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At present, googling the search terms “COVID‐19” and “Functional foods” yields nearly 500,000,000 hits, witnessing the growing interest of the scientific community and the general public in the role of nutrition and nutraceuticals during the COVID‐19 pandemic. Many compounds have been proposed as phytotherapics in the prevention and/or treatment of COVID‐19. The extensive interest of the general public and the enormous social media coverage on this topic urges the scientific community to address the question of whether which nutraceuticals can actually be employed in preventing and treating this newly described coronavirus‐related disease. Recently, the Canadian biotech pharma company “FSD Pharma” received the green light from the Food and Drug Administration to design a proof‐of‐concept study evaluating the effects of ultramicronized palmitoylethanolamide (PEA) in COVID‐19 patients. The story of PEA as a nutraceutical to prevent and treat infectious diseases dates back to the 1970s where the molecule was branded under the name Impulsin and was used for its immunomodulatory properties in influenza virus infection. The present paper aims at analyzing the potential of PEA as a nutraceutical and the previous evidence suggesting its anti‐inflammatory and immunomodulatory properties in infectious and respiratory diseases and how these could translate to COVID‐19 care.
Phytotherapics in COVID19: Why palmitoylethanolamide?
Marcella Pesce
| Luisa Seguella
| Sara Cassarano
| Laura Aurino
Walter Sanseverino
| Jie Lu
| Chiara Corpetti
| Alessandro Del Re
Martina Vincenzi
| Giovanni Sarnelli
| Giuseppe Esposito
Department of Clinical Medicine and Surgery,
University of Naples "Federico II", Naples, Italy
Department of Physiology and Pharmacology,
Sapienza University of Rome, Rome, Italy
Sequentia Biotech SL, Barcelona, Spain
Department of Human Anatomy, College of
Basic Medical Sciences, China Medical
University, Shenyang City, China
Giuseppe Esposito, Department of Physiology
and Pharmacology, Sapienza University of
Rome, Rome, Italy.
At present, googling the search terms COVID-19and Functional foodsyields
nearly 500,000,000 hits, witnessing the growing interest of the scientific community
and the general public in the role of nutrition and nutraceuticals during the COVID-
19 pandemic. Many compounds have been proposed as phytotherapics in the pre-
vention and/or treatment of COVID-19. The extensive interest of the general public
and the enormous social media coverage on this topic urges the scientific community
to address the question of whether which nutraceuticals can actually be employed in
preventing and treating this newly described coronavirus-related disease. Recently,
the Canadian biotech pharma company FSD Pharmareceived the green light from
the Food and Drug Administration to design a proof-of-concept study evaluating the
effects of ultramicronized palmitoylethanolamide (PEA) in COVID-19 patients. The
story of PEA as a nutraceutical to prevent and treat infectious diseases dates back to
the 1970s where the molecule was branded under the name Impulsin and was used
for its immunomodulatory properties in influenza virus infection. The present paper
aims at analyzing the potential of PEA as a nutraceutical and the previous evidence
suggesting its anti-inflammatory and immunomodulatory properties in infectious and
respiratory diseases and how these could translate to COVID-19 care.
COVID19, palmitoylethanolamide, phytotherapy, SARS-CoV2
The COVID-19 pandemic has hit a somber milestone with an ever-
rising death toll of 1,087,118 people worldwide, as of October
13 ( Although the
pathogenic mechanisms underlying SARS-CoV2 infection are still
obscure, the induction of an uncontrolled release of cytokines and
other pro-inflammatory mediators appears to be pivotal in severely ill
COVID-19 patients (García, 2020; Mahmudpour, Roozbeh, Keshavarz,
Farrokhi, & Nabipour, 2020; Soy et al., 2020; Tay, Poh, Rénia,
MacAry, & Ng, 2020).
On this ground, many immunosuppressive drugs have been pro-
posed to counteract this process, with encouraging results (Amin
Jafari & Ghasemi, 2020; Jamilloux et al., 2020; Magro, 2020; Tufan,
glu Güler, & Matucci-Cerinic, 2020; Ye, Wang, & Mao, 2020).
Nonetheless, dampening the inflammatory response during infectious
diseases may impair the desired host response and predispose to sec-
ondary infections. In keeping with this, a recent single-center retro-
spective case-review analyzing the clinical outcomes and secondary
infections' rates in COVID-19 patients receiving the anti-interleukin
6 inhibitor, Tocilizumab, found a significantly higher mortality rate and
occurrence of secondary infections, particularly of bacterial pneumo-
nia superinfections, in patients treated with this immunosuppressive
drug (Kimmig et al., 2020; Pettit et al., 2020). Most of these ongoing
trials, hence, reserve these drugs for severely ill patients, given their
unwanted side effects, particularly in mild forms of infection (Nguyen
et al., 2020).
Received: 17 October 2020 Accepted: 24 November 2020
DOI: 10.1002/ptr.6978
Phytotherapy Research. 2020;19. © 2020 John Wiley & Sons, Ltd. 1
Diet and nutrition are receiving growing interest from the public,
given the compiling evidence of their pivotal role in modulating the
immune function (Butler & Barrientos, 2020; Zabetakis, Lordan, Nor-
ton, & Tsoupras, 2020). Both under- and over-feeding can indeed neg-
atively impact the immune response and ensuring the adequate
amount of micronutrients or functional foods may bear the potential
to increase the host defense against viral infections (Cena &
Chieppa, 2020; Stefan, Birkenfeld, Schulze, & Ludwig, 2020).
In this context, many phytotherapics and food supplements have
been proposed by the scientific community and the general public,
yielding conflicting information on this topic (Muscogiuri, Barrea,
Savastano, & Colao, 2020; Ribeiro, Sousa, & Carvalho, 2020). The
ideal nutraceutical should have proven immunomodulatory activities
and multitargeted mechanisms of action to avoid escapismgiven
the redundancy of the immune response, while at the same time, it
should be immediately translatable to clinical settings with pharmaco-
kinetic and pharmacodynamic studies proving its efficacy and safety
in clinical settings.
Endocannabinoid-related compounds are endogenous bioactive
lipid amides with pleiotropic homeostatic properties, including
immune response regulation, control of food intake, neuroprotection,
and inhibition of pain and inflammation (De Filippis et al., 2011; Gigli
et al., 2017; Matias & Di Marzo, 2007; Pesce et al., 2018; Pesce,
Esposito, & Sarnelli, 2018; Suardíaz, Estivill-Torrús, Goicoechea,
et al., 2007; Williams & Kirkham, 1999).
These well-known multifaceted properties, the readily clinical
translatability and the lack of unwanted side effects have already
attracted attention from the scientific community toward the
repurposing of these compounds during the COVID-19 pandemic
(Costiniuk & Jenabian, 2020; Esposito et al., 2020; Onaivi &
Sharma, 2020; Tahamtan, Tavakoli-Yaraki, & Salimi, 2020).
Oleoylethanolamide (OEA), cannabidiol, palmitoylethanolamide
(PEA), and other unsaturated fatty acids have all been put forward as
promising drug candidate as a treatment potential strategy in the
novel SARS-CoV-2 pandemic (Das, 2020; Ghaffari et al., 2020;
Onaivi & Sharma, 2020). All these compounds share similar character-
istics, being endogenous naturally occurring lipids taking part in the
host immune response to a variety of noxae, including viral infections
(Cabral, Ferreira, & Jamerson, 2015; Ganley, Graessle, &
Robinson, 1958).
Among these appealing compounds, checking all the boxes of the
ideal drug candidate is PEA, a naturally occurring lipid mediator pre-
sent in peanuts or fenugreek seeds and soybean lecithin (Ganley
et al., 1958) that has an entourage effect on the endocannabinoid sys-
tem (Lambert & Di Marzo, 1999), while lacking cannabinoids' psycho-
tropic side effects (Wallace et al., 2007). Recently, PEA has been
proposed as a potential drug for COVID-19 on the ground that this
and other compounds, such as sodium chromo-glycate, can prevent
mast cell (MC)-induced pulmonary inflammation and fibrosis during
SARS-CoV2 infection (Gigante et al., 2020). Not surprisingly, since
these were the first described effects of PEA (Aloe, Leon, & Levi-
Montalcini, 1993; Facci et al., 1995), the authors mainly focused on its
role as a mast-cell stabilizer during the so-called cytokine storm
occurring in COVID-19 pneumonia (Conti et al., 2020). It is now
accepted, however, that PEA has a multitargeted action and its poten-
tial anti-viral mechanisms may be related to several other signaling
pathways, such as toll-like receptors (TLRs), peroxisome proliferators-
activated receptor-α(PPARα), nitric oxide and cyclooxygenase-2
(COX2), and S100B and GFAP signaling pathways (Esposito
et al., 2014; Sarnelli et al., 2016; Sarnelli et al., 2016).
In this manuscript, we aim to introduce this bioactive lipid media-
tor as a novel potential pharmacological alternative for the manage-
ment of COVID-19 by analyzing systematically its multifaceted
properties and the previous evidence for its clinical applicability and
effectiveness in preventing and treating acute viral respiratory
We will finally outline how its multitargeted potential directly
translates to SARS-CoV2 infection and progression, identifying
PEA molecular targets, as well as its formulation, for COVID-19
PEA has been under the spotlight of the scientific community for over
50 years given its analgesic, anti-allergic, and anti-inflammatory activi-
ties. As outlined above, Nobel-awarded Dr. Levi-Montalcini first
described that the anti-inflammatory properties of PEA were related
to the inhibition and degranulation of MCs, also known as the Auta-
coid Local Injury AntagonismALIA-mechanism (Aloe et al., 1993). It
is now recognized that the PEA anti-inflammatory and analgesic prop-
erties are also related to the direct activation of a number of recep-
tors, including the PPAR-α(Sarnelli, Gigli, et al., 2016), the vanilloid
receptor (TRPV1) (Godlewski, Offertáler, Wagner, & Kunos, 2009; Ho,
Barrett, & Randall, 2008; Petrosino et al., 2016), or the G-protein
coupled receptor GPR55 and GPR119 (Godlewski et al., 2009; Ryberg
et al., 2007).
In addition, PEA belongs to the so-called endocannabinoid-related
compounds, since it has a close structural resemblance with classical
endocannabinoids, but displays no activity on cannabinoid receptors
(Lambert & Di Marzo, 1999). Given the close resemblance to endo-
cannabinoids, PEA shares with them similar biosynthetic and catabolic
pathways. PEA is indeed substrate of the fatty acid amide hydrolase
(FAAH), the enzyme responsible for anandamide degradation. By
either competing with endocannabinoids for FAAH or inducing its
down-regulation (Ho et al., 2008), PEA could reduce endo-
cannabinoids catabolism, thus ultimately increasing their concentra-
tions (entourage effect).
Its complex pharmacodynamic profile accounts for the multiface-
ted activities exerted on a wide number of inflammatory cells and
mediators. Most of the anti-inflammatory properties of PEA arise from
its ability to antagonize nuclear factor-κB (NF-κB) signaling pathway
via the selective activation of the PPARαreceptors (Esposito
et al., 2014; Sarnelli, D'Alessandro, et al., 2016).
PPAR-αreceptors are predominantly expressed in tissues
involved in fatty acids metabolism, such as liver, heart, kidney, and
muscle, but more recently, it was also demonstrated to be expressed
on several types of immune cells, including undifferentiated mono-
cytes and differentiated human macrophages, T and B lymphocytes
(Magadum & Engel, 2018). PPARαactivation can effectively antago-
nize the NF-κB signaling pathway with a dual mechanism, either by
physically interacting with NF-κB p65 or by upregulating the expres-
sion of inhibitors of NF-κB(IκBs) in many cell types (Korbecki,
nski, & Dutka, 2019). By inhibiting NF-κB expression, PEA down-
stream regulates several genes involved in the inflammatory response.
These include pro-inflammatory cytokines (tumor necrosis factor
TNF-α, Il-1β), cell-adhesion molecules, and other signal mediators,
such as inducible nitric oxide synthase (iNOS), COX2, S100B, and
GFAP (Cipriano et al., 2015; Couch, Tasker, Theophilidou, Lund, &
O'Sullivan, 2017).
PEA potent anti-inflammatory activity has been studied in a great
variety of animal and human models for a number of disorders, fea-
tured by overactive and dysfunctional hyper-inflammation, such as
osteoarthritis, traumatic brain injury, multiple sclerosis, amyotrophic
lateral sclerosis, Alzheimer's disease, inflammatory bowel disease,
asthma and allergic contact dermatitis (Beggiato, Tomasini, &
Ferraro, 2019; Britti et al., 2017; Esposito et al., 2013; Genovese
et al., 2008; Grill et al., 2019; Russo et al., 2018; Scuderi et al., 2011).
These anti-inflammatory effects have been firstly observed in
models of neuro-inflammation. For instance, in experimental spinal
cord injury in mice, PEA administration was proven to attenuate spinal
cord inflammation and tissue injury, neutrophils infiltration and the
expression of pro-inflammatory cytokines and iNOS, as well NF-κB
upregulation (Esposito et al., 2011).
Treatment with PEA also resulted in amelioration of intestinal
inflammation in animal and human models of inflammatory bowel dis-
ease (Borrelli et al., 2015). PEA treatment, indeed, dose-dependently
decreased the expression and release of pro-inflammatory cytokines
as well as neutrophil and macrophage infiltration in both dextran
sodium sulfate-induced ulcerative colitis (UC) in mice as well as in
cultured human biopsies deriving from UC patients (Lama
et al., 2020). Importantly, PEA is also able to downregulate, via a
PPARα-dependent mechanism, the expression of Toll-like recep-
tor 4 (TLR4) in both enteric glial cells and vascular smooth cells
(Sarnelli, D'Alessandro, et al., 2016). PEA also reduces the produc-
tion of reactive oxygen species in several models of inflammation
by reducing lipoperoxidation and reduction of nitric oxide by
downregulation of iNOS (Sarnelli et al., 2018). Finally, a recent
paper from Heide et al. proposed a novel anti-inflammatory mech-
anism of action for PEA in a mouse model of bacterial meningitis.
The authors fo und that prophylactic intrap eri toneal PEA adminis-
tration significantly reduced the systemic concentration of two
pro-inflammatory bioactive lipids, namely arachidonic acid (AA) and
20-hydroxyeicosatetraenoic acid (20-HETE). The authors concluded
that PEA effects on eicosanoid acids are particularly relevant in the
setting of meningitis, since 20-HETE is a potent vasoconstrictor of
brain microvessels that contributes to the development of vasospasm
and other cerebrovascular alterations occurring in bacterial meningitis
(Heide et al., 2018).
The role of PEA as a prophylactic and/or therapeutic agent in infec-
tious disease has been proven in six pioneeristic clinical studies from
the 1970s, long before the actual discovery of its receptor targets and
mechanisms of action (Keppel Hesselink, de Boer, & Witkamp, 2013).
Early results from animal studies supported the idea that PEA was a
non-specific enhancer of the host defenses against bacterial and viral
infection while exerting at the same time potent anti-inflammatory
activities (Bachur, Masek, Melmon, & Udenfriend, 1965). This led to
the commercialization of PEA, under the brand name of Impulsin, to
prevent upper respiratory tract infections (URTIs) and in treating
influenza-like symptoms. Overall, six placebo-controlled double-blind
randomized studies were published. An overview of the number of
participants, target population, primary aims, and duration and dosage
of PEA treatment used in the studies is provided in Table 1.
Taken together, these studies all point toward the efficacy of PEA
as a prophylactic and therapeutic agent against influenza, up to
1800 mg/daily, even in pediatric populations, with no relevant side
effects. The results suggested that repeated daily administration of
Impulsin (30 mg/kg) prevented the incidence of respiratory tract
infections both in pediatric and adult populations. Additionally, pro-
phylactic treatment with Impulsin markedly diminished the number of
episodes of fever, headache, and sore throat, while it showed no sig-
nificant effect on the mean duration of disability and fever. For a com-
plete review of these studies, readers are invited to refer to the
excellent review articles by Prof. Keppel Hesselink on the topic
(Keppel Hesselink et al., 2013).
Following these in vivo trials, only one retrospective observa-
tional study tested the effects of a nutritional product, branded under
the name of Sinergathat contained PEA, as well as other
nutraceuticals, such as bovine colostrum, phenylethylamine, and the
probiotic k1uyveromyces FM B0399 in preventing URTIs in children
(Nigro, Nicastro, & Trodella, 2014). In this observational small-sized
study (167 participants, mean age 4.5 years), the authors compared
the 4-month prophylactic administration of Sinerga to bacterial
extracts in children suffering from recurrent URTIs and evaluated the
frequency of episodes of a respiratory infection that had led to the
need of prescribing antibiotics. They found a reduction of the fre-
quency of URTIs and need for antibiotics in the group supplemented
with Sinerga, with all the subjects experiencing less than two episodes
of infection in the Sinerga group compared to 51% of the bacterial
extracts group.
Unfortunately, although the interest in PEA has continuously
risen during the last two decades, following the discovery of its mech-
anisms of action and subsequent commercialization as a nutraceutical
in several countries, no further studies tested its efficacy in respira-
tory infections in humans.
On the contrary, accumulating evidence have been produced
in vitro and in animal models of other communicable diseases, particu-
larly infections of the central nervous system (CNS), including bacte-
rial meningitis and sepsis driven by Escherichia coli K1 infection, given
PEA well-known anti-inflammatory and neuroprotective effects. In
this paper, preventive treatment with PEA increased the phagocytosis
of E. coli K1 without inducing the release of cytokines by macro-
phages in vitro and delayed symptoms' onset and prolonged survival
of intracerebrally- or intraperitoneally-challenged mice in vivo (Heide
et al., 2018).
Host immune response is a double-edged sword during SARS-CoV2
infection, as well as many others featured by hyperinflammatory
states. On one hand, in the early stages of infection, it is desirable to
have a competent immune system that can neutralize the pathogen,
while limiting the collateral damage to the host tissue, to accelerate
viral clearance. On the other hand, a deranged immune response with
over-production and systemic release of proinflammatory cytokines,
the so-called cytokine stormis thought to be responsible for the
systemic inflammatory response leading to acute respiratory distress
in severely-ill COVID-19 patients (Hu, Huang, & Yin, 2020).
In this scenario, PEA offers a unique pharmacodynamic profile. Its
properties as a non-specific immune enhancer against viral infections
have been tested in randomized clinical trials (RCTs) in humans
decades ago for the prophylaxis of respiratory tract infections (Nigro
et al., 2014). Furthermore, in vitro and in vivo studies in animal models
demonstrate that PEA can increase macrophage activation and phago-
cytosis without leading to an increase in proinflammatory cytokines
(Esposito et al., 2014).
SARS-CoV2 leads to an increased release of interleukin-6 (IL-6)
and IL-1b by binding the TLRs. The activation of the TLRs by SARS-
CoV2 leads to a cascade of events downstream culminating in the
activation of NF-κB, which is involved in the overexpression of inflam-
matory cytokines adhesion molecules and chemokines (McGonagle,
Sharif, O'Regan, & Bridgewood, 2020). The main receptor target of
PEA, PPARα, induces the expression of IkB, thus inhibiting NF-κB
pathway and modulates the expression of TLRs at the cell surface.
Being at the crossroads between these two pivotal signaling systems,
PEA can modulate the aberrant crosstalk between PPARαand TLRs
and may have a synergistic effect in COVID-19 infection (Esposito
et al., 2014).
One of the pharmaco-properties of PEA, the inhibition of MC
degranulation, known as the ALIA-mechanism has already attracted
attention from the scientific community and its relevance in SARS-
CoV2 infection has been extensively described elsewhere (Aloe
et al., 1993; Gigante et al., 2020).
Furthermore, PEA and other bioactive lipids act as anti-oxidant
molecules, reducing oxidative/nitrosative stress, thus preventing
endothelial damage, which is thought to contribute to the pathogene-
sis of the systemic inflammatory response in severe COVID-19
(Schönrich, Raftery, & Samstag, 2020).
There is compelling evidence that SARS-CoV2 is able to affect
not only the respiratory and cardiovascular function but also the gas-
trointestinal (GI) tract (Ho, Ho, Ho, & Ho, 2020; Wong, Lui, &
Sung, 2020) and the CNS system (Alomari, Abou-Mrad, &
Bydon, 2020; Asadi-Pooya & Simani, 2020). PEA is mostly used as a
phytotherapic for its neuroprotective and anti-inflammatory proper-
ties, particularly in neurodegenerative and inflammatory-related bowel
disorders, where it has been shown to decrease intestinal inflamma-
tion and restore the intestinal barrier function (Couch et al., 2019;
Karwad et al., 2017). It has been hypothesized that the COVID-
19-inflammatory state could disrupt the integrity of the intestinal bar-
rier leading to a hyper-permeable leakygut, allowing bacterial trans-
location to the systemic circulation, potentially contributing to the
TABLE 1 Results from randomized trials evaluating PEA treatment in preventing acute respiratory infections
Skoda car factory
employees (MASEK,
Army workers
(MASEK, 1972b)
Army workers
(KAMLICH, 1973)
Army workers
(KAMLICH, 1974)
Army workers
(KAMLICH, 1975)
School children
(PLESNIK, 1977)
N. (PEA vs
tot. 444
(223 vs 221)
tot. 899
(436 vs 463)
tot. 901
(436 vs 465)
tot. 610
(411 vs 199)
tot. 353
(235 vs 118)
tot. 420
3×600 mg/day
For 12 days
3×600 mg/day for
3 weeks,
followed by
600 mg/day
For 6 weeks
3×600 mg/day
for 12 days,
followed by
600 mg/day
For 6 weeks
3×600 mg/day
for 12 days,
followed by
600 mg/day
For 6 weeks
3×600 mg/day
for 12 days,
followed by
600 mg/day
For 6 weeks
4×600 mg/day for
8 weeks
Results 8% (18/223) vs 14.9%
14.7% (33/223) vs 18%
31% (135/436) vs
42.5% (197/463)
22.7% (99/436) vs
34.4% (160/465)
19.7% (80/411) vs
40.7% (80/199)
10.6% (25/235) vs
28.8% (34/118)
Reduction in
45.5% 32% 34% 52% 63% 15.7%
In terms of fever, headache, sore throat.
In terms of nasal stuffines, discharge, cough.
RTIs: respiratory tract infections.
septic state of COVID-19 patients (Aktas & Aslim, 2020; Hoel
et al., 2020).
Another meaningful and interesting anti-inflammatory mechanism
of PEA that could directly translate to COVID patients, is the evidence
that its administration in mice is able to modify the levels of other bio-
active lipids in the systemic circulation. As mentioned, PEA signifi-
cantly downregulates AA and its metabolite 20-HETE, which is known
to be a potent vasoconstrictor of blood vessels, that could contribute
to vasospasm and endothelial dysfunction encountered in severe
COVID-19 (Heide et al., 2018). An overview of PEA activities and
how these could be relevant to SARS-CoV2 pathogenesis is provided
in Figure 1.
Anecdotal evidence suggest the use of nutraceuticals in fighting the
COVID-19 pandemic (Infusino et al., 2020). Long before COVID-19 was
under the lens of the scientific community, PEA had already been pro-
posed as a nutraceutical to fight viral respiratory infections. PEA has
been indeed tested in nearly 2000 individuals in RCTs as a prophylactic
treatment against viral respiratory infections, showing promising results
in the 1970s. PEA complex and redundant mechanism of action have
been unveiled many decades following these trials, showing its real
potential as an immunomodulatory compound rather than a simple
non-specific immune enhancer(Keppel Hesselink et al., 2013).
PEA formulations are readily available as a food for special medi-
cal purposes in Italy and Spain since 2008, under the brand name
Normast (Epitech Srl). With over 50 years of experience in using PEA
in clinical trials, even in pediatric populations, no significant adverse
side effects were reported (Gabrielsson, Mattsson, & Fowler, 2016),
making it an ideal nutraceutical for repurposing during the COVID-19
The interest toward this molecule as a readily useable medical
food supplement is continuously rising and is receiving increasing
attention from the scientific community, as witnessed by the recent
approval for a phase-2 clinical trial to treat patients with suspected or
confirmed COVID-19, granted by the Food and Drug Administration
(FDA). In this paper, we summarized the potential of PEA in COVID-
19 infection and believe that altogether several evidence point toward
its efficacy in respiratory infections and more importantly its very
benign side effect profile. One of the potential setbacks of PEA treat-
ment is the high doses required to achieve its therapeutic effect, fol-
lowing oral administration, given its unfavorable pharmacokinetic
profile and rapid metabolization in humans. This could limit its bio-
availability in clinical practice, and alternative strategies to efficiently
increase PEA bioavailability have been developed, such as
ultramicronized PEA (Impellizzeri et al., 2014).
In his almost prophetic-sounding statement, Professor Keppel
Hesselink states the ease of application of PEA offers the possibility
to have a quick therapeutic answer ready in case of a flu epidemic,
especially in cases of a mismatch between circulating strains and the
FIGURE 1 Multitargeted activity of PEA and its potential in SARS-CoV2 infection. PEA exhibits immunomodulatory properties, though
inhibition of TLRs and NF-κB signaling pathways. On the other hand, PEA has been tested for respiratory viral infections as a non-specific
immune enhancer (1), it can reduce lipoperoxidation and the systemic concentration of AA and 20-HETE (2), and reduce intestinal permeability (3)
[Colour figure can be viewed at]
recommendations from WHO.We consider PEA a promising nutra-
ceutical in COVID-19 infection, based on the preclinical and clinical
studies and its relative safety profile in humans. Evidence from ongo-
ing clinical trials is eagerly awaited to confirm its beneficial activities
and turn PEA into an effective nutraceutical against COVID-19.
Marcella Pesce
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How to cite this article: Pesce M, Seguella L, Cassarano S,
et al. Phytotherapics in COVID19: Why
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... Also, in other metabolite families, cucurbitane-type glycosides kinoin A, B and D in extracts of roots were identified (Achenbach et al., 1993;Kamalakkannan & Prince, 2006;Jardón-Delgado et al., 2014). In UPLC-MS analysis of CCSE-Is-EtOH, we identified different metabolites such as palmitoyl pthanolamide, a member of the fatty-acid ethanolamide family (Hoareau & Roche, 2010;Paterniti et al., 2015;Pesce et al., 2020), palmitoyl tryptamine alkaloid derived from tryptamine (Lúcio et al., 2015;Kumar et al., 2018), hippeastrine, an alkaloid which has been identified in amaryllidaceae family (Gasca et al., 2020;Martinez-Peinado et al., 2020), citepressine I, acridone alkaloid identified in the Rutaceae family (Bissim et al., 2019;Ye et al., 2021) and the phenolic compound claisarinol, which has been identified in the Anonnaceae family (Rangsinth et al., 2019). This is the first time that these metabolites are reported in CCSE-Is-Aq at the Cucurbitacea family. ...
... Therefore, palmitoyl ethanolamide has been studied due to its analgesic, antiallergic and anti-inflammatory activities. The anti-inflammatory properties of palmitoyl ethanolamide arise from its ability to antagonize the nuclear factor κB (NF-κB) signaling pathway through the selective activation of the PPARα receptors (Hoareau & Roche, 2010;Paterniti et al., 2015;Pesce et al., 2020). Palmitoyl ethanolamide constitutes an attractive therapeutic tool for Diabetes and has demonstrated efficacy and great promise of its use in treating inflammatory disorders in an animal model. ...
bervillea sonorae(S. Watson) Greene, is a plant native to Mexico, where its roots have been used traditionally for treating Diabetes Mellitus. The aim of this work was to establishment of cell cultures of stem explants of I. sonoraeand evaluation of the anti-hyperglycemic activity of cell aqueous extract on a murine model of streptozotocin-induced diabetic rats. Cell extracts had 2.29 mg palmitic acid/g extracted, and other compounds with pharmacological activities like palmitoyl ethanolamide and palmitoyl tryptamine were also identified. Diabetic rats treated with aqueous cell extract decreased glucose levels from 350 mg/dL to 145 mg/dL, AST and ALT from 164 U/L to 49 U/L and 99 U/L to 53 U/L, respectively. Additionally, therewere no changes in the cellular morphology of the pancreas, liver, kidneys, and spleen. These results revealed that the cell aqueous extract from stem explants has anti-hyperglycemic activity.
... Such peculiar activity is believed to explain PEA potential anti-inflammatory, analgesic, and anti-epileptic effects (15)(16)(17)(18). Interestingly, several PEAcontaining products are licensed as nutraceuticals or food supplements for human use in different countries, at a recommended dose of 600-1,200 mg/day (19). ...
Full-text available
Cognitive decline is believed to be associated with neurodegenerative processes involving excitotoxicity, oxidative damage, inflammation, and microvascular and blood-brain barrier dysfunction. Interestingly, research evidence suggests upregulated synthesis of lipid signaling molecules as an endogenous attempt to contrast such neurodegeneration-related pathophysiological mechanisms, restore homeostatic balance, and prevent further damage. Among these naturally occurring molecules, palmitoylethanolamide (PEA) has been independently associated with neuroprotective and anti-inflammatory properties, raising interest into the possibility that its supplementation might represent a novel therapeutic approach in supporting the body-own regulation of many pathophysiological processes potentially contributing to neurocognitive disorders. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in neurocognitive disorders, finding 33 eligible outputs. Studies conducted in animal models of neurodegeneration indicate that PEA improves neurobehavioral functions, including memory and learning, by reducing oxidative stress and pro-inflammatory and astrocyte marker expression as well as rebalancing glutamatergic transmission. PEA was found to promote neurogenesis, especially in the hippocampus, neuronal viability and survival, and microtubule-associated protein 2 and brain-derived neurotrophic factor expression, while inhibiting mast cell infiltration/degranulation and astrocyte activation. It also demonstrated to mitigate β-amyloid-induced astrogliosis, by modulating lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, reactive oxygen species production, caspase3 activation, amyloidogenesis, and tau protein hyperphosphorylation. Such effects were related to PEA ability to indirectly activate cannabinoid receptors and modulate proliferator-activated receptor-α (PPAR-α) activity. Importantly, preclinical evidence suggests that PEA may act as a disease-modifying-drug in the early stage of a neurocognitive disorder, while its protective effect in the frank disorder may be less relevant. Limited human research suggests that PEA supplementation reduces fatigue and cognitive impairment, the latter being also meta-analytically confirmed in 3 eligible studies. PEA improved global executive function, working memory, language deficits, daily living activities, possibly by modulating cortical oscillatory activity and GABAergic transmission. There is currently no established cure for neurocognitive disorders but only treatments to temporarily reduce symptom severity. In the search for compounds able to protect against the pathophysiological mechanisms leading to neurocognitive disorders, PEA may represent a valid therapeutic option to prevent neurodegeneration and support endogenous repair processes against disease progression.
... Comportamiento similar, se observa en la prevalencia de la ansiedad, siendo los factores asociados más frecuentes el padecer enfermedades crónicas, el cambio abrupto de la educación a distancia, la libertad personal, la estabilidad financiera, entre otros (Dizon-Ross et al., 2019;Borges-Machado, 2020;Killen et al., 2020;Lasheras et al., 2020;Saraswathi et al., 2020;Silva et al., 2020;Vitale et al., 2020;Alqudah et al., 2021;Kurcer et al., 2021;Rehman et al., 2021). Entre los cambios físicos identificados, se encuentra la afectación de la calidad del sueño, evidenciándose en pocas horas o mala calidad del sueño, que derivó a el uso de medicamentos y hierbas contra el insomnio (Pesce et al., 2020;Beck et al., 2021;De Sousa et al., 2021;Simonetti et al., 2021) lo que contribuye como factor de riesgo para la salud mental, con probabilidad de desarrollar trastornos de ansiedad (Kalal et al., 2020;Di Sequera et al., 2021). Por su parte, Marashi et al., (2021) recomendaron para combatir el estrés pandémico el efecto protector potencial de la actividad física sobre la salud mental y señalan la necesidad de apoyo psicológico para superar las barreras percibidas para que las personas puedan continuar siendo físicamente activas durante tiempos de pandemia. ...
El COVID-19, ha generado estrés a nivel mundial ante la ausencia del desarrollo de los hábitos diarios, causando complicaciones físicas y psicológicas. Se realizó una revisión sistemática de literatura (RSL) del tratamiento farmacológico y no farmacológico y su impacto del estrés durante la pandemia de COVID-19 desde el 2019 hasta el 2021. La estrategia de búsqueda consiguió obtener 25.078 artículos, escogidos de las 6 fuentes de investigación (Taylor & Francis, Springer Link, Wiley Online Library, ARDI, Microsoft Academic y Nature Portfolio), luego se realizó un filtrado de 4 etapas con 2 criterios de exclusión cada una de ellas, quedando solo 78 artículos, los cuáles se utilizaron para responder 4 preguntas de investigación planteadas. Se precisó alteración del bienestar emocional de la población en general, con aumento alarmante de prevalencia de ansiedad, depresión e insomnio; el presente estudio brinda información necesaria sobre los tratamientos, ya sea farmacológico (teniendo como principal en un 31,11% a los antidepresivos y antupsicóticos); como no farmacológico (teniendo como principal en un 21,62% a la telemedicina), orientados a mejorar el estado psicológico, sobretodo de la población vulnerable, que demanda abordaje integral, ante la incertidumbre asociada con la infección por SARS-CoV-2, más el efecto el aislamiento físico, que repercute negativamente sobre la salud mental, incrementando pensamientos suicidas, alucinaciones, y trastornos psiquiátricos.
... As an antagonist of the nuclear factor-κB (NF-κB) signaling pathway, PEA regulates the activation of the PPARα receptors [57,58], increasing macrophage activation and phagocytosis, without an increase in proinflammatory cytokines [57], regulating fatty acid metabolism [59,60] and reducing lipoperoxidation and reduction of nitric oxide by the downregulation of inducible nitric oxide synthase (iNOS) [61], and other signal mediators (such as aCOX2, S100B and GFAP) [62], as well as the modulation of the aberrant crosstalk between PPARα and TLRs [57,63]. ...
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COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID. Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.
... The efficacy of PEA in the prevention or treatment of bacterial and viral infections has also been reported [21]. This encouraging evidence in the literature has stimulated research as to whether PEA can be used to inhibit the pathogenesis of SARS-CoV-2 [23,24]. ...
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Lipids play a crucial role in the entry and egress of viruses, regardless of whether they are naked or enveloped. Recent evidence shows that lipid involvement in viral infection goes much further. During replication, many viruses rearrange internal lipid membranes to create niches where they replicate and assemble. Because of the close connection between lipids and inflammation, the derangement of lipid metabolism also results in the production of inflammatory stimuli. Due to its pivotal function in the viral life cycle, lipid metabolism has become an area of intense research to understand how viruses seize lipids and to design antiviral drugs targeting lipid pathways. Palmitoylethanolamide (PEA) is a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that also counteracts SARS-CoV-2 entry and its replication. Our work highlights for the first time the antiviral potency of PEA against SARS-CoV-2, exerting its activity by two different mechanisms. First, its binding to the SARS-CoV-2 S protein causes a drop in viral infection of ~70%. We show that this activity is specific for SARS-CoV-2, as it does not prevent infection by VSV or HSV-2, other enveloped viruses that use different glycoproteins and entry receptors to mediate their entry. Second, we show that in infected Huh-7 cells, treatment with PEA dismantles lipid droplets, preventing the usage of these vesicular bodies by SARS-CoV-2 as a source of energy and protection against innate cellular defenses. This is not surprising since PEA activates PPAR-α, a transcription factor that, once activated, generates a cascade of events that leads to the disruption of fatty acid droplets, thereby bringing about lipid droplet degradation through β-oxidation. In conclusion, the present work demonstrates a novel mechanism of action for PEA as a direct and indirect antiviral agent against SARS-CoV-2. This evidence reinforces the notion that treatment with this compound might significantly impact the course of COVID-19. Indeed, considering that the protective effects of PEA in COVID-19 are the current objectives of two clinical trials (NCT04619706 and NCT04568876) and given the relative lack of toxicity of PEA in humans, further preclinical and clinical tests will be needed to fully consider PEA as a promising adjuvant therapy in the current COVID-19 pandemic or against emerging RNA viruses that share the same route of replication as coronaviruses.
... In addition, the antiin ammatory action of PEA has been used for intestinal in ammation in animals and in ammatory bowel disease by decreasing the expression and release of pro-in ammatory cytokines, as well as neutrophil and macrophage in ltration in sulfate-induced ulcerative colitis. 79,80 Based on all this information, our hypothesis is that PEA may be administered either in acute phase of COVID-19 infection or in the persistent post-COVID syndrome to mitigate the SARS-CoV-2-induced in ammation. Indeed, chronic in ammation (with the persistence of cytokines and IL or other pro-in ammatory molecules) might be responsible not only for respiratory and coagulation complications, but also for the aspeci c/subjective and persistent symptoms, including fatigue. ...
COVID-19 is highly transmissive and contagious disease with a wide spectrum of clinicopathological issues, including respiratory, vasculo-coagulative, and immune disorders. In some cases of COVID-19, patients can be characterized by clinical sequelae with mild-to-moderate symptoms that persist long after the resolution of the acute infection, known as long-COVID, potentially affecting their quality of life. The main symptoms of long-COVID include persistent dyspnea, fatigue and weakness (that are typically out of proportion, to the degree of ongoing lung damage and gas exchange impairment), persistence of anosmia and dysgeusia, neuropsychiatric symptoms, and cognitive dysfunctions (such as brain fog or memory lapses). The appropriate management and prevention of potential long-COVID sequelae is still lacking. It is also believed that long-term symptoms of COVID-19 are related to an immunity over-response, namely a cytokine storm, involving the release of pro-inflammatory interleukins, monocyte chemoattractant proteins, and tissue necrosis factors. Palmitoylethanolamide (PEA) shows affinity for vanilloid receptor 1 and for cannabinoid-like G protein-coupled receptors, enhancing anandamide activity by means of an entourage effect. Due to its anti-inflammatory properties, PEA has been recently used as an early add-on therapy for respiratory problems in patients with COVID-19. It is believed that PEA mitigates the cytokine storm modulating cell-mediated immunity, as well as counteracts pain and oxidative stress. In this article, we theorize that PEA could be a potentially effective nutraceutical to treat long-COVID, with regard to fatigue and myalgia, where a mythocondrial dysfunction is hypothesizable.
... Recent studies have proposed ultramicronization (um)-PEA as a potential adjunct in therapy for COVID-19 patients, thanks to its ability to modulate inflammation and the synthesis of proinflammatory enzymes [20]. This suggests that um-PEA could be included into the COVID-19 multidrug regimen, preventing an increase in immunosuppressant dosage by planning a synergistic therapy between um-PEA and the latter [21]. ...
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Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.
... The possibility to use PEA as a molecule able to prevent and treat infectious diseases dates to the 1970s where this autacoid local injury antagonist amide (ALIAmide) was branded under the name Impulsin and was used for its immunomodulatory properties in influenza virus infection [17,18] Nowadays, ultramicronized PEA (um-PEA), a new pharmaceutical form of PEA with higher efficacy and bioavailability compared to standard PEA [19], has been authorized in an ongoing clinical trial as an add-on therapy in the treatment of SARS-CoV-2. Although there are currently several trials on the possible use of PEA as a support to anti-COVID19 therapies [20] generically based on its anti-inflammatory activity, the molecular effects of PEA in the course of hyperinflammation processes induced by SARS-CoV-2 are yet to be characterized. ...
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Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-kappaB (NF-kappaB) signalling pathway via the selective activation of the PPARalpha receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-alpha, IL-1beta) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-alpha) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in pro-inflammatory markers (TLR4, p-p38 MAPK, NF-kappaB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1beta, TNF-alpha over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in ACE-2 following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-alpha, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.
... In this scenario, PEA can explain its effects, which depend on its ability to act as a mast cell stabilizer (65). PEA has multitarget action related to several signaling pathways, which include TLR, nitric oxide, IL-6 and IL-1b by binding TLRs (66). ...
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The global scientific community is striving to understand the pathophysiological mechanisms and develop effective therapeutic strategies for COVID-19. Despite overwhelming data, there is limited knowledge about the molecular mechanisms involved in the prominent cytokine storm syndrome and multiple organ failure and fatality in COVID-19 cases. The aim of this work is to investigate the possible role of of α-lipoic acid (ALA) and palmitoylethanolamide (PEA), in countering the mechanisms in overproduction of reactive oxygen species (ROS), and inflammatory cytokines. An in vitro model of lipopolysaccharide (LPS)-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome has been used. In this model of acute lung injury, the combination effects of ALAPEA, administered before and after LPS injury, were investigated. Our data demonstrated that a combination of 50 µM ALA + 5 µM PEA can reduce ROS and nitric oxide (NO) levels modulating the major cytokines involved on COVID-19 infection when administered either before or after LPS-induced damage. The best outcome was observed when administered after LPS, thus reinforcing the hypothesis that ALA combined with PEA to modulate the key point of cytokine storm syndrome. This work supports for the first time that the combination of ALA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and acting as a powerful antioxidant.
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Background: Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and pre-dispose to secondary infections. Methods: We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. Results: One hundred eleven patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1 vs. 28.1%; p = 0.029 and fungal (5.6 vs. 0%; p = 0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2 vs. 19.3%; p = 0.020). Seven cases underwent autopsy. In three cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the four cases that had not been given tocilizumab, two showed evidence of aspiration pneumonia and two exhibited diffuse alveolar damage. Conclusions: Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, pre-dispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.
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Background: Patients with COVID-19 most commonly report respiratory symptoms, with a minority reporting gastrointestinal (GI) symptoms in currently available reports. Additionally, little is known about the symptoms of anosmia/hyposmia, ageusia, and dysgeusia anecdotally seen in COVID-19 patients, which may potentially be considered both GI and sensory/neurological manifestations of infection. We hope to clarify the prevalence of these symptoms and patterns of transmission within a family cluster. Case presentation: We interviewed 7 patients via oral inquiries and a questionnaire, collecting data on subject symptoms and their durations. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to confirm 2 of these cases. We report a familial cluster of 5 presumed and 2 confirmed COVID-19 cases, all of whom reported one or more GI symptoms and 5 of whom reported sensory symptoms of anosmia/hyposmia, ageusia/hypogeusia, and/or dysgeusia. Conclusions: This frequency of GI symptoms is high relative to currently available epidemiological reports, which also infrequently report on sensory symptoms. COVID-19 exhibits wide variation in duration, severity, and progression of symptoms, even within a familial cluster.
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Background: A high proportion of COVID-19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 and the renin-angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID-19 patients. Methods: Plasma levels of a gut leakage marker (LPS-binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL-1β, IL-18 and their regulatory proteins) were measured at three time points (day 1, 3-5 and 7-10) in 39 hospitalized COVID-19 patients and related to cardiac involvement. Results: Compared to controls, COVID-19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT-pro-BNP levels, whereas IL-18, IL-18BP and IL-1Ra were associated with higher troponin levels. Conclusion: Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut-heart axis in COVID-19.
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SARS-CoV-2 virus is an infectious agent commonly found in certain mammalian animal species and today also in humans. SARS-CoV-2, can cause a pandemic infection with severe acute lung injury respiratory distress syndrome in patients with COVID-19, that can lead to patient death across all ages. The pathology associated with pandemic infection is linked to an over-response of immune cells, including virus-activated macrophages and mast cells (MCs). The local inflammatory response in the lung that occurs after exposure to SARS-CoV-2 is due to a complex network of activated inflammatory innate immune cells and structural lung cells such as bronchial epithelial cells, endothelial cells and fibroblasts. Bronchial epithelial cells and fibroblasts activated by SARS-CoV-2 can result in the up-regulation of pro-inflammatory cytokines and induction of MC differentiation. In addition, endothelial cells which control leukocyte traffic through the expression of adhesion molecules are also able to amplify leukocyte activation by generating interleukin (IL)-1, IL-6 and CXC chemokines. In this pathologic environment, the activation of mast cells (MCs) causes the release of histamine, proteases, cytokines, chemokines and arachidonic acid compounds, such as prostaglandin D2 and leukotrienes, all of which are involved in the inflammatory network. Histamine is stored endogenously within the secretory granules of MCs and is released into the vessels after cell stimulation. Histamine is involved in the expression of chemokine IL-8 and cytokine IL-6, an effect that can be inhibited by histamine receptor antagonists. IL-1 is a pleiotropic cytokine that is mainly active in inflammation and immunity. Alveolar macrophages activated by SARS-CoV-2 through the TLR produce IL-1 which stimulates MCs to produce IL-6. IL-1 in combination with IL-6 leads to excessive inflammation which can be lethal. In an interesting study published several years ago (by E. Vannier et al., 1993), it was found that histamine as well as IL-1 are implicated in the pathogenesis of pulmonary inflammatory reaction, after micorganism immune cell activation. IL-1 in combination with histamine can cause a strong increase of IL-1 levels and, consequently, a higher degree of inflammation. However, it has been reported that histamine alone has no effect on IL-1 production. Furthermore, histamine enhances IL-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral monocytes. Therefore, since MCs are large producers of histamine in inflammatory reactions, this vasoactive amine, by increasing the production of IL-1, can amplify the inflammatory process in the lung infected with SARS-CoV-2. Here, we have proposed for the first time an emerging role for histamine released by MCs which in combination with IL-1 can cause an increase in lung inflammation induced by the viral infection SARS-CoV-2.
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Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the MPS and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.
Palmitoylethanolamide (PEA) and oleamide are two fatty acid amides which 1) share some cannabimimetic actions with L.9-tetrahydrocanna­ binol, anandamide and 2-arachidonoylglycerol, and 2) may interact with proteins involved in the biosynthesis, action and inactivation of endocannabinoids. Palmitoylethanolamide (PEA) and oleamide are two fatty acid amides which 1) share some cannabimimetic actions with L.9-tetrahydrocanna­ binol, anandamide and 2-arachidonoylglycerol, and 2) may interact with proteins involved in the biosynthesis, action and inactivation of endocannabinoids. Due to its pharmacological actions and its accumulation in damaged cells, PEA may have a physio-pathological role as an analgesic, anti-oxidant and anti-inflammatory mediator. However, its mechanism of action is puzzling. In fact, PEA does not bind to CB1 and CB2 receptors transfected into host cells, but might be a ligand for a putative CBn receptor present in the RBL-2H3 cell line. On the other hand, the analgesic effect of PEA is reversed by SR144528, a CB2 antagonist. PEA may act as an "entourage" compound for endocannabinoids, i.e. it may enhance their action for example by inhibiting their inactivation. Oleamide is a sleep inducing lipid whose mechanism of action is far from being understood. Although it does not bind with high affinity to CB1 or CB2 receptors, it exhibits some cannabimimetic actions which could be explained at least in part by 'entourage' effects. It is likely that oleamide and anandamide have common as well as distinct pathways of action. The 5-HT2A receptor appears to be a target for oleamide but the possibility of the existence of specific receptors for this compound is open. The biosynthesis and tissue distribution of oleamide remain to be assessed in order to both substantiate its role as a sleep-inducing factor and investigate its participation in other physiopathological situations.
Background Tocilizumab (TCZ) has been used in the management of COVID‐19‐related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug‐related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID‐19 patients. Methods All adult inpatients with COVID‐19 between March 1st and April 25th, 2020 that received TCZ were included. We compared the rate of late‐onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post‐TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion‐related reactions. Results Seventy‐four patients were included in each group. Seven‐teen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (p=0.013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, p=0.03). Conclusion Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ‐related toxicities, 61% of patients had a possible post‐TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID‐19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use. This article is protected by copyright. All rights reserved.