Cytokine storm induced by SARS-CoV-2 infection: The spectrum of its neurological manifestations.

The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19.

Heparanase promotes neuroinflammatory response during subarachnoid hemorrhage in rats.

BACKGROUND: Heparanase, a mammalian endo-ß-D-glucoronidase that specifically degrades heparan sulfate, has been implicated in inflammation and ischemic stroke. However, the role of heparanase in neuroinflammatory response in subarachnoid hemorrhage (SAH) has not yet been investigated. This study was designed to examine the association between heparanase expression and neuroinflammation during subarachnoid hemorrhage. METHODS: Rats were subjected to SAH by endovascular perforation, and the expression of heparanase was determined by Western blot analysis and immunofluorescence in the ipsilateral brain cortex at 24 h post-SAH. Pial venule leukocyte trafficking was monitored by using intravital microscopy through cranial window. RESULTS: Our results indicated that, compared to their sham-surgical controls, the rats subjected to SAH showed marked elevation of heparanase expression in the ipsilateral brain cortex. The SAH-induced elevation of heparanase was accompanied by increased leukocyte trafficking in pial venules and significant neurological deficiency. Intracerebroventricular application of a selective heparanase inhibitor, OGT2115, which was initiated at 3 h after SAH, significantly suppressed the leukocyte trafficking and improved the neurological function. CONCLUSIONS: Our findings indicate that heparanase plays an important role in mediating the neuroinflammatory response after SAH and contributes to SAH-related neurological deficits and early brain injury following SAH.

The Role of HMGB1 in Pial Arteriole Dilating Reactivity following Subarachnoid Hemorrhage in Rats.

High-mobility group box 1 protein (HMGB1) has been implicated in inflammatory responses, and is also associated with cerebral vasospasm after subarachnoid hemorrhage (SAH). However, there are no direct evident links between HMGB1 and cerebral vasospasm. We therefore investigated the effects of HMGB1 on pial arteriole reactivity following SAH in rats. We initially found that SAH induced a significant decrease in pial arteriole dilating responses to sciatic nerve stimulation (SNS), hypercapnia (CO2), and the topical suffusion of acetylcholine (ACh), adenosine (ADO), and s-nitroso-N-acetylpenicillamine (SNAP) over a 7-day period after SAH. The percent change of arteriolar diameter was decreased to the lowest point at 48 h after SAH, in response to dilating stimuli (i.e., it decreased from 41.0 ± 19.0% in the sham group to 11.00 ± 0.70% after SNS) (n = 5, p < 0.01). HMGB1 infusion in the lateral ventricle in normal rats for 48 h did not change the pial arteriole dilating response. In addition, inhibitors of HMGB1-receptor for advanced glycation end-product or HMGB1-toll-like receptor 2/4 interaction, or the HMBG1 antagonist did not improve pial arteriole reactivity 48 h after SAH. These findings suggest that HMGB1 may not be a major player in cerebral vascular dilating dysfunction after SAH.

Radixin: Roles in the Nervous System and Beyond.

BACKGROUND: Radixin is an ERM family protein that includes radixin, moesin, and ezrin. The importance of ERM family proteins has been attracting more attention, and studies on the roles of ERM in biological function and the pathogenesis of some diseases are accumulating. In particular, we have found that radixin is the most dramatically changed ERM protein in elevated glucose-treated Schwann cells. METHOD: We systemically review the literature on ERM, radixin in focus, and update the roles of radixin in regulating cell morphology, interaction, and cell signaling pathways. The potential of radixin as a therapeutic target in neurodegenerative diseases and cancer was also discussed. RESULTS: Radixin research has focused on its cell functions, activation, and pathogenic roles in some diseases. Radixin and other ERM proteins maintain cell shape, growth, and motility. In the nervous system, radixin has been shown to prevent neurodegeneration and axonal growth. The activation of radixin is through phosphorylation of its conserved threonine residues. Radixin functions in cell signaling pathways by binding to membrane proteins and relaying the cell signals into the cells. Deficiency of radixin has been involved in the pathogenic process of diseases in the central nervous system and diabetic peripheral nerve injury. Moreover, radixin also plays a role in cell growth and drug resistance in multiple cancers. The trials of therapeutic potential through radixin modulation have been accumulating. However, the exact mechanisms underlying the roles of radixin are far from clarification. CONCLUSIONS: Radixin plays various roles in cells and is involved in developing neurodegenerative diseases and many types of cancers. Therefore, radixin may be considered a potential target for developing therapeutic strategies for its related diseases. Further elucidation of the function and the cell signaling pathways that are linked to radixin may open the avenue to finding novel therapeutic strategies for diseases in the nervous system and other body systems.

Pathogenesis underlying hexanucleotide repeat expansions in C9orf72 gene in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.

Targeting neuroinflammation in distal symmetrical polyneuropathy in diabetes.

Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy, and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy.

Novel strategy: Identifying new markers for demyelination in diabetic distal symmetrical polyneuropathy.

Objective: To develop a novel strategy for identifying acquired demyelination in diabetic distal symmetrical polyneuropathy (DSP). Background: Motor nerve conduction velocity (CV) slowing in diabetic DSP exceeds expectations for pure axonal loss thus implicating superimposed acquired demyelination. Methods: After establishing demyelination confidence intervals by regression analysis of nerve conduction data from chronic inflammatory demyelinating polyneuropathy (CIDP), we prospectively studied CV slowing in 90 diabetic DSP patients with and without at least one motor nerve exhibiting CV slowing (groups A and B) into the demyelination range by American Academy of Neurology (AAN) criteria respectively and 95 amyotrophic lateral sclerosis (ALS) patients. Simultaneously, secretory phospholipase A2 (sPLA2) activity was assessed in both diabetic groups and 46 healthy controls. Results: No ALS patient exhibited CV slowing in more than two motor nerves based on AAN criteria or the confidence intervals. Group A demonstrated a significantly higher percentage of patients as compared to group B fulfilling the above criteria, with an additional criterion of at least one motor nerve exhibiting CV slowing in the demyelinating range and a corresponding F response in the demyelinating range by AAN criteria (70.3 % vs. 1.9 %; p < 0.0001). Urine sPLA2 activity was increased significantly in diabetic groups as compared to healthy controls (942.9 ± 978.0 vs. 591.6 ± 390.2 pmol/min/ml, p < 0.05), and in group A compared to Group B (1328.3 ± 1274.2 vs. 673.8 ± 576.9 pmol/min/ml, p < 0.01). More patients with elevated sPLA2 activity and more than 2 motor nerves with CV slowing in the AAN or the confidence intervals were identified in group A as compared to group B (35.1 % vs. 5.7 %, p < 0.001). Furthermore, 13.5 % of patients in diabetic DSP Group A, and no patients in diabetic DSP Group B, fulfilled an additional criterion of more than one motor nerve with CV slowing into the demyelinating range with its corresponding F response into the demyelinating range by AAN criteria. Conclusion: A combination of regression analysis of electrodiagnostic data and a urine biological marker of systemic inflammation identifies a subgroup of diabetic DSP with superimposed acquired demyelination that may respond favorably to immunomodulatory therapy.

Oldhamianoside II, a new triterpenoid saponin, prevents tumor growth via inducing cell apoptosis and inhibiting angiogenesis.

Oldhamianoside II is a new triterpenoid saponin that was isolated from the roots of Gypsophila oldhamiana. The present study aims to investigate the potential inhibitory activity of oldhamianoside II on tumor growth using an S180 tumor implantation mouse model. Oldhamianoside II at doses of 5.0 and 10.0 mg/kg was given with intraperitoneal injection for 10 days following subcutaneous inoculation of S180 tumor cells in anterior flank of mice. The tumor growth, the cell apoptosis, the microvessel density (MVD) in S180 tumors, the tumor cell viability, the tubular formation in vitro, and migration of tumor cells were examined. The expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and cyclooxygenase-2 (COX-2) was determined to analyze the associated mechanisms. The results showed that oldhamianoside II potently inhibited tumor cell viability in vitro. In addition, oldhamianoside II delayed tumor growth in anterior flank, induced S180 cell apoptosis, and reduced the MVD. Oldhamianoside II was also demonstrated to decrease the number of tubular structure and vessel formation in HUVEC cultures and chick embryo chorioallantoic membrane (CAM) model, respectively. Further study indicated that oldhamianoside II reduced the expression of VEGF, bFGF, and COX-2 in tumor sections. Moreover, oldhamianoside II inhibited the activity of migration and penetration to Matrigel of SGC7901 tumor cells in scratch wound and transwell chamber. In conclusion, our work defines oldhamianoside II, a new triterpenoid saponin, as a novel compound that can effectively inhibit S180 tumor growth, induce tumor cell apoptosis, prevent tumor angiogenesis, and inhibit cancer cell migration, suggesting that oldhamianoside II is a potential drug candidate for the treatment of cancer and for the prevention of metastasis.

Electrodiagnostic profile of conduction slowing in amyotrophic lateral sclerosis.

Objective: Since motor nerve conduction slowing can occur due to loss of large axons, we investigate the conduction slowing profile in amyotrophic lateral sclerosis (ALS) and identify the limits beyond which the diagnosis of exclusive axonal loss is unlikely. Methods: First, using linear regression analysis, we established the range of motor conduction slowing in 76 chronic inflammatory demyelinating polyneuropathy (CIDP) patients. Demyelinating range confidence intervals were defined by assessing conduction velocity (CV), distal latency (DML), and F-wave latency (F) in relation to distal compound muscle action potential (CMAP) amplitude of median, ulnar, fibular, and tibial nerves. Results were subsequently validated in 38 additional CIDP patients. Then, the newly established demyelination confidence intervals were used to investigate the profile of conduction slowing in 95 ALS patients. Results: CV slowing, prolonged DML, and abnormal F were observed in 22.2%, 19.6%, and 47.1% of the studied nerves respectively in ALS patients. When slowing occurred, it affected more than one segment of the motor nerve, suggesting that CMAP amplitude dependent conduction slowing caused by an exclusive loss of large axons is the main mechanism of slowing. No ALS patient had more than 2 nerves with CV slowing in the confidence interval defined by the regression equations or the American Academy of Neurology (AAN) research criteria for CIDP diagnosis. Conclusions: The presence of more than two motor nerves with CV slowing in the demyelinating range defined by the regression analysis or AAN criteria in ALS patients suggests the contribution of acquired demyelination or other additional mechanisms exist in the electrodiagnostic profile of ALS.

Mammalian target of rapamycin signaling in diabetic cardiovascular disease.

Diabetes mellitus currently affects more than 170 million individuals worldwide and is expected to afflict another 200 million individuals in the next 30 years. Complications of diabetes as a result of oxidant stress affect multiple systems throughout the body, but involvement of the cardiovascular system may be one of the most severe in light of the impact upon cardiac and vascular function that can result in rapid morbidity and mortality for individuals. Given these concerns, the signaling pathways of the mammalian target of rapamycin (mTOR) offer exciting prospects for the development of novel therapies for the cardiovascular complications of diabetes. In the cardiovascular and metabolic systems, mTOR and its multi-protein complexes of TORC1 and TORC2 regulate insulin release and signaling, endothelial cell survival and growth, cardiomyocyte proliferation, resistance to ß-cell injury, and cell longevity. Yet, mTOR can, at times, alter insulin signaling and lead to insulin resistance in the cardiovascular system during diabetes mellitus. It is therefore vital to understand the complex relationship mTOR and its downstream pathways hold during metabolic disease in order to develop novel strategies for the complications of diabetes mellitus in the cardiovascular system.

Oxidant stress and signal transduction in the nervous system with the PI 3-K, Akt, and mTOR cascade.

Oxidative stress impacts multiple systems of the body and can lead to some of the most devastating consequences in the nervous system especially during aging. Both acute and chronic neurodegenerative disorders such as diabetes mellitus, cerebral ischemia, trauma, Alzheimer's disease, Parkinson's disease, Huntington's disease, and tuberous sclerosis through programmed cell death pathways of apoptosis and autophagy can be the result of oxidant stress. Novel therapeutic avenues that focus upon the phosphoinositide 3-kinase (PI 3-K), Akt (protein kinase B), and the mammalian target of rapamycin (mTOR) cascade and related pathways offer exciting prospects to address the onset and potential reversal of neurodegenerative disorders. Effective clinical translation of these pathways into robust therapeutic strategies requires intimate knowledge of the complexity of these pathways and the ability of this cascade to influence biological outcome that can vary among disorders of the nervous system.

Erythropoietin: new directions for the nervous system.

New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control ß-catenin, glycogen synthase kinase-3ß, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders.

SARS-CoV-2 Induced Neurological Manifestations Entangles Cytokine Storm that Implicates for Therapeutic Strategies.

The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can present neurological symptoms and induce neurological complications. The involvement in both the central and peripheral nervous systems in COVID-19 patients has been associated with direct invasion of the virus and the induction of cytokine storm. This review discussed the pathways for the virus invasion into the nervous system and characterized the SARS-CoV-2 induced cytokine storm. In addition, the mechanisms underlying the immune responses and cytokine storm induction after SARS-CoV-2 infection were also discussed. Although some neurological symptoms are mild and disappear after recovery from infection, some severe neurological complications contribute to the mortality of COVID-19 patients. Therefore, the insight into the cause of SARS-CoV-2 induced cytokine storm in context with neurological complications will formulate the novel management of the disease and also further identify new therapeutic targets for COVID-19.

Raves and risks for erythropoietin.

Global use of erythropoietin (EPO) continues to increase as a proven agent for the treatment of anemia. Yet, EPO is no longer believed to have exclusive biological activity in the hematopoietic system and is now considered applicable for a variety of disorders such as diabetes, Alzheimer's disease, and cardiovascular disease. Treatment with EPO is considered to be robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. On the converse side, observations that EPO administration is not without risk have fueled controversy. Here we present recent advances that have elucidated a number of novel cellular pathways governed by EPO to open new therapeutic avenues for this agent and avert its potential deleterious effects.

Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies.

Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

A "FOXO" in sight: targeting Foxo proteins from conception to cancer.

The successful treatment for multiple disease entities can rest heavily upon the ability to elucidate the intricate relationships that govern cellular proliferation, metabolism, survival, and inflammation. Here we discuss the therapeutic potential of the mammalian forkhead transcription factors predominantly in the O class, FoxO1, FoxO3, FoxO4, and FoxO6, which play a significant role during normal cellular function as well as during progressive disease. These transcription factors are integrated with several signal transduction pathways, such as Wnt proteins, that can regulate a broad array of cellular process that include stem cell proliferation, aging, and malignancy. FoxO transcription factors are attractive considerations for strategies directed against human cancer in light of their pro-apoptotic effects and ability to lead to cell cycle arrest. Yet, FoxO proteins can be associated with infertility, cellular degeneration, and unchecked cellular proliferation. As our knowledge continues to develop for this novel family of proteins, potential clinical applications for the FoxO family should heighten our ability to limit disease progression without clinical compromise.

The Wnt signaling pathway: aging gracefully as a protectionist?

No longer considered to be exclusive to cellular developmental pathways, the Wnt family of secreted cysteine-rich glycosylated proteins has emerged as versatile targets for a variety of conditions that involve cardiovascular disease, aging, cancer, diabetes, neurodegeneration, and inflammation. In particular, modulation of Wnt signaling may fill a critical void for the treatment of disorders that impact upon both cellular survival and cellular longevity. Yet, in some scenarios, Wnt signaling can become the catalyst for disease development or promote cell senescence that can compromise clinical utility. This double edge sword in regards to the role of Wnt and its signaling pathways highlights the critical need to further elucidate the cellular mechanisms governed by Wnt in conjunction with the development of robust pharmacological ligands that may open new avenues for disease treatment. Here we discuss the influence of the Wnt pathway during cell survival, metabolism, and aging in order for one to gain a greater insight for the novel role of Wnt signaling as well as exemplify its unique cellular pathways that influence both normal physiology and disease.

OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins.

Forkhead transcription factors have a 'winged helix' domain and regulate processes that range from cell longevity to cell death. Of the mammalian forkhead family members in the O class, FoxO1, FoxO3a and FoxO4 can fill a crucial void for the treatment of disorders that include aging, cancer, diabetes, infertility, neurodegeneration and immune system dysfunction. Yet, observations that forkhead family members also can compromise clinical utility have fueled controversy and highlight the necessity to further outline the integrated cellular pathways governed by these transcription factors. Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.

FoxO proteins: cunning concepts and considerations for the cardiovascular system.

Dysfunction in the cardiovascular system can lead to the progression of a number of disease entities that can involve cancer, diabetes, cardiac ischaemia, neurodegeneration and immune system dysfunction. In order for new therapeutic avenues to overcome some of the limitations of present clinical treatments for these disorders, future investigations must focus upon novel cellular processes that control cellular development, proliferation, metabolism and inflammation. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) have increasingly become recognized as important and exciting targets for disorders of the cardiovascular system. In the present review, we describe the role of these transcription factors in the cardiovascular system during processes that involve angiogenesis, cardiovascular development, hypertension, cellular metabolism, oxidative stress, stem cell proliferation, immune system regulation and cancer. Current knowledge of FoxO protein function combined with future studies should continue to lay the foundation for the successful translation of these transcription factors into novel and robust clinical therapies.

The "O" class: crafting clinical care with FoxO transcription factors.

Forkhead Transcription Factors: Vital Elements in Biology and Medicine provides a unique platform for the presentation of novel work and new insights into the vital role that forkhead transcription factors play in both cellular physiology as well as clinical medicine. Internationally recognized investigators provide their insights and perspectives for a number of forkhead genes and proteins that may have the greatest impact for the development of new strategies for a broad array of disorders that can involve aging, cancer, cardiac function, neurovascular integrity, fertility, stem cell differentiation, cellular metabolism, and immune system regulation. Yet, the work clearly sets a precedent for the necessity to understand the cellular and molecular function of forkhead proteins since this family of transcription factors can limit as well as foster disease progression depending upon the cellular environment. With this in mind, our concluding chapter for Forkhead Transcription Factors: Vital Elements in Biology andMedicine offers to highlight both the diversity and complexity of the forkhead transcription family by focusing upon the mammalian forkhead transcription factors of the O class (FoxOs) that include FoxO1, FoxO3, FoxO4, and FoxO6. FoxO proteins are increasingly considered to represent unique cellular targets that can control numerous processes such as angiogenesis, cardiovascular development, vascular tone, oxidative stress, stem cell proliferation, fertility, and immune surveillance. Furthermore, FoxO transcription factors are exciting considerations for disorders such as cancer in light of their pro-apoptotic and inhibitory cell cycle effects as well as diabetes mellitus given the close association FoxOs hold with cellular metabolism. In addition, these transcription factors are closely integrated with several novel signal transduction pathways, such as erythropoietin and Wnt proteins, that may influence the ability of FoxOs to lead to cell survival or cell injury. Further understanding of both the function and intricate nature of the forkhead transcription factor family, and in particular the FoxO proteins, should allow selective regulation of cellular development or cellular demise for the generation of successful future clinical strategies and patient well-being.