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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 54058

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Prof. Dr. Alba Silipo

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Department of Chemical Sciences, University of Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, I-80126 Napoli, Italy
Interests: glycoconjugates; lipopolysaccharides; NMR spectroscopy; innate immunity; NMR study of protein-ligand interaction; NMR-based conformational analysis

Special Issue Information

Dear Colleagues,

About seventy percent of the Earth's surface is covered by water populated by billions of different organisms, yet research into the chemical biology of such marine organisms is limited and mostly unexplored in terms of biology and chemistry beyond. The marine system offers an ecological resource comprising a variety of aquatic plants and animals. Therefore, the marine environment represents countless and diverse resources for new drugs to combat major diseases such as cancer or malaria and a source of molecules that is able to “drive” the mammalian immunity system, i.e., immunodulators. Indeed, the aquatic organisms have to be screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. This potential is immense, and these molecules can be used as new drugs for several different purposes.

Marine drugs research is, however, still at a primary stage. Having an enormous variety with a great diversity of organisms and virgin areas of marine life, the prospects of yielding more novel products from the sea is enormous and should be pursued.

The aim of this special issue is to collect as many papers as possible on molecules deriving from marine organisms that have immunomodulatory activity, i.e., are able to modulate innate or adaptative mammalian immune responses. Amplifying such an interesting and astounding area of natural products research has also the secondary aim of getting a clearer idea of the priority of the drugs that are to be developed and possible new drug candidates of a marine origin.

Prof. Alba Silipo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

marine organisms
structure-activity relationship
immunomodulatory molecules
structural characterization
NMR spectroscopy
mass spectrometry

Published Papers (11 papers)

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Research

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15 pages, 4680 KiB

Open AccessArticle

Chitooligosaccharides Modulate Glucose-Lipid Metabolism by Suppressing SMYD3 Pathways and Regulating Gut Microflora

by Qiutong Wang, Yajie Jiang, Xuegang Luo, Chang Wang, Nan Wang, Hongpeng He, Tongcun Zhang and Liehuan Chen

Mar. Drugs 2020, 18(1), 69; https://doi.org/10.3390/md18010069 - 20 Jan 2020

Cited by 29 | Viewed by 4072

Abstract

Chitooligosaccharides (COS) have a variety of biological activities due to their positively charged amino groups. Studies have shown that COS have antidiabetic effects, but their molecular mechanism has not been fully elucidated. The present study confirmed that COS can reduce hyperglycemia and hyperlipidemia, prevent obesity, and enhance histological changes in the livers of mice with type 2 diabetes mellitus (T2DM). Additionally, treatment with COS can modulate the composition of the gut microbiota in the colon by altering the abundance of Firmicutes, Bacteroidetes, and Proteobacteria. Furthermore, in T2DM mice, treatment with COS can upregulate the cholesterol-degrading enzymes cholesterol 7-alpha-hydroxylase (CYP7A1) and incretin glucagon-like peptide 1 (GLP-1) while specifically inhibiting the transcription and expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the key enzyme in cholesterol synthesis. Furthermore, using an oleic acid-induced hepatocyte steatosis model, we found that HMGCR can be directly transactivated by SET and MYND domain containing 3 (SMYD3), a transcriptional regulator, via 5′-CCCTCC-3′ element in the promoter. Overexpression of SMYD3 can suppress the inhibitory effect of COS on HMGCR, and COS might regulate HMGCR by inhibiting SMYD3, thereby exerting hypolipidemic functions. To the best of our knowledge, this study is the first to illustrate that COS mediate glucose and lipid metabolism disorders by regulating gut microbiota and SMYD3-mediated signaling pathways. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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12 pages, 2267 KiB

Open AccessArticle

In Vivo Hepatoprotective Effects of a Peptide Fraction from Krill Protein Hydrolysates against Alcohol-Induced Oxidative Damage

by Soo Yeon Park, Ilekuttige Priyan Shanura Fernando, Eui Joeng Han, Min Ju Kim, Kyungsook Jung, Dong-Soo Kang, Chang-Bum Ahn and Ginnae Ahn

Mar. Drugs 2019, 17(12), 690; https://doi.org/10.3390/md17120690 - 07 Dec 2019

Cited by 30 | Viewed by 3296

Abstract

Background: Krill (Euphausia superba) represent the largest animal biomass on earth, and are a rich source of high-quality protein with essential amino acids. Krill-derived peptides are renowned for their antioxidant activities. Hence, these peptides may have protective effects against oxidative stress. Alcoholic liver disease is a prevalent cause of death worldwide. The present study explores the hepatoprotective effects of krill peptide hydrolysate fractions against ethanol-induced liver damage in BALB/c mice. Methods: Hydrolysis was carried out by mimicking the gastrointestinal digestion environment and the filtrate was fractionated based on molecular weight (<1 kDa, 1–3 kDa, and >3 kDa). The 1–3 kDa fraction (KPF), which indicated the highest antioxidant effect, was further investigated for its effect on weight and survival rate increase in mice and its influence on serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and liver cholesterol levels. Moreover, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels were measured, followed by Nrf2 and HO-1 expression. Histopathology studies were conducted to assess hepatic tissue damage. Results: KPF enhanced the weight and survival rate of mice while reducing serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and liver cholesterol levels. Moreover, KPF upregulated SOD, CAT, and GPx in liver tissues, while downregulating tumor necrosis factor α and interleukin-6 mRNA expression. KPF further increased Nrf2 and HO-1 expression and suppressed ethanol-induced apoptotic proteins in the liver. Histopathology of KPF-treated mice showed less hepatic tissue damage compared to ethanol-treated mice. Conclusions: Hydrolysates and bioactive peptides prepared from krill can be employed as functional foods to enhance liver function and health. Further investigations of KPF could lead to the development of functional foods. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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17 pages, 3429 KiB

Open AccessArticle

Dietary Recombinant Phycoerythrin Modulates the Gut Microbiota of H22 Tumor-Bearing Mice

by Hongtao Qi, Ying Liu, Xin Qi, Hui Liang, Huaxin Chen, Peng Jiang and Dongfeng Wang

Mar. Drugs 2019, 17(12), 665; https://doi.org/10.3390/md17120665 - 26 Nov 2019

Cited by 18 | Viewed by 3164

Abstract

Normal intestinal flora is widely involved in many functions of the host: nutritional metabolism; maintenance of intestinal microecological balance; regulation of intestinal endocrine function and nerve signal transduction; promotion of intestinal immune system development and maturation; inhibition of pathogenic bacteria growth and colonization, reduction of its invasion to intestinal mucosa, and so on. In recent years, more and more studies have shown that intestinal flora is closely related to the occurrence, development, and treatment of various tumors. It is indicated that recombinant phycoerythrin (RPE) has significant anti-tumor and immunomodulatory effects. However, little is known about the mechanism of the effect of oral (or intragastric) administration of RPE on gut microbiota in tumor-bearing animals. In this study, using high-throughput 16S rDNA sequencing, we examined the response of gut microbiota in H22-bearing mice to dietary RPE supplementation. The results showed that the abundance of beneficial bacteria in the mice intestinal flora decreased and that of the detrimental flora increased after inoculation with tumor cells (H22); following treatment with dietary RPE, the abundance of beneficial bacteria in the intestinal flora significantly increased and that of detrimental bacteria decreased. In this study, for the first time, it was demonstrated that dietary RPE could modulate the gut microbiota of the H22 bearing mice by increasing the abundance of beneficial bacteria and decreasing that of detrimental bacteria among intestinal bacteria, providing evidence for the mechanism by which bioactive proteins affect intestinal nutrition and disease resistance in animals. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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17 pages, 3177 KiB

Open AccessArticle

Deacetylphylloketal, a New Phylloketal Derivative from a Marine Sponge, Genus Phyllospongia, with Potent Anti-Inflammatory Activity in In Vitro Co-Culture Model of Intestine

by Seon Min Lee, Na-Hyun Kim, Sangbum Lee, Yun Na Kim, Jeong Doo Heo, Eun Ju Jeong and Jung-Rae Rho

Mar. Drugs 2019, 17(11), 634; https://doi.org/10.3390/md17110634 - 08 Nov 2019

Cited by 13 | Viewed by 3165

Abstract

The inflammatory bowel diseases (IBD) cause chronic inflammation of the gastrointestinal tract and include ulcerative colitis (UC) and Crohn’s disease (CD). The prevalence of IBD has been increasing worldwide, and has sometimes led to irreversible impairment of gastrointestinal structure and function. In the present study, we successfully isolated a new phylloketal derivative, deacetylphylloketal (1) along with four known compounds from the sponge genus Phyllospongia. The anti-inflammatory properties of deacetylphylloketal (1) and phyllohemiketal A (2) were evaluated using an in vitro co-culture system that resembles the intestinal epithelial environment. A co-culture system was established that consisted of human epithelial Caco-2 cells and phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophage cells. The treatment of co-cultured THP-1 cells with compounds 1 or 2 significantly suppressed the production and/or gene expression of lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2), Interleukin-6 (IL-6), IL-1β and Tumor Necrosis Factor alpha (TNF-α). The expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 were down-regulated in response to inhibition of NF-kB translocation into the nucleus in cells. In addition, we observed that 1 and 2 markedly promoted the nuclear translocation of Nrf2 and subsequent increase in the expression of heme oxygernase (HO)-1. These findings suggest the potential use of sponge genus Phyllospongia and its metabolites as a pharmaceutical aid in the treatment of inflammation-related diseases including IBD. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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13 pages, 2381 KiB

Open AccessArticle

Characterization and Immunomodulatory Effects of High Molecular Weight Fucoidan Fraction from the Sporophyll of Undaria pinnatifida in Cyclophosphamide-Induced Immunosuppressed Mice

by Hee Joon Yoo, Dong-Ju You and Kwang-Won Lee

Mar. Drugs 2019, 17(8), 447; https://doi.org/10.3390/md17080447 - 29 Jul 2019

Cited by 60 | Viewed by 5667

Abstract

Immunomodulation involves two mechanisms, immunostimulation and immunosuppression. It is a complex mechanism that regulates the pathophysiology and pathogenesis of various diseases affecting the immune system. Immunomodulators can be used as immunostimulators to reduce the side effects of drugs that induce immunosuppression. In this study, we characterized the chemical composition of high molecular weight fucoidan (HMWF) and low molecular weight fucoidan and compared their functions as natural killer (NK) cell-derived immunostimulators in vitro. We also tested the effectiveness of HMWF, which has a relatively high function in vitro, as an immunostimulator in immunosuppressed animal models. In these models, HWMF significantly restored NK cell cytotoxicity and granzyme B release to the control group level. In addition, the expression of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α also increased in the spleen. This study suggests that HMWF acts as an effective immunostimulant under immunosuppressive conditions. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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10 pages, 1298 KiB

Open AccessArticle

Ascophyllan Induces Activation of Natural Killer Cells in Mice In Vivo and In Vitro

by Wei Zhang, Takasi Okimura, Tatsuya Oda and Jun-O Jin

Mar. Drugs 2019, 17(4), 197; https://doi.org/10.3390/md17040197 - 28 Mar 2019

Cited by 16 | Viewed by 4014

Abstract

Natural marine polysaccharides have demonstrated immune stimulatory effects in both mice and humans. Our previous study compared the ability of ascophyllan and fucoidan to activate human and mouse dendritic cells (DCs). In this study, we further examined the effect of ascophyllan on the activation of mouse natural killer (NK) cells in vivo and in vitro and compared it to that of fucoidan, a well-studied natural marine polysaccharide. Specifically, administration of ascophyllan to C57BL/6 mice increased the number of NK cells in the spleen when compared to the number in PBS-treated mice. Moreover, the number of IFN-γ-producing NK cells and expression of CD69 were markedly upregulated by ascophyllan treatment. Ascophyllan treatment also induced IFN-γ production and CD69 upregulation in isolated NK cells, but did not promote cell proliferation. Finally, ascophyllan treatment increased the cytotoxicity of NK cells against Yac-1 cells. The effects of ascophyllan on NK cell activation were considerably stronger than those of fucoidan. These data demonstrated that ascophyllan promotes NK cell activation both in mice and in vitro, and its stimulatory effect on NK cells is stronger than that of fucoidan. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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14 pages, 2395 KiB

Open AccessArticle

Brevenal, a Marine Natural Product, is Anti-Inflammatory and an Immunomodulator of Macrophage and Lung Epithelial Cells

by Devon M. Keeler, Meghan K. Grandal and Jennifer R. McCall

Mar. Drugs 2019, 17(3), 184; https://doi.org/10.3390/md17030184 - 20 Mar 2019

Cited by 24 | Viewed by 5877

Abstract

Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the debilitating effects of mucus accumulation and chronic inflammation. Previous research showed that an alga-derived compound, brevenal, could attenuate the effects of inflammatory agents, but the mechanisms by which it exerted its effects remained unclear. We investigated the effects of brevenal on lipopolysaccharide (LPS) induced cytokine/chemokine production from murine macrophages and human lung epithelial cells. It was found that brevenal reduces proinflammatory mediator secretion while preserving anti-inflammatory secretion from these cells. Furthermore, we found that brevenal does not alter cell surface Toll-like receptor 4 (TLR4) expression, thereby maintaining the cells’ ability to respond to bacterial infection. However, brevenal does alter macrophage activation states, as demonstrated by reduced expression of both M1 and M2 phenotype markers, indicating this putative anti-inflammatory drug shifts innate immune cells to a less active state. Such a mechanism of action would be ideal for reducing inflammation in the lung, especially with patients suffering from chronic respiratory diseases, where inflammation can be lethal. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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16 pages, 3667 KiB

Open AccessFeature PaperArticle

Purification and Characterization of a Novel Pentadecapeptide from Protein Hydrolysates of Cyclina sinensis and Its Immunomodulatory Effects on RAW264.7 Cells

by Wei Li, Shengwang Ye, Zhuangwei Zhang, Jiachao Tang, Huoxi Jin, Fangfang Huang, Zuisu Yang, Yunping Tang, Yan Chen, Guofang Ding and Fangmiao Yu

Mar. Drugs 2019, 17(1), 30; https://doi.org/10.3390/md17010030 - 06 Jan 2019

Cited by 46 | Viewed by 4693

Abstract

In the present study, peptide fractions of Cyclina sinensis hydrolysates, with molecular weight (MW) < 3 kDa and highest relative proliferation rate of murine macrophage cell line RAW 264.7, were purified by a series of chromatographic purification methods, to obtain peptide fractions with immunomodulatory activity. The amino acid sequence of the peptide was identified to be Arg-Val-Ala-Pro-Glu-Glu-His-Pro-Val-Glu-Gly-Arg-Tyr-Leu-Val (RVAPEEHPVEGRYLV) with MW of 1750.81 Da, and the novel pentadecapeptide (named SCSP) was synthesized for subsequent immunomodulatory activity experiments. Results showed the SCSP enhanced macrophage phagocytosis, increased productions of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and up-regulated the protein level of inducible nitric oxide synthase (iNOS), nuclear factor κB (NF-κB), and NOD-like receptor protein 3 (NLRP3) in RAW 264.7 cells. Furthermore, the expression of inhibitor of nuclear factor κB-α (IκB-α) was down-regulated. These findings suggest that SCSP might stimulate macrophage activities by activating the NF-κB signaling pathway and can be used as a potential immunomodulatory agent in functional food or medicine. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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Review

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18 pages, 882 KiB

Open AccessReview

Microalgae with Immunomodulatory Activities

by Gennaro Riccio and Chiara Lauritano

Mar. Drugs 2020, 18(1), 2; https://doi.org/10.3390/md18010002 - 18 Dec 2019

Cited by 97 | Viewed by 6802

Abstract

Microalgae are photosynthetic microorganisms adapted to live in very different environments and showing an enormous biochemical and genetic diversity, thus representing an excellent source of new natural products with possible applications in several biotechnological sectors. Microalgae-derived compounds have shown several properties, such as anticancer, antimicrobial, anti-inflammatory, and immunomodulatory. In the last decade, compounds stimulating the immune system, both innate immune response and adaptive immune response, have been used to prevent and fight various pathologies, including cancer (cancer immunotherapy). In this review we report the microalgae that have been shown to possess immunomodulatory properties, the cells and the cellular mediators involved in the mechanisms of action and the experimental models used to test immunostimulatory activities. We also report information on fractions or pure compounds from microalgae identified as having immunostimulatory activity. Given the increasing interest in microalgae as new eco-friendly source of bioactive compounds, we also discuss their possible role as source of new classes of promising drugs to treat human pathologies. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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25 pages, 7029 KiB

Open AccessReview

Antimicrobial and Immunomodulatory Properties and Applications of Marine-Derived Proteins and Peptides

by Hee Kyoung Kang, Hyung Ho Lee, Chang Ho Seo and Yoonkyung Park

Mar. Drugs 2019, 17(6), 350; https://doi.org/10.3390/md17060350 - 12 Jun 2019

Cited by 114 | Viewed by 7228

Abstract

Marine organisms provide an abundant source of potential medicines. Many of the marine-derived biomaterials have been shown to act as different mechanisms in immune responses, and in each case they can significantly control the immune system to produce effective reactions. Marine-derived proteins, peptides, and protein hydrolysates exhibit various physiologic functions, such as antimicrobial, anticancer, antioxidant, antihypertensive, and anti-inflammatory activities. Recently, the immunomodulatory properties of several antimicrobial peptides have been demonstrated. Some of these peptides directly kill bacteria and exhibit a variety of immunomodulatory activities that improve the host innate immune response and effectively eliminate infection. The properties of immunomodulatory proteins and peptides correlate with their amino acid composition, sequence, and length. Proteins and peptides with immunomodulatory properties have been tested in vitro and in vivo, and some of them have undergone different clinical and preclinical trials. This review provides a comprehensive overview of marine immunomodulatory proteins, peptides, and protein hydrolysates as well as their production, mechanisms of action, and applications in human therapy. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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37 pages, 1551 KiB

Open AccessReview

Oceans as a Source of Immunotherapy

by Bilal Ahmad, Masaud Shah and Sangdun Choi

Mar. Drugs 2019, 17(5), 282; https://doi.org/10.3390/md17050282 - 10 May 2019

Cited by 21 | Viewed by 5071

Abstract

Marine flora is taxonomically diverse, biologically active, and chemically unique. It is an excellent resource, which offers great opportunities for the discovery of new biopharmaceuticals such as immunomodulators and drugs targeting cancerous, inflammatory, microbial, and fungal diseases. The ability of some marine molecules to mediate specific inhibitory activities has been demonstrated in a range of cellular processes, including apoptosis, angiogenesis, and cell migration and adhesion. Immunomodulators have been shown to have significant therapeutic effects on immune-mediated diseases, but the search for safe and effective immunotherapies for other diseases such as sinusitis, atopic dermatitis, rheumatoid arthritis, asthma and allergies is ongoing. This review focuses on the marine-originated bioactive molecules with immunomodulatory potential, with a particular focus on the molecular mechanisms of specific agents with respect to their targets. It also addresses the commercial utilization of these compounds for possible drug improvement using metabolic engineering and genomics. Full article

(This article belongs to the Special Issue Marine Immunomodulators)

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