Table A1.

Effects of oral supplementation of whole brown seaweeds or crude extracts on inflammation-related parameters.

Compound/Format	Effective Concentrations	Algal Source	Experimental Model	Inflammatory Phase 1	Significant Findings 2	Reference
EtOH extract	300–2000–5000 mg/kg; single dose	Sargassum micracanthum	BALB/c mouse; toxicity; follow-up 2 weeks	steady state	non-toxic up to 5000 mg/kg	[3]
EtOH-H2O extracts	single dose LD50 = 500–2000 mg/kg; oxidative stress reduction: 200 mg/kg/day, 4 weeks	Fucus vesiculosus	Swiss mouse; Sprague Dawley rat; toxicity: acute anti-oxidant activity: 4 weeks	steady state	LD50 acute toxic > 750 mg/kg 4 week supplementation: ↓ 13% food intake in 4 week 30–50% ↓ WBC but no change in differential counts 20–25% ↑ in liver and kidney weight ↑ PON-1 activity (protects against ox-LDL) ↑ SOD	[5]
MeOH-, hexane- or chloroform-extract	>2000 mg/kg, single dose	Cystoseira compressa (Esper)	male and female albino mouse; toxicity	steady state	no lethality in oral testing (2000 mg/kg)	[4]
EtOH extract, polyphenol-rich ultrafiltrate	100 mg/day, 8 weeks	Ascophyllum nodosum	human, BMI ≥ 25	steady state	marginal ↓ lymphocyte DNA damage in only obese =CRP =cholesterol, HDL, LDL, TG anti-oxidant =in vitro LPS-/TPA-induced pro-inflammatory cytokines in monocytes, lymphocytes =total plasma peroxide	[7]
whole, dried	4.8 g/dayay, 4 weeks	Sargassum muticum	human	steady state	↓ oxLDL (14%); correlated to ↑ total antioxidant status ↑ NK count; =lymphocyte count ↓ fatigue ↑ liver function (↓ AST, ALT)	[6]
commercial extract	2% in feed, 3 weeks	Ascophyllum nodosum	Spanish and Boer × Spanish goat; stress by transport and feed withholding	steady state	=cortisol =WBC and subset counts, but ↓ Eosinophil =phagocytosis ↓ lipid peroxidation; ↓ SOD (strain diff.) ↑ glutathione peroxidase (10–15%)	[8]
commercial extract	0.5% in feed; 41 weeks	Ascophyllum nodosum	Lohmann LSL-Lite and Lohmann Brown-Lite hens, heat stress	steady state	short-term↓ feed intake; ↑ feed/egg efficiency strain-dependent ↑ production, ↑ feed efficiency, ↑ heat stress resistance, improved ALP, ALT, GGT liver parameters	[161]
seaweed powder + anti-bacterial peptides (cecropin)	1–5% of basal diet	Laminaria japonica	Arbor Acres broiler chicks	steady state	synergistic effect of seaweed + cecropin: ↑ antibodies, ↑ lymphocytes, microbiota: ↑ Lactobacillus, ↓ E.coli ↑ feed conversion ratio	[9]
hot water extract	100–500 mg/kg in feed, 12 weeks	Sargassum oligocystum	fish, Pangasius (Pangasianodon hypophthalmus)	steady state	↑ weight, daily growth rate, feed conversion ratio ↑ WBC, RBC, Hb, Hc, platelets	[10]
seaweed meal	3–6–9% in feed, 6 weeks	Sargassum ilicifolium	fish, Asian sea bass (Lates calcarifer)	steady state	↑ growth; ↑ pancreatic enzyme activities ↑ serum Ig; (alternative) complement pathway components, lysozyme ↑ Ig in skin mucus ↑ liver SOD, IL-1β mRNA	[11]
whole seaweed	10% in feed, 8 weeks	Sargassum ilicifolium	fish, great sturgeon (Huso huso)	steady state	↑ growth ↑ serum protein, lysozyme, IgM, respiratory burst, complement ↑ Hb, RBC, WBC =TG, LDH, AST, ALT ↓ blood cholesterol ↑ survival upon Yersinia ruckeri infection (14 days infection)	[12]
aqueous extract	400 mg/kg, 8 weeks	Sargassum angustifolium	fish, rainbow trout (Oncohrynchus mykiss)	steady state	↑ weight gain ↑ Hb, Hc, RBC, WBC, total protein, albumin↑ survival and immune response to Yersinia ruckeri infection	[13]
EtOH extract	200 mg/kg, 31 days	Sargassum horneri	male C57BL/6 mouse; in vivo anti-DNP-IgE i.v. + DNP i.n. challenge	allergy	↓ nasal rubbing ↓ mast cell degranulation Proposed mechanism: Chlorophyll-C2 →↓ PI-3K + ↓ Btk, ↓ Syk active upon FcεR trigger →↓ Ca-mobilization	[15]
EtOH extract	10, 50, 100 mg/kg, 1×/day, 3 weeks	Sargassum horneri	female NC/Nga mouse; house dust mite/dayNCB skin sensibilization DNCB skin challenge (2×/week)	allergy	↓ atopic dermatitis symptoms ↓ epidermal hyperplasia, hyperkeratosis, skin dryness ↓ mast cell + eosinophil skin infiltrates ↓ IL-25, IL-33 → ↓ Rantes (CCL5), Eotaxin (CCL11), TARC (CCL17) in skin ↓ IL-4, -5, -13, ↓ IL-6, -10, IFN-γ in serum ↓ spleen size increase ↓ IgG1, IgG2a increase	[16]
EtOH extract	100–300 mg/kg/day in diet, 5 weeks	Costaria costata	male NC/Nga mouse; DNCB-induced atopic dermatitis skin allergy	allergy	↓ inflammatory cell and mast cell infiltration, epidermal thickness, erythema, hemorrhage, dead skin cell layers, skin dehydration ↓ Eotaxin and TARC (CCL17)↓ serum IgE and histamine normalization of spleen lymphocyte proliferation and cytokine production	[17]
water extract	100–300 mg/kg/day, 4 weeks	Laminaria japonica	female NC/Nga mouse; DNCB-sensitized and challenged dorsal skin	allergy	↓ dermatitis severity; ↓ inflammatory mediators ↑ skin moisture in vitro: ↓ p38 MAPK,↑ ERK, ↓ STAT1 in HaCaT human keratinocyte cell line	[18]
dried powder	1–5–10%, 6 weeks	Eisenia (=Ecklonia) arborea	female Brown Norway rat; oral OVA immunization	allergy	↓ OVA-specific IgE, ↓ total IgE (n.s. with 10% diet) ↓ serum histamine ↑ IFN-γ in spleen and MLN ↓ IL-10 in spleen and MLN	[14]
EtOH extract	0.1–0.3 g/kg/day, 3 days prior to experiment	Laminaria japonica	male SD rat; carrageenan-induced paw inflammation	1,2	↓ paw swelling, leukocyte infiltration in vitro: ↓ IκB phosphorylation → ↓ iNOS, COX2, TNF-α, IL-1β, IL-6	[19]
diethylether fraction	0.1–1 mg/mouse, 2×	Sargassum fusiforme	ICR mouse; ear-swelling after irritant	1,2	↓ ear swelling by arachidonic acid, TPA, oxazolone in vitro: ↓ mast cell degranulation by inhibiting PLA2, COX2, LOX, HA	[20]
ethyl acetate extract	200 mg/kg, 5 weeks	Eisenia bicyclis = Ecklonia bicyclis	male SD rat; isolated peritoneal Mϕ	1,2	↓ LPS-induced iNOS expression and NO production ↓ NF-κB nuclear translocation with and without LPS =(LPS-induced) tumoricidal activity against B16 melanoma	[21]
EtOH extract +/− enzyme-treatment	50–200 mg/kg, 3 weeks	Hizikia. = Sargassum fusiforme	male C57BL mouse; LPS-stimulation of isolated peritoneal Mϕ conA-induced splenic lymphocyte proliferation	1,2	↑ LPS-stimulated IL-1β, TNF-α, IL-6 by peritoneal Mϕ ↑ conA-induced splenocyte proliferation	[22]
EtOH extract	6–24 mg/kg/day, 4 days	Sargassum serratifolium	male ICR mouse; LPS i.p. (2 mg/kg), blood sampling after 2 h	1	↓ TNF, IL-1β, IL-6 confirming in vitro findings	[23]
enzymatic extract	50–200 μg/mL, 1 h prior to and during exp	Sargassum polycystum Chnoospora minima	zebrafish embryos; in vivo 24 h challenge w/H2O2 (10 μg/mL) or LPS (10 μg/mL), monitored 5d	1,2	↓ H2O2-induced ROS levels and cell death ↓ LPS-induced ROS, NO and cell death	[24]
whole seaweed	0–4% feed, 40 days	Sargassum latifolium	Barki sheep (Ovis aries); i.v. LPS challenge (1.25 μg/kg), after day.28 + day.35	2	↓ body temperature, respiration rate ↓ leukocytosis, ESR, HSP70 ↑ blood anti-oxidant capacity (CAT, SOD) ↓ damage-related molecules: malondialdehyde (MDA; lipid peroxidation product); ALAT, LDH	[25]
whole seaweed	0–4% feed, 40 days	Sargassum latifolium	Barki sheep (Ovis aries); heat stress (solar experiment 8–17) vs. mild temperature without solar exposure	2,3	↓ Δ leukocytosis, Δ ESR ↓ proinflammatory cytokines, HSP70 ↑ body weight gain, kidney function, blood anti-oxidant function	[26]
commercial extract	1% feed, 27 days prior to and during exp (10 days)	Ascophyllum nodosum	crossbred wether lamb (Ovis aries); heat stress	1,2	↓ heat stress-induced reduction of phagocyte oxidative burst ↑ SOD ↓ heat stress-induced changes in GSH-peroxidase activity ↓ lipid peroxidation ↑ leukocyte phagocytosis	[27]
EtOH and organic-purified fraction	15 mg/kg/day, 6 weeks	Turbinaria ornata	female C57BL/6J mouse; DSS-induced colitis	1,2	↓ disease activity index ↓ histopathology incl. length reduction, neutrophil infiltrate ↓ TNF ↑ FoxP3, Treg, but = Th17 ↑ IL-10	[28]
aqueous extract (AE) + probiotic mix	100–300 mg/kg, 2×/day for 7 days	Laminaria japonica	male BALB/c mouse; DSS-induced colitis	1,2	AE alone: ↓ colitis, incl. ↓ colonic IL-1. IL-6 AE + probiotics: synergistic ↓ colitis, ↓ IL-1, -6, -12p40; not IFN-γ, IL-10, IL-12p70	[29]
EtOH-extract	50–200 mg/kg/day, d.28–98	Sargassum muticum	male DBA/1J mouse; collagen-induced arthritis	1,2,3	↓ arthritis and edema ↓ IL-6, TNF, IFN-γ in serum ↓ joint degradation, inflammatory cytokines in joints possibly explained by apo-9′ fucoxanthinone (sim. effects)	[30]
GFS = hot water extract with galactofucan sulfate	therapy: 4 × 560 mg/day, 10 days, 1–24 mo. maintenance: 2 × 560 mg/day	Undaria pinnatifida	human; response in patients with active or latent Herpes infection	2	15/15 patients with active disease: ↓ symptoms or full clearance of infection no side effects inhibition of relapse in pts with latent disease	[31]
hot water extract, and HCl-EtOH extract	100 mg/kg/day (heat extract), 10 mg/kg/day (HCl-EtOH extract), for 3–7 days	Laminaria japonica	kuruma shrimp (Marsupenaeus japonicas) in vivo WSSV infection in vitro hemocyte analysis	1,2	↑ survival upon WSSV infectionhemocyte fMet-Leu-Phe stimulation: ↑ chemotaxis ↑ superoxide production ↑ phenol oxidase activity ↑ phagocytosis	[32]
hot water-EtOH extract	20–200 mg/kg; 7 weeks	Hizikia. = Sargassum fusiforme	male SD rat; ligature-induced periodontitis	3	↓ alveolar bone loss due to inflammation	[33]
hot water extract of 10 different herbs incl. S. fusiforme	10 mg/kg; 10 weeks	Sargassum fusiforme	female SD rat; induced autoimmune thyroiditis by CFA-IFA thyroglobulin immunization	3	↓ AI-thyroiditis (cellular infiltrate), ↓ auto antibodies	[34]
whole seaweed, freeze-dried, powdered	5% in chow, 8 weeks	Undaria pinnatifida	male C57BL/6J mouse, HFD+/− seaweed supplement	3	↑ total plasma cholesterol (cf. HFD) fecal cholesterol excretion ↓ ↓ MCP-1 induction obese phenotype not prevented no glycemic improvement in i.p. glucose tolerance test microbiome composition (HFD + seaweed) is closer to LFD than to HFD	[38]
whole seaweed, freeze-dried	5% in chow, 16 weeks	Undaria pinnatifida (Up), Laminaria japonica (Lj), Sargassum fulvellum (Sf), Hizikia = (Sargassum) fusiforme (Hf)	male C57BL/6N mouse, HFD+/− seaweed supplement	3	body weight or adiposity: no change cf. HFD, except HFD+Up →↑ weight + ↑ subcutaneous adipose tissue adiponectin: ↓ with HFD+Up leptin: ↓ with HFD+Lj, +Sf, +Hf insulin resistance: ↓ w/HFD+Lj blood glucose: ↓ HFD+Lj or +Hf = LFD; HFD+Up = HFD crown-like structures in adipose tissue: ↓ ↓ with all; =LFD LPS-induced pro-inflammatory cytokines by BMDM: ↓ with all	[36]
MeOH extract + carob pod	0.1%/0.9%, 4 weeks	Undaria pinnatifida	male Wistar rat, MetS after 8 weeks western diet	2,3	=body weight, fat mass or muscle =food or energy intake ↓ systolic blood pressure at low dose; ↑ at high dose =CRP ↑ insulin, =glucose ↓ non-esterified fatty acids	[37]
hot aqueous extract	500 mg/kg/day started after 2 weeks, for 2 weeks	Ecklonia cava	female Sprague Dawley rat, letrozole-induced PCOS	2,3	↓ vaginal leukocyte infiltration restore normal estrous cycle restore normal plasma hormonal levelsnormalize expression of gonadotropin- and steroid hormone-related genes = weight gain upon PCOS induction	[39]

¹ Phases of inflammation as indicated in Table 1: 1-initiation of inflammation; 2-short term amplification and regulation; 3-short- or long-term consequences. ² Symbols used: ↑—increase; ↓—decrease; =—no change.