Prospects of Marine Sterols against Pathobiology of Alzheimer’s Disease: Pharmacological Insights and Technological Advances
Abstract
:1. Introduction
2. Distribution and Pharmacokinetics of Marine Sterols
3. Pathobiology of Alzheimer’s Disease
4. Effects of Marine Sterols against Pathobiology of AD
4.1. Protection against Oxidative Stress
4.2. Protection against Neuroinflammation
4.3. Marine Sterols as Cholinesterase Inhibitors
4.4. Marine Sterols as β-Secretase Inhibitors
4.5. Marine Sterols as Neuroprotective Agent
4.6. Marine Sterols as Regulators of Cholesterol Homeostasis
5. Pharmacological Mechanism of Protective Actions of Marine Sterols against AD Pathology
6. Technological Advances toward Sterol Therapy
7. Concluding Remarks and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Sterol | Distribution | Structure | ADME/T Properties | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Lipinski’s Rule of Five | Jorgensen’s Rule of Three | Blood–Brain Barrier Permeability | Percent Human Oral Absorption | |||||||||
mol_MW | donorHB | accptHB | QPlogPo/w | QPlogS | QPPCaco | #metabolites | QPlogBB | CNS | ||||
7-dehydroerectasteroid-F | Soft coral Dendronephthya gigantea [16] | 470.691 | 1 | 5.7 | 5.766 | −7.264 | 494.218 | 5 | −1.288 | −2 | 95.962 | |
Dendronesterones-D | Octocoral Dendronephthya sp. [17] | 440.578 | 0 | 6 | 4.652 | −6.582 | 308.75 | 2 | −1.253 | −2 | 100 | |
5α-cholestan-3,6-dione | Octocoral Dendronephthya mucronate [18] | 400.643 | 0 | 4 | 5.731 | −7.143 | 1210.653 | 4 | −0.683 | 0 | 100 | |
Fucosterol | Brown algae [19,20,21,22,23,24,25,26] | 412.698 | 1 | 1.7 | 7.577 | −8.812 | 3376.384 | 6 | −0.299 | 0 | 100 | |
24-hydroperoxy-24-vinylcholesterol | E. stolonifera [27] | 444.696 | 2 | 4.15 | 6.183 | −7.195 | 1183.894 | 3 | −0.947 | −1 | 100 | |
16-O-desmethylasporyergosterol-β-d-mannoside | Fungus Dichotomomyces cejpii [28] | 572.781 | 5 | 11.9 | 3.639 | −6.171 | 149.465 | 11 | −2.149 | −2 | 74.215 | |
5α-pregn-20-en-3β-ol | Octocoral Dendronephthya mucronate [18] | 316.526 | 1 | 1.7 | 5.097 | −5.957 | 3378.51 | 3 | 0.019 | 1 | 100 | |
Cholest-4-en-3-one | Fatworm Urechis unicinctus [29] | 384.644 | 0 | 2 | 6.923 | −8.177 | 2769.384 | 2 | −0.316 | 0 | 100 | |
Saringosterol | Brwon algae [30,31] | 428.697 | 2 | 2.45 | 6.912 | −7.854 | 1981.099 | 4 | −0.655 | 0 | 100 | |
24-methylenecholestane-3β,5α,6β,19-tetraol | Soft coral Nephthea brassica [32] | 434.658 | 4 | 4.9 | 5.105 | −6.979 | 665.416 | 6 | −1.315 | −2 | 94.407 |
Anti-AD Effects | Name of Sterol | Marine Source | Dose Regimen | Experimental Model | Major Findings | Reference |
---|---|---|---|---|---|---|
Protection against oxidative stress | Fucosterol, 3,6,17-trihydroxy-stigmasta-4,7,24(28)-triene and 14,15,18,20-diepoxyturbinarin | Pelvetia siliquosa | 30 mg/kg/day for 7 days prior to CCl4 challenge | CCl4-stimualted Rat model | ↑SOD, CAT, and GPx | [20] |
Fucosterol | Edible brown alga Eisenia bicyclis | 25–400 μM | tert-BHP-induced RAW 264.7 macrophage cells | ↓ROS generation | [21] | |
Ecklonia stolonifera and Eisenia bicyclis | 25–100 μM | tert-BHP- and tacrine-induced HepG2cell injury model | ↓ROS generation ↑GSH level | [22] | ||
Brown alga Sargassum Binderi | 3.125–100 μg mL−1 | CPM-stimulated injury and inflammation in A549 epithelial cells | ↓ROS level ↑SOD, CAT, and HO-1 in cytosol, and Nrf2 in nucleus | [23] | ||
7-dehydroerectasteroid F | Soft coral Dendronephthya gigantea | 10 μM | H2O2-induced oxidative damage in PC12 cells | Nuclear translocation of Nrf2 and ↑HO-1 | [16] | |
Protection against inflammation | Fucosterol | Panida australis | 0.004, 0.2, and 10 μM | LPS- and Aβ-induced BV2 (microglial) cells | Attenuates LPS- or Aβ-induced inflammation ↓IL-6, IL-1β, TNF-α, NO, and PGE2 | [24] |
Eisenia bicyclis | 5–20 μM | LPS-stimulated RAW 264.7 murine macrophages | ↓NO production ↓iNOS and COX-2 ↓NF-κB pathway | [21] | ||
Brown seaweed Undaria pinnatifida | 10, 25, or 50 μM | LPS-induced RAW 264.7 macrophage and THP-1 human monocyte cell line | ↓iNOS, TNF-α, and IL-6 ↓DNA binding ↓phosphorylation of NF-κB, MKK3/6 and MK2 | [25] | ||
Hizikia fusiformis | 1–10 μM | CoCl2-induced hypoxia in keratinocytes | ↓IL-6, IL-1β and TNF-α ↓pPI3K and pAkt and HIF1-α accumulation | [26] | ||
Sargassum binderi | 3.125, 6.25, 12.5, 25, 50, 100 μg mL−1 | CPM-stimulated injury and inflammation in A549 epithelial cells | ↓COX-2, PGE2, TNF-α and IL-6 ↓nuclear translocation of NF-κB and phosphorylation of MAPK, ERK1/2 and JNK | [23] | ||
5α-pregn-20-en-3β-ol and 5α-cholestan-3,6-dione | Octocoral Dendronephthya mucronate (Cnidaria) | IC50 of 30.15 ± 1.05 and 35.97 ± 2.06 μM, respectively | LPS-induced RAW264.7 murine macrophage cells | ↓NO formation | [18] | |
Dendronesterones D | Octocoral Dendronephthya sp. | 10 μM | LPS-induced RAW264.7 macrophage cells | ↓iNOS and COX-2 | [17] | |
Anticholinesterase activity | Fucosterol and 24-hydroperoxy 24-vinylcholesterol | E. stolonifera | IC50 values of 421.72 ± 1.43, 176.46 ± 2.51 µM, respectively | Enzymatic assay | Selective inhibition of BChE | [27] |
Fucosterol | Panida australis | Anti-AChE (10.99–20.71%) and anti-BChE (4.53–17.53%) activities with concentrations ≤ 56 μM | Enzymatic assay | Nonselective cholinesterase inhibition | [24] | |
Sargassum horridum | - | In vitro enzymatic assay | ↓AChE activity (Non-competitive inhibition) | [47] | ||
β-Secretase inhibitory activity | Fucosterol | Eckloniastolonifera and Undaria pinnatifida | 10-100 μM (IC50 64.12 ± 1.0 μM) | In vitro enzymatic assay and In silico analysis | ↓β-secretase activity (Noncompetitive inhibition) | [48] |
Cholest-4-en-3-oneand hecogenin | Urechis unicinctus(fat innkeeper worm or marine spoon worm or penis fish) | EC50 390.6 µM and 116.3 µM, respectively | Fluorescence Resonance Energy Transfer (FRET)-based enzyme assay | Anti-BACE1 activity was comparable to curcuminoids, terpenoids, and tannins | [29] | |
Neuroprotectiveactivity | Fucosterol | Ecklonia stolonifera | 1–10 µM at 24 h before sAβ1-42 challenge (effective fucosterol conc. 5–10 µM) | sAβ1–42 (10 µM) -induced ER stress model of primary neurons and sAβ1–42-induced memory dysfunction in aging rats | Reduces apoptosis in Aβ1–42-stimulated cytotoxicity and ameliorates Aβ1–42-induced cognitive decline ↑TrkB-mediated ERK1/2 signaling ↓GRP78 expression ↑BDNF expression | [49] |
- | 0.0032 to 20 μM | Aβ-stimulated cytotoxicity in SH-SY5Y cells | Attenuates apoptosis in Aβ-induced SH-SY5Y cells ↑Ngb mRNA ↓APP mRNA and Aβ levels | [50] | ||
24(S)-Saringosterol | Sargassum fusiforme | 10 µM | Microglia-treated conditioned medium of 24(S)-Saringosterol-treated astrocytes; Mouse neuroblastoma (N2a)-APP695 cells | Aβ1−42 clearance; ↓Aβ-42 secretion; LXRβ activation | [30] | |
16-O-desmethylasporyergosterol-β-d-mannoside | Fungus Dichotomomyces cejpii | 10 μM | Aftin-5 treated N2a-APP695 cells | Moderate Aβ-42 lowering activity | [28] | |
24-methylenecholestane-3β,5α,6β,19-tetraol | Soft coral Nephthea brassica | 10 μM | Glutamate-induced neuronal injury | Promote cell survival; Negative modulation of NMDA receptor | [51] | |
Cholesterol homeostasis | Fucosterol | - | 100 or 200 μM | HEK293 cell cultures (Reporter system); THP-1-derived macrophages, Caco-2 cells and HepG2 cells | Reverses cholesterol transport; Nonselective LXR agonist ↑ABCA1, ABCG1, and ApoE ↑Intestinal NPC1L1 and ABCA1 ↑Insig-2a, that delays nuclear translocation of SREBP-1c | [52] |
Saringosterol | Sargassum fusiforme | 30 μM | Luciferase reporter assay system; HEK293T, THP-1 monocytes, HepG2, RAW264.7, THP-1 macrophages and Caco-2 cells | Selective LXRβ agonist. ↑ABCA1, ABCG1, and SREBP-1c | [31] |
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Rahman, M.A.; Dash, R.; Sohag, A.A.M.; Alam, M.; Rhim, H.; Ha, H.; Moon, I.S.; Uddin, M.J.; Hannan, M.A. Prospects of Marine Sterols against Pathobiology of Alzheimer’s Disease: Pharmacological Insights and Technological Advances. Mar. Drugs 2021, 19, 167. https://doi.org/10.3390/md19030167
Rahman MA, Dash R, Sohag AAM, Alam M, Rhim H, Ha H, Moon IS, Uddin MJ, Hannan MA. Prospects of Marine Sterols against Pathobiology of Alzheimer’s Disease: Pharmacological Insights and Technological Advances. Marine Drugs. 2021; 19(3):167. https://doi.org/10.3390/md19030167
Chicago/Turabian StyleRahman, Md. Ataur, Raju Dash, Abdullah Al Mamun Sohag, Mahboob Alam, Hyewhon Rhim, Hunjoo Ha, Il Soo Moon, Md Jamal Uddin, and Md. Abdul Hannan. 2021. "Prospects of Marine Sterols against Pathobiology of Alzheimer’s Disease: Pharmacological Insights and Technological Advances" Marine Drugs 19, no. 3: 167. https://doi.org/10.3390/md19030167