Immunomodulatory Compounds from the Sea: From the Origins to a Modern Marine Pharmacopoeia

Abstract

From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.

Full text

Citation: Cutolo, E.A.; Campitiello,
R.; Caferri, R.; Pagliuca, V.F.; Li, J.;
Agathos, S.N.; Cutolo, M.
Immunomodulatory Compounds
from the Sea: From the Origins to a
Modern Marine Pharmacopoeia. Mar.
Drugs 2024,22, 304. hps://doi.org/
10.3390/md22070304
Academic Editors: Angelo Fontana
and Carmela Gallo
Received: 27 May 2024
Revised: 24 June 2024
Accepted: 26 June 2024
Published: 28 June 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Swierland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Aribution (CC BY) license (hps://
creativecommons.org/licenses/by/
4.0/).
marine drugs
Review
Immunomodulatory Compounds from the Sea: From the
Origins to a Modern Marine Pharmacopoeia
Edoardo Andrea Cutolo 1, *,†, Rosanna Campitiello 2, 3, †, Roberto Caferri 1, Viorio Flavio Pagliuca 1, Jian Li 4,
Spiros Nicolas Agathos 4, 5 and Maurizio Cutolo 2, 3
1Laboratory of Photosynthesis and Bioenergy, Department of Biotechnology, University of Verona, Strada le
Grazie 15, 37134 Verona, Italy
2Laboratory of Experimental Rheumatology and Academic, Division of Clinical Rheumatology, Department
of Internal Medicine, University of Genoa, 16132 Genoa, Italy
3IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
4Qingdao Innovation and Development Base, Harbin Engineering University, No. 1777 Sansha Road,
Qingdao 150001, China; jian.li@hrbeu.edu.cn (J.L.); spiros.agathos@hrbeu.edu.cn (S.N.A.)
5Bioengineering Laboratory, Earth and Life Institute, Catholic University of Louvain,
B‑1348 Louvain‑la‑Neuve, Belgium
*Correspondence: edoardoandrea.cutolo@univr.it
†These authors contributed equally to this work.
Abstract: From sea shores to the abysses of the deep ocean, marine ecosystems have provided human‑
ity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharma‑
copoeias of dierent times and geographic regions and is still deeply rooted in traditional medicine.
Thanks to present‑day, large‑scale bioprospecting and rigorous screening for bioactive metabolites,
the ocean is coming back as an untapped resource of natural compounds with therapeutic poten‑
tial. This renewed interest in marine drugs is propelled by a burgeoning research eld investigating
the molecular mechanisms by which newly identied compounds intervene in the pathophysiology
of human diseases. Of great clinical relevance are molecules endowed with anti‑inammatory and
immunomodulatory properties with emerging applications in the management of chronic inam‑
matory disorders, autoimmune diseases, and cancer. Here, we review the historical development
of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug
discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine re‑
sources through biotechnology.
Keywords: bioprospecting; inammation; autoimmunity; synthetic biology; drug discovery; genetic
engineering; immunomodulation; deep sea; systemic sclerosis; rheumatoid arthritis
1. Why Does the Sea Maer for Human Health?
From the birth of human civilization to the rise of the modern global economy, the
ocean has been a core element for development, providing waterways for exploration, cul‑
tural exchanges, and trade [1]. From the philosophers of the classical antiquity to present‑
day oceanographic expeditions, the scientic study of the sea has been a constant human
endeavour stimulated by the fascination with its biological diversity [2].
The classication of marine life, however, is still far from oering a conclusive picture.
According to initial estimates, of the ~8.75 million species inhabiting the planet, ~2.2 mil‑
lion live in the oceans, ~91% of which still await description [3]. Recent reconsiderations,
however, suggest that marine biodiversity, particularly of fungi, protists, and prokaryotes,
has been signicantly underestimated, now projected to the millions [4,5].
The latest census of marine life, the World Register of Marine Species, contains
~242,000 species. Despite growing quickly (on average, 2332 new species every year), this
repository is expected to include the remaining 1–2 million undescribed species, thus en‑
tirely covering marine life, only several hundred years from now [6].
Mar. Drugs 2024,22, 304. https://doi.org/10.3390/md22070304 https://www.mdpi.com/journal/marinedrugs

Mar. Drugs 2024,22, 304 2 of 32
Oceans are still largely underexplored sources of lead compounds [7]. From coral
reefs to hydrothermal vents, the ocean is characterized by diverse habitats, including ex‑
treme environments such as the deep‑sea benthic zones [8], where unique ecosystems
thrive. Therefore, the sea is an untapped source of chemodiversity to look for secondary
metabolites and bioactive compounds with potential applications in human health, some
having already entered clinical practice [9–13]. Immune‑mediated inammatory diseases
are a signicant burden for national healthcare systems, especially in high‑income coun‑
tries, with an increasing incidence registered over the last three decades [14,15]. Moreover,
in nearly all forms of cancer, chronic inammation is involved in disease development [16].
Pharmacological immunomodulation is, therefore, crucial to restore the homeostasis of the
immune system in situations of both over‑ and under‑reaction [17,18].
Virtually all marine phyla, from phytoplankton to invertebrates, produce bioactive
compounds with pharmacological potential [19–22], including anti‑inammatory and im‑
munomodulatory properties [23–27]. Although marine pharmacology has its roots in an‑
tiquity, the ocean is witnessing a scientic renaissance propelled by interdisciplinary drug
discovery research assisted by powerful, high‑throughput technologies like untargeted
metagenomics and metabolomics [28–31].
2. Marine Pharmacology in the Mists of Time
From time immemorial, marine ora and fauna have been used in folk and tradi‑
tional medicine (TM) [32]. However, in most cases, this knowledge is orally transmied;
therefore, ethnomedicinal approaches of drug discovery are not always straightforward.
Nonetheless, since TM is the mainstay of healthcare delivery in 80% of African and Asian
countries [33,34], this heritage is a valuable resource for the identication of new bioactive
compounds [35,36].
Since the dawn of mankind, seaweeds (macroalgae) have been consumed in the diet
and for medicinal purposes [37], as revealed by archaeological records from 2500 BC sug‑
gesting the trading of kelp (Laminariales) between coastal and mountainous areas of the
Peruvian and Chilean Andes [38–40]. Similarly, the Incas from the Andean lakes of Peru
and the Aztecs in the Valley of Mexico consumed the cyanobacterial species Nostoc spp.,
Phormidium tenue, and Chroococcus turgidus [41,42].
Marine zootherapy is still practiced in West Africa, Central and South America, and
East Asia [43–48]. Recent ethnopharmacological studies described at least 300 TM uses
of marine animals globally [49,50], of which, however, only invertebrates were conrmed
sources of therapeutic compounds [51]. The overexploitation of marine animals in TM, par‑
ticularly of mammals, hawksbill sea turtles (Eretmochelys imbricata), manta rays, and devil
rays (Mobulidae), is a recognized risk factor for wildlife population decline and species
extinction [52–54], and, in turn, precludes the identication of new, potentially therapeu‑
tic compounds [55]. Therefore, international regulatory policies are urged to restrict the
hunting and marketing of threatened species and to promote the conservation of fragile
marine ecosystems [56,57].
3. The Origins of Marine Pharmacology and Immunology in the West
Descriptions of medical uses of marine animals are found in Greek and Byzantine
texts from the classical antiquity (fth century BC–7th century AD) [58,59], including the
De Materia Medica by the father of Western pharmacognosy, Pedanius Dioscorides
(40–90 AD) [60], and the De natura animalium by the Roman author Claudius Aelianus
(175–235) [61]. Similarly, seaweeds are mentioned in the Corpus Hippocraticum by Hip‑
pocrates of Kos (460–370 BC), in the Historia Plantarum by Theophrastus (350–287 BC), and
in the Naturalis Historia by Gaius Plinius Secundus (Pliny the Elder, 23–79 AD) [62,63].
Moreover, around this time, the Roman author Aulus Cornelius Celsus (25 BC–50 AD)
formulated the oldest recorded denition of inammation: “Notae vero inammationis sunt
quatuor: rubor et tumor cum calore et dolore” (the signs of inammation are four: redness,
swelling, fever, and pain) [64]. From the second century BC onwards, technology and sci‑

Mar. Drugs 2024,22, 304 3 of 32
ence [65,66] constantly owed between the Far East and the Mediterranean via the Silk
Road (Sichou zhi lu,丝绸之路), a network of land and sea trading posts connecting the
Greco‑Roman world with Mongolia and China via the Middle East, Eurasia, Persia, and
India. Besides primarily serving geopolitical interests [67], the Silk Road promoted the
reciprocal exhange of medical and pharmacological knowledge between the Far East and
the Western world [68,69].
During the Age of Discovery in the fteenth century, European countries assembled
vast collections of ora from overseas, de facto establishing global bioprospecting, although
ethnobotanical knowledge was also lost due to the forced conversion of the indigenous
peoples to Christianity, especially by the Conquistadores [70]. Nonetheless, exotic species
incessantly owed from the overseas colonies in the four corners of the world to the main
cultural centers of Europe, resulting in new discoveries in pharmacology [71] and West‑
ern medicine eventually being united in 1948 under the aegis of the International Pharma‑
copoeia of the World Health Organization [72].
In the 1960s, Western science achieved a deeper understanding of immunity and in‑
ammation with the elucidation of the structure of antibodies and their generation via ge‑
netic recombination, as well as the identication of antibody‑producing B cells, regulatory
T‑lymphocytes, and dendritic cells as antigen‑presenting cells. Ironically, the concept of
autoimmunity—the condition whereby toxic autoantibodies recognise self‑antigens, caus‑
ing chronic inammation—was formulated in 1892 by German physician Paul Ehrlich, al‑
though it was rejected as “physiologically inconceivable” and referred to as “horror auto‑
toxicus” [73]. Only in 1965 was autoimmunity recognized as a common immunological
disorder underlying the pathogenesis of chronic inammatory diseases [74]. Eventually,
the invention of monoclonal antibodies and their application in clinical practice, as well
as the discovery of cellular checkpoint control, paved the way for cancer immunotherapy
and targeted therapies for autoimmune diseases [75]. Today, a plethora of inammatory
mediators are known, including sub‑populations of immune cell types, their released solu‑
ble factors (cytokines, antibodies), and the intracellular genetic and molecular mechanisms
which sustain inammatory disease [76].
4. The Evolution of Marine Materia Medica in the Far East
Wrien records of marine ora appear in the 2500‑year‑old Chinese book the Classic
of Poetry (Shijing,诗经) [77–80]. The main pharmacological heritage in the Far East, how‑
ever, is the Bencao, a series of compendia of materia medica produced over 2000 years [81].
Among the earliest versions, the Xinxiu Bencao (新修本草,Newly Revised Materia Medica) is
the rst pharmacopoeia commissioned by Imperial order during the Tang dinasty
(618–907) and the oldest example of national codex, describing 850 medicinals, many of
which are still used in Chinese TM [82]. Under the Tang rule, China became a cosmopoli‑
tan society by incorporating foreign cultural elements introduced via the Silk Road [83],
like those found in the Haiyao Bencao (海藥本草,Overseas Pharmacopoeia or Pharmacopoeia of
Foreign Drugs) compiled by Li Xun (855‑930), a Chinese‑born Persian physician [84]. The
subsequent Zheng Lei Ben Cao (證類本草,Materia Medica Arranged According to Paern) was
compiled in 1108 AD during the Song Dynasty (960–1279) and included 1746 medicinals,
among which are two marine macroalgae: Gloiopeltis furcata (Rhodophyta) and Laminaria
(Saccharina)japonica (or sweet kelp, Phaeophyceae) [85,86]. The Bencao Tujing (圖經本草,
Illustrated Classic of Materia Medica, 1061) and the Zhu Fan Zhi (诸蕃志,A Description of Bar‑
barian Nations, 1225), also published under the Song rule, reected the impact of the Mar‑
itime Silk Road seafaring on the evolution of Chinese medical knowledge [87–89]. Under
the Mongol‑led Yuan Dynasty (1271 to 1368), scientic ideas circulated inside the Empire
via the Indian Ocean trade routes [90], and, as a result, the Islamic formulary Huihui Yaofang
(回回藥方考釋,Muslim Medicinal Recipes) became a reference Imperial medical text [91,92].
During the Great Ming Dynasty (1368–1644), the court physician Li Shizhen (1518–1593)
compiled the Bencao Gangmu (本草綱目,Compendium of Materia Medica), an outstanding
piece of scientic literature describing 1892 medicinals. This text includes a detailed de‑

Mar. Drugs 2024,22, 304 4 of 32
scription of marine fauna and ora and stood until the nineteenth century as a reference
for taxonomical classication in East Asia [93]. Notably, the Bencao Gangmu contains med‑
ical prescriptions based on seaweeds of the Ulvophyceae, Phaeophyceae, Florideohyceae,
Trebouxiophyceae, and Bangiophyceae classes; cyanobacteria of the Nostoc genus; and sea‑
horses [94,95].
The species Hippocampus kuda is known to produce an antitumor peptide with in‑
hibitory activity on major intracellular signalling cascades: the nuclear factor kB (NF‑kB)‑
mediated pathway, the Janus kinase 2/Signal Transducers and Activators of Transcription
3 (JAK2/STAT3) pathways, and the Jun N‑terminal kinase (JNK)/p38 mitogen‑activated
Protein Kinase (p38 MAPK) pathway [96–102]. Seahorses are heavily used in TM, with an
estimated annual consumption of approximately 250 tons in China and Hong Kong [103].
Such overexploitation, however, is posing a severe extinction threat to several Hippocam‑
pus species in both East Asia and Latin America [104], which are now included in the Ap‑
pendix II of the Convention on International Trade in Endangered Species of Wild Fauna
and Flora (CITES) [105] and in the Red List of the International Union for Conservation of
Nature (IUCN) [106].
During the last imperial Dynasty of the Qing (1644–1911), European missionaries vis‑
ited and established themselves in China, introducing the Christian faith and other West‑
ern cultural elements, including cartography. At the court of the Qing Emperor Shengzu,
the Flemish Jesuit and astronomer Ferdinand Verbiest (1623–1688) published the Kunyu
Quantu (坤舆全图,Full Map of the World) in 1674, one of several Chinese world maps pro‑
duced in that era. Geography oered a glimpse of the outer world, aracting the aention
of the traditionally self‑centered and self‑isolated Chinese civilization towards Western sci‑
ence (Figure 1) [107]. The Qing era was characterized by profound and irreversible changes
in the Chinese society caused by violent political upheaval and by Western colonization,
forcing the opening to foreign trade [108]. Furthermore, the end of the Imperial era was
followed by the adoption of a universal “modern” science, although TM will never be fully
replaced [109].
The opening of the Marine Biological Station of Amoy University in the 1930s under
the guidance of foreign‑trained Chinese biologists [110] marked a major leap forward in
Chinese exploration of national marine biodiversity. These endeavours continue to the
present day, with extensive bioprospecting activity being conducted in the South China
Sea, leading to newly discovered marine lead compounds [111].
Much credit for the development of Chinese mariculture in the second half of the
twentieth century goes to the US‑trained marine botanist Cheng Kui Tseng (1909–2005),
who worked at the Institute of Oceanology at Qingdao (Shandong province). This unsung
hero of the 1940s modernization movement known as “Saving the Country by Means of
Science” (科学救国) [112] contributed to the breaking of records of seaweed productivity
achieved in the northern coastal Shandong Province [113].
Standing out from the crowd, China boasts a Modern Marine Materia Medica, a sci‑
entic encyclopaedia of marine medicinal organisms and of chemicals curated by the Key
Laboratory of Marine Drugs of the Ministry of Education at the Ocean University of China
in Qingdao. Besides holding tremendous scientic value, this project, supported by the
special program “Project 908” (Comprehensive investigation and evaluation on the o‑
shore oceans of China, Zhong guo jin hai hai yang zong he diao cha yu ping jia,
中国近海海洋综合调查与评价) [114], oers a privileged insight into one of the oldest sur‑
viving human civilizations, reecting the uninterrupted continuity of Chinese culture
throughout the millennia [115].

Mar. Drugs 2024,22, 304 5 of 32
Mar. Drugs 2024, 22, 304 5 of 34
Figure 1. Marine pharmacology has come a long way, from superstitious practices to present-day
high-throughput drug discovery pipelines. During the last three decades, the bioprospecting of
marine environments has identified hundreds of lead compounds with potential applications in
the clinical management of chronic inflammatory diseases and cancer. Historically, the East and
West established their own corpuses of marine materia medica. During the last Chinese Imperial
Dynasty of the Qing (1644–1911), European missionaries visited and established themselves in
China, introducing the Christian faith and other Western cultural elements, including cartography.
At the court of the Qing Emperor Shengzu, the Flemish Jesuit and astronomer Ferdinand Verbiest
(1623–1688) published the Kunyu Quantu (坤舆全图, Full Map of the World) in 1674, one of several
Chinese world maps produced in that era. Geography offered a glimpse into the outer world, at-
tracting the attention of the traditionally self-centered and self-isolated Chinese civilization to-
wards Western science. In the modern era, these two distant cultural worlds began a cross-
fertilization of knowledge and, today, they together contribute to advancing the applications of
marine resources in human health. Reproduced from [111].
The opening of the Marine Biological Station of Amoy University in the 1930s under
the guidance of foreign-trained Chinese biologists [114] marked a major leap forward in
Chinese exploration of national marine biodiversity. These endeavours continue to the
present day, with extensive bioprospecting activity being conducted in the South China
Sea, leading to newly discovered marine lead compounds [115].
Much credit for the development of Chinese mariculture in the second half of the
twentieth century goes to the US-trained marine botanist Cheng Kui Tseng (1909–2005),
who worked at the Institute of Oceanology at Qingdao (Shandong province). This un-
sung hero of the 1940s modernization movement known as “Saving the Country by
Figure 1. Marine pharmacology has come a long way, from superstitious practices to present‑day
high‑throughput drug discovery pipelines. During the last three decades, the bioprospecting of ma‑
rine environments has identied hundreds of lead compounds with potential applications in the
clinical management of chronic inammatory diseases and cancer. Historically, the East and West
established their own corpuses of marine materia medica. During the last Chinese Imperial Dynasty
of the Qing (1644–1911), European missionaries visited and established themselves in China, intro‑
ducing the Christian faith and other Western cultural elements, including cartography. At the court
of the Qing Emperor Shengzu, the Flemish Jesuit and astronomer Ferdinand Verbiest (1623–1688)
published the Kunyu Quantu (坤舆全图,Full Map of the World) in 1674, one of several Chinese world
maps produced in that era. Geography oered a glimpse into the outer world, aracting the aen‑
tion of the traditionally self‑centered and self‑isolated Chinese civilization towards Western science.
In the modern era, these two distant cultural worlds began a cross‑fertilization of knowledge and,
today, they together contribute to advancing the applications of marine resources in human health.
Reproduced from [107].
The Yin Yang Dialectic of Autoimmunity
With the introduction of Western medicine into China in the middle seventeenth cen‑
tury, traditional Chinese medicine (TCM) started to evolve in the constant struggle be‑
tween traditionalism and modernization [116]. In TCM, spiritual and scientic concepts
coexist in a holistic discipline [117], which is in stark contrast with the reductionist Western
approach. However, some TCM principles reect key features of the immune system: bal‑
ance, defense, holism, and circadian rhythms [118]. According to TCM, healthy immune
functions require a harmonious equilibrium of Yin reserves (阴, organs, tissues, cells, and
body uids) and Yang (阳, physiological functions). The two are opposing forces constantly

Mar. Drugs 2024,22, 304 6 of 32
trying to win over one another. Yin and Yang are kept in a constant dynamic balance to pre‑
serve the Qi (气), the body’s vital energy [119], a concept analogous to Pneuma (breath of life,
spirit) from classical antiquity [120]. A persistent Yin deciency causes Shanghuo (上火), or
heat syndrome, eventually creating an “excess of pathogenesis caused by deciency” [121].
In a healthy individual, apoptosis regulates tissue homeostasis, maintaining Yin and Yang
balance. When the capacity to remove apoptotic cells is overwhelmed by tissue degrada‑
tion, the excessive exposure of auto‑antigens to the immune system breaks immunolog‑
ical tolerance, triggering autoimmunity. Remarkably, several immune components em‑
body the Yin Yang dialectic [122]. For instance, CD4+ T helper cells undergo dynamic
functional specialization via cytokine‑mediated signaling feedback [123]. Initially, a Th1
dierentiation program is activated by interleukin (IL)‑12 and interferon gamma (IFN‑γ).
Th1 cells later switch to producing the Th2‑program cytokine IL‑4 to prevent unrestrained
Th1 proliferation.
Similarly, dendritic cells undergo divergent dierentiation programs in response to
chemical stimuli [124]. Instead, regulatory T cells—a lymphocyte population which sup‑
presses immune responses and maintains self‑tolerance—can convert to inammatory
Th17 cells [125]. Finally, individual cytokines can be either Yin or Yang elements, i.e., IL‑6 is
endowed with both pro‑ and anti‑inammatory functions depending on the context [126].
Strikingly, many TCM practices either stimulate or suppress immune functions [127–129];
therefore, this ancient medical art predates the discovery of the immune system and its
complex functioning.
5. The Birth of Marine Microbiology: Sailing on the Ocean of Chemodiversity
The invention of optical instruments in the eighteenth century by Dutch lensmaker
Antonie van Leeuwenhoeck and English polymath Robert Hooke enabled the discovery
of marine microbes, marking a fundamental breakthrough in the appreciation of ocean
biodiversity [130,131]. The ensuing scientic excitement stimulated the publication of Die
Bakterien des Meeres (Bacteria of the Sea) in 1894 by German biologist Bernhard Fischer [132]
and, later, of the treatise Marine Microbiology: A Monograph on Hydrobacteriology by Ameri‑
can microbiologist Claude ZoBell [133]. Decades later, the discovery of marine cyanobac‑
teria by John Waterbury and Sallie Chisholm [134,135] provided new insights into ocean
primary productivity and revolutionized marine ecophysiology.
In the wake of the genomic and post‑genomic eras, the exploration of the ocean by
means of molecular techniques has revealed the staggering complexity of microbial bio‑
diversity [136]. Metagenomics was rst introduced in marine sciences by The Sorcerer II
Global Ocean Sampling expedition led by American biotechnologist Craig Venter
(2004–2006) [137–139]. The subsequent Malaspina (2010) and Tara Oceans expeditions
(2009–2013) further revealed the richness of microbial life from the deep‑sea
environments [140–142]. The picture of the global ocean microbial genome was recently as‑
sembled in the KAUST Metagenome Analysis Platform (KMAP) Global Ocean Gene Cata‑
log 1.0. This database contains 308.6 million gene clusters assembled from
2.102 metagenomes and represents an invaluable resource for the functional discovery of
microbial metabolic pathways [143].
5.1. Prokaryotes and Metazoan‑Associated Microbiota
Marine bacteria produce an arsenal of secondary metabolites used for inter‑ and intra‑
specic communication [144]. During evolution, key genes encoding polyketide synthases
and non‑ribosomal peptide synthetases have undergone extensive reshuing within oper‑
ons, creating a remarkable diversication of metabolic pathways [145]. A recent analysis of
marine prokaryotic genomes revealed an astonishing complexity of biosynthetic gene clus‑
ters, although only a tiny fraction of secondary metabolites has been studied [146]. A major
obstacle to microbial drug discovery, however, lies in the recalcitrance to culturability of
marine isolates, since most species naturally grow in consortia [147,148]. Moreover, many
secondary metabolites originally believed to be produced by marine invertebrates derive

Mar. Drugs 2024,22, 304 7 of 32
from the associated microbiota [149]. Mutualistic relationships between fungi and bacte‑
ria and metazoans (holobionts) are found in corals and sponges [150]. Strikingly, nearly
all bioactive polyketides and peptides isolated from the Theonella swinhoei (porifera) holo‑
biont are produced by the lamentous bacterial symbiont Entotheonella spp. [151–153]. Sim‑
ilarly, the anticancer molecule trabectedin was isolated from Candidatus Endoecteinascidia
frumentensis, the bacterial symbiont of the sea squirt Ecteinascidia turbinata [154]. How‑
ever, the study of secondary metabolites from mutualistic relationships is complicated by
the strict host dependency of endosymbionts and the alteration of holobiont composition
upon ex situ cultivation [155].
5.2. Fungi and Protists
Several Talaromyces fungal symbionts of algae and sponges [156] produce polyketides,
alkaloids, terpenoids, peptides, and lipids, with reported anti‑inammatory
potential [157,158]. Saprotrophic protists are emerging biofactories of immunomodulatory
lipids, including the omega‑3 polyunsaturated docosahexaenoic (DHA, C22:6 ω‑3) and
eicosapentaenoic acids (EPA, C20:5 ω‑3) produced by the Thraustochytrid Schizochytrium
sp. (reviewed in [159,160]), which is amenable to fermentation at a large scale in seawa‑
ter and wastewater [161]. Notably, the anti‑inammatory properties of DHA compounds
were recently reported in a clinical trial involving patients with rheumatoid arthritis [162].
5.3. Marine Eukaryotic Microalgae and Cyanoprokaryotes
Eukaryotic phytoplankton (hereafter microalgae) is potentially the richest resource for
drug discovery and a promising platform for large‑scale and low‑cost production of high‑
value metabolites [163]. Microalgae comprise a vast group of photosynthetic microbes
producing a huge repertoire of anti‑inammatory and immunomodulatory pigments and
lipids [159,164–167].
Carotenoids are lipophilic pigments [168–171] designated as carotenes (lycopene and
α‑ and β‑carotene), which contribute to light‑harvesting, and the oxygenated derivatives
xanthophylls (or ketocarotenoids: astaxanthin, fucoxanthin and lutein), which are mainly
involved in the detoxication of reactive oxidative species (ROS) generated by photosyn‑
thetic reactions. The ketocarotenoid astaxanthin is the microalgal pigment of greatest phar‑
macological value, being endowed with strong antioxidant capacity (extensively reviewed
in [159]). The biological production of astaxanthin, however, is restrained by the slow
growth of its native producer, the freshwater Chlorophyte Haematococcus lacustris (previ‑
ously named Haematococcus pluvialis) [172]. Accordingly, the establishment of optimal cul‑
tivation strategies of H. lacustris and the domestication of high‑yielding strains are key to
accruing astaxanthin accumulation [173–176].
In response to stress, several microalgae synthesize DHA, EPA[177], while the chloro‑
phyte Tetraselmis chui accumulates monogalactosyldiacylglycerols, which inhibit nitric ox‑
ide production [178–181]. The haptophyte Tisochrysis lutea (formerly known as Isochrysis
anis galbana) is the main DHA producer, although the eustigmatophytes Microchloropsis
salina,Nannochloropsis oceanica, and Microchloropsis gaditana are emerging EPA producers,
and species of the Pavlovophyceae family are sources of both carotenoids and functional
lipids [182–184]. Diatoms are widely distributed eukaryotic phytoplankton [185] which
produce valuable immunomodulatory pigments and lipids [186], particularly the genus
Thalassiosira, which accumulates human‑like prostaglandins in response to environmental
stress [187–190].
At present, China is the major world producer of microalgal biomass for human con‑
sumption [191], while the US and several European countries are at the forefront of mi‑
croalgal biotechnology research [192,193]. Bioprospecting for industrially relevant microal‑
gae, instead, is conducted worldwide, mainly in inhospitable habitats, since extremophiles
hyper‑accumulate bioactive compounds [194] and display robust growth phenotypes un‑
der co‑cultivation [195–197].

Mar. Drugs 2024,22, 304 8 of 32
The full biotechnological exploitation of non‑conventional microalgae, however, re‑
quires improvements in biomass yield and downstream processing to retrieve target
metabolites [198,199].
Finally, marine cyanoprokaryotes are emerging sources of bioactive metabolites [200],
several endowed with anti‑inammatory and immunomodulatory properties, including
polysaccharides, phenols, avonoids, and phycobiliproteins [201–204]. Notably, the light‑
harvesting pigment C‑phycocyanin is a selective inhibitor of the enzyme cyclooxigenase‑2
producing the pro‑inammatory mediator prostaglandin E2[205–208].
6. Mining the Seabed for Novel Bioactive Compounds
Considered an azoic zone until the late nineteenth century [209], the deep sea has
always stimulated the curiosity of scientists interested in the search for life in this mys‑
terious environment. Starting with the British‑led oceanographic dredging cruises of the
H.M. SS. Porcupine and Lightning (1868–1870) [210,211] and the ensuing Challenger At‑
lantic voyage led by marine zoologist Sir Charles Wyville Thomson (1872–1876) [212], the
abysses revealed remarkable biodiversity. These were followed by the French Travailleur
and Talisman expeditions (1880–1883), during which barophilic microbes were collected
and cultivated by Adolph‑Adrien Certes, a disciple of Louis Pasteur [213,214].
The excitement for these newly discovered ecosystems was felt internationally,
prompting the establishment of zoological stations dedicated to the study of marine bi‑
ology and ecology [215]. Among these, the Stazione Zoologica of Naples (Italy), founded
in 1872 by German zoologist Anton Dohrn, rapidly acquired international prestige and,
today, is a leading institution in the eld of marine bioprospecting and drug discovery
research [216]. Between 1950 and 1952, the Danish‑led Galathea Deep Sea Expedition
(1950–1952) reached sampling depths of 10,000 m below sea level, revealing the existence
of extremely barophilic bacteria [217,218] and prompting their cultivation in the labora‑
tory [219]. In 1979, the manned submersible vessel Alvin enabled the discovery of hy‑
drothermal vents in the Galápagos Rift of the East Pacic Ocean and of their associated
communities of extremophile microbes [220].
Arguably, the deep sea is the last uncharted frontier for bioprospecting [221,222].
This extreme environment is home to thermophile, halophile, alkalophile, psychrophile,
piezophile, and polyextremophile microorganisms, which produce a panoply of secondary
metabolites (the chemical structures of recently identied lead compounds from deep‑
sea organisms are shown in Figure 2, while in Table 1, their biological activity and half‑
maximal inhibitory concentration, IC50, values are provided) [223–226]. Deep‑sea biodi‑
versity and chemodiversity are currently being investigated using approaches combining
imaging, sampling, and genomics analysis with the creation of dedicated repositories, such
as the MArine Bioprospecting PATent (MABPAT) Database, which provides free access to
this constantly expanding biological landscape [227–229].
6.1. Deep‑Sea Prokaryotes
Despite their physiological adaptation to extreme environmental conditions, deep‑
sea microbes can be easily cultured under laboratory conditions, enabling detailed inves‑
tigation of their secondary metabolites and, recently, genetic engineering [230,231]. Bio‑
prospecting for anti‑inammatory compounds of deep‑sea bacteria resulted in the identi‑
cation of a macrolactin derivative (7,13‑epoxyl‑macrolactin A, a 24‑membered ring lactone,
Figure 2.1) from Bacillus subtilis B5, which strongly inhibited pro‑inammatory gene ex‑
pression and prevented the production of the inammatory mediators interleukin‑1βand
IL‑6 [232]. Another example of a bacterium‑derived compound with immunomodulatory
properties is the exopolysaccharide from Planococcus rietoensis (described in
Section 8.2) [233]. As in the case of shallow‑water species of Porifera, symbioses between
microbes and invertebrates are equally common in the deep sea, although less heteroge‑
neous, as revealed by recent investigations into the sponge‑associated microbiome [234].

Mar. Drugs 2024,22, 304 9 of 32
Therefore, deep‑sea holobionts are potential new sources of bioactive compounds
awaiting characterization.
6.2. Deep‑Sea Fungi
The advancement of deep‑sea bioprospecting is reected by the increasing number of
newly identied bioactive compounds from fungal species [235], with the Microbacterium,
Dermacoccus, Streptomyces, and Verrucosispora of the phylum actinomycota being the most
studied genera [236]. Several ascomycota species also produce anti‑inammatory com‑
pounds with inhibitory activity against nitric oxide release. These include cyclopenol (a
7‑membered 2,5‑dioxopiperazine alkaloid, Figure 2.2), derived from Aspergillus sp.; the
fusaric acid derivatives hepialiamides (Figure 2.3); and one novel hybrid polyketide hepi‑
alide (Figure 2.4) from Samsoniella hepiali. The laer also produces uridine, ergosterol, wal‑
terolactone A, (4R, 5S)‑5‑hydroxyhexan‑4‑olide, and myrothecol (Figure 2.5–10). Further‑
more, Acremonium sp. and Eutypella sp. accumulate eremophilane‑like sesquiterpenoids
(Figure 2.11) [237–241], while the Ascomycetes Penicillium oxalicum and chrysogenum pro‑
duce alkaloids and chrysamides (Figure 2.12–15), respectively, capable of suppressing the
synthesis of pro‑inammatory mediators, including the potent cytokine IL‑17 in vitro in
the case of P. chrysogenum [242,243]. Finally, the Basidiomycete Cystobasidium laryngis has
been shown to produce diphenazine derivatives with anti‑neuroinammatory properties
(Figure 2.16) [244].
Table 1. Recently discovered anti‑inammatory and immunomodulatory compounds from deep‑
sea microorganisms.
Molecule Source Organism(s) Biological Activity—Half Maximal Inhibitory
Concentration (IC50)
Development
Stage Ref.
7,13‑epoxyl‑macrolactin A Bacillus subtilis B5
(Gram‑positive
bacterium)
Suppression of inducible nitric oxide synthase,
IL‑1β, and IL‑6 expression in cultured activated
murine macrophages (IC50 N.D.). Preclinical trial [232]
Extracellular Exopolysaccharide
Planococcus rietoensis
AP‑5
(Gram‑positive
bacterium)
Stimulation of IL‑10, IL‑6, IL‑1β, and TNF‑α
production by human cultured monocytes
(IC50 N.D.). Preclinical trial [233]
Cyclopenol
(7‑membered 2,5‑dioxopiperazine
alkaloid)
Aspergillus sp.
(Ascomycota)
Suppression of nitric oxide release by cultured
activated murine macrophages via inhibition of
the NF‑κB pathway. Down‑regulation of
inducible nitric oxide synthase,IL‑1βand IL‑6 in
cultured activated murine microglia
(IC50 30 µM).
Preclinical trial [237]
Hepialiamides (fusaric acid
derivatives) Samsoniella hepiali W7
(Ascomycota) Suppression of nitric oxide release by cultured
activated murine microglia (IC50 1 µM). Preclinical trial [238]
Polyketide hepialide Samsoniella hepiali W7
(Ascomycota) Suppression of nitric oxide release by cultured
activated murine microglia (IC50 1 µM). Preclinical trial [238]
5′‑O‑acetyladenosine, uridine,
ergosterol, walterolactone A Samsoniella hepiali W7
(Ascomycota) Suppression of nitric oxide release by cultured
activated murine microglia (IC50 1 µM). Preclinical trial [238]
(4R,5S)‑5‑hydroxyhexan‑4‑olide Samsoniella hepiali W7
(Ascomycota) Suppression of nitric oxide release by cultured
activated murine microglia (IC50 426 nM). Preclinical trial [238]
2‑benzoyl tetrahydrofuran
enantiomers
(−)‑1S‑myrothecol,
(+)‑1R‑myrothecol
Myrothecium sp.
(Ascomycota)
Suppression of nitric oxide release by cultured
activated murine macrophages (IC50 1.20 and
1.41 µgmL−1). Preclinical trial [239]
Acremeremophilanes
Eremophilane‑Type
Sesquiterpenoids
Acremonium sp.
(Ascomycota) Suppression of nitric oxide release by cultured
activated murine macrophages (IC50 8 to 45 µM). Preclinical trial [240]

Mar. Drugs 2024,22, 304 10 of 32
Table 1. Cont.
Molecule Source Organism(s) Biological Activity—Half Maximal Inhibitory
Concentration (IC50)
Development
Stage Ref.
Eremophilane‑Type
Sesquiterpenoids Eutypella sp.
(Ascomycota)
Suppression of nitric oxide production by
cultured activated murine macrophages (IC50 8
to >50 µM). Preclinical trial [241]
Oxaline (A),
isorhodoptilometrin (B), and
5‑hydroxy‑7‑(2′‑hydroxypropyl)‑
2‑methyl‑chromone (C).
Penicillium oxalicum
(Ascomycota)
Suppression of nitric oxide and prostaglandin E2
production by cultured murine microglia cells.
Down‑regulation of inducible nitric oxide synthase
and cyclo‑oxygenase‑2 expression. Inhibition of
TNF‑α, IL‑1β, IL‑6, and IL‑12 production via
interference with the NF‑κB and MAPK
pathways (IC50 A 9, B 15, and C 75 µM).
Preclinical trial [242]
Dimeric nitrophenyl
trans‑epoxyamides
Chrysamides A‑C
Penicillium chrysogenum
(Ascomycota)
Suppression pro‑inammatory cytokine IL‑17
production by cultured murine naïve T cells
(IC50 C 75 µM). Preclinical trial [243]
Phenazostatins
(Diphenazine derivatives) Cystobasidium laryngis
(Basidiomycota)
Suppression of nitric oxide and IL‑6 production
by activated murine macrophages in vitro via
inhibition of NF‑κB pathway. Suppression of
IL‑1β,IL‑6, and inducible nitric oxide synthase
expression in cultured murine microglia cells
(IC50 0,30–170 µM).
Preclinical trial [244]
Mar. Drugs 2024, 22, 304 11 of 34
Figure 2. Chemical structures of recently identified immunomodulatory and anti-inflammatory
compounds from deep-sea organisms described in Table 1. (1) 7,13-epoxyl-macrolactin A from Ba-
cillus subtilis B5; (2) cyclopenol from Aspergillus sp. [241]; (3–9) hepialiamide, polyketide hepialide,
5’-O-Acetyladenosine, uridine, ergosterol, walterolactone A, and (4R, 5S)-5-hydroxyhexan-4-olide
from Samsoniella hepiali W7; (10) myrothecol from Myrothecium sp. [243]; (11) eremophilane from
Acremonium sp. and Eutypella sp. [244,245] (12–14) oxaline, isorhodoptilometrin, and 5-hydroxy-7-
(2’-hydroxypropyl)-2-methyl-chromone from Penicillium oxalicum [246]; (15) chrysamide from Pen-
icillium chrysogenum [247]; and (16) phenazostatin from Cystobasidium laryngis [248].
7. Emerging Marine Immunomodulatory Lead Compounds
7.1. Seaweeds (Macroalgae)
Seaweeds, or macroalgae, are plant-like multicellular phototrophs found in inter-
tidal waters attached to rocks or floating free in the open sea [198]. The edible red sea-
weed Porphyra dentata (Rhodophyta, Bangiales) is widely used worldwide in TM and
contains phenolic compounds which inhibit the synthesis of the pro-inflammatory sig-
naling molecule nitric oxide (NO) and suppress the NF-kB pathway in vitro [249].
Several species are farmed in the ocean due to their highly nutritious composition
and content of bioactive compounds, mainly sulfated polysaccharides [250–252]. For in-
stance, porphyran, a sulfated galactan from red seaweeds (Porphyra), stimulates the
immune function and apoptotic/autophagic processes, and is considered a candidate an-
ti-cancer drug (IC
50
20 µg/mL) [253]. Similarly, the polysaccharide fraction from
Lithothamnion muelleri (Hapalidiaceae) displayed immunomodulatory activity by inhibit-
ing the synthesis of pro-inflammatory chemokines in an animal model of arthritis [254].
Moreover, fucoidan and ulvan extracted from the brown macroalga (kelp) Undaria pin-
natifida and the green alga Ulva lactuca (IC
50
623.58–785.48 µg/mL), respectively, are po-
tent immunostimulators and antioxidants, and thus, have potential applications to re-
Figure 2. Chemical structures of recently identied immunomodulatory and anti‑inammatory
compounds from deep‑sea organisms described in Table 1. (1) 7,13‑epoxyl‑macrolactin A from
Bacillus subtilis B5; (2) cyclopenol from Aspergillus sp. [237]; (3–9) hepialiamide, polyketide hepialide,

Mar. Drugs 2024,22, 304 11 of 32
5′‑O‑Acetyladenosine, uridine, ergosterol, walterolactone A, and (4R, 5S)‑5‑hydroxyhexan‑4‑olide
from Samsoniella hepiali W7; (10) myrothecol from Myrothecium sp. [239]; (11) eremophilane from
Acremonium sp. and Eutypella sp. [240,241] (12–14) oxaline, isorhodoptilometrin, and 5‑hydroxy‑7‑
(2′‑hydroxypropyl)‑2‑methyl‑chromone from Penicillium oxalicum [242]; (15) chrysamide from Peni‑
cillium chrysogenum [243]; and (16) phenazostatin from Cystobasidium laryngis [244].
7. Emerging Marine Immunomodulatory Lead Compounds
7.1. Seaweeds (Macroalgae)
Seaweeds, or macroalgae, are plant‑like multicellular phototrophs found in intertidal
waters aached to rocks or oating free in the open sea [194]. The edible red seaweed Por‑
phyra dentata (Rhodophyta, Bangiales) is widely used worldwide in TM and contains phe‑
nolic compounds which inhibit the synthesis of the pro‑inammatory signaling molecule
nitric oxide (NO) and suppress the NF‑kB pathway in vitro [245].
Several species are farmed in the ocean due to their highly nutritious composition
and content of bioactive compounds, mainly sulfated polysaccharides [246–248]. For in‑
stance, porphyran, a sulfated galactan from red seaweeds (Porphyra), stimulates the im‑
mune function and apoptotic/autophagic processes, and is considered a candidate anti‑
cancer drug (IC50 20 µg/mL) [249]. Similarly, the polysaccharide fraction from Lithotham‑
nion muelleri (Hapalidiaceae) displayed immunomodulatory activity by inhibiting the syn‑
thesis of pro‑inammatory chemokines in an animal model of arthritis [250]. Moreover,
fucoidan and ulvan extracted from the brown macroalga (kelp) Undaria pinnatida and the
green alga Ulva lactuca (IC50 623.58–785.48 µg/mL), respectively, are potent immunostim‑
ulators and antioxidants, and thus, have potential applications to reduce the side eects
of immunosuppressive therapies [251,252]. Anti‑inammatory eects were reported for
polysaccharide extracts from Halimeda tuna (Ulvophyceae) [10] and Posidonia oceanica (Al‑
ismatales) [253], and for carrageenans derived from dierent red seaweeds (Chondrus cris‑
pus,Ahnfeltiopsis devoniensis,Sarcodiotheca gaudichaudii, and Palmaria palmata) [254]. Finally,
polysaccharide fucosterol and phlorotannins from the brown macroalgae Sargassum wightii
and Eisenia bicyclis (eckol, dieckol and 7‑phloroeckol; IC50 52.86, 51.42 and 26.87 µg/mL,
respectively) suppressed the release of pro‑inammatory mediators in animal models of
arthritis [255,256].
7.2. Invertebrates
Several marine invertebrate phyla are known producers of anti‑inammatory and im‑
munomodulatory compounds [257,258]. Corals are colonial organisms of the class An‑
thozoa (Cnidaria), typically found in reef ecosystems in tropical and sub‑tropical water.
Coral bioprospecting is mainly focussed on the octocorallia order Alcyonacea (Gorgoni‑
ans or soft corals), which is known to produce a vast repertoire of secondary metabo‑
lites of pharmacological relevance [259], mainly immunomodulatory lipid derivatives and
terpenoids [260,261]. For instance, the sesquiterpenes (C15H24) capnellenes, isolated from
the species Capnella imbricata, inhibited the expression of the pro‑inammatory enzymes
inducible nitric oxide synthase and cyclooxygenase‑2 in cultured macrophages (used at
10 µM) [262,263]. The Caribbean gorgonian Plexaura homomalla, instead, emerged as the
highest natural producer of mammalian‑like prostaglandins, which are hormone‑like oxy‑
genated metabolites of C20 fay acids involved in the modulation and resolution of inam‑
mation [264,265]. Similarly, diterpenes (C20H32) isolated from the Formosan gorgonians
Briareum excavatum (excavatolide, or excavatoid B used at 50 µM, E and F with
ED50 > 40 µg/mL) and Sinularia querciformis (11‑epi‑sinulariolide acetate; IC50 50 µM) inhib‑
ited the synthesis of several pro‑inammatory mediators in arthritis animal
models [266–268]. Lastly, peptides isolated from the venom of the jellysh Pelagia noctiluca
(Pelagiidae) strongly suppressed nitric oxide production in vitro (used at 50 µg/mL) [269].
Ascidians (Chordata, subphylum Tunicata) have emerged as novel sources of bioac‑
tive compounds, mainly derived from their innate immune system [270]. Recently, a syn‑
thetic peptide derived from the sea squirt Styela clava was shown to exert both antimicrobial

Mar. Drugs 2024,22, 304 12 of 32
and immunomodulatory activities in animal models. In particular, the clavanin‑MO pep‑
tide (used at 2 µM) promoted the synthesis of the anti‑inammatory cytokine IL‑10 while
suppressing the release of the pro‑inammatory factors IL‑12 and tumor necrosis factor‑
α(TNF‑α) upon bacterial infection [271]. Another study described the in vitro inhibitory
eects of chemical inhibitors based on the structure of metabolites from Herdmania mo‑
mus against multiple pro‑inammatory enzymes and the release of pro‑inammatory cy‑
tokines in activated macrophages (IC50 between 7.59 and 39.20 µM) [272]. Finally, although
the chemical nature of the bioactive compound(s) still awaits characterization, extracts of
the Indonesian ascidian Polycarpa aurata acted as hydrogen sulde donors in vitro, sup‑
pressing the pro‑inammatory response of cultured macrophages (used at 50 µg/mL) [273].
Gastropods of the family Muricidae (Mollusca) are known to produce mucus‑
containing bioactive molecules. A recent study showed the immunomodulatory eects
of the mucus of Bolinus brandaris, suggesting that a still‑uncharacterized compound could
trigger the immune system against cancerous cells by inducing monocyte dierentiation
(IC50 ranging between ≤1 and ~10 µg/mL) [274]. Moreover, lipids extracted from the mus‑
sel Mytilus coruscus exerted a strong anti‑inammatory eect in a murine arthritis model,
reducing the levels of the pro‑inammatory mediators leukotriene B₄, prostaglandin E₂,
and thromboxane B₂, but also of the cytokines IL‑1β, IL‑6, interferon‑γ, and tumor necro‑
sis factor‑α[275]. Notably, a similar preparation was tested in a clinical trial involving
rheumatoid arthritis patients with similar outcomes [276]. Finally, the two sea hares Aplysia
fasciata and Aplysia punctata (Anaspidea) were shown to produce immunomodulatory
lipids which suppressed the activity of pro‑inammatory enzymes and nitric oxide pro‑
duction in vitro (IC50 77 and 74 µg/mL, respectively) [277].
Echinodermata are another phylum of marine animals which synthesize bioactive
compounds with immunomodulatory properties [278]. Echinozoa, or sea urchins, are the
best‑studied group, with a recent example of an anti‑inammatory lead compound identi‑
ed in Scaphechinus mirabilis (described in detail in Section 8.1) [279]. Another example in‑
cludes Isostichopus badionotus, whose extracts suppress the expression of pro‑inammatory
genes in vivo [280]. Moreover, a recent study described the anti‑inammatory activity
of the protein cargo of extracellular vesicles of the sea cucumber (Holothuroidea) Sticho‑
pus japonicus, showing a strong inhibition of the release of pro‑inammatory cytokines by
cultured synoviocytes, a cell type involved in the pathogenesis of osteoarthritis (used at
10 µg/mL) [281].
Lastly, the phylum Porifera contains several species of marine sponges, especially
of the genus Hyrtios, which are sources of bioactive compounds, mainly alkaloids and ter‑
penoids [282]. Early studies have reported the in vitro and in vivo anti‑inammatory activ‑
ity of scalaristerol (5alpha,8alpha‑dihydroxycholest‑6‑en‑3beta‑ol) and callysterol (ergosta‑
5,11‑dien‑3beta‑ol), isolated from Scalarispongia aqabaensis (Thorectidae) and Callyspongia
siphonella (Callyspongidae), respectively [283], and from Aplysina caissara (Aplysinidae),
Haliclona sp. (Chaliunidae), and Dragmacidon reticulatum (Axinellidae), although the chem‑
ical nature of their bioactive compounds could not be identied [284]. Recently, stular‑
ins (bromotyrosine acids) isolated from Ecionemia acervus (Ancorinidae) strongly inhibited
the activity of pro‑inammatory enzymes and the release of inammatory cytokines from
cultured macrophages (tested range between 5 and µM) [285]. Similarly, the brominated
alkaloid aeroplysinin derived from Aplysina aerophoba displayed inhibitory eects on cul‑
tured vascular endothelial cells by suppressing the NF‑kB pathway (IC50 3µM) [286]. Fur‑
thermore, the norditerpene dihydrogracilin A, derived from the Antarctic sponge Dendrilla
membranosa (Darwinellidae), suppressed the NF‑kB pathway in cultured human peripheral
blood mononuclear cells and dampened the production of the pro‑inammatory cytokine
IL‑6 (tested range between 0.3 and 10 µM) [287]. Finally, lipids extracted from Halichondria
sitiens exerted immunomodulatory eects on cultured dendritic cells (used at 10 µg/mL)
by suppressing the secretion on the pro‑inammatory cytokines IL‑12 and Il‑6, but also
prevented the production of IFN‑γby CD4+ T lymphocytes, thus blocking the so‑called
Th1‑type immune response (explained in detail in Section 8.2) [288].

Mar. Drugs 2024,22, 304 13 of 32
7.3. Mangrove Habitats
Mangrove forests are threatened coastal habitats at the interface between terrestrial
and marine tropical environments in which salt‑tolerant plants (halophytes) create unique
ecosystems hosting a plethora of interacting microorganisms [289]. Mangroves are widely
consumed in the TM of Southern India [290–293], and recent ethnopharmacological stud‑
ies have isolated several phytochemicals with anti‑inammatory and immunomodulatory
properties from Aegiceras corniculatum [294], Rhizophora mucronata [295], and Sonneratia
apetala [296]. Notably, the leaf extracts from A. corniculatum inhibited the production of pro‑
inammatory cytokines (TNF‑α, IL‑6, and IL‑12) by in vitro cultured immune cells [295],
while the extracts from Lumniera racemosa displayed anti‑angiogenic properties (IC50 rang‑
ing between 2,57 and 4,95 µM) [297]. Moreover, agalloide terpenoids from Ceriops decan‑
dra (tested at 100 µM), and, mainly, Excoecaria agallocha, suppressed NF‑kB pathway ac‑
tivation [298–300]. Besides providing new phytopharmaceuticals, mangrove forests are
suitable habitats for bioprospecting microbial compounds [301]. For instance, two new
sesquiterpenoid derivatives (elgonenes M and N used at 5 and 20 µM, respectively) were
identied in the fungus Roussoella sp. after isolation from a mangrove sediment, which
inhibited the synthesis of pro‑inammatory cytokines by cultured immune cells [302].
8. Marine Pharmacology, Quo Vadis?
Several marine lead compounds are currently being assessed in pre‑clinical and clin‑
ical studies, while seven marine drugs have already received “rst‑in‑class” status, i.e.,
are endowed with “new and unique mechanism(s) of action” [303–306]. Most marine
drugs in clinical use nd application in cancer immunotherapy, as antibody–drug con‑
jugates and in the management of chronic inammatory conditions (reviewed in detail
in [307,308]). Two examples of recently identied marine molecules are provided in the
following paragraphs.
8.1. The Sea Urchin Echinochrome A and Its Applications in Systemic Sclerosis
Systemic sclerosis (SSc) is a rare immune‑mediated connective tissue disease charac‑
terized by microvascular damage followed by aberrant autoimmune responses of the skin
and internal organs, including the gastrointestinal tract, kidneys, lungs, and heart [309]. Fi‑
brosis is a hallmark of SSc pathogenesis. This process is driven by activated pro‑brotic my‑
obroblasts, highly dierentiated cells which produce contractile proteins such as alpha‑
smooth muscle actin, resulting in excessive extracellular matrix deposition [310]. Although
myobroblasts contribute to the physiological process of wound healing in damaged tis‑
sues, their aberrant activation contributes to diuse brosis and chronic
inammation [311,312]. Innate immune cells—particularly monocytes and macro‑
phages—are established mediators of the brotic process in SSc [313]. Therefore, the dis‑
covery of novel immunomodulatory and anti‑brotic molecules is of great clinical rele‑
vance for slowing SSc progression.
The marine compound Echinochrome A (6‑ethyl‑2,3,5,7,8‑pentahydroxy‑1,4‑naphtho
quinone, EchA) is a natural pigment from the echinoderm Scaphechinus mirabilis [314] en‑
dowed with antioxidant anti‑brotic properties [315–318]. Recently, it was reported that
EchA reduced collagen deposition and alleviated dermal thickness in an SSc animal
model [279]. In this study, bleomycin was inoculated in the mouse skin for three weeks
to induce dermal injury and to activate pro‑inammatory immune cells. The administra‑
tion of EchA suppressed dierent mechanisms involved in the brotic process, includ‑
ing broblast activation and myobroblast maturation; tumor growth factor (TGF)‑β1‑
mediated expression of smooth muscle actin; phosphorylation of pro‑brotic transcription
factors in skin broblasts; and, nally, dierentiation of macrophages into both M1 and M2
cells (Figure 3). These eects resulted in lower serum concentrations of pro‑inammatory
cytokines TNF‑αand IFN‑γ. Overall, EchA is a promising marine lead compound with
anti‑brotic properties and, thus, potential application in the clinical management of SSc.
Recently, a novel administration system based on polymeric nanobers was developed to

Mar. Drugs 2024,22, 304 14 of 32
improve the water solubility of EchA. This pharmacological advance is expected to pro‑
mote the controlled release of the drug, enhancing its bioavailability [319].
Mar. Drugs 2024, 22, 304 15 of 34
Figure 3. Antifibrotic activity of EchA in SSc model. EchA reduces skin cell infiltration (M1 and M2
macrophages) and myofibroblast activation, ameliorating skin thickness. Cytokines (IL), cluster of
differentiation (CD), reactive oxygen species (ROS), protein-coupled receptor signaling pathway
(CCL), transforming growth factor (TGF-β), platelet-derived growth factor receptors (PDGF-Rs),
fibroblast growth factor receptor (FGFRs), and Echinochrome A (EchA). Figure created with Bio-
render (accessed on 12 June 2024), based on [283].
8.2. Deep-Sea Bacteria Exopolysaccharides and Their Applications in Cancer Immunotherapy
The interplay between immunity and tumorigenesis is a cornerstone of cancer biol-
ogy, since the immune system exerts a multifaceted influence in terms of thwarting tu-
mor initiation, progression, and metastasis [324]. Cancer immunotherapy emerged in the
late twentieth century with the observation by American physician William Coley that
sarcomas shrunk following inoculation of the tumor mass with killed bacteria [325]. It is
now well established that tumor recognition and rejection by the immune system in-
volve a complex dialogue between adaptive and innate immune cell types, including
CD8+ cytotoxic T cells, CD4+ helper T (Th) cells (Th1, Th2, and Th17 lineages), regulato-
ry T cells (Tregs), and myeloid-derived suppressor cells [326]. Moreover, macrophages—
highly adaptable phagocytic immune cells [327]—can act as antigen-presenting cells
(APCs) and differentiate into classically activated (M1) and alternatively activated (M2)
types, with the former promoting inflammation and the latter fostering tissue repair
[328]. M1 and M2, however, are the extremes of a broader cell type spectrum [329–331],
since macrophages are known to interfere with tumorigenesis by influencing angiogene-
sis, fibrosis, and tumor cell phagocytosis. Moreover, macrophages orchestrate immuno-
surveillance by expressing costimulatory molecules like CD86 (B7-2) or T cell inhibitory
molecules and promote the recruitment of immunosuppressive T-reg cells [332].
CD86 presented by APCs can bind either to cytotoxic T lymphocyte antigen 4
(CTLA-4) or CD28 on the surface of CD4+ and CD8+ T cells, causing their inhibition or
activation, respectively [333]. Notably, upon cytokine signaling, APCs mediate the “im-
Figure 3. Antibrotic activity of EchA in SSc model. EchA reduces skin cell inltration (M1 and
M2 macrophages) and myobroblast activation, ameliorating skin thickness. Cytokines (IL), cluster
of dierentiation (CD), reactive oxygen species (ROS), protein‑coupled receptor signaling pathway
(CCL), transforming growth factor (TGF‑β), platelet‑derived growth factor receptors (PDGF‑Rs), ‑
broblast growth factor receptor (FGFRs), and Echinochrome A (EchA). Figure created with Biorender
(accessed on 12 June 2024), based on [279].
8.2. Deep‑Sea Bacteria Exopolysaccharides and Their Applications in Cancer Immunotherapy
The interplay between immunity and tumorigenesis is a cornerstone of cancer biol‑
ogy, since the immune system exerts a multifaceted inuence in terms of thwarting tumor
initiation, progression, and metastasis [320]. Cancer immunotherapy emerged in the late
twentieth century with the observation by American physician William Coley that sarco‑
mas shrunk following inoculation of the tumor mass with killed bacteria [321]. It is now
well established that tumor recognition and rejection by the immune system involve a com‑
plex dialogue between adaptive and innate immune cell types, including CD8+ cytotoxic
T cells, CD4+ helper T (Th) cells (Th1, Th2, and Th17 lineages), regulatory T cells (Tregs),
and myeloid‑derived suppressor cells [322]. Moreover, macrophages—highly adaptable
phagocytic immune cells [323]—can act as antigen‑presenting cells (APCs) and dierenti‑
ate into classically activated (M1) and alternatively activated (M2) types, with the former
promoting inammation and the laer fostering tissue repair [324]. M1 and M2, how‑
ever, are the extremes of a broader cell type spectrum [325–327], since macrophages are
known to interfere with tumorigenesis by inuencing angiogenesis, brosis, and tumor
cell phagocytosis. Moreover, macrophages orchestrate immunosurveillance by expressing

Mar. Drugs 2024,22, 304 15 of 32
costimulatory molecules like CD86 (B7‑2) or T cell inhibitory molecules and promote the
recruitment of immunosuppressive T‑reg cells [328].
CD86 presented by APCs can bind either to cytotoxic T lymphocyte antigen 4 (CTLA‑
4) or CD28 on the surface of CD4+ and CD8+ T cells, causing their inhibition or activa‑
tion, respectively [329]. Notably, upon cytokine signaling, APCs mediate the “immune
synapse”, activating cytotoxic CD8+ T cells thanks the stimulatory and inhibitory receptors
programmed cell death 1 (PD‑1) and CTLA‑4 [330]. Despite immune surveillance, neoplas‑
tic cells can still escape the immune system defense mechanisms [331]. Immunotherapy
aims at overcoming this phenomenon by unleashing the host immune system against ma‑
lignant cells. At present, immunotherapy approaches have been successful in promoting
positive clinical responses across multiple cancer types [331].
The discovery of immune checkpoint inhibitors by American physician D. R. Leach
prompted the use of antibodies to block CTLA‑4 and trigger robust immune responses
to achieve tumor shrinkage [332]. Currently, immune checkpoint inhibitors such as anti‑
CTLA‑4, anti‑PD‑1, and anti‑PD‑L1 are regularly used in clinical practice to target regula‑
tory pathways in T cells, essentially to reactivate the immune response against malignant
cells [333,334]. However, the consequence of excessive activation of the immune system
is the onset of autoimmune diseases such as rheumatic polymyalgia or serum‑negative
arthritis [335]. In this context, the dysregulation of the delicate balance between M1/M2
macrophages contributes to the pathogenesis of autoimmune diseases such as rheumatoid
arthritis [336]. The understanding of the complex interplay between cancer and autoim‑
munity represents a continuously advancing area of study. Therefore, the identication of
novel immunoactive molecules is crucial to developing new therapeutic strategies.
A recent study described the immunostimulating eect of a marine exopolysaccha‑
ride (EPS) produced by the deep‑sea psychrotolerant Gram‑positive bacterium Planococcus
rietoensis AP‑5 [233]. This compound was tested on in vitro‑cultured THP‑1 monocytes
dierentiated into macrophage‑like cells and treated with dierent EPS concentrations (5,
10, 20, 50, and 100 µg/mL). The authors reported negligible cell toxicity at low dosages, but
increased phagocytic activity and high cytokine (IL‑10, IL‑6, IL‑1β, and TNF‑α) produc‑
tion, suggesting strong immunoregulatory properties of EPS on innate immune responses
and, thus, a potential application of this marine polysaccharide as a complementary agent
in cancer immunotherapy (Figure 4).

Mar. Drugs 2024,22, 304 16 of 32
Mar. Drugs 2024, 22, 304 17 of 34
Figure 4. Immune surveillance and immunotherapy with immune checkpoint inhibitors. Illustra-
tion of in vitro EPS immunostimulant effect on monocyte-derived macrophages. Cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), antigen-presenting
cell (APC), cytotoxic T-Lymphocyte antigen 4 (CTLA4), T cell receptor (TCR), cytokines (IL), clus-
ter of differentiation (CD), human monocytic cell line (THP-1), tumor necrosis factor (TNF), phor-
bol 12-myristate13-acetate (PMA), and extracellular polysaccharides s(EPS). Figure created with
Biorender (accessed on 12 June 2024), based on [237].
8.3. Synthetic Biology and Molecular Pharming in Microalgae
The genetic manipulation of microalgal genomes represents a booming field in bio-
technology, projecting photosynthetic microbes as viable alternatives to conventional
heterotrophic hosts (bacteria and yeasts) for the production of high-value recombinant
therapeutics [341,342]. Advanced genetic tools are constantly being developed to: (i)
achieve high-expression of foreign DNA sequences coupled to synthetic cis-acting regu-
latory elements [343,344]; (ii) introduce multigene expression constructs [345]; (iii) con-
duct iterative editing interventions in the nuclear genome [346]; and (iv) exploit the chlo-
roplast genome for metabolic engineering and production of recombinant proteins
[347,348]. Microalgae are suitable platforms for producing recombinant protein-based
therapeutics since they perform eukaryotic post-translational modifications and can be
engineered to secrete heterologous products in the cultivation media [349]. Different
classes of recombinant therapeutics can be produced in microalgae, including full-length
antibodies [350], anti-cancer cytokines [351], and immune receptors [352].
Furthermore, genetic egineering can be employed to enhance the yield of functional
metabolites. For instance, endogenous metabolic circuits can be rewired to hyperaccu-
mulate specific pathway intermediates or modified to accumulate non-native metabo-
lites. Alternatively, entirely new biosynthetic pathways can be introduced to produce ex-
Figure 4. Immune surveillance and immunotherapy with immune checkpoint inhibitors. Illus‑
tration of in vitro EPS immunostimulant eect on monocyte‑derived macrophages. Cytotoxic T‑
lymphocyte‑associated protein 4 (CTLA‑4), programmed cell death 1 (PD‑1), antigen‑presenting cell
(APC), cytotoxic T‑Lymphocyte antigen 4 (CTLA4), T cell receptor (TCR), cytokines (IL), cluster of
dierentiation (CD), human monocytic cell line (THP‑1), tumor necrosis factor (TNF), phorbol 12‑
myristate13‑acetate (PMA), and extracellular polysaccharides s(EPS). Figure created with Biorender
(accessed on 12 June 2024), based on [233].
8.3. Synthetic Biology and Molecular Pharming in Microalgae
The genetic manipulation of microalgal genomes represents a booming eld in biotech‑
nology, projecting photosynthetic microbes as viable alternatives to conventional
heterotrophic hosts (bacteria and yeasts) for the production of high‑value recombinant
therapeutics [337,338]. Advanced genetic tools are constantly being developed
to: (i) achieve high‑expression of foreign DNA sequences coupled to synthetic cis‑acting
regulatory elements [339,340]; (ii) introduce multigene expression constructs [341];
(iii) conduct iterative editing interventions in the nuclear genome [342]; and (iv) exploit
the chloroplast genome for metabolic engineering and production of recombinant pro‑
teins [343,344]. Microalgae are suitable platforms for producing recombinant protein‑based
therapeutics since they perform eukaryotic post‑translational modications and can be en‑
gineered to secrete heterologous products in the cultivation media [345]. Dierent classes
of recombinant therapeutics can be produced in microalgae, including full‑length antibod‑
ies [346], anti‑cancer cytokines [347], and immune receptors [348].
Furthermore, genetic egineering can be employed to enhance the yield of functional
metabolites. For instance, endogenous metabolic circuits can be rewired to hyperaccu‑
mulate specic pathway intermediates or modied to accumulate non‑native metabolites.
Alternatively, entirely new biosynthetic pathways can be introduced to produce exotic

Mar. Drugs 2024,22, 304 17 of 32
metabolites starting from endogenous substrates [349,350]. Metabolic engineering in the
model freshwater chlorophyte Chlamydomonas reinhardtii resulted in the synthesis of the
non‑native ketocarotenoid astaxanthin via overexpression of two heterologous biosynthetic
genes [351] and via CRISPR‑Cas9‑based gene inactivation coupled to transgenesis [352]. In
this respect, the recent genome annotation of Haematococcus lacustris is expected to facili‑
tate the genetic engineering of astaxanthin accumulation, both in the native producer and
in heterologous hosts [353].
Indeed, although most genetic tools have been established in Chlamydomonas rein‑
hardtii, engineering strategies are currently being tested in non‑conventional strains, in‑
cluding the marine rhodophyte Porphyridium purpureum, in which the expression of a gly‑
cosylated viral antigen was recently reported [354]. This is expected to signicantly expand
the range of therapeutic uses of microalgae, with respect to both recombinant protein ex‑
pression [355] and hyper‑accumulation of high‑value pigments and lipids [356–359]. Fi‑
nally, current developments of synthetic biology in marine cyanobacteria are expected to
introduce signicant novelties into the biomanufacturing of therapeutics in these highly
productive photosynthetic microbes [360,361].
8.4. The Marine Viral Dark Maer and Its Potential for Medical Biotechnology
Despite not nding a place in the tree of life, viruses are the undisputed engines of evo‑
lution in the marine biosphere and are major drivers of its biogeochemical
cycles [362,363]. The genetic complexity of the “marine viral dark maer” is just begin‑
ning to surface through recent studies [364], and is expected to bring about not only new
insights into ecophysiological dynamics, but also innovations in biomedicine [365,366].
Historically, viruses have been a source of inspiration in the development of biomedical
applications like vaccine production, cellular transfection, and phage therapy, to name a
few. Of particular interest are phytoplankton‑infecting viruses like Phycodnaviridae [367]
and Cyanophages [368], infecting marine eukaryotic microalgae and cyanoprokaryotes, re‑
spectively. Moreover, certain structural features of viral proteins have broader relevance
for biotechnology. One example is inteins, self‑cleavable protein splicing elements en‑
riched in marine viral genomes, which have been engineered into valuable biotechnolog‑
ical tools [369,370]. However, due to the scarcity of reports describing the use of marine
viruses in biotechnology, at present, it is dicult to predict their impact on future devel‑
opments of biomedical applications.
9. Conclusions
Marine pharmacology has come a long way, from superstitious practices to present‑
day high‑throughput drug discovery pipelines. During the last three decades, the bio‑
prospecting of marine environments has identied hundreds of lead compounds with po‑
tential applications in the clinical management of chronic inammatory diseases and can‑
cer. Several of these will likely be implemented as complementary agents in the clinical
practice along with already established therapeutics, such as anti‑cytokines, monoclonal
antibodies, and immune checkpoint inhibitors.
It should be noted, however, that the developing “ocean blue economy” is threaten‑
ing marine biodiversity due to the intense activities of shipping, transportation, sheries,
tourism, and renewable energy production. Among these, seabed mining has been pro‑
posed as a severe cause of biodiversity erosion [371–374], and the ecological impact of this
industrial activity was revealed by metagenomics analysis showing a reduction of deep‑
sea microbial biodiversity [375]. Indeed, in contrast with land environments, the high seas
are still a largely ungoverned and vast “no man’s land” lacking sustainable planning for
resource management [376].
Moreover, anthropogenic climate change has manifold impacts on marine ecophysiol‑
ogy. It should be noted that the distribution of global marine plankton follows latitudinal
gradients, with a steady decline towards the poles. On the one hand, ocean warming is
expected to cause a tropicalization of plankton diversity in temperate and polar waters,

Mar. Drugs 2024,22, 304 18 of 32
puing at risk these under‑explored fragile ecosystems and, thus, precluding future bio‑
prospecting endeavours [377]. On the other hand, ocean acidication, a direct consequence
of rising atmospheric CO2levels, is suggested to interfere with the metabolism of marine
ora, particularly of seaweeds, aecting their polysaccharide, fay acid, and secondary
metabolite composition and prole and potentially altering their reported pharmacologi‑
cal uses [378]. Therefore, the ultimate frontier of marine pharmacology lies in the devel‑
opment of sustainable biomanufacturing platforms of therapeutic compounds, away from
low‑yielding and threatened natural producers, through synthetic biology approaches in
photosynthetic microbes.
Author Contributions: Conceptualization, E.A.C.; writing—original draft preparation, E.A.C., R.C.
(Rosanna Campitiello); writing—review and editing, M.C., S.N.A., R.C. (Roberto Caferri), V.F.P., J.L.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: Wewish to thank Arianna (Cai Hang) for assistance with the revision of Chinese
writing in the text.
Conicts of Interest: The authors declare no conict of interest.
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