Biologic Potential of Human Umbilical Cord Derived Mesenchymal Stem Cells Exposed to Maternal Smoking and Active Sars-Cov-2 Infection at Delivery

Purpose of Study: COVID-19 caused by the SARS-CoV-2 virus has led to a worldwide pandemic with cytokine storm as the leading cause of morbidity and mortality. It is known that pregnant women are at higher risk of viral infections given an alteration in immune response. Mothers who smoke cigarettes during pregnancy are even at higher risk. The infection varies from asymptomatic to severe disease in pregnant women depending upon the degree of inflammation and cytokine storm. At present, limited data are available to show the effects of simultaneous maternal smoking and SARS-CoV-2 infection on the biologic efficacy of human umbilical cord derived mesenchymal stem cells (MSCs). We hypothesized that SARS-CoV-2 infection in combination with smoking of the pregnant mother at the time of delivery will lead to an alteration in the growth and differential potential of cord-derived MSCs. Our aims included collection, isolation and growth of human umbilical cord derived MSCs followed by assessment of their differentiation potential. Methods Used: The study was approved by the Institutional IRB. The umbilical cords were collected from the following groups of pregnant mothers at the time of delivery: Normal (non-smoking and negative SARS-CoV-2 infection), Smoker (smoking with negative SARS-CoV-2), Covid Smoker (smoking with positive SARS-CoV-2 infection) and Covid non-smoker (non-smoking with positive SARS-CoV-2 infection). Plastic adherent cells were harvested from 3 pooled human umbilical cords from each group. These cells were cultured and underwent immunodepletion per International Society for cellular therapy guidelines to isolate MSCs. MSCs were cultured in MSC-culture media to assess the duplication time. Similarly, MSCs were cultured in differentiation media (adipocytes and osteocytes) to assess differentiation time. Summary of Results: Picture shows the duplication and differentiation time from each group. Smoker group showed the longest duplication and differentiation time. Covid non-smoker group showed the shortest duplication and differentiation time. Covid Smoker group showed similar duplication and differentiation time as normal controls. All these results were statistically significant (T-test). Conclusion(s): Maternal smoking and active SARS-CoV-2 infection at the time of delivery alters the growth and differentiation potential of cord-derived MSCs. Further in vitro and in vivo studies are currently in progress to determine how this change effects the biological potential of these cells.

Comparison of Perindopril vs. Losartan With Regard to Pro-Coagulation Factors in Adipocytes Exposed to Sars-Cov-2 Spike Protein

Background: Obesity is a strong risk factor for more severe Covid-19 infection as adipocytes play an important role in intermediating the spreading, replication, and release of SARS-COV-2. An increase in pro-coagulation factors (tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)) was observed in Covid-19 patients with moderate to severe symptoms and is reported to be associated with Angiotensin-converting enzyme 2 (ACE2) overexpression. Cardiovascular medications affecting ACE2, such as Perindopril and Losartan, are hypothesized to have an effect on Covid-19 infection-related coagulopathy. This study aims to identify and compare the effect of perindopril and losartan on TF and PAI-1 levels in adipocytes exposed to SARS-COV-2 spike protein. Method(s): Adipocytes were isolated enzymatically from adipose tissue obtained from an obese male donor. Adipocytes were then exposed to SARS-COV-2 S1 spike protein for 24 hours. After exposure, perindopril and losartan were added to the culture medium. ACE2, TF, and PAI-1expression were measured 2 hours later using ELISA. Result(s): SARS-CoV-2 spike protein exposure increased ACE2, TF, and PAI-1 expression. Perindopril addition discernible reduced the tissue factor (TF) expression (4.843 +/- 0.396) compared to a positive control (6.857 +/- 0.228) (p=0.005) but not losartan (5.624 +/- 0.606) (p=0.111). Perindopril was also able to lower PAI-1 expressions (3.484 +/- 0.252) compared to a positive control (4.865 +/- 0.115) (p=0.001), but the losartan did so more effectively (2.633 +/- 0.269) (p=0.000). Conclusion(s): Losartan and perindopril both have the ability to lower pro-coagulation factors, proving the value of ACEIs/ARBs in preventing thrombotic complications in Covid-19 patients.Copyright © 2023

Infection and obesity: Two sides of the same coin

Obesity is a chronic disease exceeding epidemic proportions whose multifactorial etiology constrains available treatment options. Obesity therapies have focused on lifestyle interventions targeting food intake and/or physical activity but neglect the potential of microbial causal factors. With rising obesity rates, the need for accelerated therapies may be achieved through microbe-specific vaccines targeting cause-specific etiologies. Obesity is a risk factor for increased susceptibility to numerous infectious diseases. This chapter aims to address the bidirectional relationship between obesity and such microbes by investigating the mechanisms and causality of this relationship through correlationally linked infections of microbial origins like influenza and COVID-19. Additionally, this chapter captures how several microbes contribute to obesity through variable transmission mechanisms as well as the cascade of their effects across host biochemistries known as "Infectobesity.” Identifying contributory roles of pathogens in obesity will assist the development of vaccinations against a growing yet underestimated subtype of obesity. © 2023 Elsevier Inc. All rights reserved.

Perindopril Reduce SARS-COV-2 Spike-ACE2 Binding, ACE2 Overexpression and Cytokine Storm in Adipocyte Cell Infected with SARS-COV-2

Background and Aims: The SARS-CoV-2 virus can infect adipocyte cells via ACE2 Receptor thus triggering ACE2 overexpression and cytokine storms which cause lethal complications. Hence, we explore the effect of Perindopril on the expression of ACE2, IL-6, IL-1B TNF-alpha in adipocyte cultures infected by SARS-CoV-2 spike protein and identify the possible mechanism involved. Material(s) and Method(s): Adipocyte culture obtained from a healthy and obese donor was divided into 4 triplicate groups (P0: negative control without treatment;P1: positive control (SARS-CoV-2 spike protein);P2: SARS-CoV-2 spike protein + exposure to Perindopril 0.5 muM);P3: SARS-CoV-2 spike protein + anti-ACE2 antibody 100 mug/mL;and evaluated at 24 and 48 hours. ACE2 expression was evaluated using immunofluorescence. IL-6, TNFalpha, and IL-1B were evaluated using ELISA. SARS-COV-2 Spike-ACE2 Binding was evaluated using Competitive ELISA. Data analysis was performed using SPSS 25.0 software. Result(s): At first 24 hours of incubation, perindopril treatment has the highest ACE2 expression compared to negative control, positive control and anti-ACE2 antibody (113.52+/-0.34 ng/mL vs 13.3+/-0.87 ng/mL, 90.2+/-2.73 ng/mL, 17.3+/-0.11 ng/mL, p<0.01), lower ACE-ACE2R binding compared to anti-ACE2 antibody group (169.52+/-4.07 ng/mL vs 290.71+/-6.22 ng/mL, p<0.01) and higher IL-6 expression compared to positive control group (64.65+/-0.12 ng/mL vs 60.08+/-0.77 ng/mL p<0.01). Interestingly, after 48 hours, perindopril treatment was shown to prevent further increase of ACE2 expression compared to a positive control (47.37+/-0.76 ng/mL vs 80.31+/-5.37 ng/mL, p<0.01), higher SARS-COV-2 Spike-ACE2 binding compared to anti-ACE2 antibody group (143.68+/-3.68 ng/mL vs 103.1+/-9.49 ng/mL, p<0.01), and lower IL-6 expression compared to the positive control group (42.66+/-1.94 ng/mL vs 90.93+/-2.48 ng/mL p<0.01). However, no significant difference in TNFalpha and IL-1B expression between perindopril treatment and positive control in both 24 and 48 hours. Conclusion(s): This study showed that perindopril reduces cytokine storm by preventing ACE-2 and IL-6 overexpression via an increasing number of SARS-COV-2 Spike-ACE2 competitive binding in adipocyte culture infected with SARS-COV-2 spike protein. A further clinical trial is needed to prove the benefit of perindopril in obese patients with COVID-19.

Characterization of Mesenchymal Cell from BAL of post COVID-19 patient whit fibrosis

Increasing number of severe COVID 19 patients develop pulmonary Fibrosis, but the management of this complication is still unclear due to a lack of clinical trials. Aim of this study was to characterize mesenchymal cells (MC) isolated from 10 broncho-alveolar lavage (BAL, at 2 months after discharge) from patients with COVID19 fibrosis (COVID19-f) and to compare them with those isolated from 8 patients with collagen tissue diseaseassociated interstitial fibrosis(CTD-ILD). BAL fluid (BALf) levels of TGFbeta, VEGF, TIMP2, RANTES, IL6, IL8, and PAI1 were assessed by ELISA. Primary MC foci were cultured and expanded in D-MEM +10% FBS, characterized by flow cytometry and osteogenic and adipogenic differentiation. Collagen 1 production (+/-TGF-beta) was tested by WB and mRNA expression. BALf cytokine and GF levels were comparable in the two groups. Efficiency of MC isolation from BAL was 100% in COVID-f compared to 65% in CTD-ILD. MC antigen surface expression of CD105, CD73, CD90 (>90%, respectively), CD45, CD34, CD19 and HLA-DR (<5%, respectively) was comparable. None of MC samples differentiated in adipocytes, while COVID19-f were positive for calcium deposition. COVID19-f MC showed at WB, higher Collagen 1 production with respect to CTD-ILD with TGF-beta stimulation. Our preliminary data suggest MC from COVID19-f share several features with CTD-ILD but might have a higher response to fibrogenic and differentiation signals.

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.

Adipocytes Encapsulating Telratolimod Recruit and Polarize Tumor-Associated Macrophages for Cancer Immunotherapy.

Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8+ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.

What is the role of brown adipose tissue in metabolic health: lessons learned and future perspectives in the long COVID?

Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID. The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID. The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokines, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review. It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomena which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.

What is the role of brown adipose tissue in metabolic health: lessons learned and future perspectives in the long COVID?

Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID. The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID. The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokinins, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review. It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomenons which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.

Adipocytes in obesity: A perfect reservoir for SARS-CoV-2?

Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVID-19. As lipid metabolism is key to adipocyte function, and viruses are capable of exploiting and manipulating lipid metabolism of host cells for their own benefit of infection, we hypothesize that adipocytes could not only impair host immune defense against viral infection, but also facilitate SARS-CoV-2 entry, replication and assembly as a reservoir to boost the viral infection in obesity. The latter of which could mainly be mediated by SARS-CoV-2 hijacking the abnormal lipid metabolism in the adipocytes. If these were to be confirmed, an approach to combat COVID-19 in people with obesity by taking advantage of the abnormal lipid metabolism in adipocytes might be considered, as well as modifying lipid metabolism of other host cells as a potential adjunctive treatment for COVID-19.

Dipeptidylpeptidase (DPP)-4 inhibitor therapy increases circulating levels of antiinflammatory soluble frizzle receptor protein (sFRP)-5 which is decreased in severe COVID-19 disease

Background and Aim Obesity and type 2 diabetes (T2D) show an increased risk for a severe COVID-19 disease. Treatment with DPP4 inhibitor (DPP4i) results in reduced mortality and better clinical outcome. Here, we aimed to identify potential mechanisms for the observed DPP4i effect in COVID-19. Methods We compared T2D subjects with (cases) and without (controls) DPP4i treatment (N=69), as well as patients hospitalised for severe COVID-19 and healthy controls (N=34) with regard to serum concentrations of soluble frizzle receptor protein 5 (sFRP5) using univariate statistics. Furthermore, we isolated pre-adipocytes, mature adipocytes and macrophages from adipose tissue biopsies (N=100) and performed western-blotting for sFRP5 and Wnt5a expression. Results In T2D patients, we identified a significant increase of the anti-inflammatory adipokine sFRP5 in relation to DPP4 inhibition. sFRP5 is a specific antagonist to Wnt5a, a glycopeptide secreted by adipose tissue macrophages acting proinflammatory in various diseases. We therefore examined sFRP5 levels in patients hospitalised for severe COVID-19 and found significant lower levels compared to healthy controls. Since sFRP5 might consequently be a molecular link for the beneficial effects of DPP4i in COVID-19, we further aimed to identify the exact source of sFRP5 in adipose tissue on cellular level. Results from western-blotting in adipose tissues showed a sFRP5 expression specifically in mature adipocytes of subcutaneous and omental adipose tissue. Conclusion In summary, our data suggest that DPP4i increase serum levels of anti-inflammatory sFRP5 which might be beneficial in COVID-19, reflecting a state of sFRP5 deficiency.

The Endocrine Adipose Organ: A System Playing a Central Role in COVID-19.

In the last 30 years the adipose cell has been object of several studies, turning its reputation from an inert cell into the main character involved in the pathophysiology of multiple diseases, including the ongoing COVID-19 pandemic, which has changed the clinical scenario of the last two years. Composed by two types of tissue (white and brown), with opposite roles, the adipose organ is now classified as a real endocrine organ whose dysfunction is involved in different diseases, mainly obesity and type 2 diabetes. In this mini-review we aim to retrace the adipose organ history from physiology to physiopathology, to provide therapeutic perspectives for the prevention and treatment of its two main related diseases (obesity and type 2 diabetes) and to summarize the most recent discoveries linking adipose tissue to COVID-19.

Unconventional Functions of Amino Acid Transporters: Role in Macropinocytosis (SLC38A5/SLC38A3) and Diet-Induced Obesity/Metabolic Syndrome (SLC6A19/SLC6A14/SLC6A6).

Amino acid transporters are expressed in mammalian cells not only in the plasma membrane but also in intracellular membranes. The conventional function of these transporters is to transfer their amino acid substrates across the lipid bilayer; the direction of the transfer is dictated by the combined gradients for the amino acid substrates and the co-transported ions (Na+, H+, K+ or Cl-) across the membrane. In cases of electrogenic transporters, the membrane potential also contributes to the direction of the amino acid transfer. In addition to this expected traditional function, several unconventional functions are known for some of these amino acid transporters. This includes their role in intracellular signaling, regulation of acid-base balance, and entry of viruses into cells. Such functions expand the biological roles of these transporters beyond the logical amino acid homeostasis. In recent years, two additional unconventional biochemical/metabolic processes regulated by certain amino acid transporters have come to be recognized: macropinocytosis and obesity. This adds to the repertoire of biological processes that are controlled and regulated by amino acid transporters in health and disease. In the present review, we highlight the unusual involvement of selective amino acid transporters in macropinocytosis (SLC38A5/SLC38A3) and diet-induced obesity/metabolic syndrome (SLC6A19/SLC6A14/SLC6A6).

Plasma Leptin Is Increased in Intensive Care Patients with COVID-19-An Investigation Performed in the PronMed-Cohort.

COVID-19 has shaken the world and intensive care units (ICU) have been challenged by numerous patients suffering from a previously unknown disease. Leptin is a polypeptide pleiotropic hormone, mainly expressed by adipocytes. It acts as a proinflammatory cytokine and is associated with several conditions, known to increase the risk of severe COVID-19. Very little is known about leptin in severe viral disorders. Plasma leptin was analyzed in 222 out of 229 patients with severe COVID-19 on admission to an ICU at Uppsala University Hospital, a tertiary care hospital in Sweden, and compared to plasma leptin in 25 healthy blood donors. COVID-19 was confirmed by positive PCR. Leptin levels were significantly higher in patients with COVID-19 (18.3 ng × mL-1; IQR = 30.4), than in healthy controls (7.8 ng × mL-1; IQR = 6.4). Women had significantly higher leptin values (22.9 ng × mL-1; IQR = 29.8) than men (17.5 ng × mL-1; IQR = 29.9). Mortality at 30 days was 23% but was not associated with increased leptin levels. Neither median duration of COVID-19 before admission to ICU (10 days; IQR = 4) or median length of ICU stay (8 days; IQR = 11) correlated with the plasma leptin levels. Leptin levels in COVID-19 were higher in females than in males. Both treatment (e.g., use of corticosteroids) and prophylaxis (vaccines) have been improved since the start of the COVID-19 pandemic, which may contribute to some difficulties in deciphering relations between COVID-19 and leptin.

Three states of stromal cells-solid, liquid, and aerosol-and innovative delivery methods not previously reported.

Clinical applications of stromal cells obtained mechanically from adipose tissue are quite popular methods. However, generally accepted protocols still do not exist. In this study, three new delivery methods using different protocols are presented as innovative methods in accordance with an approach called "Indication-based protocols." In mechanical methods, before cutting the fat tissue with ultra-sharp blades, which we define as "Adinizing," mixing it with different liquids such as saline or plasma provides the stromal cells in liquid form with high number and viability as a final product. At the same time, since stromal cells and extracellular matrix are preserved by mechanical methods, it was deemed appropriate to use the term total stromal cells (TOST) instead of stromal vascular fraction for this final product, unlike the product obtained with the enzyme. TOST can be combined with plasma and used for dermal filling in "solid" form. In addition to this filling effect, it will also cause a change in the tissue regeneratively. Finally, the stromal cells obtained from liquid can be applied clinically in aerosol form with the help of nebulizer. We believe that three innovative delivery methods can be used successfully in the treatment of many clinical situations in the future.

Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids.

Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs.

Obesity, Nutrients and the Immune System in the Era of COVID-19.

The past year has shown that obesity is a risk factor for severe complications of SARS-CoV-2 infection. Excess fat mass during obesity is known to be a risk factor for chronic diseases but also for severe infections and infectious complications. We have focused here on the elements responsible for this particular susceptibility to infections and more specifically to COVID-19. Excess fat is, in itself, responsible for alterations of the immune system by disrupting the production and function of immune cells. Indeed, hypertrophic adipocytes produce more pro-inflammatory adipokines (including cytokines). The increase in their apoptosis induces a release of pro-inflammatory compounds into the circulation and a recruitment of pro-inflammatory macrophages into the adipose tissue. A chronic systemic inflammatory state is then observed. In addition, diet, apart from its role in the development of adipose tissue, can also affect the immune system, with excess simple sugars and saturated fats exerting pro-inflammatory effects. This inflammation, the adipokines released by the adipocytes, and the infiltration of lipids into the lymphoid organs affects the production of immune cells and, directly, the functions of these cells. The alteration of the immune system increases the risk of infection as well as complications, including secondary bacterial infections and septic states, and increases infection-related mortality. During COVID-19, the chronic inflammatory state promotes the cytokine shock, characteristic of severe forms, caused in particular by excessive activation of the NLRP3 inflammasome. Furthermore, in obese subjects, the already present endothelial dysfunction will render endothelial inflammation (endotheliitis) due to viral infiltration all the more severe. Added to this is a state of hypercoagulability and a decrease in respiratory capacity, leading to a risk of severe COVID-19 with cardiovascular complications, acute respiratory distress syndrome, and disseminated intravascular coagulation, which can lead to multiple organ failure and even death.