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Reinventing the Penumbra - the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

TRANSLATIONAL STROKE RESEARCH (2023)

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Article Clinical Neurology

Forecasting stroke-like episodes and outcomes in mitochondrial disease

Yi Shiau Ng et al.

Summary: This study aimed to determine the characteristics of mitochondrial stroke-like episodes and develop a risk-prediction model. The m.3243A>G variant was found to be the most common genetic cause of stroke-like episodes. The clinical, radiological, EEG, and neuropathological features of stroke-like episodes were consistent with medically refractory epilepsy. Patients with different genetic variants had different disease trajectories and prognoses. The risk-prediction model for the m.3243A>G variant showed good performance. Patients with pathogenic mitochondrial DNA variants were more likely to have radiological and pathological features of neurodegeneration compared to those with POLG-related episodes.

BRAIN (2022)

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Article Clinical Neurology

Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy

Yu Young Jeong et al.

Summary: This study reveals that mitochondrial distribution deficits and Parkin-mediated mitophagy are key factors in early tauopathy-related synaptic pathogenesis. Enhancing synaptic mitochondrial supply can protect against synaptic damage and cognitive impairment in tauopathy mouse models.

BRAIN (2022)

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Review Immunology

Metabolic adaptation of lymphocytes in immunity and disease

Nicole M. Chapman et al.

Summary: Adaptive immune responses mediated by T cells and B cells are crucial for protective immunity against pathogens and tumors. Understanding how metabolic plasticity and adaptation dictate functional specialization of immune cells is fundamental to our understanding and therapeutic modulation of the immune system. Extensive progress has been made in characterizing the effects of metabolic networks on immune cell fate and function in different immunological contexts.

IMMUNITY (2022)

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Review Cell Biology

The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders

Sheng Zhang et al.

Summary: Lipophagy is a form of selective autophagy that degrades intracellular lipid droplets, and it plays a significant role in regulating lipid storage, energy balance, and disease development and treatment.

CELL DEATH & DISEASE (2022)

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Article Multidisciplinary Sciences

Stroke induces disease-specific myeloid cells in the brain parenchyma and pia

Carolin Beuker et al.

Summary: The authors of this study found a stroke-associated myeloid cell population in the brain parenchyma that shares similarities with neurodegenerative microglia. These cells, primarily derived from resident microglia, exhibit a lipid-phagocytosing phenotype. Blocking specific markers on these cells can partially improve stroke outcomes.

NATURE COMMUNICATIONS (2022)

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Review Chemistry, Medicinal

Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Qing-zhang Tuo et al.

Summary: Ischemic stroke caused by arterial occlusion is a common type of stroke that involves multiple cell death pathways such as apoptosis, necroptosis, and autophagy. Understanding these pathways may reveal new neuroprotective interventions for ischemic stroke.

MEDICINAL RESEARCH REVIEWS (2022)

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Article Biology

Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice

Shanshan Song et al.

Summary: New research shows that disease-associated microglia in neurodegenerative brains have elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The study also reveals that genetic blockade of microglial NHE1 stimulates oxidative phosphorylation and boosts phagocytosis function, which is associated with tissue remodeling and post-stroke cognitive function recovery.

COMMUNICATIONS BIOLOGY (2022)

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Article Hematology

PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke

Nirav Dhanesha et al.

Summary: This study found that nuclear pyruvate kinase muscle 2 (PKM2) is upregulated in neutrophils after ischemic stroke, promoting inflammatory response. By genetically deleting PKM2 in myeloid cells, the study showed reduced inflammation and damage after stroke. Furthermore, inhibiting PKM2 nuclear translocation improved functional outcomes after stroke.

BLOOD (2022)

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Review Clinical Neurology

Neuroprotection in Acute Ischemic Stroke: A Brief Review

Alastair M. Buchan et al.

Summary: Despite decades of experiments and clinical experiences with numerous agents, no neuroprotection strategy has been proven beneficial in humans. With the advancement of endovascular therapies, neuroprotection is set to become the next frontier in acute stroke care.

CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES (2022)

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Article Cell Biology

Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease

Rui-Yuan Pan et al.

Summary: The dysregulation of microglial function in Alzheimer's disease is associated with the glycolysis/H4K12la/PKM2 positive feedback loop. Inhibiting this loop can ameliorate pathological changes and cognitive deficits in a mouse model. This suggests that disrupting the positive feedback loop may be a potential therapeutic approach for treating AD.

CELL METABOLISM (2022)

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Article Cardiac & Cardiovascular Systems

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Matthias Endres et al.

Summary: Inflammation and immune mechanisms play crucial roles in the development, complications, and outcomes of ischemic stroke. Anti-inflammatory drugs show promise in preventing stroke, and the COVID-19 pandemic has highlighted the association between infections and cerebrovascular events. Different immune cells and molecules contribute to cerebral damage and chronic inflammation after stroke. Chronic systemic inflammation and comorbid infections can affect recovery after stroke and increase the risk of recurrence. Immune mechanisms may also play a role in specific complications of stroke.

CIRCULATION RESEARCH (2022)

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Review Immunology

Exploring epigenetic reprogramming during central nervous system infection

Zachary Van Roy et al.

Summary: Epigenetics focuses on adaptable transcriptional regulation, influencing cell identity and function. During CNS infection, epigenetic mechanisms play a significant role in controlling immune cell maturation and antimicrobial properties. Researchers use epigenetic marks to organize immune cell populations' activation states and inflammatory processes in response to CNS infection.

IMMUNOLOGICAL REVIEWS (2022)

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Article Critical Care Medicine

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization

R. David Andrew et al.

Summary: The spreading depolarizations (SD) theory provides a better explanation for acute neuronal injury caused by brain ischemia than the theory of excessive glutamate release. The challenges in developing therapeutic strategies based on more informed basic science are highlighted, calling for a shift in focus towards understanding the molecular biology of SD initiation and propagation.

NEUROCRITICAL CARE (2022)

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Article Critical Care Medicine

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention

R. David Andrew et al.

Summary: In this review, the mechanism and impact of spreading depolarization (SD) in the gray matter following blood flow loss are discussed. The initiation and propagation of SD are explored, along with the challenges and pitfalls in studying SD. The review concludes with a summary of the research direction and ongoing debates regarding SD.

NEUROCRITICAL CARE (2022)

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Article Clinical Neurology

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

Willeke F. Westendorp et al.

Summary: Stroke is one of the leading causes of death and disability worldwide. After stroke, the brain undergoes neuroinflammation which triggers a systemic immune suppression, making patients vulnerable to infections. Pneumonia and urinary tract infections are the most common infections in stroke patients, and they contribute to unfavorable outcomes and increased mortality. Preventive antibiotic therapy does not improve functional outcomes, highlighting the need for immunomodulatory approaches to prevent stroke-associated infections and improve long-term prognosis.

STROKE (2022)

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Article Geriatrics & Gerontology

Neurons Release Injured Mitochondria as Help-Me Signaling After Ischemic Stroke

Li Gao et al.

Summary: Mitochondrial dysfunction is a major cause of neuronal death after stroke, and intercellular mitochondrial transfer shows promise as a potential therapeutic approach. Neurons release more mitochondria when exposed to challenges like acidosis, hydrogen peroxide, NMDA, or glutamate, which are then engulfed by adjacent astrocytes. This transfer may serve as a signaling mechanism to mediate the interaction between neurons and astrocytes.

FRONTIERS IN AGING NEUROSCIENCE (2022)

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Review Cardiac & Cardiovascular Systems

Clinical Imaging of the Penumbra in Ischemic Stroke: From the Concept to the Era of Mechanical Thrombectomy

Lucie Chalet et al.

Summary: This article provides an overview of the evolution of ischemic penumbra imaging methods, including their respective strengths and limitations. It also maps the current intellectual structure of the field using bibliometric analysis and explores future directions.

FRONTIERS IN CARDIOVASCULAR MEDICINE (2022)

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Article Cell Biology

Role of pericytes in blood-brain barrier preservation during ischemia through tunneling nanotubes

Francesco Pisani et al.

Summary: Tunneling nanotubes (TNT) play a crucial role in the functional communication between BBB cells, allowing the transfer of functional mitochondria from pericytes and endothelial cells to astrocytes. Under conditions of ischemia/reperfusion, TNT formation is upregulated, and pericytes rescue astrocytes from apoptosis by transferring functional mitochondria through TNT.

CELL DEATH & DISEASE (2022)

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Article Cell Biology

Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease

Larissa Traxler et al.

Summary: This study investigated the metabolic changes and transcriptional alterations in sporadic Alzheimer's disease (AD) utilizing induced neurons (iNs) from AD patients. The pathological isoform switching of PKM2 was found to contribute to neuronal vulnerability and loss in AD. Chemical modulation of PKM2 could reverse these changes and enhance neuronal resilience against cell death.

CELL METABOLISM (2022)

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Article Cell Biology

Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5)

Zhenguo Yang et al.

Summary: In stroke patients, autophagy activation leads to abnormal aggregation of CLDN5 in BMECs, causing BBB breakdown. Meanwhile, autophagy also contributes to the degradation of CAV1 and aggregated CLDN5, alleviating BBB impairment.

AUTOPHAGY (2021)

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Article Neurosciences

Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum

Marijn Kuijpers et al.

Summary: This study demonstrates that loss of neuronal autophagy leads to selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory neurotransmission and compromised postnatal viability in vivo. The elevated excitatory neurotransmission is caused by increased calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. Neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain.

NEURON (2021)

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Article Multidisciplinary Sciences

Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy

Xing Li et al.

Summary: The study demonstrates that SUMOylated ANXA1 promotes the beneficial phenotype polarization of microglia by suppressing NF-κB activation and proinflammatory mediators. SUMOylated ANXA1 targets the IKK complex to enhance IKKα degradation and facilitates the interaction between IKKα and NBR1 for selective autophagy-mediated degradation, leading to improved neurological function in cerebral ischemia. Up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.

SCIENCE ADVANCES (2021)

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Article Clinical Neurology

Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions

Vasu Saini et al.

Summary: This review provides an up-to-date overview of stroke and large vessel occlusion (LVO) globally, as well as the eligibility and access to IV thrombolysis (IVT) and mechanical thrombectomy (MT) worldwide. Despite advances in treatment eligibility in the past 5 years, access to acute stroke care and utilization of MT or IVT remains low, highlighting a significant gap among eligible patients. Multiple global initiatives are currently in progress to improve systems of care and bridge this gap.

NEUROLOGY (2021)

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Review Biochemistry & Molecular Biology

Microglial phagocytosis of neurons in neurodegeneration, and its regulation

Claire A. Butler et al.

Summary: Recent evidence suggests that excessive microglial phagocytosis of live neurons and synapses contributes to neurodegeneration in animal models of various brain diseases. Factors regulating microglial phagocytosis of neurons could be potential treatment targets to prevent neurodegeneration induced by excessive microglial phagocytosis of live neurons and synapses.

JOURNAL OF NEUROCHEMISTRY (2021)

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Review Pharmacology & Pharmacy

Targeting the Immune System for Ischemic Stroke

Shenpeng R. Zhang et al.

Summary: Stroke is a leading cause of death with limited treatment options, leading to disabilities and complications for survivors. Immune cell-mediated inflammatory injury plays a crucial role in exacerbating stroke development, while balancing pro- and anti-inflammatory mechanisms is key to improving long-term outcomes.

TRENDS IN PHARMACOLOGICAL SCIENCES (2021)

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Article Biology

The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle

Carlos Manlio Diaz-Garcia et al.

Summary: Research has shown that when neurons engage in intense periods of activity, calcium uptake into mitochondria leads to the accumulation of mitochondrial NADH, triggering aerobic glycolysis. The role of calcium in mitochondrial responses is primarily achieved through the activation of dehydrogenases in the tricarboxylic acid cycle.

ELIFE (2021)

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Article Cell Biology

Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease

Jonghee Han et al.

Summary: PKM2 functions as a positive regulator of gamma-secretase, promoting the production of A beta in AD and exacerbating impairment of spatial and recognition memory.

CELL REPORTS (2021)

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Article Clinical Neurology

CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage

Yueyang Liu et al.

Summary: The study demonstrates that CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, leading to accumulation of substrates and aggravating neuronal cell damage in cerebral ischemia. The findings highlight the crucial role of CAPN1 in regulating autophagy-lysosomal pathway defects and neuronal damage in the context of cerebral ischemia.

STROKE (2021)

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Article Genetics & Heredity

Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation

Bin Han et al.

Summary: In this study, it was found that PGC-1 alpha expression in microglia was increased shortly after ischemic stroke, leading to reduced neurological deficits and decreased production of proinflammatory cytokines. Additionally, PGC-1 alpha promoted autophagy and mitophagy through ULK1, ultimately reducing NLRP3 activation.

GENOME MEDICINE (2021)

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Review Biochemistry & Molecular Biology

Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke

Yun Hwa Choi et al.

Summary: Stroke disrupts homeostatic balance in the brain, leading to accumulation of cell debris, fluid, and immune cells within the central nervous system. The communication between peripheral immune system and CNS plays a crucial role in regulating post-stroke brain homeostasis and influencing recovery outcomes. Therapeutic manipulation of peripheral systems may offer new approaches for treating stroke injuries.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Pharmacology & Pharmacy

3-Methyladenine prevents energy stress-induced necrotic death of melanoma cells through autophagy-independent mechanisms

Milica Kosic et al.

Summary: The study showed that 3-methyladenine (3MA) can prevent cancer cell death induced by energy stress through autophagy-independent mechanisms, possibly involving JNK suppression and decrease of oxidative stress. It highlights the need for caution when using 3MA as an autophagy inhibitor.

JOURNAL OF PHARMACOLOGICAL SCIENCES (2021)

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Article Neurosciences

Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation

Naoki Iwasa et al.

Summary: This study utilized cerebral organoids derived from human induced pluripotent stem cells to evaluate the impact of ischemic stroke on human cerebral tissue. Pathway analysis revealed significant relationships between various metabolic pathways and the complement and coagulation cascades. Key markers of neuronal cells in response to OGD/R were identified as the fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2).

FRONTIERS IN CELLULAR NEUROSCIENCE (2021)

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Review Cell Biology

Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease

Elena V. Mitroshina et al.

Summary: Hypoxia is a common pathological condition induced by various events, with the body's adaptation to it being crucial for health and disease. HIFs, a family of transcription factors, play a key role in cellular responses to hypoxia and are increasingly viewed as potential targets for treating a range of hypoxia-associated diseases. The role of HIFs in adaptation to hypoxia is universal across tissue types, including the CNS, where they are involved in regulating neurogenesis, nerve cell differentiation, and neuronal apoptosis, potentially offering new therapeutic opportunities.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Article Medicine, Research & Experimental

A novel cell-penetrating peptide targeting calpain-cleavage of PSD-95 induced by excitotoxicity improves neurological outcome after stroke

Sara Ayuso-Dolado et al.

Summary: Postsynaptic density protein-95 (PSD-95) is critical for signaling complex assembly at excitatory synapses and interference of its processing by excitotoxicity could be a promising therapeutic target for stroke and other excitotoxicity-associated pathologies.

THERANOSTICS (2021)

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Review Biochemistry & Molecular Biology

Neuronal cell life, death, and axonal degeneration as regulated by the BCL-2 family proteins

James M. Pemberton et al.

Summary: Axonal degeneration and neuronal cell death are regulated by BCL-2 family proteins, with potential influences from other cell death pathways. Deciphering the subsets of proteins required and separately regulating these outcomes is essential for future research and pharmacological interventions.

CELL DEATH AND DIFFERENTIATION (2021)

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Article Cell Biology

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons

Xia Zhang et al.

Summary: This study revealed that in a model of oxygen-glucose deprivation, autophagy dysfunction leads to impairment of synaptic structures. Dysfunctional lysosomal storage during ischemic stress affects the balance of autophagy-lysosomal machinery crucial for maintaining neuronal synaptic function.

AUTOPHAGY (2021)

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Lactate topography of the human brain using hyperpolarized 13C-MRI

Casey Y. Lee et al.

NEUROIMAGE (2020)

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Review Clinical Neurology

Complex Clearance Mechanisms After Intraventricular Hemorrhage and rt-PA Treatment-a Review on Clinical Trials

Bert Bosche et al.

TRANSLATIONAL STROKE RESEARCH (2020)

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Review Cell Biology

Mitochondria as multifaceted regulators of cell death

Florian J. Bock et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2020)

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Syed Suhail Andrabi et al.

PROTOPLASMA (2020)

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Allosteric Regulation of BH3 Proteins in Bcl-xL Complexes Enables Switch-like Activation of Bax

Christian Bogner et al.

MOLECULAR CELL (2020)

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NATURE NEUROSCIENCE (2020)

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Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis

Thomas J. Wubben et al.

SCIENTIFIC REPORTS (2020)

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ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress

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Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury

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Autophagosome biogenesis: From membrane growth to closure

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Review Endocrinology & Metabolism

Hyperpolarized 13C MRI: A novel approach for probing cerebral metabolism in health and neurological disease

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Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

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ACTA NEUROPATHOLOGICA COMMUNICATIONS (2020)

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NATURE REVIEWS MOLECULAR CELL BIOLOGY (2020)

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Delta opioid peptide [d-Ala2, d-Leu5] enkephalin confers neuroprotection by activating delta opioid receptor-AMPK-autophagy axis against global ischemia

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Infection as a Stroke Risk Factor and Determinant of Outcome After Stroke

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STROKE (2020)

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Cell Death Triggered by the Autophagy Inhibitory Drug 3-Methyladenine in Growing Conditions Proceeds With DNA Damage

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Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain

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Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia

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PKM2 Involved in Neuronal Apoptosis on Hypoxic-ischemic Encephalopathy in Neonatal Rats

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CELL (2019)

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A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease

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CELL METABOLISM (2019)

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Lipid Reshaping and Lipophagy Are Induced in a Modeled Ischemia-Reperfusion Injury of Blood Brain Barrier

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Eileen Guelke et al.

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Validation of MRI Determination of the Penumbra by PET Measurements in Ischemic Stroke

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Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state

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AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis

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Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury

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Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195-and [18F]FDG-PET study

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Oxidative Stress Disrupts Oligodendrocyte Maturation

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Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery

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Membrane Binding by tBid Initiates an Ordered Series of Events Culminating in Membrane Permeabilization by Bax

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Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia

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Triggering the succinate receptor GPR91 on dendritic cells enhances immunity

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BAD: undertaker by night, candyman by day

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Bcl-XL inhibits membrane permeabilization by competing with Bax

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Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling

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Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction

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Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak

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Hydrogen peroxide-induced alterations of tight junction proteins in bovine brain microvascular endothelial cells

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BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis

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BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF

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Reactive oxygen radicals in signaling and damage in the ischemic brain

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Review Endocrinology & Metabolism

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