The influence of renin angiotensin aldosterone system (RAAS), endothelial nitric oxide synthase (eNOS) and erythropoietin (EPO) on COVID-19 complications.

Certain aspects of the renin-angiotensin-aldosterone system (RAAS) have eluded deserved attention such as the role of erythropoietin (EPO) and nitric oxide (NO) both of which appear to significantly modulate COVID-19 disease course. Furthermore, renin-angiotensin-aldosterone system (RAAS) and endothelial NO synthase (eNOS) genetic polymorphisms additionally impact on EPO and NO homeostasis and have extensive implications on pharmacological disease management.

Too hard to die: Exercise training mediates specific and immediate SARS-CoV-2 protection.

Several mechanisms may explain how exercise training mechanistically confers protection against coronavirus disease 2019 (COVID-19). Here we propose two new perspectives through which cardiorespiratory fitness may protect against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Physical exercise-activated adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling induces endothelial nitric oxide (NO) synthase (eNOS), increases NO bio-availability, and inhibits palmitoylation, leading to specific and immediate SARS-CoV-2 protection. AMPK signaling also induces angiotensin 1-7 release and enhances eNOS activation thus further mediating cardio- and reno-protection. Irisin, a myokine released from skeletal muscles during aerobic exercise, also participates in the AMPK/Akt-eNOS/NO pathway, protects mitochondrial functions in endothelial cells, and antagonizes renin angiotensin system proinflammatory action leading to reductions in genes associated with severe COVID-19 outcomes. Collectively, all the above findings point to the fact that increased AMPK and irisin activity through exercise training greatly benefits molecular processes that mediate specific, immediate, and delayed SARS-CoV-2 protection. Maintaining regular physical activity levels is a safe and affordable lifestyle strategy against the current and future pandemics and may also mitigate against obesity and cardiometabolic disease syndemics. Move more because a moving target is harder to kill.

Age and genotype dependent erythropoietin protection in COVID-19.

Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a "bait" for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

Novel Use of Intraarticular Granulocyte Colony Stimulating Factor (hG-CSF) Combined with Activated Autologous Peripheral Blood Stem Cells Mobilized with Systemic hG-CSF: Safe and Efficient in Early Osteoarthritis.

Osteoarthritis (OA) tends to occur in older individuals frequently burdened with comorbidities and diverse pharmacological interactions. As articular cartilage has low regenerative power, potent local tissue engineering approaches are needed to support chondrogenic differentiation. Acellular preparation methods as well as approaches to coax endogenous reparative cells into the joint space appear to have limited success. Supported by our in-vitro and clinical studies, we propose that our novel intra-articular administration of human granulocyte colony stimulating factor (IA-hG-CSF) combined with autologous activated peripheral blood stem cells (AAPBSC) is safe and offers treatment advantages not seen with other cellular interventions in early osteoarthritis.

A Southeast Asian Perspective on the COVID-19 Pandemic: Hemoglobin E (HbE)-Trait Confers Resistance Against COVID-19.

As of November 25, 2020, over 60 million people have been infected worldwide by COVID-19, causing almost 1.43 million deaths. Puzzling low incidence numbers and milder, non-fatal disease have been observed in Thailand and its Southeast (SE) Asian neighbors. Elusive genetic mechanisms might be operative, as a multitude of genetic factors are widely shared between the SE Asian populations, such as the more than 60 different thalassemia syndromes (principally dominated by the HbE trait). In this study, we have plotted COVID-19 infection and death rates in SE Asian (SEA) countries against heterozygote HbE and thalassemia carrier prevalence. COVID-19 infection and death incidence numbers appear inversely correlated with the prevalence of HbE and thalassemia heterozygote populations. We posit that the evolutionary protective effect of the HbE and other thalassemic variants against malaria and the dengue virus may extend its advantage to resistance to COVID-19 infection, as HbE heterozygote population prevalence appears to be positively correlated with immunity to COVID-19. Host immune system modulations induce antiviral interferon responses and alter structural protein integrity, thereby inhibiting cellular access and viral replication. These changes are possibly engendered by HbE carrier miRNAs. Proving this hypothesis is important, as it may shed light on the mechanism of viral resistance and lead to novel antiviral treatments. This development can thus guide decision-making and action to prevent COVID-19 infection.

The First Asian, Single-Center Experience of Blastocyst Preimplantation Genetic Diagnosis with HLA Matching in Thailand for the Prevention of Thalassemia and Subsequent Curative Hematopoietic Stem Cell Transplantation of Twelve Affected Siblings.

RESULTS: In 221 cycles from 138 patients (104 cycles requiring HLA matching), 90.5% had embryo(s) biopsied for genetic testing. There were 119 embryo transfers for thalassemia (76) and thalassemia-HLA cases (43), respectively, resulting in overall clinical pregnancy rates of 54.6%, implantation rates of 45.7%, and live birth rates of 44.1%. Our dataset included fifteen PGD-HLA live births with successful HSCT in twelve affected siblings, 67% using umbilical cord blood stem cells (UCBSC) as the only SC source. CONCLUSIONS: We report favorable thalassemia PGD and PGD-HLA laboratory and clinical outcomes from a single center. The ultimate success in PGD-HLA is of course the cure of a thalassemia-affected sibling by HSCT. Our PGD-HLA HSCT series is the first and largest performed entirely in Asia with twelve successful and two pending cures and predominant UCBSC use.