Developing natural marine products for treating liver diseases

Table 1 Bioactive marine compounds and extracts used for treating liver diseases

Type of activity	Organism	Species	Active compound/extract	Associated mechanism	Disease/model	Ref.
Antioxidative and anti-inflammatory
	Fish	Chum salmon	MCPs	Attenuated serum superoxide dismutase and malondialdehyde levels, thus counteracting increased total cholesterol and TAG levels	ALD/rat model, alcohol- induced	[33]
	Fish	Cod	Oil, n-3 fatty acid	Fluidization of microsomal membranes	DILI/mouse model, acetaminophen-induced	[45]
	Fish	Menhaden fish	Rich in n-3 PUFAs	Regulation of TLR4 and NOD signaling pathways	Liver injury/pig model, LPS- induced	[44]
	Krill	Antarctic krill (Euphausia superba)	PPC, peptides	Increased total antioxidant capacity in plasma, increased liver gene expression of mitochondrial SOD2, and reduced plasma level of the inflammatory mediator IL-2	NAFLD/rat model, HFD-induced	[11]
				Upregulated SOD, CAT, and GPx in liver tissues, downregulated TNF-α and IL-6 mRNA expression, increased Nrf2 and HO-1 expression, and suppressed ethanol-induced apoptotic proteins in the liver	ALD/mouse model, ethanol-induced	[34]
	Shellfish	Meretrix	Oligopeptides	Regulating NF-κB-dependent anti-inflammation signaling pathways to inhibit inflammation; regulating AMPK-α, PPAR-α, and SREBP-1c to improve lipid-metabolism disorders; regulating Bcl-2/Bax anti-apoptosis signaling pathways to prevent liver cell apoptosis	NAFLD/mouse model, HFD-induced	[25]
	Starfish/algae	Haematococcus pluvialis	Astaxanthin	Exerted antioxidant and anti-inflammatory activities by increasing SOD, CAT, and GPX activity and GSH, and reducing lipid peroxidation in the liver; inhibited the expression of inflammatory factors such as TNF- and ROS production; inhibited MAPK and NF-B pathways	NAFLD/mouse model, HFD-induced; ALD/mouse mode, alcohol-induced; DILI/mouse model, APAP, ConA, LPS-induced liver IR, ischemia-induced	[14]
	Algae	Seaweed	Fucoxanthin	Activating the Nrf2-mediated signaling pathway and downregulating the expression of the TLR4-mediated NF-κB signaling pathway	ALD/mouse model, alcohol-induced	[31]
	Algae	Laminaria japonica	UAOS	Increasing both AMPKα and ACC phosphorylation	NAFLD/mouse model, HFD-induced	[18]
	Algae	Red alga (Laurencia tristicha)	Aplysin (a marine bromosesquiterpene)	Revivified erythrocyte membrane fluidity, attenuated glutathione depletion, restored antioxidase activities, and reduced malondialdehyde overproduction	ALD/rat model, alcohol-induced	[30]
	Algae	Brown seaweed (Sargassum thunbergia)	Indole-4-carboxaldehyde	Anti-inflammatory activity against MGO-induced inflammation in human hepatocytes by preventing increased expression of pro-inflammatory genes and AGE formation	Inflammation/cell model, methylglyoxal-induced	[17]
	Algae	Fucus vesiculosus	Fucoidan	Suppressing hepatic production of inflammatory cytokines such as TGF-β1, COX-2, and NO; enhancing the oxidant-defense systems by upregulating the hepatoprotective enzyme hemeoxygenase-1	ALD/mouse model, alcohol-induced	[32]
	Algae	Hypnea muciformis	Ethanolic extract	Regulated activities/levels of lipid-peroxidation byproducts, antioxidant enzymes, and biotransforming phase I and II enzymes in the circulation	DILI/rat model/CCl4-induced	[43]
Gut microbiota modulation
	Sea cucumber	Stichopus japonicus	Sulfated polysaccharide	Preventing HFD‐induced gut disorders, as indicated by enriched levels of the probiotic Akkermansia and reduced endotoxin‐bearing Proteobacteria, improved SCFA and endotoxin (LPS) levels, and improved gut tissue index	NAFLD/mouse model, HFD-induced	[12]
	Algae	Spirulina platensis	95% ethanol extracts (SPL95, major fatty acids)	AMPK-signal pathway; downregulated mRNA and protein levels of SERBP-1c, 3-hydroxy-3-methyl glutaryl coenzyme A reductase, and acetyl-CoA carboxylase pathway members; upregulated levels of adenosine 3,5-monophosphate-activated protein kinase-α in the liver; enrichment of beneficial bacteria including Prevotella, Alloprevotella, Porphyromonadaceae, Barnesiella, and Paraprevotella; decreasing microbes such as Turicibacter, Romboutsia, Phascolarctobacterium, Olsenella, and Clostridium XVIII	NAFLD/rat model, HFD-induced	[21]
	Fungus	Aspergillus versicolor LZD-44-03-derived asperlin	Asperlin	Increased energy expenditure and enhanced thermogenic gene expression in adipose tissues, increased diversity and shifted structure of gut microbiota	NAFLD and obesity/mouse model, HFD-induced	[22]
Lipid metabolism improvement
	Fish	Fish	Fish oil, omega-3-PUFA	Downregulated sterol regulatory element binding protein 1c (SREBP-1c) and upregulated peroxisome proliferator activated receptor α (PPAR-α) which would favour fatty acid oxidation and reduce steatosis	NAFLD/human study, meta-analysis, RCT	[9]
	Starfish	Asterias amurensis	Oil, n-3 PUFA	Enhanced fatty acid β-oxidation and suppressed TG and cholesterol synthesis	NAFLD/mouse model, HFD-induced	[10]
	Shrimp shell	Chitosan oligosaccharide	COS23 (Chitosan oligosaccharide)	Regulated lipid-related pathways, especially inhibition of the expression of FFA synthesis-related and inflammation-related genes, altered plasma lipid profiles, decreased abundance of Mucispirillum and increased abundance of Coprococcus in gut microbiota, and protected the intestinal barrier by up-regulating the expression of tight junction-related genes	NAFLD and obesity/mouse model, HFD-induced	[23]
	Algae	Red seaweed	Palmaria mollis (bacon-like taste)	Upregulated the expression of genes involved in PPAR pathways, and downregulated the PPAR pathways	NAFLD and obesity/zebrafish and mouse model, HFD-induced	[20]
	Algae	Green algae	SPX (a carotenoid)	Suppression of LXRα activity, and downregulation of nuclear transcription factor SERBP-1c and a set of related genes	NAFLD/cell model, LXRα agonist-induced	[15]
	Algae	Spirulina platensis	95% ethanol extract (SPL95)	Downregulating the expression of SERBP-1c, 3-hydroxy-3-methyl glutaryl coenzyme A reductase, and members of the acetyl CoA carboxylase pathway; upregulating adenosine 3,5-monophosphate-activated protein kinase-α in the liver; enrichment of beneficial bacteria	NAFLD/rat model, HFD-induced	[21]
	Algae	Brown alga (Ishige okamurae)	DPHC	Stimulated AMPK and ACC phosphorylation in both liver and epididymal adipose tissue, reduced the expression of critical enzymes for lipogenesis, including PPARr, C/EBP, SERBP-1c, FABP4, and FAS	NAFLD and obesity/mouse model, HFD-induced	[19]
	Algae	Fucus vesiculosus	Fucoidan	Improved MetS via ROS-mediated regulation of JNK, pAkt, and AMPK signaling pathways	NAFLD/mouse model, HFD-induced; NAFLD/cell model, sodium palmitate-induced	[16]
	Fungus	Aspergillus versicolor LZD-44-03-derived asperlin	Asperlin	Increased energy expenditure and enhanced thermogenic gene expression in adipose tissue, and increased diversity and shifted structure of the gut microbiota	NAFLD and obesity/ mouse model, HFD-induced	[22]
Antiviral
	Sponge	Dactylospongia metachromia	Metachromin A, merosesquiterpene	Inhibited HBV production via impairment of the viral promoter activity	HBV/cell model	[47]
	Sponge	Red sea sponge (Amphimedon spp.)	Nakinadine B and 3,4-dihydro-6-hydroxymanzamine A	Anti-HCV NS3 helicase and protease activities	HCV/cell model	[38]
	Formosan soft coral	Lobophytum crassum	Lobohedleolide	Suppressing HCV replication by inhibiting JNK phosphorylation, leading to reduced c-Jun phosphorylation and C/EBP expression, and reduced COX-2 expression	HCV/cell model	[40]
	Ascidian	Styela plicata	Effective components (peptides, alkaloids, saponins, macrolides, terpenoids)	Increased serum IL-2; reduced serum HBV DNA levels	HBV/mouse model, HBV-transgenic	[46]
	Algae	Cladosiphon okamuranus Tokida	Fucoidan	Inhibited expression of the HCV replicon	HCV/cell model; chronic HCV infection, and HCV-related cirrhosis and hepatocellular carcinoma/human study	[39]
	Fungus (a sponge associated fungus)	Trichoderma harzianum	Two new sesquiterpene-based analogues, namely, harzianoic acids A (1) and B	Blocking the entry step in the HCV life cycle, potentially targeting the viral E1/E2 proteins and the host cell protein CD81, reducing HCV RNA levels	HCV/cell model	[37]
Anti-cholestatic
	Sponge	Theonella swinhoei	Theonellasterol	Selective FXR antagonism, increased MRP4 expression	Cholestasis/HepG2 cells; cholestasis/mouse model, BDL-induced	[48]
Anti-fibrotic
	Algae	Cladosiphon okamuranus; Fucus vesiculosus	Fucoidan	Reduced TGF-β1 expression	Liver fibrosis/mouse model, DEN-induced; Liver fibrosis/mouse model, alcohol-induced	[32,51]
	Starfish/algae	haematococcus pluvialis	Astaxanthin	Antioxidant, apoptotic, lipid peroxidation, and autophagy activities; regulation of TGF-1/Smads pathway; downregulating the expression of HDACs	Liver fibrosis/mouse model, CCl4 and BDL-induced; liver fibrosis/rat model, CCl4-induced; liver fibrosis/cell model	[14]
	Algae	Arthrospira platensis	Spirulina liquid extract	Interfering with the TGF-β pathway, reducing inflammation and oxidative stress, and reversing the hepatotoxic bile acid profile	Liver fibrosis/mouse model, Western diet-induced	[52]
	Sea urchin	Sea urchin eggs	Ovothiol A	Negatively regulating redox homeostasis and the activation of key fibrotic markers TGF-β, α-SMA, and TIMP-1	Liver fibrosis (CCl4 model)	[50]
Anti-tumor
	Sponge	Pseudoceratina spp.	Heterocyclic alkaloids, ceratamines A and B	Disruption of microtubule dynamics, antimitotic agents	HCC/in vitro, rat liver microsomes	[58]
	Sponge	Crambe crambe	Crambescidin-816	Inhibition of cell–cell adhesion; interference with tight junction formation, cell-matrix adhesion, and focal adhesions; altered cytoskeleton dynamics; inhibited cell migration	HCC/cell model	[60]
	Erylus spp. sponges	Actinomycetales isolated from Erylus genera		Cytotoxic bioactivity	HCC/cell model	[61]
	Soft coral	Spongodes spp.	Steroid (MESP)	Inhibition of STAT3 phosphorylation	HCC/cell model	-
	Soft coral	Sinularia flexibilis	11-epi-sinulariolide acetate/sinulariolide/sinularin	Suppressed phosphorylation of members in the ERK, JNK, MAPK, and FAK/PI3K/AKT/mTOR pathways; reduced MMP-2, MMP-9, and uPA expression; inhibited HCC migration, invasion, and cell metastasis; increased G2/M cell-cycle arrest; induced apoptosis; activated DNA-damage responses	HCC/cell model	-
	Shellfish	Arca subcrenata Lischke	Protein (ASP-3)	Reduced VEGFR2 phosphorylation, and altered the downstream components of the VEGF signaling pathways	HCC/cell model; HCC/transgenic zebrafish model	-
	Shrimp, crab	Chitin from shells	Chitosan oligosaccharides	Cytotoxicity	HCC/cell model	-
	Jellyfish	Nemopilema nomurai	Venom	Dual inhibition of the Akt and mTOR signaling pathways	HCC/tumor xenograft animal model	-
	Sea urchin	Paracentrotus lividus Oocytes	Ovothiols	Antioxidant capacity, hydrogen peroxide generation	HCC/cell model	-
	Starfish/algae	haematococcus pluvialis	Astaxanthin	Regulating JAK1/STAT3, NF-kB, Wnt/beta catenin; inhibiting the binding of AFB1 to liver DNA and plasma albumin; reducing reactive oxygen metabolites/biological antioxidant potential ratio; regulating nucleoside diphosphate kinase (NPK) nm-23	Hepatoma/rat model, AFB1-induced; HCC/mouse model, DEN-induced; HCC/cell model	[14]
	Algae	Undaria pinnatifida	Fucoidans	Induced apoptosis via the ROS-mediated mitochondrial pathway	HCC/cell model	-
	Microorganisms	Mangrove endophytic fungus	SZ-685C	Induced apoptosis through the Akt/FOXO pathway	HCC/ cell model; HCC/xenografted tumor model	-
	Fungus	Aspergillus terreus strain PF-26, associated with marine sponges	(+)Terrein	Induced cell-cycle arrest in G2/M phase; decreased expression of proteins related to cell morphology (fibronectin, N-cadherin, and vimentin); altered expression of genes related to cell-cycle progression	HCC/cell model	[59]
	Bacteria	Bacillus spp. 11 (EPS11)	Bacterial polysaccharide	Blocking cell adhesion and attenuating filiform structure formation	HCC/cell model	-

ACC: Acetyl-CoA carboxylase; AFB1: Aflatoxin B1; ALD: Alcohol-induced liver damage; AMPK: Adenosine monophosphate-activated protein kinase; AMPKα: AMP-activated protein kinase α; C/EBP: CCAAT/enhancer binding protein alpha; CAT: Catalase; DEN: Diethylnitrosamine; DPHC: Diphlorethohydroxycarmalol; HDAC: Histone deacetylase; GPX: Glutathione peroxidase; HFD: High-fat diet; IL-2: Interleukin-2; IL-6: Interleukin-6 mRNA; JNK: c-Jun N-terminal kinase; LPS: Lipopolysaccharide; LXRα: Liver X receptor α; MCP: Marine collagen peptide; mTOR: Mammalian target of rapamycin; NAFLD: Non-alcoholic fatty liver disease; NF-B: Nuclear factor-kappa B; NOD: Nucleotide-binding oligomerization domain protein; Nrf2: Nuclear factor erythrocyte-2-related factor 2; pAkt: Protein kinase B; PPAR: Proliferator-activated receptor alpha; PPAR: Peroxisome proliferator-activated receptor gamma; PPC: Phospholipid-protein complex; PUFA: Polyunsaturated fatty acid; ROS: Reactive oxygen species; SCFA: Short-chain fatty acid; SERBP-1c: Sterol regulatory element-binding protein-1c; SOD: Superoxide dismutase; STAT3: Signal transducer and activator of transcription 3; TGF-β1: Transforming growth factor beta 1; TLR4: Toll-like receptor 4; TNF: Tumor necrosis factor ; RCT: Randomized controlled trial; UAOS: Unsaturated alginate oligosaccharides; VEGFR: Vascular endothelial growth factor receptor.