Friend or foe: role of pathological tau in neuronal death.

Neuronal death is one of the most common pathological hallmarks of diverse neurological diseases, which manifest varying degrees of cognitive or motor dysfunction. Neuronal death can be classified into multiple forms with complicated and unique regulatory signaling pathways. Tau is a key microtubule-associated protein that is predominantly expressed in neurons to stabilize microtubules under physiological conditions. In contrast, pathological tau always detaches from microtubules and is implicated in a series of neurological disorders that are characterized by irreversible neuronal death, such as necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent neuronal death and phagocytosis by microglia. However, recent studies have also revealed that pathological tau can facilitate neuron escape from acute apoptosis, delay necroptosis through its action on granulovacuolar degeneration bodies (GVBs), and facilitate iron export from neurons to block ferroptosis. In this review, we briefly describe the current understanding of how pathological tau exerts dual effects on neuronal death by acting as a double-edged sword in different neurological diseases. We propose that elucidating the mechanism by which pathological tau affects neuronal death is critical for exploring novel and precise therapeutic strategies for neurological disorders.

Epidermal growth factor receptor promotes high-fructose nonalcoholic fatty liver disease by inducing mitochondrial fission in zebrafish.

Mitochondrial function has a pivotal role in the pathogenesis of NAFLD. Mitochondrial dynamics is a foundational activity underlying the maintenance of mitochondrial function in bioenergetics, the maintenance of MtDNA, calcium homeostasis, reactive oxygen species metabolism, and quality control. Loss of mitochondrial plasticity in terms of functions, morphology and dynamics may also be the critical switch from NAFLD/NASH to HCC. However, the cause of mitochondrial fission in NAFLD remains unclear. Recent studies have reported that EGFR can bind to Mfn1 and interfere with its polymerization. In this study, we investigated whether EGFR binds to Mfn1 in NAFLD, and whether reducing their binding can improve NAFLD in zebrafish model. Our results demonstrated that EGFR was activated in hepatocytes from high fructose (HF)-induced NAFLD zebrafish and interfered with Mfn1 polymerization, leading to reduction of MtDNA. Suppression of EGFR activation or mitochondrial translocation significantly improved mitochondrial morphology and increased mitochondrial DNA, ultimately preventing hepatic steatosis. In conclusion, these results suggest that EGFR binding to Mfn1 plays an important role in NAFLD zebrafish model and that inhibition of their binding could be a potential therapeutic target.

Extracellular Matrix Biomarkers in Colorectal Cancer.

The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.

Progress in the regulatory mechanism of mitophagy in chronic cerebral ischemic neuronal injury.

Chronic cerebral ischemia (CCI) is a common clinical syndrome that can impact various cerebrovascular diseases. Its pathological mechanism of injury involves energy imbalance, oxidative stress, inflammatory response, and many other processes. Neuronal damage occurs in a complex and multifaceted manner. This article provides a detailed discussion of the activation and inhibition mechanisms of mitophagy under cerebral ischemia and considers the advantages and disadvantages of mitophagy in the recovery process of ischemic brain injury. Finally, we address the future direction of research on neuronal injury and the regulatory mechanisms of mitophagy in chronic cerebral ischemia. Future studies should focus on drug intervention at specific regulatory points and the cross-regulation of related signaling pathways to comprehensively deepen understanding of the mechanisms of neuronal injury in chronic cerebral ischemia. Promising interventions could potentially improve the treatment and outcomes of chronic cerebral ischemia.

Research progress on high-concentration oxygen therapy after cerebral hemorrhage.

Recently, the role of high-concentration oxygen therapy in cerebral hemorrhage has been extensively discussed. This review describes the research progress in high-concentration oxygen therapy after cerebral hemorrhage. High-concentration oxygen therapy can be classified into two treatment methods: hyperbaric and normobaric high-concentration oxygen therapy. Several studies have reported that high-concentration oxygen therapy uses the pathological mechanisms of secondary ischemia and hypoxia after cerebral hemorrhage as an entry point to improve cerebral oxygenation, metabolic rate, cerebral edema, intracranial pressure, and oxidative stress. We also elucidate the mechanisms by which molecules such as Hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor, and erythropoietin (EPO) may play a role in oxygen therapy. Although people are concerned about the toxicity of hyperoxia, combined with relevant literature, the evidence discussed in this article suggests that as long as the duration, concentration, pressure, and treatment interval of patients with cerebral hemorrhage are properly understood and oxygen is administered within the treatment window, it can be effective to avoid hyperoxic oxygen toxicity. Combined with the latest research, we believe that high-concentration oxygen therapy plays an important positive role in injuries and outcomes after cerebral hemorrhage, and we recommend expanding the use of normal-pressure high-concentration oxygen therapy for cerebral hemorrhage.

The Role of the Complement System in Synaptic Pruning after Stroke.

Stroke is a serious disease that can lead to local neurological dysfunction and cause great harm to the patient's health due to blood cerebral circulation disorder. Synaptic pruning is critical for the normal development of the human brain, which makes the synaptic circuit completer and more efficient by removing redundant synapses. The complement system is considered a key player in synaptic loss and cognitive impairment in neurodegenerative disease. After stroke, the complement system is over-activated, and complement proteins can be labeled on synapses. Microglia and astrocytes can recognize and engulf synapses through corresponding complement receptors. Complement-mediated excessive synaptic pruning can cause post-stroke cognitive impairment (PSCI) and secondary brain damage. This review summarizes the latest progress of complement-mediated synaptic pruning after stroke and the potential mechanisms. Targeting complement-mediated synaptic pruning may be essential for exploring therapeutic strategies for secondary brain injury (SBI) and neurological dysfunction after stroke.

Mechanisms and therapeutic targets of mitophagy after intracerebral hemorrhage.

Mitochondria are dynamic organelles responsible for cellular energy production. In addition to regulating energy homeostasis, mitochondria are responsible for calcium homeostasis, clearance of damaged organelles, signaling, and cell survival in the context of injury and pathology. In stroke, the mechanisms underlying brain injury secondary to intracerebral hemorrhage are complex and involve cellular hypoxia, oxidative stress, inflammatory responses, and apoptosis. Recent studies have shown that mitochondrial damage and autophagy are essential for neuronal metabolism and functional recovery after intracerebral hemorrhage, and are closely related to inflammatory responses, oxidative stress, apoptosis, and other pathological processes. Because hypoxia and inflammatory responses can cause secondary damage after intracerebral hemorrhage, the restoration of mitochondrial function and timely clearance of damaged mitochondria have neuroprotective effects. Based on studies on mitochondrial autophagy (mitophagy), cellular inflammation, apoptosis, ferroptosis, the BNIP3 autophagy gene, pharmacological and other regulatory approaches, and normobaric oxygen (NBO) therapy, this article further explores the neuroprotective role of mitophagy after intracerebral hemorrhage.

High-resolution magnetic resonance vessel wall imaging provides new insights into Moyamoya disease.

Moyamoya disease (MMD) is a rare condition that affects the blood vessels of the central nervous system. This cerebrovascular disease is characterized by progressive narrowing and blockage of the internal carotid, middle cerebral, and anterior cerebral arteries, which results in the formation of a compensatory fragile vascular network. Currently, digital subtraction angiography (DSA) is considered the gold standard in diagnosing MMD. However, this diagnostic technique is invasive and may not be suitable for all patients. Hence, non-invasive imaging methods such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are often used. However, these methods may have less reliable diagnostic results. Therefore, High-Resolution Magnetic Resonance Vessel Wall Imaging (HR-VWI) has emerged as the most accurate method for observing and analyzing arterial wall structure. It enhances the resolution of arterial walls and enables quantitative and qualitative analysis of plaque, facilitating the identification of atherosclerotic lesions, vascular entrapment, myofibrillar dysplasia, moyamoya vasculopathy, and other related conditions. Consequently, HR-VWI provides a new and more reliable evaluation criterion for diagnosing vascular lesions in patients with Moyamoya disease.

Normobaric hyperoxia alleviates complement C3-mediated synaptic pruning and brain injury after intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease, and the complement cascade exacerbates brain injury after ICH. As the most abundant component of the complement system, complement component 3 (C3) plays essential roles in all three complement pathways. However, the effects of C3 on neurological impairment and brain injury in ICH patients and the related mechanism have not been fully elucidated. Normobaric hyperoxia (NBO) is regarded as a treatment for ICH patients, and recent clinical studies also have confirmed the neuroprotective role of NBO against acute ICH-mediated brain damage, but the underlying mechanism still remains elusive. AIMS: In the present study, we investigated the effects of complement C3 on NBO-treated ICH patients and model mice, and the underlying mechanism of NBO therapy in ICH-mediated brain injury. RESULTS: Hemorrhagic injury resulted in the high plasma C3 levels in ICH patients, and the plasma C3 levels were closely related to hemorrhagic severity and clinical outcomes after ICH. BO treatment alleviated neurologic impairments and rescued the hemorrhagic-induced increase in plasma C3 levels in ICH patients and model mice. Moreover, the results indicated that NBO exerted its protective effects of on brain injury after ICH by downregulating the expression of C3 in microglia and alleviating microglia-mediated synaptic pruning. CONCLUSIONS: Our results revealed that NBO exerts its neuroprotective effects by reducing C3-mediated synaptic pruning, which suggested that NBO therapy could be used for the clinical treatment of ICH.

Current evidence of synaptic dysfunction after stroke: Cellular and molecular mechanisms.

BACKGROUND: Stroke is an acute cerebrovascular disease in which brain tissue is damaged due to sudden obstruction of blood flow to the brain or the rupture of blood vessels in the brain, which can prompt ischemic or hemorrhagic stroke. After stroke onset, ischemia, hypoxia, infiltration of blood components into the brain parenchyma, and lysed cell fragments, among other factors, invariably increase blood-brain barrier (BBB) permeability, the inflammatory response, and brain edema. These changes lead to neuronal cell death and synaptic dysfunction, the latter of which poses a significant challenge to stroke treatment. RESULTS: Synaptic dysfunction occurs in various ways after stroke and includes the following: damage to neuronal structures, accumulation of pathologic proteins in the cell body, decreased fluidity and release of synaptic vesicles, disruption of mitochondrial transport in synapses, activation of synaptic phagocytosis by microglia/macrophages and astrocytes, and a reduction in synapse formation. CONCLUSIONS: This review summarizes the cellular and molecular mechanisms related to synapses and the protective effects of drugs or compounds and rehabilitation therapy on synapses in stroke according to recent research. Such an exploration will help to elucidate the relationship between stroke and synaptic damage and provide new insights into protecting synapses and restoring neurologic function.

The neuroprotective effects of normobaric oxygen therapy after stroke.

BACKGROUND: Stroke, including ischemic and hemorrhagic stroke, is a severe and prevalent acute cerebrovascular disease. The development of hypoxia following stroke can trigger a cascade of pathological events, including mitochondrial dysfunction, energy deficiency, oxidative stress, neuroinflammation, and excitotoxicity, all of which are often associated with unfavorable prognosis. Nonetheless, a noninvasive intervention, referred to as normobaric hyperoxia (NBO), is known to have neuroprotective effects against stroke. RESULTS: NBO can exert neuroprotective effects through various mechanisms, such as the rescue of hypoxic tissues, preservation of the blood-brain barrier, reduction of brain edema, alleviation of neuroinflammation, improvement of mitochondrial function, mitigation of oxidative stress, reduction of excitotoxicity, and inhibition of apoptosis. These mechanisms may help improve the prognosis of stroke patients. CONCLUSIONS: This review summarizes the mechanism by which hypoxia causes brain injury and how NBO can act as a neuroprotective therapy to treat stroke. We conclude that NBO has significant potential for treating stroke and may represent a novel therapeutic strategy.

Normobaric hyperoxia therapy in acute ischemic stroke: A literature review.

Background: Ischemic stroke is one of the most severe cerebrovascular diseases that leads to disability and death and seriously endangers health and quality of life. Insufficient oxygen supply is a critical factor leading to ischemic brain injury. However, effective therapies for ischemic stroke are lacking. Oxygen therapy has been shown to increase oxygen supply to ischemic tissues and improve prognosis after cerebral ischemia/reperfusion. Normobaric hyperoxia (NBHO) has been shown to have neuroprotective effects during ischemic stroke and is considered an appropriate neuroprotective therapy for ischemic stroke. Evidence indicates that NBHO plays a neuroprotective role through different mechanisms in acute ischemic stroke. Recent studies have also reported that combinations with other drug therapies can enhance the efficacy of NBHO in ischemic stroke. Here, we aimed to provide a summary of the potential mechanisms underlying the use of NBHO in ischemic stroke and an overview of the benefits of NBHO in ischemic stroke. Methods: We screened 83 articles on PubMed and other websites. A quick review was conducted, including clinical trials, animal trials, and reviews of studies in the field of NBHO treatment published before July 1, 2023. The results were described and synthesized, and the bias risk and evidence quality of all included studies were assessed. Results: The results were divided into four categories: the mechanism of NBHO, animal and clinical trials of NBHO, the clinical application and prospects of NBHO, and adverse reactions of NBHO. Conclusion: NBHO is a simple, non-invasive therapy that may be delivered early after stroke onset, with promising potential for the treatment of acute ischemic stroke. However, the optimal therapeutic regimen remains uncertain. Further studies are needed to confirm its efficacy and safety.

Research progress of mitophagy in chronic cerebral ischemia.

Chronic cerebral ischemia (CCI), a condition that can result in headaches, dizziness, cognitive decline, and stroke, is caused by a sustained decrease in cerebral blood flow. Statistics show that 70% of patients with CCI are aged > 80 years and approximately 30% are 45-50 years. The incidence of CCI tends to be lower, and treatment for CCI is urgent. Studies have confirmed that CCI can activate the corresponding mechanisms that lead to mitochondrial dysfunction, which, in turn, can induce mitophagy to maintain mitochondrial homeostasis. Simultaneously, mitochondrial dysfunction can aggravate the insufficient energy supply to cells and various diseases caused by CCI. Regulation of mitophagy has become a promising therapeutic target for the treatment of CCI. This article reviews the latest progress in the important role of mitophagy in CCI and discusses the induction pathways of mitophagy in CCI, including ATP synthesis disorder, oxidative stress injury, induction of reactive oxygen species, and Ca2+ homeostasis disorder, as well as the role of drugs in CCI by regulating mitophagy.

Association of plasma MMP-2 levels and prognosis of patients with intracerebral hemorrhage: a prospective cohort study.

Objective: The role of MMP-2 in patients with ICH is controversial and the impact of plasma MMP-2 level on clinical outcome is still unclear. Materials and methods: In this study, the peripheral venous blood was acquired from 93 patients with ICH and 88 healthy controls within 24 h of hospitalization and at enrollment. We retrospectively investigated plasma MMP-2 levels of patients and healthy controls. The edema volume, the NIHSS score, the GCS score, and mRS were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma MMP-2 levels with clinical outcomes. In addition, the plasma MMP-14 levels and complement C4 level were tested to explore the relationship with plasma MMP-2 level. Results: There was a significant reduction of plasma MMP-2 levels in ICH patients than that in healthy controls (38.02 ± 1.71 vs. 54.03 ± 2.15, p < 0.0001), and MMP-2 is negatively correlated with the edema volume (r = -0.2187, p < 0.05), NIHSS score (r = -0.2194, p < 0.05), blood leucocyte count (r = -0.2549, p = 0.012), and complement C4 level (r = -0.2723, p = 0.005). There is positive correlation between MMP-2 level and GCS score (r = 0.2451, p = 0.01) and MMP-14 level (r = 0.7013, p = 0.005). The multivariate analysis revealed that reduced plasma MMP-2 level is associated with elevated edema volume (OR = 0.2604, 95% CI [0.07 to 0.84], p = 0.02). Conclusion: The plasma MMP-2 level in patients with ICH is significantly lower than that of healthy controls, and plasma MMP-2 level may be a prognostic factor. Plasma MMP-2 levels are correlated with the clinical outcomes of patients and negatively correlated with blood leucocyte count and complement C4 level in patients with ICH.

Research progress of endogenous hematoma absorption after intracerebral hemorrhage.

Non-traumatic intraparenchymal brain hemorrhage is referred to as intracerebral hemorrhage (ICH). Although ICH is associated with a high rate of disability and case fatality, active intervention can significantly lower the rate of severe disability. Studies have shown that the speed of hematoma clearance after ICH determines the patient's prognosis. Following ICH, depending on the hematoma volume and mass effect, either surgical- or medication-only conservative treatment is chosen. The goal of promoting endogenous hematoma absorption is more relevant because surgery is only appropriate for a small percentage of patients, and open surgery can cause additional trauma to patients. The primary method of removing hematoma after ICH in the future will involve understanding how to produce and manage macrophage/microglial endogenous phagocytic hematomas. Therefore, it is necessary to elucidate the regulatory mechanisms and key targets for clinical purposes.

High plasma complement C4 levels as a novel predictor of clinical outcome in intracerebral hemorrhage.

Objective: The complement cascade is activated and contributes to the brain injury after intracerebral hemorrhage (ICH). Complement component 4 (C4), an important component of complement cascade, has been associated with severity of neurological impairment that occurs during ICH. However, the correlation of plasma complement C4 levels with hemorrhagic severity and clinical outcome in ICH patients has not been reported. Materials and methods: This study is a monocentric, real-world, cohort study. In this study, we measured the plasma complement C4 levels of 83 ICH patients and 78 healthy controls. The hematoma volume, the National Institutes of Health Stroke Scale (NIHSS) score, the Glasgow Coma Scale (GCS) score, and the permeability surface (PS) were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma complement C4 levels to hemorrhagic severity and clinical outcomes. The contribution of complement C4 to secondary brain injury (SBI) was assessed by changes in plasma C4 levels between admission and at day 7 after ICH. Results: There was a significant elevation of plasma complement C4 levels in ICH patients than in healthy controls (40.48 ± 1.07 vs. 35.25 ± 0.60, p < 0.0001), and the plasma complement C4 levels were closely related to the hemorrhagic severity. Moreover, plasma complement C4 levels of patients were positively correlated with the hematoma volume (r = 0.501, p < 0.001), NIHSS score (r = 0.362, p < 0.001), the GCS score (r = -0.490, p < 0.001), and PS (r = 0.683, p = 0.045) following ICH. Logistic regression analysis also confirmed that patients with high plasma complement C4 levels show a poor clinical outcome after ICH (p < 0.001). Meanwhile, the elevated plasma levels at day 7 after ICH indicated the correlation of complement C4 with SBI (p < 0.01). Conclusion: Plasma complement C4 levels are significantly elevated in ICH patients and positively correlated with the illness severity. Thus, these findings highlight the importance of complement C4 in brain injury after ICH and provide a novel predictor of clinical outcome for this disease.

Effect of ferroptosis on chronic cerebral hypoperfusion in vascular dementia.

Vascular dementia (VaD) is the second most prevalent type of dementia after Alzheimer's disease and is caused by impaired nerve cell function resulting from cerebrovascular disease and vascular risk factors. Chronic cerebral hypoperfusion (CCH) is a common pathological and physiological state that may result from cerebral ischemia and hypoxia, causing widespread diffuse lesions in the brain parenchyma which leads to progressive nerve damage. Transferrin (TF) and transferrin receptor 1 (TfR1), two proteins involved in iron uptake, were upregulated by CCH, whereas ferroprotein (FPN), a protein involved in iron efflux, was downregulated. This process may involve various mechanisms including tau and iron regulatory proteins (IRP). CCH can also exacerbate lipid peroxidation caused by an iron imbalance by inhibiting glutathione peroxidase 4 (Gpx4) synthesis and some Gpx4 independent pathways through cystine/glutamate transporters (system Xc-), ultimately leading to ferroptosis in nerve cells and accelerating the progression of VaD.

Epigenetic regulation of synaptic disorder in Alzheimer's disease.

Synapses are critical structures involved in neurotransmission and neuroplasticity. Their activity depends on their complete structure and function, which are the basis of learning, memory, and cognitive function. Alzheimer's disease (AD) is neuropathologically characterized by synaptic loss, synaptic disorder, and plasticity impairment. AD pathogenesis is characterized by complex interactions between genetic and environmental factors. Changes in various receptors on the postsynaptic membrane, synaptic components, and dendritic spines lead to synaptic disorder. Changes in epigenetic regulation, including DNA methylation, RNA interference, and histone modification, are closely related to AD. These can affect neuronal and synaptic functions by regulating the structure and expression of neuronal genes. Some drugs have ameliorated synaptic and neural dysfunction in AD models via epigenetic regulation. We reviewed the recent progress on pathological changes and epigenetic mechanisms of synaptic dysregulation in AD to provide a new perspective on this disease.

Ferroptosis, a Potential Therapeutic Target in Alzheimer's Disease.

Cell death is a common phenomenon in the progression of Alzheimer's disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.

The role of pathological tau in synaptic dysfunction in Alzheimer's diseases.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-ß (Aß) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.