain almost entirely unknown. Understanding how pharmabiotics exert their beneficial effects is critical for the establishment of definitive selection criteria for certain pharmabiotic strategies for specific clinical conditions. Scientifically accredited evidence of efficacy and studies to elucidate the molecular mechanisms of host-microbiota interactions are needed to lend credence to the use of pharmabiotic strategies in clinical medicine.

scholarly journals Mycobacterium tuberculosisinhibits human innate immune responses via the production of TLR2 antagonist glycolipids

2017 ◽  
Vol 114 (42) ◽  
pp. 11205-11210 ◽  
Author(s):  
Landry Blanc ◽  
Martine Gilleron ◽  
Jacques Prandi ◽  
Ok-ryul Song ◽  
Mi-Seon Jang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Cell Envelope ◽  
Costimulatory Molecule ◽  
Immune Defense ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Reporter System

Mycobacterium tuberculosisis a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by whichM. tuberculosiscircumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate ofM. tuberculosisof the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity. We identified severalM. tuberculosismutants inducing a NF-κB activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-κB activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition ofM. tuberculosisby this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used byM. tuberculosisto undermine innate immune defense. Sulfoglycolipids are major and specific lipids ofM. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute toM. tuberculosisvirulence.

scholarly journals New Insights into Molecular Mechanisms Mediating Adaptation to Exercise; A Review Focusing on Mitochondrial Biogenesis, Mitochondrial Function, Mitophagy and Autophagy

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2639
Author(s):  
Fiona Louise Roberts ◽  
Greg Robert Markby
Keyword(s):  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Therapeutic Intervention ◽  
Molecular Mechanisms ◽  
Good Health ◽  
Mechanisms Of Action ◽  
The Body ◽  
Adaptive Responses ◽  
Beneficial Effects ◽  
Adaptation To Exercise

Exercise itself is fundamental for good health, and when practiced regularly confers a myriad of metabolic benefits in a range of tissues. These benefits are mediated by a range of adaptive responses in a coordinated, multi-organ manner. The continued understanding of the molecular mechanisms of action which confer beneficial effects of exercise on the body will identify more specific pathways which can be manipulated by therapeutic intervention in order to prevent or treat various metabolism-associated diseases. This is particularly important as exercise is not an available option to all and so novel methods must be identified to confer the beneficial effects of exercise in a therapeutic manner. This review will focus on key emerging molecular mechanisms of mitochondrial biogenesis, autophagy and mitophagy in selected, highly metabolic tissues, describing their regulation and contribution to beneficial adaptations to exercise.

scholarly journals Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants

2021 ◽  
Vol 11 ◽  
Author(s):  
Guang Han Ong ◽  
Benedict Shi Xiang Lian ◽  
Takumi Kawasaki ◽  
Taro Kawai
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Host Cells ◽  
Vaccine Adjuvants ◽  
Immune Reactions ◽  
Safety And Reliability ◽  
Pathogen Recognition Receptors ◽  
Acquired Immune Responses ◽  
Molecular Patterns

Adjuvants are used to maximize the potency of vaccines by enhancing immune reactions. Components of adjuvants include pathogen-associated molecular patterns (PAMPs) and damage-associate molecular patterns (DAMPs) that are agonists for innate immune receptors. Innate immune responses are usually activated when pathogen recognition receptors (PRRs) recognize PAMPs derived from invading pathogens or DAMPs released by host cells upon tissue damage. Activation of innate immunity by PRR agonists in adjuvants activates acquired immune responses, which is crucial to enhance immune reactions against the targeted pathogen. For example, agonists for Toll-like receptors have yielded promising results as adjuvants, which target PRR as adjuvant candidates. However, a comprehensive understanding of the type of immunological reaction against agonists for PRRs is essential to ensure the safety and reliability of vaccine adjuvants. This review provides an overview of the current progress in development of PRR agonists as vaccine adjuvants, the molecular mechanisms that underlie activation of immune responses, and the enhancement of vaccine efficacy by these potential adjuvant candidates.

scholarly journals ATF6β is a host cellular target of the Toxoplasma gondii virulence factor ROP18

2011 ◽  
Vol 208 (7) ◽  
pp. 1533-1546 ◽  
Author(s):  
Masahiro Yamamoto ◽  
Ji Su Ma ◽  
Christina Mueller ◽  
Naganori Kamiyama ◽  
Hiroyuki Saiga ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Virulence Factor ◽  
Molecular Mechanisms ◽  
Host Cells ◽  
Type I ◽  
Cellular Functions ◽  
Susceptibility To Infection ◽  
Pathogenic Action ◽  
Acute Toxoplasmosis

The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum–bound transcription factor ATF6β. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6β-dependent pathogenicity by interacting with ATF6β and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6β and for parasite virulence. Consistent with a key role for ATF6β in resistance against this intracellular pathogen, ATF6β-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6β-dependent immune responses is a novel pathogenic mechanism induced by ROP18.

scholarly journals Perturbations of a Kinase-Pseudokinase Module Activate Plant Immunity

2019 ◽  
Author(s):  
D. Patrick Bastedo ◽  
Derek Seto ◽  
Alexandre Martel ◽  
Madiha Khan ◽  
Inga Kireeva ◽  
...  
Keyword(s):  
Immune Response ◽  
Arabidopsis Thaliana ◽  
Immune Responses ◽  
Pseudomonas Syringae ◽  
Molecular Mechanisms ◽  
Kinase Domain ◽  
Host Cells ◽  
In Planta ◽  
Plant Host ◽  
Model Plant

ABSTRACTThe Pseudomonas syringae acetyltransferase HopZ1a is delivered directly into host cells by the type III secretion system to promote bacterial growth. However, in the model plant host Arabidopsis thaliana, HopZ1a activity results in an effector-triggered immune response (ETI) that limits bacterial proliferation. HopZ1a-triggered immunity requires the nucleotide-binding, leucine-rich repeat domain (NLR) protein, ZAR1, and the ZED1 pseudokinase. Here we demonstrate that HopZ1a can acetylate members of a family of ‘receptor-like cytoplasmic kinases’ (RLCK family VII; also known as PBS1-like kinases, or PBLs) and promote their interaction with ZED1 and ZAR1 to form a ZAR1/ZED1/PBL ternary complex. Interactions between ZED1 and PBL kinases are determined by the pseudokinase features of ZED1, and mutants designed to restore ZED1 kinase motifs can (1) bind to PBLs, (2) recruit ZAR1, and (3) trigger immunity in planta, all independently of HopZ1a. Our results suggest that interactions between these two RLCK families are promoted by perturbations of structural features that distinguish active from inactive kinase domain conformations. We propose that effector-induced interactions between ZED1/ZRK pseudokinases (RLCK family XII) and PBL kinases (RLCK family VII) provide a sensitive mechanism for detecting perturbations of either kinase family and activating ZAR1-mediated ETI.AUTHOR SUMMARYAll plants must ward off potentially infectious microbes, and those grown in large-scale crop operations are especially vulnerable to the rapid spread of disease by successful pathogens. Although many bacteria and fungi can supress plant immune responses by producing specialized virulence proteins called ‘effectors’, these effectors can also trigger immune responses that render plants resistant to infection. We studied the molecular mechanisms underlying one such effector-triggered immune response elicited by the bacterial effector HopZ1a in the model plant host Arabidopsis thaliana. We have shown that HopZ1a promotes binding between a ZED1, a ‘pseudokinase’ required for HopZ1a-triggered immunity, and several ‘true kinases’ (known as PBLs) that are likely targets of HopZ1a activity in planta. HopZ1a-induced ZED1-PBL interactions also recruit ZAR1, an Arabidopsis ‘resistance protein’ previously implicated in HopZ1a-triggered immunity. Importantly, ZED1 mutants that restore degenerate kinase motifs can bridge interactions between PBLs and ZAR1 (independently of HopZ1a) and trigger immunity in planta. Our results suggest that equilibria between active and inactive kinase domain conformations regulate ZED1-PBL interactions and formation of ternary complexes with ZAR1. Improved models describing molecular interactions between immunity determinants, effectors and effector targets will inform efforts to exploit natural diversity for development of crops with enhanced disease resistance.

The Effects and Action Mechanisms of Phytoestrogens on Vasomotor Symptoms During Menopausal Transition: Thermoregulatory Mechanism

2018 ◽  
Vol 20 (2) ◽  
pp. 192-200 ◽  
Author(s):  
Haryati Ahmad Hairi ◽  
Ahmad Nazrun Shuid ◽  
Nurul ‘Izzah Ibrahim ◽  
Jamia Azdina Jamal ◽  
Norazlina Mohamed ◽  
...  
Keyword(s):  
Body Temperature ◽  
Molecular Mechanisms ◽  
Core Body Temperature ◽  
Hot Flashes ◽  
Mechanisms Of Action ◽  
Menopausal Transition ◽  
Vasomotor Symptoms ◽  
Beneficial Effects ◽  
Action Mechanisms ◽  
Core Body

Background: Phytoestrogens have recently been claimed to positively influence menopausal discomforts, including hot flashes. However, little is known about the influence of phytoestrogens on core body temperature during oestrogen fluctuation at menopause. Objective: Previously published findings showed that phytoestrogens could relieve menopausal complaints, thus, the present review was aimed at assessing the effects of phytoestrogens on thermoregulatory mechanism during menopausal transition. Results: The molecular mechanisms underlying hot flashes are complex. Oestrogen fluctuations cause hypothalamic thermoregulatory centre dysfunction, which leads to hot flashes during menopause. The phytoestrogens of interest, in relation to human health, include isoflavones, lignans, coumestans, and stilbenes, which are widely distributed in nature. The phytoestrogens are capable of reducing hot flashes via their oestrogen-like hormone actions. The potential effects of phytoestrogens on hot flashes and their molecular mechanisms of action on thermoregulatory centre are discussed in this review. Conclusion: The effects of phytoestrogens on these mechanisms may help explain their beneficial effects in alleviating hot flashes and other menopausal discomforts.

scholarly journals Collective Clustering Dynamics of SARS-COV-2 Particles

2020 ◽  
Author(s):  
Arturo Tozzi ◽  
James F. Peters ◽  
Isabella Annesi-Maesano ◽  
Gennaro D'Amato
Keyword(s):  
Immune Responses ◽  
Cultured Cells ◽  
Therapeutic Strategies ◽  
Clinical Severity ◽  
Host Cells ◽  
Beneficial Effects ◽  
Viral Particles ◽  
Novel Therapeutic Strategies ◽  
Clustering Dynamics ◽  
Clustering Behavior

Collective spread of aggregated viral particles may have beneficial effects on viral capability to survive in the external environment, to counteract immune responses, and to successfully colonize host cells. Here we ask whether SARS-Cov-2 particles, responsible for COVID-19, display collective clustering behavior. Looking at microphotographs and movies of SARS-Cov-2 particles emerging from the surface of cultured cells, we describe single virions that tend to aggregate in progressively larger globular assemblies, until a network-like appearance is achieved. When SARS-Cov-2 particles stick into each other, the squeezing of single virions leads to improved viral package in host’s fluids. We discuss how these findings might explain both the ability to spread of SARS-Cov-2 and the clinical severity of COVID-19 in humans, paving the way to novel therapeutic strategies to mechanically disrupt collective clustering.

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