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One new 1,4-bis-phenyl-1,4-butanedione glycoside (14), one new eudesmane-type sesquiterpenoid (16), and 16 known compounds were isolated from the leaves and stems of Nelumbo nucifera Gaertn. The structures of the isolated compounds were elucidated by interpretation of their 1D and 2D NMR spectroscopic and HRESIMS data. Time-dependent density functional theory calculations and Electronic Circular Dichroism (ECD) spectroscopy was used to determine absolute configurations of the new eudesmane-type sesquiterpenoid (16). All the isolated compounds were examined for their antiosteoclastogenic activity. Preliminarily results of the TRAP staining on RAW 264.7 cells indicated that compounds 1 and 11 possess potential inhibitory effects on RANKL-induced osteoclast formation. Further bioassay investigation was carried out to reveal that compounds 1 and 11 suppressed RANKL-induced osteoclast formation in a concentration-dependent manner with the inhibition up to 55% and 78% at the concentration of 10 µM, respectively. In addition, the structure-activity relationship analysis showed that the 1,3-dioxole substitute and the double bond at C-6a/C-7 in the aporphine skeleton may be responsible for the antiosteoclastogenic activity. The findings provided valuable insights for the discovery and structural modification of aporphine alkaloids as the antiosteoclastogenic lead compounds.

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An undescribed 1,3-diphenylpropane derivative, kazinol V and six undescribed prenylated flavonoids, broussonols F-H and broussonols K-M were isolated from the roots of Broussonetia kazinoki Siebold, together with 12 known compounds. This is the first report of the isolation and structure determination of broussonol I from a natural source. The chemical structure of the undescribed compounds was determined using conventional NMR and HRMS data. Absolute configurations were assigned using time-dependent density functional theory calculations and Electronic Circular Dichroism (ECD) spectroscopy. The isolated compounds were screened for their effects on RANKL-induced osteoclast formation using RAW264.7 cells. Among them, broussonols F, G, and K showed strong, dose-dependent antiosteoclastogenic activities. Broussonol K exhibited the most potent inhibitory activity and possessed bone resorption suppressive activity.

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In this study, chemical investigation of methanol extract of the air-dried fruits of Luffa cylindrica led to the identification of a new δ-valerolactone (1), along with sixteen known compounds (2-17). Their chemical structures including the absolute configuration were elucidated by extensive spectroscopic analysis and electronic circular dichroism analysis, as well as by comparison with those reported in the literature. For the first time in literature, we have examined the binding potential of the isolated compounds to highly conserved protein, Mpro of SARS-CoV-2 using the molecular docking technique. We found that the isolated saponins (14-17) bind to the substrate-binding pocket of SARS-CoV-2 Mpro with docking energy scores of -7.13, -7.29, -7.47, and -7.54 kcal.mol-1, respectively, along with binding abilities equivalent to an already claimed N3 protease inhibitor (-7.51 kcal.mol-1).

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The white-flowered leaves of Eclipta prostrata L. together with leaves of Scoparia dulcis and Cynodon dactylon are mixedly boiled in water and given to diabetic patients resulting in the significant improvement in the management of diabetes. However, the active constituents from this plant for antidiabetic and anti-obesity properties are remaining unclear. Thus, this study was to discover anti-diabetes and anti-obesity activities through protein tyrosine phosphatases (PTP)1B inhibitory effects. We found that the fatty acids (23, 24) showed potent PTP1B inhibition with IC50 values of 2.14 and 3.21 µM, respectively. Triterpenoid-glycosides (12-15) also exhibited strong to moderate PTP1B inhibitory effects, with IC50 values ranging from 10.88 to 53.35 µM. Additionally, active compounds were investigated for their PTP1B inhibitory mechanism and docking analysis. On the other hand, the anti-inflammatory activity from our study revealed that compounds (1-4, 7, 8, 10) displayed the significant inhibition nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Especially, compound 9 showed the potent inhibitory effects in LPS-induced NO production on RAW264.7 cell. Therefore, further Western blot analysis was performed to identify the inhibitory expression including heme oxygenase-1 (HO-1) and inhibitor of kappaB (IκB) phosphorylation.

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Myristica fragrans Houtt. (Myristicaceae), an aromatic evergreen tree, is well known as a commercial source of mace (aril) and nutmeg (seed), which have long been widely used as spices in the culinary field. In addition, various parts of M. fragrans have been used in folk medicine for treating several diseases. Since its extensive uses in the culinary sector and folk medicine, M. fragrans has long attracted a great deal of attention from pharmacologists and chemists. Numerous studies have indicated that M. fragrans contains diverse phytochemicals such as lignans, neolignans, diphenylalkanes, phenylpropanoids, and terpenoids, which exhibit many of pharmacological activities. Among them, macelignan (1), meso-dihydroguaiaretic acid (2), myristicin (111), and malabaricone C (Mal C, 104) are the most active compounds. The aim of this review is to comprehensively summarize the phytochemical and pharmacological properties of M. fragrans that have reported to date.

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Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC50 values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC50 = 15.10 µM) and ursolic acid (IC50 = 11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC50 values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1-11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications.

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One achiral tetra-aryl cyclobutane [rheundulin A (1)] and three stilbene glycosides [rheundulins B-D (2-4)] were isolated from the methanol extract of Rheum undulatum L., along with eight known compounds (5-12). Structural determination of the new compounds (1-4) was accomplished using comprehensive spectroscopic methods. Compound 1 represents the first example of a dimeric stilbene linked via a cyclobutane ring from the Rheum genus. All isolates were screened for their inhibition against α-glucosidase. Among them, stilbene derivatives (5 and 6) showed strong inhibitory effects on α-glucosidase with IC50 values of 0.5 and 15.4 µM, respectively, which were significantly higher than that of the positive control, acarbose (IC50 = 126.8 µM). Rheundulin A (1) showed moderate α-glucosidase inhibition with an IC50 value of 80.1 µM. In addition, kinetic analysis and molecular docking simulation of the most active compound (5) with α-glucosidase were performed for the first time. Kinetic studies revealed that compound 5 competitively inhibited the active site of α-glucosidase (Ki = 0.40 µM), while 6 had a mixed-type inhibitory effect against α-glucosidase (Ki = 15.34 µM). Molecular docking simulations of 5 and 6 demonstrated negative-binding energies, indicating high proximity to the active site and tight binding to α-glucosidase enzyme.

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Kadsura coccinea (Lem.) A. C. Smith has been used as a tonic, decongestant, and digestive agent. The roots are also employed in traditional medicine to treat chronic enteritis, acute gastritis, duodenal ulcers, rheumatic pain in bone, and traumatic injuries. In the present study, we have described the biological evaluation of constituents from the roots of K. coccinea with PTP1B and AChE inhibitory activities for the first time in literature. A new compound (1), kadcoccilactone T, and 24 known ones (2‒25) were isolated and identified using spectroscopic methods. All the isolates were examined for PTP1B and AChE inhibitory activities. Compounds 4 and 8 expressed strong PTP1B inhibition with IC50 values of 1.57 ± 0.11 and 3.99 ± 1.08 µM, respectively. Apparently, these compounds were further studied for PTP1B enzyme kinetic analysis. The result indicated that compounds 4 and 8 exhibited mixed-type inhibition with the Κi values of 4.97 and 3.26 µM, respectively.

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Three new sesquilignans, zijusesquilignans A-C (1-3), together with fifteen known compounds (4-18), were isolated from fruits of Ziziphus jujuba var. inermis Rehder (Rhamnaceae). Their chemical structures were established using spectroscopic analyses including 1D- and 2D-NMR, HR-EIMS, and ECD spectra. These compounds were assessed for their inhibitory effects on nitric oxide (NO) production. Of these compounds, 1-3 and 17 displayed inhibitory effects on NO production, with IC50 values ranging from 18.1 to 66.4 µM. Pretreatment with 1 and 17 significantly suppressed LPS-induced expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein in cells. Moreover, compounds 1-3, 7, 9, and 17 exhibited cytotoxic activities against three human tumor cell lines, with IC50 values ranging from 8.4 to 44.9 µM.

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Hizikia fusiformis (Harvey) Okamura is an edible marine alga that has been widely used in Korea, China, and Japan as a rich source of dietary fiber and essential minerals. In our previous study, we observed that the methanol extract of H. fusiformis and its non-polar fractions showed potent protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibition. Therefore, the aim of the present study was to identify the active ingredient in the methanol extract of H. fusiformis. We isolated a new glycerol fatty acid (13) and 20 known compounds including 9 fatty acids (1-3, 7-12), mixture of 24R and 24S-saringosterol (4), fucosterol (5), mixture of 24R,28R and 24S,28R-epoxy-24-ethylcholesterol (6), cedrusin (14), 1-(4-hydroxy-3-methoxyphenyl)-2-[2-hydroxy -4-(3-hydroxypropyl)phenoxy]-1,3-propanediol (15), benzyl alcohol alloside (16), madhusic acid A (17), glycyrrhizin (18), glycyrrhizin-6'-methyl ester (19), apo-9'-fucoxanthinone (20) and tyramine (21) from the non-polar fraction of H. fusiformis. New glycerol fatty acid 13 was identified as 2-(7'- (2″-hydroxy-3″-((5Z,8Z,11Z)-icosatrienoyloxy)propoxy)-7'-oxoheptanoyl)oxymethylpropenoic acid by spectroscopic analysis using NMR, IR, and HR-ESI-MS. We investigated the effect of the 21 isolated compounds and metabolites (22 and 23) of 18 against the inhibition of PTP1B and α-glucosidase enzymes. All fatty acids showed potent PTP1B inhibition at low concentrations. In particular, new compound 13 and fucosterol epoxide (6) showed noncompetitive inhibitory activity against PTP1B. Metabolites of glycyrrhizin, 22 and 23, exhibited competitive inhibition against PTP1B. These findings suggest that H. fusiformis, a widely consumed seafood, may be effective as a dietary supplement for the management of diabetes through the inhibition of PTP1B.

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As part of our ongoing program to develop anti-inflammatory agents, an extract derived from Saururus chinensis collected in Korea was found to inhibit nitric oxide (NO) production in RAW264.7 cells. Bioassay-guided fractionation led to the isolation two new (1 and 2) and six known dineolignans (3-8). To the best of our knowledge, manassatin B1 (3) was isolated from S. chinensis for the first time. All structures were elucidated using extensive spectroscopic analysis. Of these compounds, 2 and 8 inhibited lipopolysaccharide (LPS)-induced production of NO and showed IC50 values of 5.80 and 1.52 µM, respectively. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was also significantly suppressed by the administration of 2 and 8. In addition, these lignans induced the expression of heme oxygenase-1 (HO-1) in a concentration-dependent manner. Nuclear translocation of nuclear-E2-related factor 2 (Nrf2), a key regulator of HO-1 protein expression, was also induced in RAW264.7 cells treated with 2 and 8. These findings suggested that these lignans exerted anti-inflammatory effects in RAW264.7 cells through modulation of the Nrf2/HO-1 pathway and that they were potential HO-1 inducers for preventing or treating inflammation.

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The author would like to include conflict of interest statement of the online published article. The correct conflict of interest statement should read as.

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Of the 32 Trichosanthes species in China, T. kirilowii Maxim. is the most renowned species used in traditional Chinese medicine and has diverse pharmacological properties. However, most of the phytochemical studies of T. kirilowii have focused on the fruits and seeds. In our investigation of the chemical constituents of T. kirilowii roots, two previously undescribed sterols [trichosanhemiketal A and B (1 and 2)], together with 13 known compounds, were isolated and their structures were elucidated. To the best of our knowledge, this represents the first isolation of compounds with a 13,14-seco-13,14-epoxyporiferastane (1-2) skeleton from the Cucurbitaceae family. The anti-inflammatory activity of the isolated compounds was determined through an analysis of their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW264.7 cells. Of the compounds, 4, 5, 6, and 8 showed significant inhibitory activities, with IC50 values of 8.5, 15.1, 25.4, and 28.5 µM, respectively. In addition, compound 4 inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in a concentration-dependent manner.

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The inhibitory mechanism of 2-carbomethoxy-2,3-epoxy-3-prenyl-1,4-naphthoquinone (CMEP-NQ) against apoptosis induced by the microtubule-damaging agents (MDAs), nocodazole (NOC) and 2-methoxyestradiol (2-MeO-E2), or a DNA-damaging agent (DDA), camptothecin (CPT) were investigated in human Jurkat T cell clones (J/Neo and J/BCL-XL cells). Treatment of J/Neo cells with NOC, 2-MeO-E2, or CPT caused cytotoxicity and apoptotic DNA fragmentation but these events were significantly attenuated in the presence of CMEP-NQ. Although not only MDA (NOC or 2-MeO-E2)-induced mitotic arrest, CDK1 activation, and BCL-2, BCL-XL and BIM phosphorylation, but also DDA (CPT)-induced S-phase arrest and ATM-CHK1/CHK2-p53 pathway activation were not or were barely affected in the presence of CMEP-NQ, the levels of anti-apoptotic BAG3 and MCL-1, which were markedly downregulated after MDA- or DDA-treatment, were rather elevated by CMEP-NQ. Under the same conditions, MDA- or DDA-induced mitochondrial apoptotic events including BAK activation, mitochondrial membrane potential (Δψm) loss, caspase-9 activation, and PARP cleavage were significantly inhibited by CMEP-NQ. While MDA- or DDA-induced sub-G1 peak and Δψm loss were abrogated in J/BCL-XL cells, MDA-induced mitotic arrest and DDA-induced S-arrest were more apparent in J/BCL-XL cells than in J/Neo cells. Simultaneously, the induced cell cycle arrest in J/BCL-XL cells was not significantly disturbed by CMEP-NQ. MDA- or DDA-treatment caused intracellular reactive oxygen species (ROS) production; however, MDA- or DDA-induced ROS production was almost completely abrogated in J/BCL-XL cells. MDA- or DDA-induced ROS production in J/Neo cells was significantly suppressed by CMEP-NQ, but the suppressive effect was hardly observed in J/BCL-XL cells. Together, these results show that CMEP-NQ efficiently protects Jurkat T cells from apoptotic cell death via the elevation of BAG3 and MCL-1 levels, which results in the inhibition of intrinsic BAK-dependent mitochondrial apoptosis pathway, as does the overexpression of BCL-XL.

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Stilbene derivatives, the principal constituent of Rheum undulatum L., are known to have a wide range of biological activities, such as anti-allergic, anti-diabetic, antioxidant, and anti-inflammatory activities. A phytochemical study on the methanol extract of Korean rhubarb (R. undulatum L.) led to the isolation of nine stilbene derivatives (1-9) and one flavonoid (10). All structures were elucidated based on a comprehensive analysis of spectroscopic data. Compound 1 (5-methoxy-cis-rhapontigenin) was elucidated as a new compound, while compound 2 (5-methoxy-trans-rhapontigenin) was isolated from a natural source for the first time. Among the isolated compounds, stilbene derivatives (7-9) showed a strong inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) with IC50 values ranging from 4.25 to 6.78 µM, which was significantly higher than that of the positive control, ursolic acid (IC50 = 11.34 µM). Furthermore, for the first time, kinetic analysis and molecular docking simulations were performed in order to understand the inhibition type as well as the interaction and binding mode of the active stilbenes (7-9) with PTP1B. Our results showed that the types of PTP1B inhibition were noncompetitive for ɛ-viniferin (8) and mixed for piceatannol (7) and δ-viniferin (9). Docking simulations of these stilbenes demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B.

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As part of our continuing research to obtain pharmacologically active compounds from Morus alba L. (Moraceae), four Diels-Alder type adducts (DAs) [morusalbins A-D], one isoprenylated flavonoid [albanin T], together with twenty-one known phenolic compounds were isolated from its root bark. The chemical structures were established using NMR, MS, and ECD spectra. The DAs including morusalbins A-D, albasin B, macrourin G, yunanensin A, mulberrofuran G and K, and albanol B exhibited strong inhibitory activities against both protein tyrosine phosphatase 1B (PTP1B) (IC50, 1.90-9.67 µM) and α-glucosidase (IC50, 2.29-5.91 µM). In the kinetic study, morusalbin D, albasin B, and macrourin G showed noncompetitive PTP1B inhibition, with Ki values of 0.33, 1.00, and 1.09 µM, respectively. In contrast, these DAs together with yunanensin A produced competitive inhibition of α-glucosidase, with Ki values of 0.64, 0.42, 2.42, and 1.19 µM, respectively. Furthermore, molecular docking studies revealed that these active DAs have high affinity and tight binding capacity towards the active site of PTP1B and α-glucosidase.

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Five new compounds, 9,3'-dimethoxyhierochin A (1), 6-oxo-trans-neocnidilide (2), (±)-(3E)-trans-6-hydroxy-7-methoxydihydroligustilide (3), (±)-cnidiumin (4), and 6-(1-oxopentyl)-salicylic acid methyl ester (5), together with twenty known compounds (6-25), were isolated from the rhizome of Cnidium officinale. The chemical structures of new compounds were established by NMR spectroscopic techniques, mass spectrometry, Mosher's method, and CD spectrum. Their anti-inflammatory activities were evaluated against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. Compounds 7, 13, and 14 showed inhibitory effects with IC50 values of 5.1, 24.5, and 27.8 µM, respectively. In addition, compounds 7, 13, and 14 reduced LPS-induced inducible nitric oxide synthase (iNOS) expression and cyclooxygenase-2 (COX-2) protein in a concentration-dependent manner.

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Four undescribed 23,24-O-isopropylidene-19(18 → 17)-abeo-28-noroleanane-derived spirocyclic triterpenoids and an undescribed 28-noroleanane-derived spirocyclic triterpenoid, together with five known 28-noroleanane-derived spirocyclic triterpenoids, were isolated and identified. In addition, three undescribed iridoid glucosides and four known ones were also identified. All the isolates were identified using spectroscopic techniques, and the absolute configurations of 28-noroleanane-derived spirocyclic triterpenoids were determined by CD method for the first time. Additionally, the alkaline hydrolysis method and HPLC analysis were applied to confirm the moieties of the iridoid glucosides. The fraction and isolates were evaluated for cytotoxic activity on cervical cancer (Hela), human promyelocytic leukemia (HL-60), and breast cancer (MCF-7) cell lines. Among them, phlomisu E possessed an aldehyde group showed the most potent cytotoxic effect with IC50 value less than 10 µM.

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Five new lactones, litsenolide F1 (1), lisealactone H1 (10), lisealactone H2 (11), akolactone D (13), and akolactone E (14), along with thirteen known compounds were isolated from the pericarps of Litsea japonica (Thunb.) Jussieu. Their chemical structures were elucidated by extensive spectroscopic analyses, including 1D and 2D NMR, HRMS, and chemical methods. The isolated compounds were evaluated for their inhibitory effects on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Among them, 2-alkylidene-3-hydroxy-4-methylbutanolide derivatives (compounds 1-9) exhibited the most potent activity, with IC50 values in the range of 2.9-12.8 µM. In additon, compounds 1, 3, 4, and 6 showed inhibition of iNOS and COX-2 expression in concentration-dependent manner. Compound 3 suppresses mRNA expression of iNOS, COX-2, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells. Based on these evidence, the isolated lactones from L. japonica could be promissing candidates for the development of new anti-inflammatory agents.

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Hizikia fusiformis (Harvey) Okamura is a brown seaweed widely used in Korea and Japan, and it contains different therapeutically active constituents. In the present study, we investigated the activities of glycyrrhizin isolated from H. fusiformis, including its metabolites, 18α- and 18ß-glycyrrhetinic acid against Alzheimer's disease (AD) via acetyl and butyrylcholinesterase and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition. Among these three compounds, 18ß-glycyrrhetinic acid (IC50 = 8.93 ± 0.69 µM) demonstrated two fold potent activity against BACE1 compared to the positive control, quercetin (IC50 = 20.18 ± 0.79 µM). Additionally, glycyrrhizin with an IC50 value of 20.12 ± 1.87 µM showed similarity to quercetin, while 18α-glycyrrhetinic acid showed moderate activity (IC50 = 104.35 ± 2.84 µM). A kinetic study revealed that glycyrrhizin and 18ß-glycyrrhetinic acid were non-competitive and competitive inhibitiors of BACE1, demonstrated via K i values of 16.92 and 10.91 µM, respectively. Molecular docking simulation studies evidently revealed strong binding energy of these compounds for BACE1, indicating their high affinity and capacity for tighter binding to the active site of the enzyme. These data suggest that glycyrrhizin isolated from the edible seaweed, H. fusiformis and its metabolite, 18ß-glycyrrhetinic acid demonstrated selective inhibitory activity against BACE1 to alleviate AD.

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