marine drugs

Review
Sea Urchin Pigments: Echinochrome A and Its Potential
Implication in the Cytokine Storm Syndrome
Tamara Rubilar 1,2, *, Elena S. Barbieri 2,3 , Ayelén Gazquez 4 and Marisa Avaro 1

1 Laboratorio de Química de Organismos Marinos, Instituto Patagónico del Mar, Universidad Nacional de la
Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina; [email protected]
2 Laboratorio de Oceanografía Biológica, Centro Para el Estudio de Sistemas Marinos (CESIMAR), CONICET,
Puerto Madryn 9120, Chubut, Argentina; [email protected]
3 Laboratorio de Virología, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan
Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina
4 Instituto Tecnológico de Chascomús, The Chascomús Technological Institute (INTECH), CONICET-UNSAM,
Chascomús 7130, Buenos Aires, Argentina; [email protected]
* Correspondence: [email protected]; Tel.: +54-9-280-4204909

Abstract: Background: Echinochrome A (EchA) is a pigment from sea urchins. EchA is a polyhy-
droxylated 1,4-naphthoquinone that contains several hydroxyl groups appropriate for free-radical
scavenging and preventing redox imbalance. EchA is the most studied molecule of this family and is
an active principle approved to be used in humans, usually for cardiopathies and glaucoma. EchA
is used as a pharmaceutical drug. Methods: A comprehensive literature and patent search review



was undertaken using PubMed, as well as Google Scholar and Espacenet search engines to review


these areas. Conclusions: In the bloodstream, EchA can mediate cellular responses, act as a radical
Citation: Rubilar, T.; Barbieri, E.S.; scavenger, and activate the glutathione pathway. It decreases ROS imbalance, prevents and limits
Gazquez, A.; Avaro, M. Sea Urchin lipid peroxidation, and enhances mitochondrial functions. Most importantly, EchA contributes to the
Pigments: Echinochrome A and Its
modulation of the immune system. EchA can regulate the generation of regulatory T cells, inhibit
Potential Implication in the Cytokine
pro-inflammatory IL-1β and IL-6 cytokine production, while slightly reducing IL-8, TNF-α, INF-α,
Storm Syndrome. Mar. Drugs 2021, 19,
and NKT, thus correcting immune imbalance. These characteristics suggest that EchA is a candidate
267. https://doi.org/10.3390/
drug to alleviate the cytokine storm syndrome (CSS).
md19050267

Academic Editors: Natalia

Keywords: cytokine storm syndrome; natural products; sea urchin; pigments; spinochromes
P Mishchenko, Elena A. Vasileva and
Marc Diederich

Received: 25 February 2021 1. Introduction

Accepted: 23 April 2021 A wide scope of published research indicates that the molecule echinochrome A
Published: 11 May 2021 (EchA) is a potent free-radical scavenger, diminishing reactive oxygen species (ROS) and
preventing redox imbalance [1]. In addition, EchA can enhance the immune system
Publisher’s Note: MDPI stays neutral response and, in terms of mitochondrial functioning, helps to increase glutathione (GSH)
with regard to jurisdictional claims in levels [2–4]. In the following sections, we describe the how EchA can contribute to alleviate
published maps and institutional affil-
the Cytokine Storm Syndrome (CSS). First, we describe the pharmacological applications
iations.
of EchA, and then address the mechanisms by which EchA decreases ROS and maintains
redox balance. The second section details how EchA influences the immune system
response. Finally, we highlight the major issues regarding CSS and examine the potential
role of EchA as an agent alleviating CSS.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland. 2. Echinochrome A and Its Pharmacological Applications
This article is an open access article Polyhydroxylated 1,4-naphthoquinones are pigments found in sea urchin shells,
distributed under the terms and
spines, gonads, coelomic fluid, and eggs, commonly known as spinochromes [5–8]. Quinones
conditions of the Creative Commons
are known to have pharmacological properties [9]. In particular, the spinochromes contain
Attribution (CC BY) license (https://
several hydroxyl groups. These groups are appropriate for free-radical scavenging, which
creativecommons.org/licenses/by/
diminishes ROS and prevents redox imbalance [10] (Figure 1). Echinochrome A (EchA,
4.0/).

Mar. Drugs 2021, 19, 267. https://doi.org/10.3390/md19050267 https://www.mdpi.com/journal/marinedrugs

Mar. Drugs 2021, 19, 267 2 of 11

6-ethyl-2,3,5,7,8-pentahydroxy-1,4-naphthoquinone) is the most researched molecule of

this family and is the active substance in the drug Histochrome™. This drug was de-
veloped, patented, and approved in Russia (PN002363/02-2003, EP1121929A1). This
pharmaceutical preparation comprises the biologically active additive dietary supple-
ment, Thymarin® , which is orally ingested (Sanitary-Epidemiological Conclusion No.
77.99.03.935.Á.000138.06.04 dated 14 June 2004, TU 9350-064-02698170-2004; RU2340216C1).
The chemistry and pharmacokinetics of EchA [11] were investigated and EchA was used
in orally ingested formulations [12], complying with the Lipinski Rule of five for orally
available compounds (data not published). We summarize the focus of our investigation
in terms of pharmacological effects in Table 1. The bioactive actions of spinochromes
are numerous, indicating that spinochromes can potentially be used for several different
medical conditions. We focus on the effect of EchA on the redox imbalance and on the
immune system due to its impact on CSS.

Figure 1. Chemical structures of 1,4-polyhydroxylated naphthoquinone derivatives from sea urchins. Created with
JSME-Jmol (accessed on 9 September 2020).

Table 1. Pharmacological effects of spinochromes.

Spinochrome Effect Experimental model Reference

Spinochrome D, E Antiallergic effect Guinea pigs [13]
Echinochrome A Antigen-stimulated degranulation in cellular systems RBL-2H3 cells [14]
Echinochrome A Antioxidant on bleomycin-induced pulmonary fibrosis Rats [15]
Inflammatory bowel disease and correcting immune
Echinochrome A Mouse [16]
system imbalance
Mar. Drugs 2021, 19, 267 3 of 11

Table 1. Cont.

Spinochrome Effect Experimental model Reference

Echinochrome A Cardioprotective activity Human [17]
Echinochrome A Acetylcholinesterase inhibition H9c2 and A7r5 cells [18]
Echinochrome A Antistress effect Bone marrow cells in SHK mice [19]
Amelioration of intraocular inflammation (uveitis)
Echinochrome A Lewis rats [20]
caused by endotoxins
Decreased risk of atherogenesis and improvement of
Echinochrome A Human [21]
glutathione metabolism
Rat cardiac myoblast H9c2 cells
Echinochrome A Cardiomyocyte protection against toxic agents [1]
and isolated rat cardiomyocytes.
Echinochrome A Reduction in diabetic complications in liver Wistar albino rats [22]
Improvement of the musculoskeletal system and the
Echinochrome A metabolism of lipids and proteins in both types of Wistar albino rats [23]
diabetes mellitus
Improvement in the renal function and ameliorating
Echinochrome A Winstar albino rats [3]
renal histopathological
Echinochrome A Enhancement in exercise capacity Sprague–Dawley rats [24]
Prevention and/or deceleration of PD-like
Echinochrome A Rats [25]
neurodegeneration
Hepatoprotective effect against intrahepatic
Echinochrome A Rats [26]
cholestasis induced by toxic agents
Echinochrome A Enhancing cardiomyocyte differentiation Mouse embryonic stem cells [27]
Echinochrome A Potentiating the effectiveness of antitumor therapy Ehrlich ascites carcinoma model [28]
Human cardiomyocyte cell line
Cardioprotective against the cytotoxicity of
Echinochrome A (AC16) and human breast cancer [29]
doxorubicin
cell line (MCF-7)
Echinochrome A Liver antiseptic Albino rats [30]
Improvement in lipid profile, liver functions, kidney
Echinochrome A Rats [31]
functions, and antioxidant markers
Cardioprotective against the cytotoxicity of
Echinochrome A AC16 human cardiomyocyte cells [4]
doxorubicin
Echinochrome A Hypolipidemia in obesity Rats [31]
Prevention of atherosclerotic inflammation, SOD3
Echinochrome A Human [12]
mimetic, improves the response of the immune system
Protective effects on the extracellular matrix of vocal
Echinochrome A Ovariectomized rats [32]
folds in
Antitumor activity, decreases lipid peroxidation, and Ehrlich ascites carcinoma tumor
Echinochrome A [33]
improves antioxidant status model in mice
Echinochrome A Anti-inflammatory effect Rats [34]

3. Echinochrome A and Redox Imbalance

Free radicals (superoxide, hydroxyl radicals, nitric oxide, and peroxynitrite) are de-
structive molecules when they are imbalanced. This imbalance generates oxidative stress
that can produce different types of damage to varying degrees: protein deterioration, DNA
damage, lipid peroxidation, and can even result in cell death and organ failure [35–37]. The
human body incorporates a complex antioxidant network that fights against free radicals
to resist vital biomolecular damage. The first line of defense in the antioxidant network
is generated by endogenous enzymes, superoxide dismutase (SOD), catalase (CAT), and
Mar. Drugs 2021, 19, 267 4 of 11

glutathione peroxidase (GPX) [38]. SOD catalyzes the dismutation of superoxide to oxygen
and hydrogen peroxide. Hydrogen peroxides are key in mediating systemic signals and
regulating transcription factors such as the protein complex NF-κB. This transcription
factor is important in controlling inflammatory responses. Such responses include nuclear
factor erythroid 2-related factor 2 (Nrf2), which stimulates the transcription of target genes,
resulting in an antioxidant response [39], and protects cells from inflammation [40]. An-
other such response is mediated by peroxisome proliferator-activated receptors (PPAR-γ),
which regulate cell metabolism and heat shock proteins [41]. CAT constitutes an important
enzymatic defense as it allows for the independent control and maintenance of H2 O2 in
cell culture, ensuring the decomposition of hydrogen peroxide into water and oxygen [42].
GPX uses glutathione (GSH) to reduce hydrogen peroxide and other peroxides, such as
hydroperoxides and xenobiotics.
The second line of antioxidant defense comprises the balance of various antioxidant
compounds, such as GSH, which is partly regulated by GPX and neutralizes or eliminates
free radicals into harmless redox species [38]. An ideal antioxidant compound should
scavenge ROS and break down modular networks to avoid lipid peroxidation and GSH
depletion [38].
EchA treatment in diabetic mice showed a glucose concentration reduction as well
as a general increase in glutathione-S-transferase (GST), SOD, and CAT activities. It also
evidenced an incremental increase in GSH and oxide nitrogen concentration, and improved
general renal function [3]. In addition, the malondialdehyde (MDA) concentration, a
generally accepted marker of lipid peroxidation, diminished when mice were treated with
EchA [3]. EchA administration also showed indications of improving liver function in
diabetic mice and diminishing glucose and MDA concentrations. Furthermore, there was a
general increase in the levels of insulin and the activities of GST, GPx, and SOD enzymes, as
well as a general increase in the GSH concentration [22]. In Wistar albino rats with diabetes
mellitus, EchA treatment also resulted in a reduction in glucose and MDA levels, but
simultaneously showed increases in GST, SOD, and GPx activities. GSH concentration also
increased in Wistar albino rats [22]. In addition, EchA was noted as potentially comprising
an alternative antiseptic remedy due to the finding that its administration to Winstar albino
rats improved their liver function by counterbalancing hepatic oxidative stress through the
increase in the GSH concentration, as well as of SOD, CAT GPX and GST activities, and
by downregulating MDA and nitric oxide [30]. EchA applied as an antitumor treatment
in Swiss albino mice with Erlich ascites tumors also resulted in increases in CAT and
GST activities, as well as an increased in GSH concentration. This effectively reduced the
tumor volume [33]. In hyperlipidemic rats, EchA administration showed hypolipidemic
effects and a significant increase in antioxidant markers, such as GST, CAT, and GSH.
Furthermore, EchA in these rats showed a reduction in MDA [31]. In postnatal rats, EchA
was also observed to diminish the severity of bleomycin-induced oxidative stress in the
lungs, preventing the hypertrophy of interalveolar connective tissue and peribronchial
lymphoid infiltration [15]. In cardiomyocytes treated with doxorubicin, EchA produced
a decrease in ROS [1], whereas spinochrome D, a structural analog to EchA, showed an
increase in the ATP production, the oxygenation of cells, and increased GSH levels [1,29].
In humans, EchA treatments have resulted in improvements in glucose metabolism,
inhibition of lipid peroxidation processes, and an increase in CAT activity and GSH
concentration [12,21]. The increase in hydrogen peroxide by EchA generates increases in
peroxisomes and mitochondria in cells, leading to an increase in CAT activity [12,21,43]. In
humans, EchA showed nitric-oxide- and hydrogen-peroxide-mimicking effects in endothe-
lial and smooth muscle vascular cells. This generated vasodilation and reduced ischemia
and hypoxia [12,44].
Overall, the effects of EchA appear to implicate its potential role as an ideal antioxidant.
This is due to its ability to neutralize ROS, chelate metals, and serve as an intracellular
messenger, promoting hydroperoxides decomposition, avoiding lipid peroxidation, and
increasing GSH production. As a consequence, mitochondria perform better, and the
Mar. Drugs 2021, 19, 267 5 of 11

oxygen and ATP levels increase in the cell [12,21,43,44]. In summary, EchA acts as a
primary antioxidant by attacking superoxides, but also works as a secondary antioxidant
by increasing the hydrogen peroxide level, mimicking the SOD enzyme, and triggering the
GSH pathway (Figure 2).

Figure 2. EchA mediates cellular responses, acts as a radical scavenger preventing lipid peroxidation,
improves mitochondrial activity, and activates the glutathione pathway, diminishing the overall ROS
imbalance. Created with BioRender.com (accessed on 9 September 2020).

4. Echinochrome A and Immune System Response

As free radicals play an important role in the regulation of cytokines, growth factors,
cell signaling, immunomodulators, etc. [45], maintaining redox imbalance also affects
the regulation of these pathways. EchA is able to induce changes in the T-helper link
and increase the number of B-lymphocytes and human leukocyte antigens (HLA-DR),
triggering the cooperation among immune cells, as well as increasing antigen processing
and presentation [12] (Figure 3). This relationship between EchA and the immune response
has been observed in studies on the influenza virus using EchA as an adjuvant in antisera
preparations [46], as well as using EchA treatments applied orally or by injection [12]. In
addition, EchA regulates the immune response by promoting the generation of regulatory
T cells (Tregs). These Tregs cells play a critical role in inhibiting T cell proliferation and
cytokine production. Tregs control the immune response to antigens and help prevent
autoimmune diseases, without affecting the Th1 or Th2 populations. As Tregs functions are
key immunomodulators regulating the activation of other Th cells, EchA may contribute
to correct immune imbalances by inducing the Tregs population [16]. As EchA acts as an
agonist for aryl hydrocarbon receptors (Ahr), it is able to switch the immune response
toward Th1 and inhibit the NF-κB pathway (Figure 4) [12]. It was shown that EchA
can not only highly decrease proinflammatory cytokines IL-1β and IL-6, but can also
slightly reduce IL-8, TNF-α, INF-α, and NKT [12] (Figure 4), helping with the decrease in
cellular inflammation. Generally, M1 macrophages mediate excessive and persistent pro-
inflammatory effects, and M2 macrophages contribute to the regeneration and resolution
of inflammatory tissues. EchA was shown to diminish the secretion of TNF-α derived from
M1 macrophages in a dose-dependent manner and to increase the level of basal secretion of
IL-10-inducing M2 macrophages. This change in the immune response leads to a decrease
in cellular inflammation [16]. In addition, the hydrogen peroxide produced by EchA
in the bloodstream induces the overexpression of a co-activator of the PGC-1α, PPAR-γ
receptor [21,43,47], up-regulating Fas (CD95+) and Fas-ligand (CD178+) [48], primarily in
the activated cells in the immune system, such as Th1 and NK cells [48,49]. EchA can boost
the immune response because it intensifies the intercellular cooperation of immune cells
and increases the process and presentation of antigen.
Mar. Drugs 2021, 19, 267 6 of 11

Figure 3. EchA may increase human leukocyte antigens (HLA-DR) in B lymphocytes, increasing
antigen processing and presentation. Created with BioRender.com.

Figure 4. Proposed inhibition of NF-κB pathway by EchA through aryl hydrocarbon receptor (Ahr).
Created with BioRender.com.

5. Cytokine Storm Syndrome

The term cytokine storm syndrome (CSS) has received much attention, both in popular
media and scientific literature during the last twelve months due to CSS being a common
occurrence in COVID-19 patients with comorbidities [50–55]. CSS is a systemic inflamma-
tory response mediated by cytokines resulting in overwhelming systemic inflammation,
hemodynamic instability, multiple organ dysfunction, sepsis, fever, hyperferritinemia, and,
in many cases, death [56–58]. The cytokines function comprises intercellular signaling and
communication. Cytokines are small proteins that, by binding to the receptor, trigger a
variety of responses, including immune and inflammatory responses [57]. As cytokines
are part of the innate immune system, CSS is not a disease in and of itself, but rather
comprises a hyperactive response of the immune system to infectious agents, malignant
tumors, rheumatic diseases, iatrogenic injury, and immunotherapeutic drugs; however,
infection agents like viruses and bacteria are the most common cause [54,55]. With CSS,
the release of cytokines is injurious to the host cells and damages the organs, which is
sometimes irreparable [58–60]. CSS is triggered by the release cytokines interferon (IFN)-
γ, tumor necrosis factor (TNF), and interleukin (IL)-1, IL-6, and IL-18 [61–64]. Despite
Mar. Drugs 2021, 19, 267 7 of 11

the significant amount of research on this topic, the pathogenesis of CSS is not yet fully
understood. Still, it appears to be generally agreed upon that there is an imbalance in
proinflammatory and anti-inflammatory agents and pathways during CSS. As a result, the
majority of the treatments comprise immunosuppression together with treatment seeking
to control the initial trigger of the production of CSS [57,59,65]. However, it is the combi-
nation of pharmaceutical, nutraceutical, and adjunctive treatments that might help in the
fight against CSS. When CSS occurs, an inability to resolve the inflammation arises, causing
catastrophic damage [66]. As a result, the ability to sufficiently regulate the inflammatory
response may prevent the body from systemic inflammation. Cytokine balance needs to be
restored to effectively resolve the inflammation caused by environmental influences, such
as infection agents.
During CSS, release of cytokines increased, specifically IL-1 β, IL-6, and TNF-α; all
of the cytokines comprise proinflammatory factors [57,67] leading to an increase in ROS
production by the mitochondria [68]. In turn, ROS activates signal transduction path-
ways, such as NF-κB, which also stimulate the production of pro-inflammatory cytokines,
generating increased inflammation and redox imbalance [66]. GSH is the most impor-
tant intracellular system in scavenging these ROS [69,70]. However, the presence of ROS
overproduction often leads to GSH depletion [69], which has serious consequences in
the protective functions of organs, often leading to an immunocompromized state due
to the impairment of the functions of lymphocytes, macrophages, and neutrophils. In
some cases, GSH depletion triggers lymphopenia through the activation of the apoptotic
cascade [71,72]. In this context, to counterbalance oxidative stress, it is most important to
prevent GSH depletion and its negative consequences during CSS.

6. Echinochrome A and Cytokine Storm Syndrome

Although no specific treatment exists for CSS, immunosuppression, anti-inflammatory
and antioxidant treatments have been suggested to be suitable approaches in reducing and
modulating CSS, and the resulting hyper-inflammation and GSH depletion
(Table 2). IL-1- and IL-6-inhibiting agents were found to diminish CSS by preventing
inflammation. Anakinra is an IL-1-inhibiting agent that is able to block IL-1 by competi-
tively inhibiting their binding to IL-1 receptors [73,74]. Although other agents may inhibit
IL-1, such as canakinumab and rilonacept, further research is needed [54]. Tocilizumab is
an IL-6-inhibiting agent (monoclonal antibody) that binds to soluble and membrane-bound
IL-6 receptors, and was proven to be an efficient therapy to alleviate CSS when combined
with T cell engaged therapy [75]. However, this was shown not to apply to every case of
CSS [76]. Curcumin was shown to suppress multiple cytokines in conditions associated
with CSS. Still, curcumin is poorly absorbed from the intestinal tract, hence, requiring intra-
venous formulations [77]. As EchA is able to reduce the production of pro-inflammatory
cytokines IL-1β and IL-6, to increase anti-inflammatory cytokines such as IL-10 [12], and
to diminish TNF-α secretion [19,28], EchA may help to restore the proinflammatory and
anti-inflammatory balance and, as such, aid in the alleviation of CSS.

Table 2. Proposed treatments for CSS.

Treatment Effect in CSS Reference

Anakinra IL-1-inhibiting agent [73]
Canakinumab IL-1-inhibition agent [54]
Rilonacep IL-1-inhibition agent [54]
Tocilizumab IL-6-inhibiting agent [75]
Curcumin Cytokines suppressor [77]
Enzyme CAT Antioxidant agent: cytokine production regulator through the GSH pathway [78]
N-acetylcysteine (NAC) IL-6-inhibiting agent through the GSH pathway [66]
Mar. Drugs 2021, 19, 267 8 of 11

The counterbalancing of oxidative stress is crucial in CSS [50] to prevent GSH de-
pletion and its disastrous consequences [69]. Counterbalancing oxidative stress is also
important in avoiding signal transduction pathways that stimulate pro-inflammatory cy-
tokines production [66]. As a result, treatments that are able to reduce ROS can help with
treating CSS. The use of the enzyme CAT was proposed as CAT was to have an anti-
inflammatory effect by regulating cytokine production and providing protection against
oxidative injury in human leukocytes and alveolar epithelial cells [78]. This enzyme is safe
and commonly used as a food additive and dietary supplement. N-acetylcysteine (NAC)
was also suggested for use in preventing CSS [66], as it is a prodrug to L-cysteine and,
in turn, L-cysteine is a precursor to GSH. NAC was shown to inhibit the production of
pro-inflammatory cytokine IL-6 in H5N1-infected lung cells [79]. However, current clinical
evidence indicates that its bioavailability is low [80]. Considering all these factors, EchA
may play a crucial role in CSS treatment as one of its most important characteristics is that
it can increase GSH metabolism and, as such, prevent the GSH depletion found in CSS
patients [3,12,21,22,30,43,44].
In summary, EchA may provide multiple impacts including the reduction in in-
flammation, ROS scavenging, and the induction of GSH pathways. In addition, EchA’s
pharmacological activities, low toxicity level [5], and high bioavailability according to
Lipinski’s rule of five (data unpublished) all strongly support the view that EchA can
potentially be used in CSS therapy.

Author Contributions: T.R. conceived the idea and content and wrote the paper. E.S.B. and A.G.
performed the literature search, and participated actively in the discussion and writing of the paper.
M.A. participated in the patent search and the discussion of the paper. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: The authors thank Kathleen C. Anderson for the English correction and review
and Augusto Crespi for reading the manuscript and discussions.
Conflicts of Interest: The authors declare no conflict of interest.

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