RESUMO
Direct endothelial injury by viruses and dysregulation of clotting mechanisms due to cytokine storm are the major precipitating factors of mortality in COVID-19; both are attributed to a fundamental dysregulation of the immune system. While immune dysregulation can be attributed to several factors, the risk of associated thrombogenic disruption varies across individuals. This variation depends on several factors, such as comorbidities, including diabetes, hypertension, and cardiovascular diseases. When considering ethnic variations, the vulnerability of Caucasians, African Americans and Hispanics needs to be addressed before arriving at strategies to handle thromboembolic complications, which have been identified in recent reports as the leading causes of mortality in COVID-19. Although evaluation of D-dimer and prothrombin during admission is considered to predict prognosis and mortality, there are no preventive or prophylactic strategies before hospital admission. Herein, we present our perspectives on the effect of regular supplementation with the biological response modifier beta glucan based on its relevance to immune modulation. This effect is of paramount importance in decreasing the development of severe COVID-19 and reducing mortality against the background of coagulopathy, especially in vulnerable populations.
RESUMO
The Republic of Panama has the second most unequally distributed wealth in Central America, has recently entered the list of countries affected by the COVID-19 pandemic, and has one of the largest testing rate per inhabitant in the region and consequently the highest incidence rate of COVID-19, making it an ideal location to discuss potential scenarios for assessing epidemic preparedness, and to outline research opportunities in the Region of the Americas. We address two timely important questions: What are the unique risks of COVID-19 in Panama that could help other countries in the Region be better prepared? And what kind of scientific knowledge can Panama contribute to the regional and global study of COVID-19? This paper provides suggestions about how the research community could support local health authorities plan for different scenarios and decrease public anxiety. It also presents basic scientific opportunities about emerging pandemic pathogens towards promoting global health from the perspective of a middle income country.
La República de Panamá es el segundo país de Centroamérica con la distribución más desigual de la riqueza, ha resultado afectado recientemente por la pandemia de COVID-19 y tiene una de las mayores tasas de pruebas diagnósticas por habitante de la región y, por consiguiente, la mayor tasa de incidencia de COVID-19. Estos aspectos la convierten en un lugar ideal para examinar posibles escenarios de evaluación de la preparación para la epidemia y para plantear oportunidades de investigación en la Región de las Américas. Se abordan dos preguntas importantes y oportunas: ¿Cuáles son los riesgos singulares de la COVID-19 en Panamá que podrían ayudar a otros países de la Región a estar mejor preparados? y ¿Qué tipo de conocimiento científico puede aportar Panamá al estudio regional y mundial de la COVID-19? En este artículo se presentan sugerencias sobre la forma en que la comunidad de investigadores podría apoyar a las autoridades sanitarias locales a planificar medidas ante diferentes escenarios y disminuir la ansiedad de la población. También se presentan oportunidades científicas básicas sobre patógenos pandémicos emergentes para promover la salud mundial desde la perspectiva de un país de ingresos medios.
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The mesenchymal stem cell (MSC) is being broadly studied in clinical trials. Contrary to the early paradigm of cell replacement and differentiation as a therapeutic mechanism of action, evidence is mounting that the secretions of the cells are responsible for their therapeutic effects. These secretions include molecules and extracellular vesicles that have both local and distant effects. This review summarizes the up- and down-regulation of MSC anti-inflammatory, immune modulating, anti-tumor, and regenerative secretions resulting from different stimuli including: a) hypoxia, which increases the production of growth factors and anti-inflammatory molecules; b) pro-inflammatory stimuli that induce the secretion of immune modulating and anti-inflammatory factors; and c) 3 dimensional growth which up regulates the production of anti-cancer factors and anti-inflammatory molecules compared to monolayer culture. Finally we review in detail the most important factors present in conditioned medium of MSC that can be considered protagonists of MSC physiological effects including HGF, TGF-b, VEGF, TSG-6, PGE2 and galectins 1, and 9. We conclude that there is potential for the development of acellular therapeutic interventions for autoimmune, inflammatory, and malignant diseases and tissue regeneration from cellular secretions derived from MSCs cultured under the appropriate conditions.
Assuntos
Técnicas de Cultura de Células/métodos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Exossomos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismoRESUMO
OBJECTIVE: In this pilot clinical study, we report the beneficial effects of beta glucans derived from two strains AFO-202 and N-163 of a black yeast Aureobasidium pullulans on the biomarkers for cytokine storm and coagulopathy in COVID-19 patients. METHODS: A total of 24 RT-PCR positive COVID-19 patients were recruited and randomly divided into three groups (Gr): Gr. 1 control (n = 8) - Standard treatment; Gr. 2: Standard treatment + AFO-202 beta glucan (n = 8); and Gr. 3, Standard treatment + combination of AFO-202 and N-163 beta glucans (n = 8) for 30 days. RESULTS: There was no mortality or requirement of ventilation of the subjects in any of the groups. There was a decrease in D-Dimer values (751 ng/ml to 143.89 ng/ml) and IL-6 values (7.395-3.16 pg/ml) in Gr. 1 in 15 days but the levels increased to abnormal levels on day 30 (D-Dimer: 202.5 ng/ml; IL-6 55.37 pg/ml); which steadily decreased up to day 30 in groups 2 (D-dimer: 560.99 ng/dl to 79.615; IL-6: 26.18-3.41 pg/ml) and 3 (D-dimer: 1614 ng/dl to 164.25 ng/dl; IL-6: 6.25-0.5 pg/ml). The same trend was observed with ESR. LCR and LeCR increased while NLR decreased significantly in Gr. 3. CD4 + and CD8 + T cell count showed relatively higher increase in Gr.3. There was no difference in CRP within the groups. CONCLUSION: As these beta glucans are well known food supplements with a track record for safety, larger multi-centric clinical studies are recommended to validate their use as an adjunct in the management of COVID-19 and the ensuing long COVID-19 syndrome.
Assuntos
Aureobasidium , Tratamento Farmacológico da COVID-19 , COVID-19 , Síndrome da Liberação de Citocina , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Interleucina-6/análise , beta-Glucanas/administração & dosagem , Biomarcadores/sangue , COVID-19/sangue , COVID-19/diagnóstico , Terapias Complementares/métodos , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Suplementos Nutricionais , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Projetos Piloto , SARS-CoV-2 , Resultado do TratamentoRESUMO
The incidence of cancer, which is the second leading cause of mortality globally, continues to increase, although continued efforts are being made to identify effective treatments with fewer sideeffects. Previous studies have reported that chronic microinflammation, which occurs in diseases, including diabetes, along with weakened immune systems, may ultimately lead to cancer development. Chemotherapy, radiotherapy and surgery are the mainstream approaches to treatment; however, they all lead to immune system weakness, which in turn increases the metastatic spread. The aim of the present review was to provide evidence of a biological response modifier ßglucan [ßglucan vaccine adjuvant approach to treating cancer via immune enhancement (BVACCIEN)] and its beneficial effects, including vaccineadjuvant potential, balancing metabolic parameters (including blood glucose and lipid levels), increasing peripheral blood cell cytotoxicity against cancer and alleviating chemotherapy side effects in animal models. This suggests its value as a potential strategy to provide longterm prophylaxis in immunocompromised individuals or genetically prone to cancer.
Assuntos
Adjuvantes de Vacinas/administração & dosagem , Hospedeiro Imunocomprometido/imunologia , Neoplasias/imunologia , Neoplasias/prevenção & controle , beta-Glucanas/imunologia , Animais , HumanosRESUMO
Conventional vaccines to combat COVID-19 through different approaches are at various stages of development. The complexity of COVID-19 such as the potential mutations of the virus leading to antigenic drift and the uncertainty on the duration of the immunity induced by the vaccine have hampered the efforts to control the COVID-19 pandemic. Thus, we suggest an alternative interim treatment strategy based on biological response modifier glucans such as the Aureobasidium pullulans AFO-202-derived ß-glucan, which has been reported to induce trained immunity, akin to that induced by the Bacille Calmette-Guérin vaccine, by epigenetic modifications at the central level in the bone marrow. These ß-glucans act as pathogen-associated molecular patterns, activating mucosal immunity by binding with specific pathogen recognition receptors such as dectin-1 and inducing both the adaptive and innate immunity by reaching distant lymphoid organs. ß-Glucans have also been used as immune adjuvants for vaccines such as the influenza vaccine. Therefore, until a conventional vaccine is widely available, an orally consumable vaccine adjuvant that acts like biosimilars, termed as the wide-spectrum immune-balancing food-supplement-based enteric (ß-WIFE) vaccine adjuvant approach, with well-reported safety is worth in-depth investigation and can be considered for a clinical trial.
Assuntos
Medicamentos Biossimilares , COVID-19 , beta-Glucanas , Adjuvantes Imunológicos , Vacina BCG , Humanos , Imunidade Inata , Pandemias , SARS-CoV-2 , CônjugesRESUMO
Background: The COVID-19 pandemic has been causing varying severities of illness. Some are asymptomatic and some develop severe disease leading to mortality across ages. This contrast triggered us explore the causes, with the background that a vaccine for effective immunization or a drug to tackle COVID-19 is not too close to reality. We have discussed strategies to combat COVID-19 through immune enhancement, using simple measures including nutritional supplements. Discussion: A literature search on mortality-related comorbid conditions was performed. For those conditions, we analyzed the pro-inflammatory cytokines, which could cause the draining of the immune reservoir. We also analyzed the immune markers necessary for the defense mechanism/immune surveillance against COVID-19, especially through simple means including immune enhancing nutritional supplement consumption, and we suggest strategies to combat COVID-19. Major comorbid conditions associated with increased mortality include cardiovascular disease (CVD), diabetes, being immunocompromised by cancer, and severe kidney disease with a senile immune system. Consumption of Aureobasidium pullulans strain (AFO-202) beta 1,3-1,6 glucan supported enhanced IL-8, sFAS macrophage activity, and NK cells' cytotoxicity, which are major defense mechanisms against viral infection. Conclusion: People with co-morbid conditions who are more prone to COVID-19-related deaths due to immune dysregulation are likely to benefit from consuming nutritional supplements that enhance the immune system. We recommend clinical studies to validate AFO-202 beta glucan in COVID-19 patients to prove its efficacy in overcoming a hyper-inflammation status, thus reducing the mortality, until a definite vaccine is made available.
Assuntos
Betacoronavirus , Doenças Cardiovasculares/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Diabetes Mellitus/epidemiologia , Suplementos Nutricionais , Neoplasias/epidemiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Insuficiência Renal Crônica/epidemiologia , Actinobacteria/química , Biomarcadores/sangue , COVID-19 , Doenças Cardiovasculares/imunologia , Comorbidade , Infecções por Coronavirus/dietoterapia , Infecções por Coronavirus/mortalidade , Citocinas/sangue , Diabetes Mellitus/imunologia , Humanos , Hospedeiro Imunocomprometido , Neoplasias/imunologia , Pandemias , Pneumonia Viral/dietoterapia , Pneumonia Viral/mortalidade , Insuficiência Renal Crônica/imunologia , SARS-CoV-2 , beta-Glucanas/farmacologia , beta-Glucanas/uso terapêuticoRESUMO
ABSTRACT The Republic of Panama has the second most unequally distributed wealth in Central America, has recently entered the list of countries affected by the COVID-19 pandemic, and has one of the largest testing rate per inhabitant in the region and consequently the highest incidence rate of COVID-19, making it an ideal location to discuss potential scenarios for assessing epidemic preparedness, and to outline research opportunities in the Region of the Americas. We address two timely important questions: What are the unique risks of COVID-19 in Panama that could help other countries in the Region be better prepared? And what kind of scientific knowledge can Panama contribute to the regional and global study of COVID-19? This paper provides suggestions about how the research community could support local health authorities plan for different scenarios and decrease public anxiety. It also presents basic scientific opportunities about emerging pandemic pathogens towards promoting global health from the perspective of a middle income country.(AU)
RESUMEN La República de Panamá es el segundo país de Centroamérica con la distribución más desigual de la riqueza, ha resultado afectado recientemente por la pandemia de COVID-19 y tiene una de las mayores tasas de pruebas diagnósticas por habitante de la región y, por consiguiente, la mayor tasa de incidencia de COVID-19. Estos aspectos la convierten en un lugar ideal para examinar posibles escenarios de evaluación de la preparación para la epidemia y para plantear oportunidades de investigación en la Región de las Américas. Se abordan dos preguntas importantes y oportunas: ¿Cuáles son los riesgos singulares de la COVID-19 en Panamá que podrían ayudar a otros países de la Región a estar mejor preparados? y ¿Qué tipo de conocimiento científico puede aportar Panamá al estudio regional y mundial de la COVID-19? En este artículo se presentan sugerencias sobre la forma en que la comunidad de investigadores podría apoyar a las autoridades sanitarias locales a planificar medidas ante diferentes escenarios y disminuir la ansiedad de la población. También se presentan oportunidades científicas básicas sobre patógenos pandémicos emergentes para promover la salud mundial desde la perspectiva de un país de ingresos medios.(AU)
Assuntos
Humanos , Fatores Socioeconômicos , Surtos de Doenças , Infecções por Coronavirus/epidemiologia , Pandemias/prevenção & controle , Panamá/epidemiologia , América Latina/epidemiologiaRESUMO
Emerging evidences on the nuclear localization of alpha-Synuclein in neurons and a close look in to its primary sequence/structural organization led us to examine its DNA binding ability. Subsequently, we first time demonstrated the interaction of DNA with alpha-Synuclein which was also confirmed by others. We recently showed that double-stranded oligos induce partial folding in alpha-Synuclein and promote its aggregation, where as single-strand circular DNA and supercoiled plasmid DNA induced a helix-rich conformation and protected the protein from fibrillation. In turn, alpha-Synuclein modulates DNA conformation from B- to an altered B-form, which may affect DNA transactions. Interestingly, amyloid-beta peptides and prion proteins implicated in Alzheimer's disease and Prion diseases respectively, were also shown to have DNA binding activity which suggests that DNA binding may be a common property of many amyloidogenic proteins associated with various neurodegenerative disorders. In this review, we debate the biological significance of DNA-alpha-Synuclein interactions; it's beneficial vs. toxic role in relevance to Parkinson's disease.
Assuntos
DNA/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Núcleo Celular/metabolismo , DNA/química , DNA/genética , Humanos , Modelos Biológicos , Conformação de Ácido Nucleico , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ligação Proteica , Dobramento de Proteína , alfa-Sinucleína/químicaRESUMO
Amyloid-beta (Abeta) accumulates in several types of retinal degeneration and in Alzheimer's disease (AD), but its source has been unclear. We detected the neuronal 695 amino acid form of amyloid-beta protein precursor (AbetaPP) in the normal retina and AbetaPP751 in the retinal pigment epithelium (RPE) and anterior eye tissues. Similar to the brain, alpha- and beta-secretases cleaved AbetaPP to soluble derivatives (sAbetaPP) alpha or beta and membrane-bound C-terminal fragments alpha or beta in the retina and RPE. Levels of sAbetaPP were particularly high in the vitreous and low in aqueous humor revealing a molecular barrier for AbetaPP. In contrast, Abeta40 and Abeta42 levels were only 50% lower in the aqueous than the vitreous humor, indicating relatively barrier-free movement of Abeta. These studies demonstrated a relatively high yield of AbetaPP and Abeta in the ocular fluids, which may serve as a trackable marker for AD. In addition, failure of free clearance from the eye may trigger retina degeneration in a manner similar to Abeta-related neurodegeneration in AD.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Olho/metabolismo , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Humor Aquoso/química , Humor Aquoso/metabolismo , Líquidos Corporais/metabolismo , Química Encefálica/fisiologia , Bovinos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Cicloeximida/farmacologia , Ensaio de Imunoadsorção Enzimática , Olho/anatomia & histologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Inibidores da Síntese de Proteínas/farmacologia , Retina/metabolismo , Retina/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Corpo Vítreo/metabolismoRESUMO
DNA stability and conformation are important in the life cycle of an organism. The DNA instability is postulated to be one of the risk factors for neuronal death in neurodegenerative disorders. Among all other risk factors, amyloid is one of the most important risk factor for neurodegeneration. Abeta(42) is implicated in Alzheimer's disease (AD). Studies from our lab and elsewhere have shown that Abeta(42) could cause DNA damage and alter DNA stability in vitro and there are no mechanistic studies to understand Abeta induced genomic instability under in vivo condition. The present study aims to characterize Abeta(42) induced DNA instability and also to map the changes in DNA conformation in vivo and its correlation to brain structural changes. The aged (4yr) New Zealand rabbits are intracisternally injected with Abeta(42) and are sacrificed after 25 days, when the rabbits developed AD like behavior. Genomic DNA is isolated from frontal cortex (FC), hippocampus (H) and midbrain (M) regions of Abeta(42) injected and control rabbit brain. The DNA stability parameters are analyzed. And the results showed that DNA is damaged in FC and H; where as in M, DNA is in condensed state. The DNA conformation study evidenced the presence of C-, pi- and psi-type DNA in conformations in FC, H and M of Abeta injected rabbit brain regions respectively. But in control rabbit brain, DNA is in B-conformation in all the brain regions studied. Magnetic resonance imaging (MRI) studies showed no significant changes in brain structure between control and Abeta(42) injected aged rabbit brain regions. The mechanism of Abeta(42) induced neurodegeneration through genomic instability is discussed in detail.
Assuntos
Envelhecimento/fisiologia , Peptídeos beta-Amiloides/toxicidade , Química Encefálica/efeitos dos fármacos , Química Encefálica/genética , Fragmentos de Peptídeos/toxicidade , Animais , Dicroísmo Circular , DNA/biossíntese , DNA/genética , DNA/isolamento & purificação , Dano ao DNA/efeitos dos fármacos , Desoxirribonuclease I/metabolismo , Eletroforese em Gel de Ágar , Etídio/metabolismo , Hipocampo/patologia , Imageamento por Ressonância Magnética , Mesencéfalo/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Conformação de Ácido Nucleico/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Coelhos , TemperaturaRESUMO
A close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer's disease (AD) has been clearly established in a number of studies, although the underlying biochemical mechanisms remain obscure. This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease. However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD so that the term "metal targeted strategies" seems now more appropriate. Indeed, brain metal redistribution rather than brain metal scavenging and removal is the major goal of this type of intervention. The most recent developments in metal targeted strategies for AD will be discussed using, as useful examples, clioquinol, curcumin, and epigallocatechin, and the future perspectives will also be outlined.