Table 1. Effects of marine bioactive substances against periodontitis through in vitro studies

Publication year	Kind of sample	Sample	Kind of source	Organisms	Stimulator	Cell	Outcomes	Ref
2019	Application	S. persica extract-loaded COL hybrid constructs	Cnidaria	Rhizostoma pulmo	-	HPLF	↑Cell proliferation	Arslan & Kantarcioğlu, 2019
2019	Extract	ECE	Phaeophyceae	Ecklonia cava	Pg LPS	RAW 264.7	Non cytotoxicity↓ NO and PGE2 production↓ COX-2 activity↓ mRNA expression of IL-1β, IL-6, iNOS, and TNF-α↑ Activation of Nrf-2/HO-1 pathway↓ Phosphorylation of NF-κB pathway	Kim et al., 2019b
2019	Compound	Marine bromophenol & extract	Rhodophyta	Kappaphycus alvarezii	-	-	Antibacterial effect on Porphyromonas gingivalis↓ Rgp activity ↓ Hemagglutination↓ mRNA expression of HgA, PPAD, and Rgp	Cherian et al., 2019
2020	Application	Chitosan-loaded gel	Chordata	Chanos chanos	-	-	Antibacterial effect on P. gingivalis and Aggregatibacter actinomycetemcomitan	Achmad et al., 2020a
2020	Application	COL-sodium alginate-TiO2 matrix	Chordata	Tilapia	-	HPLF	Non cytotoxicity↑Level of ALP and OCN↑Mineralization↑mRNA expression of ALP, COL, OCN, and RUNX-2↑Protein expression of COL, OCN, and RUNX-2	Elango et al., 2020
2020	Application	Dox:CS/CMCS-NPs	Unknown	Unknown	Pg LPS & ATP	HGF	Antibacterial effect on P. gingivalisNon cytotoxicity↓ mRNA and protein expression of ASC and NLRP3↓ mRNA and protein expression of IL-1β ↓ mRNA expression and activation of Caspase-1	Xu et al., 2020
2020	Application	PVA/COL hydrogel	Chordata	Tilapia	-	HPLF & HGF	↑Cell viability and proliferation when increased COL ratio in both cell lines↑Cell adhesion when increased COL ratio in both cell lines	Zhou et al., 2020
2020	Application	Resveratrol and Celastrol-loaded fish COL/chitosan film	Combination(Chordata & unknown)	Tilapia & unknown	-	HPLF & BMM	↑Proliferation of HPLF↑Differentiation to TRAP-positive cell from BMM	Wang et al., 2020a
2020	Application	Surfactin-loaded ĸ-carrageenan oligosaccharides entangled cellulose nanofibers	Unknown	Unknown	-	RAW 264.7	Non cytotoxicityAntibacterial effect on P. gingivalisAnti-biofilm effect of P. gingivalis and Streptococcus mutans↓ Metabolic activity of P. gingivalis and S. mutans↑MDA level on P. gingivalis and S. mutans↑Cell death of P. gingivalis and S. mutans	Johnson et al., 2020
2020	Compound	Alkaloids	Porifera	Agelas dilatata	-	-	Antibacterial effect on P. aeruginosaAnti-biofilm effect on P. aeruginosa	Pech-Puch et al., 2020
2020	Compound	Biseokeaniamide A	Cyanobacteria	Okeania sp.	LPS	RAW 264.7	Non cytotoxicity↓ NO production↓ Expression of IL-1β↓ Protein expression of iNOS↓ Protein expression of IκBα	Ohno et al., 2020
2020	Compound	Cadex2870	Pseudomonadota	Catenovulum sp.	-	-	Anti-biofilm effect on S. mutansScavenging effect on the formed plaque biofilm of S. mutans	Deng et al., 2020
2020	Compound	DHA & EPA	Unkonwn	Unkonwn	-	-	Antibacterial effect on Streptococcus oralis, Actinomyces naeslundii, Veillonella parvula, Fusobacterium nucleatum, P. gingivalis, and Aggregatibacter actinomycetemcomitansAnti-biofilm effect on Streptococcus sp. and Aggregatibacter sp.	Ribeiro-Vidal et al., 2020
2020	Compound	M101	Annelida	Arenicola marina	Pg LPS stimulation or P. gingivalis infection	HOEC	Antibacterial effect on P. gingivalisNon cytotoxicity↓ mRNA expression of NF-κB, TNF-α, and RANKL↓ Protein expression of TNF-α↓ Protein expression of IL-1β, IL-8, IP-10, and RANTES↑Protein expression of IL-10, IL-2, IL-4, IL-11, IL-15, PDGF-BB, and TGF-β1↑Release of ICAM-1, M-CSF, and TIMP-2↑mRNA expression of Resolvin-E1 receptor	Batool et al., 2020
2020	Compound	2,2-bis(6-bromo-1H-indol-3-yl) ethanamine & its fluorinated analogue	Unknown	Unknown	-	-	Antimicrobial activity on S. mutansAntibacterial activity against S. mutans in plasmaAnti-biofilm effect against S. mutansInducted VBNC↓ Oxacillin resistance in S. mutans	Campana et al., 2020
2020	Extract	Algae EtOH extracts(ATEE, DDEE, GFEE, HJEE, MSEE, & SCEE)	Rhodophyta & Phaeophyceae	ATEE, DDEE, GFEE, HJEE, MSEE & SCEE	Pg LPS	HGF	Non cytotoxicity↓ NO production(ATEE, HJEE, GFEE, and SCEE)↓ Protein expression of iNOS(ATEE and HJEE)	Yoon et al., 2020
2021	Application	Atorvastatin solid-loaded gel formulation	Unknown	Unknown	TNF-α	HGF	↓ Release of IL-1β, IL-6, IL-8, IL-10, TGF-β1, TGF-β2, and TGF-β3	Özdoğan et al., 2021
2021	Application	Ginsenoside Rg1 and amelogenin-loaded injectable glycol chitosan/aldehyde-modified hyaluronic acid hydrogel	Unknown	Unknown	-	HBMSC	Non cytotoxicity	Guo et al., 2021
2021	Application	Minocycline-loaded chitosan/cyclodextrin mouthwash	Unknown	Unknown	-	-	Antibacterial effect on P. gingivalis Anti-biofilm effect on P. gingivalis	Li et al., 2021
2021	Application	Xn2%-HA1%-M101 gels	Annelida	A. marina	-	HOEC	Non cytotoxicityAntibacterial effect on P. gingivalis	Özçelik et al., 2021
2021	Extract	Agarum clathratum MeOH extract	Phaeophyceae	A. clathratum	Pg LPS	THP-1	Non cytotoxicity↓ mRNA and protein expression of IL-1β	Han et al., 2021
2021	Extract	ECE	Phaeophyceae	E. cava	LPS	HGF	Non cytotoxicity↓ PGE2 production↓ ROS production↓ Phosphorylation of MAPK pathway↓ mRNA expression of COX-2, IL-6, MMP-2, and MMP-8↓ mRNA expression of MIP-1α and SDF-1	Jung et al., 2021
2021	Extract	KAE, KAEA, KAC	Rhodophyta	K. alvarezii	-	Vero & KB-3-1	High antioxidant activityAntimicrobial activity on Bacillus subtilis, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Candida albicansHigh cell viability on Vero (KAC)High cytotoxicity on KB-3-1 (KAE)	Sharan & Vennila, 2021
2021	Extract	Squid skin liposome	Mollusca	Dosidicus gigas	RANKL/M-CSF	RAW 264.7	Non cytotoxicity↓ PGE2 level↓ Osteoclast maturation↓ Bone resorption pit area↓ TRAP activity↓ mRNA expression of NFATc1, c-Src, Cathepsin K, DC-STAMP RANK, and TRAP	Kao et al., 2021
2021	Compound	EPA	Unknown	Unknown	Pg LPS or heat-inactivated Pg LPS	HGF	Non cytotoxicity↓ mRNA expression of IL-1β and IL-6↓ Protein expression of IL-6↑mRNA and protein expression of HO-1	Ke-cong et al., 2021
2021	Compound	Epiloliolide	Phaeophyceae	Sargassum horneri	Pg LPS	HPDL	↑Proliferation, migration, mineralization↓ Protein expression of NLRP3, COX-2, and iNOS↑Phosphorylation of PKA/CREB pathway↑mRNA expression of ALP, OPN, and RUNX-2↓ mRNA expression of IL-1β, IL-6, and TNF-α↓ Release of IL-1β, IL-6, and TNF-α	Kim et al., 2021a
2022	Application	FDCD	Unknown	Unknown	-	MC3T3-E1 & RAW 264.7	Antibacterial effect on Enterococcus faecalisAnti-biofilm effect on E. faecalisInduction of cell leakageNon cytotoxicity↑ROS production inside bacterial cell↑Macrophage migration	Tang et al., 2022
2022	Application	Jellyfish COL scaffolds	Cnidaria	Aurelia aurita	-	hMSC	↑Cell proliferation	Rachmawati et al., 2021
2022	Compound	M101	Annelida	A. marina	P. gingivalis at MOI 100 or inducing hypoxia with CoCl2	HOEC	Antioxidant effectAnti-hypoxic effect↑Cell migration↓ mRNA expression of GLUT-1, GLUT-3, HIF-1α, and MMP-9	Batool et al., 2022
2022	Extract	Turbinaria conoides PE extract	Phaeophyceae	T. conoides	-	-	Antibacterial effect on Streptococcus sp. and Actinomycetes sp.	Magesh et al., 2022
2022	Extract	Sargassum Wightii PE extract	Phaeophyceae	S. Wightii	-	-	Antibacterial effect on S. mutans	Magesh et al., 2020

HPLF, human periodontal ligament fibroblast; ECE, Ecklonia cava ethanol extract; Pg LPS, Porphyromonas gingivalis lipopolysaccharide; NO, nitric oxide; PGE₂, prostaglandin E₂; COX-2, cyclooxygenase-2; IL, interleukin; iNOS, inducible nitric oxygen synthase; TNF-α, tumor necrosis factor alpha; HO-1, heme oxygenase-1; Rgp, Arginine specific gingipain; HgA, hemagglutinin A; PPAD, peptidyl arginine deiminase; ALP, alkaline phosphatase; OCN, osteocalcin; COL, collagen; RUNX-2, runt-related transcription factor 2; Dox:CS/CMCS-NPs, doxycycline-containing chitosan/carboxymethyl chitosan nanoparticles; ATP, adenosine triphosphate; HGF, human gingival fibroblast; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; NLRP3, NOD-like receptor pyrin domain-containing protein 3; PVA, poly (vinyl alcohol); BMM, bone marrow-derived macrophages; TRAP, tartrate resistant acid phosphatase; MDA, malondialdehyde; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HOEC, human oral epithelial cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; RANKL, receptor activator of nuclear factors κB ligand; RANTES, regulated upon activation, normal T cell expressed and presumably secreted; PDGF-BB, platelet-derived growth factor-BB; TGF, transforming growth factor; ICAM-1, intercellular adhesion molecule 1; M-CSF, macrophage colony-stimulating factor; TIMP, tissue inhibitors of matrix metalloproteinases; VBNC, viable but non-culturable cells; EtOH, ethanol; ATEE, Asparagopsis taxiformis; DDEE, Distromium decumbens; GFEE, Galaxaura fastigiata; HJEE, Hypnea japonicay; MSEE, Myelophycus simplex; SCEE, Scytosiphon canaliculatus; HBMSC, human bone marrow mesenchymal cell; MeOH, methanol; THP-1, human monocytic leukemia cell; ROS, reactive oxygen species; MMP, matrix metalloproteinase; MIP-1α, macrophage inflammatory protein-1 alpha; SDF, stromal cell-derived factor; KAE, Kappaphycus alvarezii extracts ethanol extract; KAEA, Kappaphycus alvarezii extracts ethyl acetate extract; KAC, Kappaphycus alvarezii extracts chloroform extract; DC-STAMP, dendritic cell specific transmembrane protein; HPDL, human periodontal derived ligament cells; PKA, protein kinase A; CREB, cAMP response element-binding protein; OPN, osteopontin; FDCD, fucoidan-derived carbon dots; hMSC, human mesenchymal stem cell; GLUT, glucose transporters; HIF, hypoxia inducible factor; PE, petroleum ether.