p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function

AbstractAlzheimer’s disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.

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New Insights Into the Role of Aberrant Hippocampal Neurogenesis in Epilepsy

Frontiers in Neurology ◽

10.3389/fneur.2021.727065 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peng Chen ◽

Fuchao Chen ◽

Yue Wu ◽

Benhong Zhou

Keyword(s):

Molecular Mechanisms ◽

Wide Spectrum ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Future Directions ◽

The Past ◽

The Central Nervous System ◽

Spontaneous Recurrent Seizures ◽

Patients With Epilepsy

Data accumulated over the past four decades have confirmed that adult hippocampal neurogenesis (HN) plays a key role in the wide spectrum of hippocampal pathology. Epilepsy is a disorder of the central nervous system characterized by spontaneous recurrent seizures. Although neurogenesis in persistent germinative zones is altered in the adult rodent models of epilepsy, the effects of seizure-induced neurogenesis in the epileptic brain, in terms of either a pathological or reparative role, are only beginning to be explored. In this review, we described the most recent advances in neurogenesis in epilepsy and outlooked future directions for neural stem cells (NSCs) and epilepsy-in-a-dish models. We proposed that it may help in refining the underlying molecular mechanisms of epilepsy and improving the therapies and precision medicine for patients with epilepsy.

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The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions

Blood ◽

10.1182/blood-2012-11-427765 ◽

2013 ◽

Vol 122 (6) ◽

pp. 885-892 ◽

Cited By ~ 55

Author(s):

Maria Mastrogiannaki ◽

Pavle Matak ◽

Carole Peyssonnaux

Keyword(s):

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Absorption ◽

Hypoxia Inducible Factor ◽

Therapeutic Strategies ◽

The Past ◽

Pathological Conditions ◽

Per Se ◽

Key Genes

Abstract Although earlier, seminal studies demonstrated that the gut per se has the intrinsic ability to regulate the rates of iron absorption, the spotlight in the past decade has been placed on the systemic regulation of iron homeostasis by the hepatic hormone hepcidin and the molecular mechanisms that regulate its expression. Recently, however, attention has returned to the gut based on the finding that hypoxia inducible factor-2 (HIF-2α) regulates the expression of key genes that contribute to iron absorption. Here we review the current understanding of the molecular mechanisms that regulate iron homeostasis in the gut by focusing on the role of HIF-2 under physiological steady-state conditions and in the pathogenesis of iron-related diseases. We also discuss implications for adapting HIF-2–based therapeutic strategies in iron-related pathological conditions.

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Sugar glues for broken neurons

BioMolecular Concepts ◽

10.1515/bmc-2012-0042 ◽

2013 ◽

Vol 4 (3) ◽

pp. 233-257 ◽

Cited By ~ 16

Author(s):

Vimal P. Swarup ◽

Caitlin P. Mencio ◽

Vladimir Hlady ◽

Balagurunathan Kuberan

Keyword(s):

Therapeutic Strategies ◽

Matrix Proteins ◽

Cell Surface Molecules ◽

Cns Development ◽

Cns Disorders ◽

Surface Molecules ◽

The Past ◽

The Central Nervous System ◽

Neurological Processes

AbstractProteoglycans (PGs) regulate diverse functions in the central nervous system (CNS) by interacting with a number of growth factors, matrix proteins, and cell surface molecules. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major glycosaminoglycans present in the PGs of the CNS. The functionality of these PGs is to a large extent dictated by the fine sulfation patterns present on their glycosaminoglycan (GAG) chains. In the past 15 years, there has been a significant expansion in our knowledge on the role of HS and CS chains in various neurological processes, such as neuronal growth, regeneration, plasticity, and pathfinding. However, defining the relation between distinct sulfation patterns of the GAGs and their functionality has thus far been difficult. With the emergence of novel tools for the synthesis of defined GAG structures, and techniques for their characterization, we are now in a better position to explore the structure-function relation of GAGs in the context of their sulfation patterns. In this review, we discuss the importance of GAGs on CNS development, injury, and disorders with an emphasis on their sulfation patterns. Finally, we outline several GAG-based therapeutic strategies to exploit GAG chains for ameliorating various CNS disorders.

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The Microbiota–Gut–Brain Axis and Alzheimer Disease. From Dysbiosis to Neurodegeneration: Focus on the Central Nervous System Glial Cells

Journal of Clinical Medicine ◽

10.3390/jcm10112358 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2358

Author(s):

Maria Grazia Giovannini ◽

Daniele Lana ◽

Chiara Traini ◽

Maria Giuliana Vannucchi

Keyword(s):

Alzheimer Disease ◽

Glial Cells ◽

Cell Types ◽

The Past ◽

The Central Nervous System ◽

Diseased State ◽

The Brain ◽

Alzheimer Disease Pathogenesis ◽

Brain Homeostasis

The microbiota–gut system can be thought of as a single unit that interacts with the brain via the “two-way” microbiota–gut–brain axis. Through this axis, a constant interplay mediated by the several products originating from the microbiota guarantees the physiological development and shaping of the gut and the brain. In the present review will be described the modalities through which the microbiota and gut control each other, and the main microbiota products conditioning both local and brain homeostasis. Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer disease, will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of the major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed, focusing on Alzheimer disease pathogenesis.

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Infectious disease-associated encephalopathies

Critical Care ◽

10.1186/s13054-021-03659-6 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Maria C. Barbosa-Silva ◽

Maiara N. Lima ◽

Denise Battaglini ◽

Chiara Robba ◽

Paolo Pelosi ◽

...

Keyword(s):

Infectious Disease ◽

Cognitive Deficits ◽

Brain Function ◽

Cell Activation ◽

Therapeutic Strategies ◽

Barrier Dysfunction ◽

Glial Cell Activation ◽

The Central Nervous System ◽

Underlying Mechanisms

AbstractInfectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

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The Role of microRNAs in the Regulation of Apoptosis in Lung Cancer and Its Application in Cancer Treatment

BioMed Research International ◽

10.1155/2014/318030 ◽

2014 ◽

Vol 2014 ◽

pp. 1-19 ◽

Cited By ~ 26

Author(s):

Norahayu Othman ◽

Noor Hasima Nagoor

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

High Frequency ◽

Tumor Suppressor Genes ◽

Molecular Mechanisms ◽

Lung Carcinogenesis ◽

The Past ◽

Late Stage Diagnosis ◽

Anticancer Treatment

Lung cancer remains to be one of the most common and serious types of cancer worldwide. While treatment is available, the survival rate of this cancer is still critically low due to late stage diagnosis and high frequency of drug resistance, thus highlighting the pressing need for a greater understanding of the molecular mechanisms involved in lung carcinogenesis. Studies in the past years have evidenced that microRNAs (miRNAs) are critical players in the regulation of various biological functions, including apoptosis, which is a process frequently evaded in cancer progression. Recently, miRNAs were demonstrated to possess proapoptotic or antiapoptotic abilities through the targeting of oncogenes or tumor suppressor genes. This review examines the involvement of miRNAs in the apoptotic process of lung cancer and will also touch on the promising evidence supporting the role of miRNAs in regulating sensitivity to anticancer treatment.

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Immunotherapeutics for AD: A Work in Progress

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210903101522 ◽

2021 ◽

Vol 20 ◽

Author(s):

Anuja Sharma ◽

Jaspreet Singh Anand ◽

Yatender Kumar

Keyword(s):

Tau Protein ◽

Therapeutic Strategy ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Amyloid Β ◽

Therapeutic Strategies ◽

Genetic Defects ◽

Multiple Factors ◽

Neurodegenerative Process ◽

Epigenetic Regulations

: Alzheimer's Disease (AD), often called the 'Plague of the 21st Century,' is a progressive, irreversible neurodegenerative disorder that leads to the degeneration and death of neurons. Multiple factors, such as genetic defects, epigenetic regulations, environmental factors, or cerebrovascular damage, are a manifestation of the neurodegenerative process that begins to occur decades before the onset of disease. To date, no treatment or therapeutic strategy has proven to be potent in inhibiting its progress or reversing the effects of the disease. The ever-increasing numbers and lack of sufficient therapies that can control or reverse the effects of the disease have propelled research in the direction of devising efficient therapeutic strategies for AD. This review comprehensively discusses the active and passive immunotherapies against Amyloid-β and Tau protein, which remain the popular choice of targets for AD therapeutics. Some of the prospective immunotherapies against Aβ plaques have failed due to various reasons. Much of the research is focused on targeting Tau, specifically, targeting the mid-region of extracellular Tau due to their potential to prevent seeding and hence the spread of neurofibrillary tangles (NFTs). Thus, there is a need to thoroughly understand the disease onset mechanisms and discover effective therapeutic strategies.

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Peripheral tissue–brain interactions in the regulation of food intake

Proceedings of The Nutrition Society ◽

10.1017/s0029665107005368 ◽

2007 ◽

Vol 66 (1) ◽

pp. 131-155 ◽

Cited By ~ 50

Author(s):

Miguel López ◽

Sulay Tovar ◽

María J. Vázquez ◽

Lynda M. Williams ◽

Carlos Diéguez

Keyword(s):

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Developed Countries ◽

Peripheral Tissue ◽

Feeding Regulation ◽

Pharmacological Targets ◽

The Central Nervous System ◽

Treatment Of Obesity ◽

Brain Interactions

More than 70 years ago the glucostatic, lipostatic and aminostatic hypotheses proposed that the central nervous system sensed circulating levels of different metabolites, changing feeding behaviour in response to the levels of those molecules. In the last 20 years the rapid increase in obesity and associated pathologies in developed countries has involved a substantial increase in the knowledge of the physiological and molecular mechanism regulating body mass. This effort has resulted in the recent discovery of new peripheral signals, such as leptin and ghrelin, as well as new neuropeptides, such as orexins, involved in body-weight homeostasis. The present review summarises research into energy balance, starting from the original classical hypotheses proposing metabolite sensing, through peripheral tissue–brain interactions and coming full circle to the recently-discovered role of hypothalamic fatty acid synthase in feeding regulation. Understanding these molecular mechanisms will provide new pharmacological targets for the treatment of obesity and appetite disorders.

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Skin and Gut Microbiome in Psoriasis: Gaining Insight Into the Pathophysiology of It and Finding Novel Therapeutic Strategies

Frontiers in Microbiology ◽

10.3389/fmicb.2020.589726 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lihui Chen ◽

Jie Li ◽

Wu Zhu ◽

Yehong Kuang ◽

Tao Liu ◽

...

Keyword(s):

Therapeutic Strategy ◽

Therapeutic Strategies ◽

Intestinal Microbiome ◽

Core Microbiome ◽

The Core ◽

The World ◽

Novel Therapeutic Strategies ◽

Insight Into ◽

Gaining Insight

Psoriasis affects the health of myriad populations around the world. The pathogenesis is multifactorial, and the exact driving factor remains unclear. This condition arises from the interaction between hyperproliferative keratinocytes and infiltrating immune cells, with poor prognosis and high recurrence. Better clinical treatments remain to be explored. There is much evidence that alterations in the skin and intestinal microbiome play an important role in the pathogenesis of psoriasis, and restoration of the microbiome is a promising preventive and therapeutic strategy for psoriasis. Herein, we have reviewed recent studies on the psoriasis-related microbiome in an attempt to confidently identify the “core” microbiome of psoriasis patients, understand the role of microbiome in the pathogenesis of psoriasis, and explore new therapeutic strategies for psoriasis through microbial intervention.

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The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽

10.3390/cancers13184576 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4576

Author(s):

Hung-Yu Lin ◽

Hui-Wen Ho ◽

Yen-Hsiang Chang ◽

Chun-Jui Wei ◽

Pei-Yi Chu

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Drug Resistant ◽

Therapeutic Targeting ◽

The Past ◽

Regulated Cell Death ◽

Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

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