Spirulina for Protection Against COVID-19 via Regulating ACE2, FNDC5, and NLRP3: A Triple-Blind Randomized Placebo-Controlled Trial in Obese Adults

Background: Spirulina may protect individuals against viral infections and promote health in obese subjects. This study is designed to investigate the impacts of spirulina on obesity to find a hope to protect this population against COVID-19. Material(s) and Method(s): In a double-blinded randomized placebo-controlled trial, 24 obese subjects (Mean age: 44.83+/-3.04 years;mean weight: 111.95+/-22.55kg;body mass index (BMI): 40.31+/-6.03kg/m2) were randomly allocated to spirulina (n=12) or control (Co, n=12) groups. Spirulina was administered 2 gr/day for 8 weeks and the Co group received a placebo for a similar period. Before and after the administration of spirulina, the anthropometric measurements were calculated for each subject. Furthermore, ACE2, NLRP3, and FNDC5 gene expression were examined in adults with obesity. Result(s): Our findings demonstrated that spirulina could not effective in normalizing body weight (BW), BMI, and waist-hip ratio (WHR). Spirulina administration significantly upregulated the gene expression of FNDC5 and significantly reduced NLRP3 and ACE2 gene expression in obese subjects compared with the Co-group. Furthermore, by increasing FNDC5 the gene expression of NLRP3 and ACE2 was significantly reduced. Conclusion(s): While administration of spirulina for eight weeks could not affect the anthropometric measurements, it showed the greatest impact on the gene expression of NLRP3, ACE2, and FNDC5, emplacing its potential in the protection of obese cases against COVID-19.Copyright © 2023 Journal of Cellular & Molecular Anesthesia. All rights reserved.

COVID-19: Could Irisin Become the Handyman Myokine of the 21st Century?

The ongoing Coronavirus disease 2019 (COVID-19) outbreak in China has become the world's leading health headline and is causing major panic and public concerns. After emerging in the City of Wuhan, China, COVID-19 has spread to several countries becoming a worldwide pandemia. Among the studies on COVID-19, it has been demonstrated that novel coronavirus pneumonia is closely associated with inflammatory storms. Controlling the inflammatory response may be as important as targeting the virus. Irisin is a muscle-contraction-induced immunomodulatory myokine related to physical activity. Irisin drives the "browning" of white adipocytes, so enhancing metabolic uncoupling and hence caloric expenditure. Irisin has been clearly shown to be a handyman molecule by exerting beneficial effects on adipose tissues, pancreas, and bone through "cross-talk" between skeletal muscle-adipocyte, skeletal muscle-pancreas, and skeletal muscle-bone, respectively. Irisin has been proposed as a promising strategy for early diagnosis and treatment of various types of cancers, neurological diseases and inflammatory conditions. Irisin has been demonstrated to suppress the immune response, too. The importance of irisin is demonstrated by the increase in the number of scientific papers and patents in recent years. The identification of irisin receptor should greatly facilitate the understanding of irisin's function in exercise and human health. This review examines the structure and recent advances in activi-ties of irisin, suggesting it for further studies on the prevention and cure of COVID-19. Nowadays, studies on irisin plasma levels and physical activity may be useful tools to further investigate the prevention of COVID-19. Irisin may be suggested as a potential novel intervention for COVID-19 by mitigating inflammatory storms, suppressing the immune response and simultaneously alleviating neurological dis-orders such as depression and anxiety.Copyright © 2020 Bentham Science Publishers.

Irisin, Exercise, and COVID-19.

Muscle and adipose tissue produce irisin during exercise. Irisin is thermogenic adipomyokine, improves glucose and lipid metabolism, and ameliorates the effects of obesity-driven inflammation, metabolic syndrome, and diabetes. In addition, exercise-induced irisin activates anti-inflammatory pathways and may play an essential role in improving the outcomes of inflammatory conditions, such as coronavirus disease (COVID-19). COVID-19 infection can activate different intracellular receptors and modulate various pathways during the course of the disease. The cytokine release storm (CRS) produced is significant because it promotes the context for systemic inflammation, which increases the risk of mortality in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). In addition, viral infection and the resulting organ damage may stimulate the mitogen-activated protein kinase(MAPK) and toll-like receptor 4 (TLR4)/toll interleukin receptor (TIR)-domain-containing adaptor (MyD88) pathways while negatively modulating the AMP-activated protein kinase (AMPK) pathway, leading to increased inflammatory cytokine production. Exercise-induced irisin may counteract this inflammatory modulation by decreasing cytokine production. Consequently, increased irisin levels, as found in healthy patients, may favor a better prognosis in patients with SARS-CoV2. This review aims to explore the molecular mechanisms underlying the anti-inflammatory properties of irisin in mitigating CRS and preventing severe outcomes due to infection with SARS-CoV2.

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.

Effect of sleeve gastrectomy on the expression of meteorin-like (METRNL) and Irisin (FNDC5) in muscle and brown adipose tissue and its impact on uncoupling proteins in diet-induced obesity rats.

BACKGROUND: Bariatric surgery is well established as a treatment for obesity and associated complications. This procedure improves metabolic homeostasis through changes in energy expenditure. We hypothesized that sleeve gastrectomy (SG) improves metabolic homeostasis by modulating energy expenditure and enhancing thermogenesis through increasing the expression level of meteorin-like protein (METRNL) and fibronectin type III domain-containing protein 5 (FNDC5/Irisin) through uncoupling proteins 1/2/3 (UCP1, UCP2, and UCP3). OBJECTIVES: To study the effect of SG on the levels of proteins involved in thermogenesis process. SETTING: Laboratory rats at Kuwait University. METHODS: Male Sprague-Dawley rats, aged 4 to 5 weeks, were divided into 2 groups, control (n = 11) and diet-induced obesity (DIO) (n = 22). The control group was fed regular rat chow ad libitum, whereas the DIO group was fed cafeteria diet "high-fat/carbohydrate diet" ad libitum. At 21 weeks, rats in the DIO group that weighed 20% more than the control group animals underwent surgery. These rats were randomly subdivided into Sham and SG operation groups. Gene expression was evaluated, and enzyme-linked immunosorbent assays were employed to assess the changes in gene and protein levels in tissue and circulation. RESULTS: The protein expression data revealed an increase in METRNL levels in the muscles and white adipose tissue of SG animals. METRNL level in circulation in SG animals was reduced compared with control and Sham rats. The level of Irisin increased in the muscle of SG animals compared with the control and Sham group animals; however, a decrease in Irisin level was observed in the white adipose tissue and brown adipose tissue of SG animals compared with controls. Gene expression analysis revealed decreased METRNL levels in muscle tissues in the SG group compared with the control group animals. Increased expression of FNDC5 (Irisin), UCP2, and UCP3 in the muscle tissue of SG animals was also observed. Furthermore, the levels of UCP1, UCP2, UCP3, and METRNL in the brown adipose tissue of SG animals were upregulated. No significant alteration in the gene expression of Irisin was observed in brown adipose tissue. CONCLUSIONS: Sleeve gastrectomy induces weight loss through complex mechanisms that may include browning of fat.

Fetuin-A Deficiency but Not Pentraxin 3, FGF-21, or Irisin, Predisposes to More Serious COVID-19 Course.

Analysis of liver biopsy specimens showed that SARS-CoV-2 might have led to liver damage. This study aimed to evaluate the role of selected hepatokines and myokines in the development and progression of COVID-19. Seventy patients with laboratory-confirmed COVID-19 and 20 healthy volunteers were enrolled in the study. Irisin, pentraxin 3, fetuin-A, and FGF-21 serum concentrations and biochemical parameters were assessed using an immunoenzymatic method with commercially available enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) kits. Serum fetuin-A concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers. The serum concentration of FGF-21 was significantly increased in obese COVID-19 patients compared to overweight ones. Moreover, the FGF-21 level was higher in COVID-19 patients diagnosed with metabolic syndrome than in patients without metabolic syndrome. PTX3 concentration was higher in COVID-19 patients with higher HOMA-IR values than those with lower HOMA-IR values. COVID-19 patients with HOMA-IR ≤ 3 and >3 had significantly lower fetuin-A levels than the control group. Irisin concentration was significantly decreased in the HOMA-IR ≤ 3 COVID-19 subgroup when comparing with the control group. Lower levels of fetuin-A observed in COVID-19 patients despite higher HOMA-IR, CRP, and ferritin levels, pneumonia, patients requiring ICU care suggests that fetuin-A deficiency predisposes to more severe COVID-19 course. Upregulated pentraxin 3 may be used as a potential predictor of COVID-19 severity.

FNDC5 expression closely correlates with muscle fiber types in porcine longissimus dorsi muscle and regulates myosin heavy chains (MyHCs) mRNA expression in C2C12 cells.

BACKGROUND: Irisin (a glycosylated protein) is cleaved from fibronectin type III domain-containing protein 5 (FNDC5), which is expressed mainly in animal muscle tissues and has multiple metabolic regulatory activities. However, their roles in controlling myofiber types in skeletal muscle remain unclear. METHODOLOGY: Two different commercial hybridized pigs, LJH (a crossed pig containing Chinese native pig genotypes) and DLY (Duroc × Landrace × Yorkshire) were selected to analyze FNDC5 mRNA expression and the mRNA composition of four adult myosin heavy chain (MyHC) isoforms (IIIaIIxIIb) in the longissimus dorsi (LD) muscle. C2C12 myoblasts were cultured to investigate the effects of FNDC5 on the four MyHCs mRNA expressive levels, using small interfering RNA for depletion and a eukaryotic expression vector carrying FNDC5 for overexpression. ZLN005 (a small molecule activator of FNDC5's upstream control gene PGC1α) or recombinant human irisin protein were also used. RESULTS: In LD muscle, LJH pigs had the higher FNDC5 mRNA level, and MyHC I or IIa proportion than DLY pigs (P <  0.05). For C2C12 cells in vitro, small interfering RNA (si-592) silencing of FNDC5 expression markedly reduced MyHC IIa mRNA levels (P <  0.05), while FNDC5 overexpression significantly increased MyHC IIa mRNA levels (P <  0.05). Exogenous irisin increased the mRNA levels of PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), FNDC5, MyHCI, MyHCIIa, NRF1 (nuclear respiratory factor 1), VEGF (vascular endothelial growth factor), and TFAM (mitochondrial transcription factor A,) (P <  0.05), and the enzyme activities of SDH (succinate dehydrogenase), CK (creatine kinase), and MDH (malate dehydrogenase) in C2C12 myotubes (P <  0.05). These results showed that FNDC5 mRNA expression had a significant association with the characteristics of myofiber types in porcine muscle, and participated in regulating MyHCs mRNA expression of C2C12 myogenic differentiation cells in vitro. FNDC5 could be an important factor to control muscle fiber types, which provides a new direction to investigate pork quality via muscle fiber characteristics.

Irisin modulates genes associated with severe coronavirus disease (COVID-19) outcome in human subcutaneous adipocytes cell culture.

Obesity patients are more susceptible to develop COVID-19 severe outcome due to the role of angiotensin-converting enzyme 2 (ACE2) in the viral infection. ACE2 is regulated in the human cells by different genes associated with increased (TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN and ADAM10) or decreased (TRIB3) virus replication. RNA-seq data revealed 14857 genes expressed in human subcutaneous adipocytes, including genes mentioned above. Irisin treatment increased by 3-fold the levels of TRIB3 transcript and decreased the levels of other genes. The decrease in FURIN and ADAM10 expression enriched diverse biological processes, including extracellular structure organization. Our results, in human subcutaneous adipocytes cell culture, indicate a positive effect of irisin on the expression of multiple genes related to viral infection by SARS-CoV-2; furthermore, translatable for other tissues and organs targeted by the novel coronavirus and present, thus, promising approaches for the treatment of COVID-19 infection as therapeutic strategy to decrease ACE2 regulatory genes.