Role of spleen tyrosine kinase in tumor necrosis factor like weak inhibitor of apoptosis induced dopaminergic neuronal cell death and microglial activation in invitro and in vivo models of Parkinson disease

Tweak and TNF family members are novel regulators of acute and chronic inflammation. Tweak / Fn14 interaction appears to be involved in angiogenesis, inflammation, proliferation, migration, cytokine production, cytotoxicity and apoptosis. Thus, TWEAK can induce both cell death and proliferation. Recently, TWEAK has been shown to be associated with neurodegenerative effects in an MPTP mouse model of PD. Despite numerous studies demonstrating TWEAK’s ability to cause cell death in diverse cell types the mechanism(s) by which TWEAK-induce dopaminergic cell death remain poorly defined. Therefore in an attempt to better understand the molecular basis of TWEAK-induced dopaminergic neurotoxicity we evaluated the apoptotic effect of TWEAK and associated molecular mechanisms using N27 dopaminergic neuronal cells. TWEAK-induced a time dependent increase in ROS generation, mitochondrial dysfunction, caspase activation, and NFkB activation. Additionally, a concurrent activation of SYK and proteolytic cleavage of PKC delta was evidenced in TWEAK treated cells. In contrast a marked down regulation of p-GSK 3b (Ser 9) and Akt activity was evidenced in TWEAK treated cells. Intriguingly, inhibition of SYK activity via R708 attenuated TWEAK-induced loss of dopaminergic cell viability. Likewise, SN50, NFkB inhibitor and Quercetin, a ubiquitous bioactive plant flavonoid attenuated TWEAK-induced apoptotic cell death further highlighting the pivotal role of NFkB and mitochondria dependent oxidative stress signaling events in the mechanism of dopaminergic neurodegeneration. Taken together, our studies demonstrate the involvement SYK/NFkB signaling axis and mitochondrial dysfunction in TWEAK-induced apoptotic cell death. In the next series of studies we determined the effects of TWEAK on microglia. A growing body of evidence suggests that persistent microglial activation and accompanying oxidative stress may act as co-conspirators in mediating dopaminergic neurodegeneration in the substantia nigra in PD pathogenesis. Previously we demonstrated that PKC delta a redox sensitive kinase is a critical determinant of microglial activation response in response to diverse inflammagens. More recently, SYK, has been implicated in the activation of inflammatory cells in response to infection. Therefore, in the current study we hypothesized that SYK may act as an upstream regulator of NLRP3 inflammasome thereby leading to a heightened microglial activation response in TWEAK stimulated cells. In the present study we systematically elucidated the signaling network underlyingTWEAK-induced microglial activation response. A concentration dependent increase in SYK activation and accompanying increase in kinase activity was evidenced in TWEAK treated cells. Our results with pharmacological inhibitors and siRNA mediated gene silencing revealed the regulatory role of SYK in ER stress response (ERS), NOX2 upregulation, GSK 3β activation as well as autophagolysosomal system (ALS) and mitochondrial dysfunction. Taken together our findings demonstrate a role for SYK signaling network in mediating TWEAK triggered inflammatory response by positively regulating NLRP3 inflammasome activation and ERS in an autophagy dependent manner. We have discovered the pivotal role of SYK in mediating dopaminergic neurodegeneration as well as heightened microglial activation response upon TWEAK treatment. By inhibiting SYK activation we can limit dopaminergic neuronal degeneration as well as microglial activation response in response to diverse inflammagens including TWEAK. Our studies further highlight the therapeutic advantage of targeting SYK for the treatment of inflammation related disorders including PD

Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network

PURPOSE: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. METHODS: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. RESULTS: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. CONCLUSION: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network

The original version of this Article contained an error in the spelling of the author Geoffrey S. Ginsburg, which was incorrectly given as Geoffrey Ginsburg. This has now been corrected in both the PDF and HTML versions of the Article. Erratum for Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network. [Genet Med. 2019

Role of spleen tyrosine kinase in tumor necrosis factor like weak inhibitor of apoptosis induced dopaminergic neuronal cell death and microglial activation in invitro and in vivo models of Parkinson disease

Tweak and TNF family members are novel regulators of acute and chronic inflammation. Tweak / Fn14 interaction appears to be involved in angiogenesis, inflammation, proliferation, migration, cytokine production, cytotoxicity and apoptosis. Thus, TWEAK can induce both cell death and proliferation. Recently, TWEAK has been shown to be associated with neurodegenerative effects in an MPTP mouse model of PD. Despite numerous studies demonstrating TWEAK’s ability to cause cell death in diverse cell types the mechanism(s) by which TWEAK-induce dopaminergic cell death remain poorly defined. Therefore in an attempt to better understand the molecular basis of TWEAK-induced dopaminergic neurotoxicity we evaluated the apoptotic effect of TWEAK and associated molecular mechanisms using N27 dopaminergic neuronal cells. TWEAK-induced a time dependent increase in ROS generation, mitochondrial dysfunction, caspase activation, and NFkB activation. Additionally, a concurrent activation of SYK and proteolytic cleavage of PKC delta was evidenced in TWEAK treated cells. In contrast a marked down regulation of p-GSK 3b (Ser 9) and Akt activity was evidenced in TWEAK treated cells. Intriguingly, inhibition of SYK activity via R708 attenuated TWEAK-induced loss of dopaminergic cell viability. Likewise, SN50, NFkB inhibitor and Quercetin, a ubiquitous bioactive plant flavonoid attenuated TWEAK-induced apoptotic cell death further highlighting the pivotal role of NFkB and mitochondria dependent oxidative stress signaling events in the mechanism of dopaminergic neurodegeneration. Taken together, our studies demonstrate the involvement SYK/NFkB signaling axis and mitochondrial dysfunction in TWEAK-induced apoptotic cell death. In the next series of studies we determined the effects of TWEAK on microglia. A growing body of evidence suggests that persistent microglial activation and accompanying oxidative stress may act as co-conspirators in mediating dopaminergic neurodegeneration in the substantia nigra in PD pathogenesis. Previously we demonstrated that PKC delta a redox sensitive kinase is a critical determinant of microglial activation response in response to diverse inflammagens. More recently, SYK, has been implicated in the activation of inflammatory cells in response to infection. Therefore, in the current study we hypothesized that SYK may act as an upstream regulator of NLRP3 inflammasome thereby leading to a heightened microglial activation response in TWEAK stimulated cells. In the present study we systematically elucidated the signaling network underlyingTWEAK-induced microglial activation response. A concentration dependent increase in SYK activation and accompanying increase in kinase activity was evidenced in TWEAK treated cells. Our results with pharmacological inhibitors and siRNA mediated gene silencing revealed the regulatory role of SYK in ER stress response (ERS), NOX2 upregulation, GSK 3β activation as well as autophagolysosomal system (ALS) and mitochondrial dysfunction. Taken together our findings demonstrate a role for SYK signaling network in mediating TWEAK triggered inflammatory response by positively regulating NLRP3 inflammasome activation and ERS in an autophagy dependent manner. We have discovered the pivotal role of SYK in mediating dopaminergic neurodegeneration as well as heightened microglial activation response upon TWEAK treatment. By inhibiting SYK activation we can limit dopaminergic neuronal degeneration as well as microglial activation response in response to diverse inflammagens including TWEAK. Our studies further highlight the therapeutic advantage of targeting SYK for the treatment of inflammation related disorders including PD.</p

Adjuvants in COVID-19 vaccines: innocent bystanders or culpable abettors for stirring up COVID-heart syndrome

COVID-19 infection is a multi-system clinical disorder that was associated with increased morbidity and mortality. Even though antiviral therapies such as Remdesvir offered modest efficacy in reducing the mortality and morbidity, they were not efficacious in reducing the risk of future infections. So, FDA approved COVID-19 vaccines which are widely administered in the general population worldwide. These COVID-19 vaccines offered a safety net against future infections and re-infections. Most of these vaccines contain inactivated virus or spike protein mRNA that are primarily responsible for inducing innate and adaptive immunity. These vaccines were also formulated to contain supplementary adjuvants that are beneficial in boosting the immune response. During the pandemic, clinicians all over the world witnessed an uprise in the incidence and prevalence of cardiovascular diseases (COVID-Heart Syndrome) in patients with and without cardiovascular risk factors. Clinical researchers were not certain about the underlying reason for the upsurge of cardiovascular disorders with some blaming them on COVID-19 infections while others blaming them on COVID-19 vaccines. Based on the literature review, we hypothesize that adjuvants included in the COVID-19 vaccines are the real culprits for causation of cardiovascular disorders. Operation of various pathological signaling events under the influence of these adjuvants including autoimmunity, bystander effect, direct toxicity, anti-phospholipid syndrome (APS), anaphylaxis, hypersensitivity, genetic susceptibility, epitope spreading, and anti-idiotypic antibodies were partially responsible for stirring up the onset of cardiovascular disorders. With these mechanisms in place, a minor contribution from COVID-19 virus itself cannot be ruled out. With that being said, we strongly advocate for careful selection of vaccine adjuvants included in COVID-19 vaccines so that future adverse cardiac disorders can be averted

Do COVID-19 viral infection and its mRNA vaccine carry an equivalent risk of myocarditis? Review of the current evidence, insights, and future directions

According to recent epidemiological analysis, the percentage of world population infected with COVID-19 by end of December 2020 is approximately 12.56%1. COVID induced acute care and ICU hospitalization rates are around 9.22 (95% CI: 18.73–19.51), and 4.14 (95% CI: 4.10–4.18) per 1000 population1. Although therapeutic strategies such as antivirals, intravenous immunoglobulins and corticosteroids have shown modest efficacy in reducing the disease progression, they are not disease specific and only temper the immune mediated attack on the systemic tissues. Therefore, clinicians started to rely on mRNA COVID-19 vaccines, which are clinically efficacious in reducing the incidence, disease severity and systemic complications of COVID-19 infections. Nevertheless, usage of COVID-19 mRNA vaccines is also associated with cardiovascular complications such as myocarditis and pericarditis. On the other hand, COVID-19 infections itself are associated with cardiovascular complications such as myocarditis. The underlying signaling pathways for occurrence of COVID-19 and mRNA COVID-19 vaccine induced myocarditis are quite different although there is some overlap in autoimmunity and cross reactivity mechanisms. With media reports highlighting the cardiovascular complications of COVID-19 vaccines such as myocarditis, general population have become more hesitant and uncertain regarding the safety and efficacy of these mRNA vaccines. We plan to review the current literature and provide insights into their pathophysiological mechanisms for myocarditis and offer recommendations for further research studies in this regard. This will hopefully dispel some doubts and encourage more people to be vaccinated for preventing the risk of COVID-19 induced myocarditis and other associated cardiovascular complications

COVID-19 HEART unveiling as atrial fibrillation: pathophysiology, management and future directions for research

Abstract Background COVID-19 infections are known to cause numerous systemic complications including cardiovascular disorders. In this regard, clinicians recently noticed that patients recovering from COVID-19 infections presented with diverse set of cardiovascular disorders in addition to those admitted to ICU (intensive care unit). COVID-19 heart has multifaceted presentation ranging from dysrhythmias, myocarditis, stroke, coronary artery disease, thromboembolism to heart failure. Atrial fibrillation is the most common cardiac arrhythmia among COVID-19 patients. In the background section, we briefly discussed epidemiology and spectrum of cardiac arrhythmias in COVID-19 patients. Main body In this state-of-the-art review we present here, we present the information regarding COVID-19-induced A-fib in sections, namely mechanism of action, clinical presentation, diagnosis and treatment. Unfortunately, its occurrence significantly increases the mortality and morbidity with a potential risk of complications such as cardiac arrest and sudden death. We included separate sections on complications including thromboembolism and ventricular arrhythmias. Since its mechanism is currently a gray area, we included a separate section on basic science research studies that are warranted in the future to comprehend its underlying pathogenic mechanisms. Conclusions Taken together, this review builds upon the current literature of COVID-19-induced A-fib, including pathophysiology, clinical presentation, treatment and complications. Furthermore, it provides recommendations for future research moving forward that can open avenues for developing novel remedies that can prevent as well as hasten clinical recovery of atrial fibrillation in COVID-19 patients

Agrochemicals-Induced Dopaminergic Neurotoxicity: Role of Mitochondria-Mediated Oxidative Stress and Protein Clearance Mechanisms

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder that is characterized by the progressive loss of substantia nigral dopaminergic neurons resulting in the pronounced depletion of striatal DA levels which subsequently leads to the expression of cardinal features of PD including tremor, bradykinesia, rigidity and postural instability. The mechanisms underlying the selective loss of dopaminergic neurons remain poorly understood; however, studies conducted in post mortem PD brains and experimental PD models have implicated oxidative stress and mitochondrial dysfunction in the mechanism of dopaminergic neurodegeneration. In recent years, the etiology of several neurodegenerative diseases including PD has been linked to low dose and chronic exposure to a variety of agrochemicals including paraquat, rotenone and dieldrin. Here we discuss how several of these pesticides share common mechanistic events, including oxidative stress, mitochondrial impairment/complex I inhibition, abnormal protein aggregation and post translational modifications (PTMs) of proteins including α-synuclein, as well as dopaminergic cell death. Furthermore, intersecting and parallel effects of environmental neurotoxicants on protein clearance mechanisms and mitochondrial function are addressed and hence provide novel insights that might be beneficial in the development of targeted therapies for PD

Long term impact of epicardial left atrial appendage ligation on systemic hemostasis : LAA HOMEOSTASIS-2

Background: Recent data suggest that epicardial left atrial appendage closure (LAAC) is associated with several short-term neurohormonal effects. However, the long-term effects are currently unknown. Objective: To investigate the effects of percutaneous epicardial left atial appendage (LAA) exclusion using LARIAT on neurohormonal profiles at long-term follow-up. Methods: In a prospective single centre study, 60 patients with long-standing, persistent atrial fibrillation (AF) LARIAT were treated. The major hormones of the adrenergic system, renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides were assessed before the intervention and at regular intervals during the following two years. Results: In patients with epicardial LAAC, atrial natriuretic peptide (ANP) levels were significantly increased from baseline at 24 h and decreased at 7 days, 1 month, and 3 months, while remaining unchanged at 12 and 24 months. Noradrenaline levels were significantly lower at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months, while epinephrine levels decreased significantly at 1 month, 6 months, 12 months, and 24 months. Plasma renin activity significantly decreased at 7 days, 1 month, 6 months, 12 months, and 24 months, while aldosterone levels significantly decreased at 6 months, 12 months, and 24 months. Endothelin-1 and vasopressin showed a significant increase and decrease, respectively, at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months. There was also a significant decrease in systolic and diastolic blood pressure at 3 months, 6 months, 1 year, and 2 years after the intervention. Conclusions: Epicardial LAAC in AF patients is associated with persistent neurohormonal changes favouring blood pressure reduction