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\begin{document}

\title{Ocean \& seas: Novel biomedical resources for anti-infection of
SARS-CoV-2}



\author[1]{Chunsong Hu}%
\affil[1]{Nanchang University}%


\vspace{-1em}



  
  \date{March 14, 2025}


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\selectlanguage{english}
\begin{abstract}
This article briefly reviews ocean and seas as huge and novel biomedical
resources for anti-infection, which includes tuberculosis, H. Pylori,
and HIV infection as well as SARS-CoV-2, and as promising biomedical
resources for infection-induced major non-communicable diseases (mNCDs),
such as cardiovascular disease, diabetes, and cancer. These marine
natural products (MNPs) and organisms include sea cucumbers, sea snake,
sponge, marine algae and microalgae, etc. As key biomedical resources
for the discovery of marine drugs, bioactive molecules, and agents for
treatment of infectious diseases and mNCDs, MNPs have bioactive
potentials of antioxidant, anti-infection, anti-inflammatory,
anticoagulant, anti-diabetic effects, and cancer treatment. In addition,
their anti-inflammatory mechanisms for infectious diseases are also
involved. It's time to protect ocean ecosystem for human better
sustainable development in the new era of ocean economy.%
\end{abstract}%



\sloppy


\textbf{Introduction}

According to a comprehensive survey of deep coral reefs in the high
seas, researchers think that policymakers should give more attention to
protection of ocean ecosystems and marine~mammals {[}1, 2{]}. Whether
the United Nations Ocean Conference in Lisbon in 2020 will be
rescheduled in 2021 or not, there aren't yet the answer {[}3{]}. But it
should be a priority for the future of this global ecosystem due to a
linkage with sources of sustainable food, energy, materials,
biomedicine, and many others.

Currently, ocean economy is accelerating development in the globe and
has become a vital support for human sustainable development. Marine
organisms have been considered as promising biomedical resources, marine
drugs have long been used and exhibit unique advantages in clinical
practices. Hence, it is a great task to protect and develop ocean
resources and prevent and control ocean pollution since some compounds
are valuable tools in biomedicine and applications {[}4, 5{]}.

\textbf{Ocean \& seas: Huge biomedical resources for anti-infection}

As biomedical scientists, we know that marine products are beneficial to
human health. The scientists are developing chemicals and novel
therapeutic drugs from marine natural products (MNPs) with
anti-tuberculosis activity and H. pylori infection {[}6, 7{]}, and
defensive effects against viral infection, including the SARS-CoV-2 and
HIV-1 {[}8, 9{]}. We expect that these compounds could be employed to
treat and prevent infectious diseases, including COVID-19 and AIDS, if
truly having significant antiviral activities. However, there are still
huge challenges in the discovery and development of marine drugs.

The crude extracts from marine organisms contain compounds capable of
inhibiting inflammation and potential bioactive molecules {[}10{]}.
Echinochrome pigment extracted from sea urchin has an insightful
antiulcer healing effect {[}11{]}. Bis (3-bromo-4,5-dihydroxybenzyl)
ether (BBDE,
C\textsubscript{14}H\textsubscript{12}Br\textsubscript{2}O\textsubscript{5}),
a novel bromophenol isolated from the red alga Polysiphonia morrowii
{[}12{]}, is useful for treating inflammatory diseases due to the
inhibition of LPS-induced inflammation in macrophage cells by inhibiting
the ROS-mediated ERK signaling pathway and reducing inflammatory
mediators.

As we known, MNPs are important biomedical resources for anti-infection.
There are more than 1600 new steroidal structures isolated from marine
organisms. Some steroids can regulate the farnesoid X receptor (FXR) and
the pregnane X receptor (PXR). Novel FXR and PXR agonists and
antagonists can target human diseases, e.g., intestinal inflammation
{[}13{]}. Marine invertebrate glycans (ascidians and sea cucumbers)
could be used as starting material for new therapeutics due to
anticoagulant activity and anti-inflammation {[}14{]}.

Sea cucumbers are widely consumed in traditional medicine and food.
Holothuria grisea agglutinin (HGA) has demonstrated the ability to
modulate the inflammatory response in models of inflammation in vivo.
Moreover, it is the first marine invertebrate lectin that showed an
anti-inflammatory effect {[}15{]}. Fucosylated chondroitin sulfate (fCS)
extracted from the sea cucumber Holothuria forskali, as an inhibitor of
selectin interactions, plays vital roles in inflammation and metastasis
progression {[}16{]}. Sea cucumbers-derived sterol sulfate effectively
attenuated inflammation by increasing serum adiponectin and reducing
pro-inflammatory cytokine release {[}17{]}.

A novel cathelicidin (Hc-CATH) from the sea snake Hydrophis
cyanocinctus, has potent both antimicrobial and anti-inflammatory
activity by inhibiting the LPS-induced production of nitric oxide (NO)
and pro-inflammatory cytokines such as TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}and IL-6, is a
potent candidate for the development of peptide antibiotics {[}18{]}. A
small-molecule compound isolated from marine-derived fungus,
bis-N-norgliovictin, significantly inhibits lipopolysaccharide (LPS,
ligand of TLR4)-induced tumor necrosis factor-\selectlanguage{greek}α \selectlanguage{english}(TNF-\selectlanguage{greek}α\selectlanguage{english}) production, and
exhibits potent anti-inflammatory effect both in vitro and in vivo
{[}19{]}. Hence, it can be a useful therapeutic candidate for the
treatment of sepsis and other inflammatory diseases.

As a novel marine metabolite isolated from the sponge Fasciospongia
cavernosa, Cacospongionolide B showed topical anti-inflammatory activity
and reduced the inflammatory response of adjuvant arthritis {[}20{]},
could be used as new anti-inflammatory agents. Four drug candidates from
novel bioactive sponge {[}21{]}: IPL576,092, HTI-286 (Taltobulin),
EPI-506 (Ralaniten acetate), and AQX-1125, can be used for treatment of
not only inflammation but also cancer.

As bioactive molecules with the anti-inflammatory activity,
microalgae-derived Oxylipins (OXLs) have the therapeutic potential in
inflammatory diseases {[}22{]}, could act as agonist of PPAR-\selectlanguage{greek}γ \selectlanguage{english}and
consequently inhibit NF\selectlanguage{greek}κ\selectlanguage{english}B signaling pathway activation, thus lowering
the production of inflammatory markers. Avarol is a marine
sesquiterpenoid hydroquinone with anti-inflammatory and antipsoriatic
properties {[}23{]}, it inhibits several key biomarkers up-regulated in
the inflammatory response of psoriatic skin. The marine compound
didemnin B decreases the activity of the cell types implicated in liver
inflammation and fibrosis in vitro {[}24{]}.

\textbf{Ocean \& seas: Novel biomedical resources for anti-SARS-CoV-2}

As an enveloped RNA virus, coronavirus is a major cause of human
respiratory diseases. The spike glycoprotein (SGP) is known as the main
target of antibodies having neutralizing potency and is also considered
as an attractive target for therapeutic or vaccine development. MNPs as
key and novel biomedical resources for the discovery of drugs to combat
the COVID-19 pandemic, will be more and more valuable.

Among MNPs library, 17 potential SARS-CoV-2 main protease
(M\textsuperscript{pr}) inhibitors have been identified by
structure-based techniques, and one of these compounds could be
bioactive {[}25{]}. Marine bacteria and fungi-derived bioactive 15
compounds showed promising potential roles against SARS-CoV-2 RNA
dependent RNA polymerase (RdRp) and methyltransferase (nsp16) {[}26{]}.
Some new MNPs compounds (bioactive peptides) isolated from marine
organisms (such as vertebrates, invertebrates, seaweeds, or sea
microorganisms) have a role of prevention on SARS2-Cov infection due to
potential ACE inhibition and anti-hypertensive activities {[}27{]}.

For example, some bioactive agents from marine polysaccharides and
polysaccharide-based vaccine adjuvants were developed for the fight
against SARS-CoV-2 and were used as therapeutic agents and vaccines of
COVID-19 {[}28{]}. A naturally existing sulfated polysaccharide,
lmbda-carrageenan (\selectlanguage{greek}λ-\selectlanguage{english}CGN), purified from marine red algae, could be a
promising antiviral agent for preventing infection with several
respiratory viruses since this polyanionic compound exerts antiviral
activity by targeting viral attachment to cell surface receptors and
preventing virus entry {[}29{]}. Novel marine sulfated polysaccharides
can be developed further for prophylactic as well as therapeutic
purposes due to potent anti-SARS-CoV-2 activity and affinity to the SGP
{[}30{]}.

Carbohydrate-binding agents (CBAs) from MNPs like lectins from marine
algae have shown antiviral activities against SARS-CoV-2 due to
targeting of N-linked glycans of the SGP envelope of CoV, and could also
serve as an attractive therapeutic approach for developing novel
antivirals {[}31{]}. As SARS-CoV-2 M\textsuperscript{pro}~inhibitors,
five MNPs (a benzo{[}f{]}pyrano{[}4,3-b{]}chromene, notoamide I,
emindole SB beta-mannoside, and two bromoindole derivatives) were the
most promising marine drug-like leads {[}32{]}.

Up-to-date, FDA-approved marine drugs have the potential to inhibit the
biological activity of SARS-CoV-2 main protease since they can bind at
its active site and displace water molecules at this site {[}33{]}. The
nontoxic and non-immunogenic polyphosphate (polyP), a physiological,
metabolic energy (ATP)-providing polymer, could possibly also exert a
protective effect against SARS-CoV-2-cell attachment {[}34{]}.

Thus, these marine drugs which are already in clinical use for cancer
treatment can also be used as a potential alternative to prevent and
treat infected individuals with SARS-CoV-2. Hence, the MNPs and their
derivatives could be a promising source of structurally diverse new
anti-RNA virus therapeutics {[}35{]}.

\textbf{Ocean \& seas: Promising biomedical resources for
infection-related mNCDs}

Generally speaking, chronic or acute infection highly links with
cardiovascular disease (hypertension, myocardial infarction, arrhythmia,
heart failure, and stroke), diabetes, cancer, respiratory and renal
diseases as well as the related CDC strips or Re-CDC strips {[}36,
37{]}. Some MNPs have numerous health benefits, such as antioxidant,
anti-infection, anti-inflammatory, anticoagulant, anti-diabetic effects,
and cancer treatment {[}38, 39{]}. Thus, marine drugs are not just
suitable for infectious diseases, but also for prevention and treatment
major noncommunicable diseases (mNCDs).

A study found that mineral-balanced deep sea water {[}magnesium
(Mg):calcium (Ca)=3:1{]} (MB-DSW) has anti-atopic dermatitis activity
due to regression of inflammatory chemokines {[}40{]}. Other studies
found that MB-DSW has anti-diabetic and anti-obesity action {[}41{]} due
to the stimulatory effect on mitochondrial biogenesis and function and
enriched with Mg and Ca, and the effects on cholesterol metabolism
{[}42{]} due to prevention of the high glucose- or FFA/glucose-induced
increase of cellular cholesterol levels (is its potential just like
statin drugs?), and the role of the prevention of ultraviolet
light-induced skin cancer development {[}43{]} due to enhancing skin
cell clearance through the activation of autophagic cell death.

In addition, recombinant photoproteins from different marine organisms
as a promising analytical tool have a big role in biomedical research
fields {[}44{]}, such as the measurement of Ca\textsuperscript{2+}~in
different intracellular compartments of animal cells, as labels in the
design and development of binding assays as well as the emerging use of
bioluminescence.

\textbf{Conclusion and Prospects}

Totally, this is a new era of ocean economy since biomedicine~and
particularly AIDS research are indeed a growth industry {[}45{]}. The
microbial flora, for example, K. pneumoniae HSL4 {[}46{]}, is highly
associated with industrial applications, this microbial fermentation and
related biosynthesis could be also used in the field of biomedicine. New
biomedical resources and novel biotechnologies will help to control and
combat the current COVID-19 pandemic {[}47{]}. Whatever, MNPs are worthy
of developing biomedical agents for universal health coverage when
combined with a magic ``polypill''---
``environment-sleep-emotion-exercise-diet'' intervention {[}E(e)SEEDi{]}
{[}48{]}.

However, marine radioactivity is a threat to human health or the
environment {[}49{]}. Thus, ocean environment and marine microbes play
strong roles in healthy ecosystems {[}50, 51{]}. Moreover, there are
correlations between an ocean-atmosphere and human health {[}52{]},
environmentally acquired infections and human disease {[}53, 54{]}.
Hence, only healthy ocean and seas can meet human hope in the future.
It's time to protect ocean ecosystem for human better sustainable
development.

Currently, due to the challenge of malnutrition (undernutrition and
overnutrition) in China {[}55{]}, for example, having suboptimal intakes
of seafood {[}56{]}, as food lovers {[}57{]}, we should improve
nutrition status with effective strategies. Since there is a link
between nutrition status and COVID-19 {[}58{]}, we should assess
positively the nutritional risks in COVID-19 cases with useful tools
{[}59, 60{]}, so as to promote nutritional care and the nutrition
management in these patients {[}61{]}. And by the online-to-offline
(O2O) food delivery {[}62{]} during the COVID-19 pandemic, people will
combat effectively the SARS-CoV-2 and its variants.

\textbf{Abbreviations}

Carbohydrate-binding agents (CBAs); fCS: Fucosylated chondroitin
sulfate; FXR:

farnesoid X receptor; HGA: Holothuria grisea agglutinin; MB-DSW:

mineral-balanced deep sea water; mNCDs: major non-communicable diseases;
MNPs:

marine natural products; NO: nitric oxide; lipopolysaccharide (LPS);
O2O:

online-to-offline; PXR: pregnane X receptor; RdRp: RNA dependent RNA

polymerase; SGP : spike glycoprotein; TNF-\selectlanguage{greek}α: \selectlanguage{english}tumor necrosis factor-\selectlanguage{greek}α.

\selectlanguage{english}\textbf{Acknowledgments}

The reviewers and editors are gratefully acknowledged for critical
review.

\textbf{Author contributions}

CH drafted the manuscript. CH contributed to the critical revisions of
the manuscript. CH is the corresponding author. All authors read and
approved the final manuscript.

\textbf{Funding}

No funding was received for this work.

\textbf{Availability of data and materials}

Not applicable.

\textbf{Ethics approval and consent to participate}

Not applicable.

\textbf{Consent for publication}

Not applicable.

\textbf{Competing interests}

No competing interests.

\textbf{Author details}

Chunsong Hu, MD, PhD, Associate Professor of Medicine, Nanchang
University, Department of Cardiovascular Medicine, Hospital of Nanchang
University, Jiangxi Academy of Medical Science, No. 461 Bayi Ave,
Nanchang 330006, Jiangxi, China. Tel: (0086) 189 7081 6800; Email:
cnhucs@163.com; ORCID: 0000-0002-0590-3909

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