Reshaping endoplasmic reticulum quality control through the unfolded protein response

Molecular Cell, Год журнала: 2022, Номер 82(8), С. 1477 - 1491

Опубликована: Апрель 1, 2022

Язык: Английский

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A guide to understanding endoplasmic reticulum stress in metabolic disorders

Molecular Metabolism, Год журнала: 2021, Номер 47, С. 101169 - 101169

Опубликована: Янв. 20, 2021

The global rise of metabolic disorders, such as obesity, type 2 diabetes, and cardiovascular disease, demands a thorough molecular understanding the cellular mechanisms that govern health or disease. endoplasmic reticulum (ER) is key organelle for function adaptation and, therefore disturbed ER function, known "ER stress," feature disorders. As stress remains poorly defined phenomenon, this review provides general guide to nature, etiology, consequences in We define by its stressor, which driven proteotoxicity, lipotoxicity, and/or glucotoxicity. discuss implications disorders reviewing evidence implicating phenotypes communication, protein quality control, calcium homeostasis, lipid carbohydrate metabolism, inflammation development dysfunction. In mammalian biology, phenotypically functionally diverse platform nutrient sensing, critical cell type-specific control hepatocytes, adipocytes, muscle cells, neurons. these distinct, transient state functional imbalance, usually resolved activation adaptive programs unfolded response (UPR), ER-associated degradation (ERAD), autophagy. However, challenges proteostasis also impact glucose metabolism vice versa. ER, sensing measures are integrated failure adapt leads aberrant dysfunction, insulin resistance, inflammation. conclusion, intricately linked wide spectrum functions component maintaining restoring health.

Язык: Английский

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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Язык: Английский

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ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

Redox Biology, Год журнала: 2020, Номер 37, С. 101696 - 101696

Опубликована: Авг. 27, 2020

Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, mechanisms how ROS sense metabolic stress, regulate pathways initiate proliferation, inflammation cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features functions, eleven types can be classified into seven functional groups: stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions triple ROS. 2) Among generation systems, mitochondria consume most amount oxygen; nine generated; thus, mitochondrial systems serve as central hub connecting with inflammasome activation, trained immunity immunometabolic pathways. 3) Increased nuclear production significantly promotes in comparison to that other organelles. Nuclear a convergent decision-makers connect unbearable alarming stresses death. 4) Balanced levels indicate physiological homeostasis various processes subcellular organelles cytosol, while imbalanced present alarms pathological processes. these analyses, propose working model new integrated network sensing Our provides novel insights roles bridging inflammation, tumorigenesis; provide therapeutic targets treating those diseases. (Word count: 246).

Язык: Английский

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XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury

Redox Biology, Год журнала: 2022, Номер 52, С. 102305 - 102305

Опубликована: Март 28, 2022

Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, function mechanism in thioacetamide (TAA)-induced acute injury (ALI) remains unknown. Here, we investigated effects inhibition on promoting hepatocellular pyroptosis activate STING signaling ALI. While both TAA- LPS-induced ALI triggered hepatocytes, hepatocyte-specific knockout mice exhibited exacerbated with increased enhanced activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing a cGAS- dose-dependent manner. deficiency ROS production promote activating NLRP3/caspase-1/GSDMD signaling, facilitated extracellular release mtDNA. Moreover, impaired mitophagy was found deficient reversed PINK1 overexpression. Mitophagy restoration also inhibited mice. Activation XBP1-mediated pathway were observed human livers Collectively, these findings demonstrate that promotes hepatocyte impairing mtDNA/cGAS/STING providing potential therapeutic targets for

Язык: Английский

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Autophagy and the hallmarks of aging

Ageing Research Reviews, Год журнала: 2021, Номер 72, С. 101468 - 101468

Опубликована: Сен. 24, 2021

Язык: Английский

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Endoplasmic reticulum stress-mediated cell death in liver injury

Cell Death and Disease, Год журнала: 2022, Номер 13(12)

Опубликована: Дек. 19, 2022

The endoplasmic reticulum is an important intracellular organelle that plays role in maintaining cellular homeostasis. Endoplasmic stress (ERS) and unfolded protein response (UPR) are induced when the body exposed to adverse external stimuli. It has been established ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, pyroptosis, through three major transmembrane receptors on ER membrane, inositol requirement enzyme 1α, kinase-like kinase activating transcription factor 6. These modes of play occurrence development various diseases, such as neurodegenerative inflammation, metabolic liver injury. As largest organ, rich enzymes, carries out functions metabolism secretion, body's main site synthesis. Accordingly, a well-developed system present hepatocytes help perform its physiological functions. Current evidence suggests closely related stages injury, caused by may be key In addition, increasing modulating great potential for treating This article provided comprehensive overview relationship between four types death. Moreover, we discussed mechanism UPR injuries their therapeutic strategies.

Язык: Английский

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ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis

Journal of Hepatology, Год журнала: 2023, Номер 79(2), С. 362 - 377

Опубликована: Март 28, 2023

Язык: Английский

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Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis

Neurobiology of Disease, Год журнала: 2021, Номер 154, С. 105360 - 105360

Опубликована: Апрель 1, 2021

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that thought to exist on a clinical pathological spectrum. FTD ALS linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) neuropathology, such as inclusions of ubiquitinated, misfolded proteins TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes cause or when mutated encode localize lysosome modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, acidification, autophagy, TFEB activity. In this review, we summarize evidence dysfunction, caused mutations C9orf72, GRN, MAPT, TMEM106B) toxic-gain function aggregation TDP-43 tau), is an important pathogenic disease mechanism ALS. Further studies into normal many these required will help uncover mechanisms dysfunction Mutations polymorphisms for also occur other age-dependent diseases, Alzheimer's APOE, PSEN1, APP) Parkinson's GBA, LRRK2, ATP13A2) disease. A more complete understanding common unique features across spectrum neurodegeneration guide development therapies devastating diseases.

Язык: Английский

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Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories

Frontiers in Psychiatry, Год журнала: 2023, Номер 14

Опубликована: Май 11, 2023

In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up 27% patients with MDD associated more severe, chronic, treatment-resistant trajectory. Inflammation not unique depression has transdiagnostic effects suggesting shared underlying psychopathologies metabolic disorders. Research supports association but necessarily causation Putative mechanisms link dysregulation the HPA axis immune cell glucocorticoid resistance resulting in hyperactivation peripheral system. The extracellular release DAMPs DAMP-PRR signaling creates feed forward loop that accelerates central inflammation. Higher plasma levels inflammatory cytokines, most consistently interleukin IL-1β, IL-6, TNF-α, are correlated greater depressive symptomatology. Cytokines sensitize axis, disrupt negative feedback loop, further propagate reactions. Peripheral inflammation exacerbates (neuroinflammation) through several including disruption blood-brain barrier, cellular trafficking, activation glial cells. Activated cells chemokines, reactive oxygen nitrogen species into extra-synaptic space dysregulating neurotransmitter systems, imbalancing excitatory inhibitory ratio, disrupting neural circuitry plasticity adaptation. particular, microglial toxicity plays role pathophysiology neuroinflammation. Magnetic resonance imaging (MRI) studies show reduced hippocampal volumes. Neural dysfunction such as hypoactivation between ventral striatum ventromedial prefrontal cortex underlies melancholic phenotype Chronic administration monoamine-based antidepressants counters response, delayed therapeutic onset. Therapeutics targeting mediated immunity, generalized specific pathways, nitro-oxidative have enormous potential advance treatment landscape. Future clinical trials will need include system perturbations biomarker outcome measures facilitate novel antidepressant development. this overview, we explore correlates elucidate pathomechanisms development biomarkers therapeutics.

Язык: Английский

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