Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 62
Filter
1.
Marine Drugs ; 20(4):253, 2022.
Article in English | ProQuest Central | ID: covidwho-1810015

ABSTRACT

This paper examined the toxins naturally produced by marine dinoflagellates and their effects on increases in β-amyloid plaques along with tau protein hyperphosphorylation, both major drivers of Alzheimer’s disease (AD). This approach is in line with the demand for certain natural compounds, namely those produced by marine invertebrates that have the potential to be used in the treatment of AD. Current advances in AD treatment are discussed as well as the main factors that potentially affect the puzzling global AD pattern. This study focused on yessotoxins (YTXs), gymnodimine (GYM), spirolides (SPXs), and gambierol, all toxins that have been shown to reduce β-amyloid plaques and tau hyperphosphorylation, thus preventing the neuronal or synaptic dysfunction that ultimately causes the cell death associated with AD (or other neurodegenerative diseases). Another group of toxins described, okadaic acid (OA) and its derivatives, inhibit protein phosphatase activity, which facilitates the presence of phosphorylated tau proteins. A few studies have used OA to trigger AD in zebrafish, providing an opportunity to test in vivo the effectiveness of new drugs in treating or attenuating AD. Constraints on the production of marine toxins for use in these tests have been considered. Different lines of research are anticipated regarding the action of the two groups of toxins.

2.
Frontiers in Aging Neuroscience ; 2022.
Article in English | ProQuest Central | ID: covidwho-1771049

ABSTRACT

Alzheimer disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before disease symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signal pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted towards metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in “omics”-based biomarkers in AD.

3.
Am J Respir Cell Mol Biol ; 2022 Mar 29.
Article in English | MEDLINE | ID: covidwho-1765223

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is currently causing a pandemic and has been termed Coronavirus disease 2019 (COVID-19). The elderly or those with preexisting conditions like diabetes, hypertension, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, or kidney dysfunction are more likely to develop severe cases when infected. COVID-19 patients admitted to the intensive care unit (ICU) have higher mortality than non-ICU patients. Critical illness has consistently posed a challenge not only in terms of mortality, but also in regard to long-term outcomes of survivors. Patients who survive acute critical illness including, but not limited to, pulmonary and systemic insults associated with ARDS, pneumonia, systemic inflammation, and mechanical ventilation, will likely suffer from Post-ICU Syndrome (PICS), a phenomenon of cognitive, psychiatric, and/or physical disability following treatment in the ICU. Post-ICU morbidity and mortality continues to be a cause for concern when considering large-scale studies showing 12-month mortality risks of 11.8% to 21%. Previous studies have demonstrated that multiple mechanisms, including cytokine release, mitochondrial dysfunction and even amyloids may lead to end-organ dysfunction in patients. We hypothesize that COVID-19 infection will lead to PICS via potentially similar mechanisms as other chronic critical illness and cause long-term morbidity and mortality in patients. We consider a variety of mechanisms and questions that not only consider the short-term impact of the COVID-19 pandemic, but its long-term effects that may not yet be imagined. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

4.
Biomedicines ; 10(3)2022 Mar 14.
Article in English | MEDLINE | ID: covidwho-1760357

ABSTRACT

The oral microbiome, forming a biofilm that covers the oral structures, contains a high number of microorganisms. Biofilm formation starts from the salivary pellicle that allows bacterial adhesion-colonization-proliferation, co-aggregation and biofilm maturation in a complex microbial community. There is a constant bidirectional crosstalk between human host and its oral microbiome. The paper presents the fundamentals regarding the oral microbiome and its relationship to modulator factors, oral and systemic health. The modern studies of oral microorganisms and relationships with the host benefits are based on genomics, transcriptomics, proteomics and metabolomics. Pharmaceuticals such as antimicrobials, prebiotics, probiotics, surface active or abrasive agents and plant-derived ingredients may influence the oral microbiome. Many studies found associations between oral dysbiosis and systemic disorders, including autoimmune diseases, cardiovascular, diabetes, cancers and neurodegenerative disorders. We outline the general and individual factors influencing the host-microbial balance and the possibility to use the analysis of the oral microbiome in prevention, diagnosis and treatment in personalized medicine. Future therapies should take in account the restoration of the normal symbiotic relation with the oral microbiome.

5.
Expert Rev Clin Immunol ; 18(4): 413-423, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1758481

ABSTRACT

INTRODUCTION: The inflammatory myopathies (IM) have now evolved into distinct subsets requiring clarification about their immunopathogenesis to guide applications of targeted therapies. AREAS COVERED: Immunohistopathologic criteria of IM with a focus on complement, anti-complement therapeutics, and other biologic immunotherapies. The COVID19-triggered muscle autoimmunity along with the correct interpretation of muscle amyloid deposits is discussed. EXPERT OPINION: The IM, unjustifiably referred as idiopathic, comprise Dermatomyositis (DM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). In DM, complement activation with MAC-mediated endomysial microvascular destruction and perifascicular atrophy is the fundamental process, while innate immunity activation factors, INF1 and MxA, sense and secondarily enhance inflammation. Complement participates in muscle fiber necrosis from any cause and may facilitate muscle-fiber necrosis in NAM but seems unlikely that myositis-associated antibodies participate in complement-fixing. Accordingly, anti-complement therapeutics should be prioritized for DM. SARS-CoV-2 can potentially trigger muscle autoimmunity, but systematic studies are needed as the reported autopsy findings are not clinically relevant. In IBM, tiny amyloid deposits within muscle fibers are enhanced by inflammatory mediators contributing to myodegeneration; in contrast, spotty amyloid deposits in the endomysial connective tissue do not represent 'amyloid myopathy' but only have diagnostic value for amyloidosis due to any cause.


Subject(s)
COVID-19 , Dermatomyositis , Myositis , Dermatomyositis/diagnosis , Humans , Muscles/pathology , Myositis/diagnosis , Plaque, Amyloid , SARS-CoV-2
6.
J Alzheimers Dis ; 85(4): 1573-1582, 2022.
Article in English | MEDLINE | ID: covidwho-1745159

ABSTRACT

BACKGROUND: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer's disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. OBJECTIVE: We aim to explore the difference in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. METHODS: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n = 34) and sd-SCD (n = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. RESULTS: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F = 5.033, p = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F = 12.309, p = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. CONCLUSION: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals.


Subject(s)
Amyloid/metabolism , Cognitive Dysfunction/pathology , Aged , Brain/pathology , Female , Humans , Male , Neuropsychological Tests/statistics & numerical data , Positron-Emission Tomography
8.
Physiotherapy (United Kingdom) ; 114:e34-e35, 2022.
Article in English | EMBASE | ID: covidwho-1706728

ABSTRACT

Keywords: Soft tissue trauma, Advanced Practice Physiotherapist, Fracture Clinic Purpose: A large amount of patients were identified in Fracture Clinic with soft tissue trauma who did not necessarily need to see a doctor. We proposed that we could reduced the demands on doctors in Fracture Clinic and the foot-fall through the hospital, whilst improving patient outcomes and patient satisfaction by having these patients seen instead in an advanced practice physiotherapist-led STTC. Aims of the pilot: 1. Reduce the number of patients in Fracture Clinic requiring medical review 2. Standardise pathways of care 3. Provide patients with earlier specialised physiotherapy management 4. Maintain or improve outcomes and patient satisfaction Methods: A quality improvement approach was used with an Action Research Methodology. Results: Less patients with Soft tissue trauma required medical review. Reduced patient foot-fall through the hospital (59% of patients discharged at first contact compared to 35% of patients in Fracture Clinic). Management pathways for patients with soft tissue trauma were standardised. Patients received early specialist physiotherapy management. Also reduced number of referrals to physiotherapy and a reduced average number of subsequent physiotherapy follow-up appointments. We received outstanding patient satisfaction (95% rated extremely likely to recommend the service to friends and family;97/100 achieved on the VSQ-9 satisfaction questionnaire) Conclusion(s): The Soft Tissue Trauma Clinic utilises expert clinicians who provide a highly effective and cost-efficient service that reduces demand on Fracture Clinic whilst delivering excellent patient outcomes and satisfaction. Depending on funding, we are hoping the service can be made substantive, and then expanded to be included in the Trust's Trauma management pathway. Impact: We’ve demonstrated that patients with Soft tissue trauma can be successfully managed without needing to see a doctor in Fracture Clinic. Adopting an APP led-soft tissue trauma clinic could aid the post-COVID Orthopaedic Recovery Plan by releasing a Registrar from Fracture clinic to do other activities, such as elective orthopaedic clinics or additional theatre lists. We were able to reduce the footfall through the hospital. More patients were discharged at first contact in the STTC with fewer requiring additional follow-up appointments because patients were seeing the right person at the right time. 59% of patients were appropriately discharge at their first attendance in the STTC compared to 35% in Fracture clinic. We managed to agree with the Orthopaedic team Standardised care pathways for patients with STT. In line with the NHS Long-term plan, if we can standardise care pathways we can:- Reduced unwarranted variation which in-turn will reduce variations in outcomes and inequalities. - We can ensure an evidenced base and best practice model is followed as suggested by the ‘GIRFT’ as opposed to research literature and anecdotal evidence that suggests a lot of variation in patient management by current fracture clinic services. We were able to provide patients with earlier specialist physiotherapy management. We know the earlier we can provide suitable management advice we are more likely to improve a patient's function and their return to work, reduce patient anxiety, and reduce long-term pain and disability. We also reduced the length of a patient's rehabilitation and need for further physiotherapy. Funding acknowledgements: Not funded

9.
Biochem J ; 479(4): 537-559, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1705036

ABSTRACT

Post-acute sequelae of COVID (PASC), usually referred to as 'Long COVID' (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, 'brain fog', tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of 'COVID', although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous 'amyloid' form of fibrin that (like other ß-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.


Subject(s)
Amyloid , Anticoagulants/therapeutic use , COVID-19 , Lung , SARS-CoV-2/metabolism , Thrombosis , Amyloid/blood , Amyloid/chemistry , COVID-19/blood , COVID-19/drug therapy , Fibrin/chemistry , Fibrin/metabolism , Humans , Lung/metabolism , Lung/virology , Thrombosis/drug therapy , Thrombosis/metabolism , Thrombosis/virology
10.
Critical Care Medicine ; 50(1 SUPPL):71, 2022.
Article in English | EMBASE | ID: covidwho-1692054

ABSTRACT

INTRODUCTION/HYPOTHESIS: COVID-19 has been associated with distinct types of neuronal damage. We hypothesize that the progression of neurological damage will be related to an imbalance between neurodegeneration, neuroinflammatory, and neuroprotective markers, therefore suggesting a potential mechanism for the emergence of adverse, chronic outcomes. METHODS: 105 patients admitted to an urban, academic hospital with a diagnosis of COVID-19 were enrolled. Serum neuroprotective (clusterin, fetuin), neurodegenerative (τ, phosphorylated τ, amyloids, TDP43, NRGN, NCAM-1, and KLK6), and neuroinflammatory (CCL23, YKL40, MIF) markers were collected. These were analyzed longitudinally in conjunction with immune system activators (RAGE, IL-34) using the multiplex platform. Electronic medical records were used to collect demographic and clinical data. RESULTS: Of the 105 patients, 5 were diagnosed with stroke within 28 days of admission, followed by an additional 6 strokes occurring by 6 months, or a 9.5% occurrence of stroke overall. Serum levels of Amyloid β42 declined significantly for the general population 7 days after admission when compared to initial collections (p< 0.001), while Amyloid β40, KLK6, and MIF declined and recovered within the same 7 days (p< 0.001, p< 0.001, p=0.003). The neuroprotective markers fetuin and clusterin were particularly dynamic with fetuin decreasing and restoring in less than 7 days (p=0.02) and clusterin remaining low after admission (p< 0.001). Most patients had persistently elevated CCL23 levels, with the stroke patient cohort having the highest values (p=0.018). The IL-6 levels of stroke patients were significantly higher compared to their non-stroke counterparts one week after admission (p=0.001), while IL-8 levels fluctuated before declining (p< 0.001). CONCLUSIONS: Our data reveals elevations in neuronal damage in the 7 days following hospital admission for COVID-19 patients. The down-regulation of fetuin and clusterin is particularly compelling as their declines may be linked to the elevated neuronal injury seen with increased neuroinflammatory markers, specifically CCL23 and IL-6. Serum levels of neurodegeneration markers proved complex, therefore possibly suggesting a more dynamic relationship to the neural abnormalities seen in COVID-19 patients.

11.
J Proteome Res ; 21(4): 975-992, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1683912

ABSTRACT

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.


Subject(s)
COVID-19 , Biomarkers , Humans , Plasma , Proteomics , Retrospective Studies
12.
Peptides ; 151: 170766, 2022 05.
Article in English | MEDLINE | ID: covidwho-1676880

ABSTRACT

Angiotensin-converting enzyme-2, or ACE2, is primarily a zinc-dependent peptidase and ectoenzyme expressed in numerous cell types and functioning as a counterbalance to ACE in the renin-angiotensin system. It was discovered 21 years ago more than 40 years after the discovery of ACE itself. Its primary physiological activity is believed to be in the conversion of angiotensin II to the vasodilatory angiotensin-(1-7) acting through the Mas receptor. As such it has been implicated in numerous pathological conditions, largely in a protective mode which has led to the search for ACE2 activatory mechanisms. ACE2 has a diverse substrate specificity allowing its participation in multiple peptide pathways. It also regulates aspects of amino acid transport through its homology with a membrane protein, collectrin. It also serves as a viral receptor for the SARS virus, and subsequently SARS-CoV2, driving the current COVID-19 pandemic. ACE2 therefore provides a therapeutic target for the treatment of COVID and understanding the biological events following viral binding can provide insight into the multiple pathologies caused by the virus, particularly inflammatory and vascular. In part this may relate to the ability of ACE2, like ACE, to be shed from the cell membrane. The shed form of ACE2 (sACE2) may be a factor in determining susceptibility to certain COVID pathologies. Hence, for just over 20 years, ACE2 has provided numerous surprises in the field of vasoactive peptides with, no doubt, more to come but it is its central role in COVID pathology that is producing the current intense interest in its biology.


Subject(s)
COVID-19 , Pandemics , Angiotensin-Converting Enzyme 2 , Humans , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , RNA, Viral , Renin-Angiotensin System/physiology , SARS-CoV-2
13.
J Neurochem ; 2022 Feb 08.
Article in English | MEDLINE | ID: covidwho-1673193

ABSTRACT

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1ß, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPß (p = 0.03) as well as amyloid ß (Aß) 40 (p = 5.2 × 10-8 ), Aß42 (p = 3.5 × 10-7 ), and Aß42/Aß40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPß. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPß. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPß. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

14.
Gastro Hep Adv ; 1(3): 393-402, 2022.
Article in English | MEDLINE | ID: covidwho-1670508

ABSTRACT

Background and Aims: Apolipoprotein A1 (A1) and haptoglobin (HP) serum levels are associated with the spread and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We have constructed and validated a multivariable risk calculator (A1HPV6) integrating A1, HP, alpha2-macroglobulin, and gamma glutamyl transferase to improve the performances of virological biomarkers. Methods: In a prospective observational study of hospitalized patients with nonsevere SARS-CoV-2 infection, A1HPV6 was constructed in 127 patients and validated in 116. The specificity was assessed in 7482 controls representing the general population. The primary diagnostic endpoint was the area under the receiver operating characteristic curve in patients with positive SARS-CoV-2 PCR. The primary prognostic endpoint was the age-and sex-adjusted risk of A1HPV6 to predict patients with WHO-stage > 4 (W > 4) severity. We assessed the kinetics of the A1HPV6 components in a nonhuman primate model (NHP), from baseline to 7 days (D7) after SARS-CoV-2 infection. Results: The area under the receiver operating characteristic curve for A1HPV6 was 0.99 (95% CI 0.97-0.99) in the validation subset, which was not significantly different from that in the construction subset, 0.99 (0.99-0.99; P = .80), like for sensitivity 92% (85-96) vs 94% (88-97; P = .29). A1HPV6 was associated with W > 4, with a significant odds ratio of 1.3 (1.1-1.5; 0.002). In NHP, A1 levels decreased (P < .01) at D2 and normalized at D4; HP levels increased at D2 and peaked at D4. In patients, A1 concentration was very low at D2 vs controls (P < .01) and increased at D14 (P < .01) but was still lower than controls; HP increased at D2 and remained elevated at D14. Conclusion: These results validate the diagnostic and prognostic performances of A1HPV6. Similar kinetics of apolipoprotein A1, HP, and alpha-2-macroglobulin were observed in the NHP model. ClinicalTrials.gov number, NCT01927133.

15.
Int J Pept Res Ther ; 28(2): 59, 2022.
Article in English | MEDLINE | ID: covidwho-1650638

ABSTRACT

The COVID-19 (coronavirus disease 2019) pandemic that took over the world in December 2019 has had everlasting devastating impacts on the lives of people globally. It manifests a huge symptom spectrum ranging from asymptomatic to critically ill patients with an unpredictable outcome. Timely diagnosis and assessment of disease severity is imperative for effective treatment. Possibilities exist that by the time symptoms appear the viral load might increase beyond control. However, it is advisable to get adequately diagnosed as soon as the first symptom appears. There is an immediate requirement of reliable biomarkers of COVID-19 manifesting an early onset for effective clinical management, stratification of high risk patients and ensuring ideal resource allocation. In this review, we attempt to explore and describe important polypeptide inflammatory biomarkers, namely C-reactive protein, Procalcitonin, Ferritin, Lactate Dehydrogenase, Serum amyloid A, Interleukin-6, Tumor necrosis factor-alpha and LIGHT used in the detection and management of COVID-19. Viral pathogenesis and the role of these inflammatory biomarkers is highlighted, based on the evidences available till date. An integrative data monitoring along with their correlation with the natural disease progression is of utmost importance in the management of COVID-19. So further research and in-depth analysis of these biomarkers is warranted in the present scenario.

16.
Int J Mol Sci ; 23(3)2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1649889

ABSTRACT

Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta (Aß) plaques from improper amyloid-beta precursor protein (APP) cleavage. Following studies of inflammation caused by coronavirus-2019 (COVID-19) infection, this study investigated the impact of COVID-19 on APP expression. A meta-analysis was conducted utilizing QIAGEN Ingenuity Pathway Analysis (IPA) to examine the link between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the modulation of APP expression upon virus binding the Angiotensin-converting enzyme-2 (ACE2) receptor. A Core Analysis was run on the infection by severe acute respiratory syndrome (SARS) coronavirus node, which included molecules affected by SARS-CoV-2, revealing its upstream regulators. Intermediary molecules were found between the upstream regulators and ACE2 and between ACE2 and APP. Activation of the upstream regulators downregulated the expression of ACE2 with a Z-score of -1.719 (p-value = 0.086) and upregulated APP with a Z-score of 1.898 (p-value = 0.058), showing a less than 10% chance of the results occurring by chance and pointing to an inverse relationship between ACE2 and APP expression. The neuroinflammation signaling pathway was the fifth top canonical pathway involved in APP upregulation. The study results suggest that ACE2 could be downregulated by SARS-CoV-2, resulting in APP upregulation, and potentially exacerbating the onset and progression of AD.


Subject(s)
Amyloid beta-Protein Precursor/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , SARS-CoV-2/physiology , Amyloid beta-Protein Precursor/metabolism , Angiotensin-Converting Enzyme 2/genetics , COVID-19/metabolism , COVID-19/pathology , Gene Expression Regulation , Humans , Plaque, Amyloid/genetics , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction/genetics
17.
Acs Nano ; : 11, 2022.
Article in English | Web of Science | ID: covidwho-1623164

ABSTRACT

We demonstrate that a conserved coronavirus spike protein peptide forms amyloid structures, differing from the native helical conformation and not predicted by amyloid aggregation algorithms. We investigate the conformation and aggregation of peptide RSAIEDLLFDKV, which is a sequence common to many animal and human coronavirus spike proteins. This sequence is part of a native alpha-helical S2 glycoprotein domain, close to and partly spanning the fusion sequence. This peptide aggregates into beta-sheet amyloid nanotape structures close to the calculated pI = 4.2, but forms disordered monomers at high and low pH. The beta-sheet conformation revealed by FTIR and circular dichroism (CD) spectroscopy leads to peptide nanotape structures, imaged using transmission electron microscopy (TEM) and probed by small-angle X-ray scattering (SAXS). The nanotapes comprise arginine-coated bilayers. A Congo red dye UV-vis assay is used to probe the aggregation of the peptide into amyloid structures, which enabled the determination of a critical aggregation concentration (CAC). This peptide also forms hydrogels under precisely defined conditions of pH and concentration, the rheological properties of which were probed. The observation of amyloid formation by a coronavirus spike has relevance to the stability of the spike protein conformation (or its destabilization via pH change), and the peptide may have potential utility as a functional material. Hydrogels formed by coronavirus peptides may also be of future interest in the development of slow-release systems, among other applications.

18.
Biomed Rep ; 16(2): 13, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1603250

ABSTRACT

In view of the rapid spread of COVID-19 and the high mortality rate of severe cases, reliable risk stratifying indicators of prognosis are necessary to decrease morbidity and mortality. The aim of the present study was to evaluate the value of serum amyloid A (SAA) and carcinoembryonic antigen (CEA) as prognostic biomarkers in comparison to other predictors, including C-reactive protein (CRP) and ferritin levels. This study included 124 patients diagnosed with COVID-19, and they were assigned to one of two groups: Mild and severe, based on the severity of the infection. Radiological and laboratory investigations were performed, including evaluation of CRP, ferritin, D-Dimer, SAA and CEA levels. Significantly higher levels of CRP, ferritin, D-Dimer, SAA and CEA were observed in severe cases. SAA was significantly correlated with CRP (r=0.422, P<0.001), ferritin (r=0.574, P<0.001), CEA (r=0.514, P<0.001) and computed tomography severity score (CT-SS; r=0.691, P<0.001). CEA was correlated with CRP (r=0.441, P<0.001), ferritin (r=0.349, P<0.001) and CT-SS (r=0.374, P<0.001). Receiver operator characteristic (ROC) curves for performance of SAA, CEA, ferritin, CRP and SAA showed the highest AUC value of 0.928, with a specificity of 93.1%, and a sensitivity of 98.5% at a cut-off of 16 mg/l. The multi-ROC curve for SAA and ferritin showed 100% specificity, 100% sensitivity and 100% efficiency, with an AUC of 1.000. Thus, combining SAA and ferritin may have guiding significance for predicting COVID-19 severity. SAA alone showed the highest prognostic significance. Both SAA and CEA were positively correlated with the CT-SS. Early monitoring of these laboratory markers may thus provide significant input for halting disease progression and reducing mortality rates.

19.
Blood ; 138:868, 2021.
Article in English | EMBASE | ID: covidwho-1582312

ABSTRACT

Background: Within seconds of antigen-encounter, B-cell receptor (BCR) signaling induces dramatic changes of cell membrane lipid composition, including >40-fold increases of local PIP3-concentrations within lipid rafts. While several structural elements, including pleckstrin homology (PH) domains have been identified as PIP3-binding proteins, the underlying mechanisms that amplify BCR-signaling to assemble large signaling complexes within lipid rafts within 15 to 30 seconds, remained elusive. To understand the mechanistic and biophysical requirements for PIP3 accumulation during normal B-cell activation and acute oncogenic transformation, we identified PIP3-interacting proteins by cell-surface proteomic analyses. Results: In addition to proteins known to bind PIP3 with their PH-domains, we identified the short 133 aa protein IFITM3 (interferon-inducible transmembrane protein 3) as a top-ranking PIP3 scaffold. This was unexpected because IFITM3 was previously identified as endosomal protein that blocks viral infection by stiffening endosomal membranes to firmly contain viral cargo. Previous studies revealed that polymorphisms that lead to the expression of truncated IFITM3 are associated with increased susceptibility to viral infections, including SARS-CoV2. Among known cell membrane lipids, PIP3 has the highest negative charge. Instead of a PH-domain, IFITM3 laterally sequestered PIP3 through electrostatic interactions with two basic lysine residues (K83 and K104) located at the membrane-solution interface. Together with three other basic lysine and arginine residues K83 and K104 form a conserved intracellular loop (CIL), which enable IFITM3 to efficiently capture two PIP3 molecules. Bivalent PIP3-binding of the IFITM3-CIL enables a crosslinking mechanism that results in dramatic amplification of B-cell activation signals and clustering of large signaling complexes within lipid rafts. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, B-cell activation and oncogenic kinases induced phosphorylation at IFITM3-Y20, resulting in translocation of IFITM3 from endosomes and massive accumulation at the cell surface. Ifitm3ˉ /ˉ naïve B-cells developed at normal numbers, however, activation by antigen encounter was compromised. In Ifitm3ˉ /ˉ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors and impaired PI3K-signaling. Ifitm3ˉ /ˉ B-cells were unable to undergo affinity maturation and di not contribute to germinal center formation upon immunization. Analyses of gene expression and clinical outcome data from patients in six clinical cohorts for pediatric and adult B-ALL, mantle cell lymphoma, CLL and DLBCL, we consistently identified IFITM3 as a top-ranking predictor of poor clinical outcome. Inducible activation of BCR-ABL1 and NRAS G12D rapidly induced development of B-ALL but failed to transform and initiate B-ALL from Ifitm3ˉ /ˉ B-cell precursors. Conversely, the phospho-mimetic IFITM3-Y20E mutation, mimicking phosphorylation of the IFITM3 N-terminus at Y20 induced constitutive membrane localization of IFITM3, spontaneous aggregation of large oncogenic signaling complexes and readily initiated transformation in a genetic model of pre-malignant B-cells. Conclusions: We conclude that phosphorylation of IFITM3 upon B-cell activation induces a dynamic switch from antiviral effector functions in endosomes to oncogenic signal-amplification at the cell-surface. IFITM3-dependent amplification of PI3K-signaling is critical to enable rapid expansion of activated B-cells. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signaling complexes and amplify PI3K-signaling for malignant transformation and initiation of B-lymphoid leukemia and lymphoma. [Formula presented] Disclosures: Weinstock: SecuraBio: Consultancy;ASELL: Consultancy;Bantam: Consultancy;Abcuro: Research Funding;Verastem: Research Funding;Daiichi Sankyo: Consultancy, Research Funding;AstraZeneca: Consultanc ;Travera: Other: Founder/Equity;Ajax: Other: Founder/Equity.

20.
Blood ; 138:1673, 2021.
Article in English | EMBASE | ID: covidwho-1582219

ABSTRACT

Background: Light-chain amyloidosis (AL-A) is a rare, severe, progressive, systemic disorder with high mortality caused by immunoglobulin (Ig) light chains that misfold and aggregate into amyloid fibrils that deposit in multiple organs, leading to progressive organ dysfunction/damage and death. Prognosis is poor for patients with cardiac involvement (characterized by high levels of cardiac troponin T and N-terminal brain natriuretic peptide). Median survival is 24 and 4 months for Mayo Stage IIIa and IIIb AL-A, respectively, based on the 2013 European Modification of the 2004 Mayo Staging system. For most patients, standard of care (SOC) is anti-plasma cell dyscrasia (PCD) therapy to suppress plasma cell proliferation, halt generation of amyloidogenic free light chains, and stop deposition of new amyloid fibrils and further organ decline. However, a critical need exists for therapies that accelerate the removal of deposited fibrils. CAEL-101 is a monoclonal antibody that binds to misfolded Ig light chains in amyloid fibrils. In Phase 1 and 2, CAEL-101 (with and without concurrent PCD SOC) was well tolerated up to 1000 mg/m 2. Preliminary Phase 2 data (NCT04304144) suggest improvements in cardiac and renal biomarkers in some patients. Objective: To evaluate the efficacy and safety of CAEL-101 versus placebo when administered concurrently with SOC anti-PCD therapy in treatment-naïve patients with cardiac AL-A, Mayo Stages IIIb (NCT04504825;Study 1) or IIIa (NCT04512235;Study 2). Methods: These international, multicenter, double-blind, randomized, phase 3 trials, initiated in 2020, are enrolling patients at over 70 sites in 14 countries. Newly diagnosed adults with AL-A stage IIIb or IIIa based on the 2013 European Modification of 2004 Mayo Staging (Wechalekar AD et al. Blood 2013;121:3420. Dispenzieri A, et al. J Clin Oncol. 2004;22:3751), measurable hematologic disease, and histopathological diagnosis of amyloidosis with cardiac involvement are eligible. Patients cannot have any other form of amyloidosis, symptomatic orthostatic hypotension, or supine systolic blood pressure <90 mmHg. Patients in Mayo Stages IIIb (N=111) and IIIa (N=267) are randomized 2:1 to receive once-weekly intravenous infusions of CAEL-101 (1000 mg/m 2) or placebo for 4 weeks, followed by maintenance dosing every 2 weeks. In these event-driven studies, treatment will continue to a minimum of 54 deaths for Study 1 and 77 deaths for Study 2 (a minimum treatment duration of 12 months is expected). Patients will receive concurrent anti-PCD therapy per the institutional protocol for SOC and will be followed to death from any cause or until end of study (Figure). The primary endpoint is overall survival (defined as the time from first dose of study drug to date of death, with censoring at last known living date), and will be analyzed via time-to-event log-rank statistics. Functional, quality of life, and echocardiography measures are targeted secondary endpoints. Results: Patient baseline characteristics and demographics are presented (Table). As of July 17, 2021, 9/13 (69.2%) patients in Study 1 and 23/39 (59%) patients in Study 2 have received at least 4 doses of CAEL-101 concurrently with anti-PCD therapy. Discussion: These ongoing trials will evaluate the efficacy and safety of CAEL-101 as first-in-class treatment to reduce amyloid burden in patients with cardiac AL-A. Notably, Study 1 (Mayo Stage IIIb) is the first randomized, placebo-controlled efficacy clinical trial to formally assess the effects of a pharmacological in this severely ill population. Because the median expected survival for Mayo Stage IIIb patients is far shorter than for Mayo Stage IIIa patients, the resulting sample size required for the Mayo Stage IIIB study is less (111 patients) than for the Mayo Stage IIIA study (267 patients). Importantly, these studies include patients identified as Stage III and IV based on the 2012 Mayo staging system (Kumar S. et al. J Clin Oncol. 2012;30:989). These trials are ongoing in a challenging environment. The approval of daratumumab i 2021 changed the landscape and modified the SOC, requiring appropriate protocol amendments. While the COVID pandemic affected all people, it had a greater impact on patients with AL amyloidosis, a rare disease that can only be treated effectively by a coordinated team of experts at centers of excellence. [Formula presented] Disclosures: Wechalekar: Alexion, AstraZeneca Rare Disease: Consultancy;Caelum Biosciences: Other: Clinical Trial Funding;Janssen: Consultancy;Celgene: Honoraria;Takeda: Honoraria;Amgen: Research Funding. Silowsky: Caelum Biosciences: Current Employment. Daniel: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment. Quarta: Alexion, AstraZeneca Rare Disease: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Tulchinskiy: Caelum Biosciences: Consultancy. Bhattacharyya: Alexion, AstraZeneca Rare Disease: Current Employment. Liedtke: Karyopharm: Membership on an entity's Board of Directors or advisory committees;Kite: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Kura Oncology: Membership on an entity's Board of Directors or advisory committees;Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;Alnylam: Membership on an entity's Board of Directors or advisory committees;Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding.

SELECTION OF CITATIONS
SEARCH DETAIL