Previously, we reported the anti-diabetic effect of Morus alba root bark and the compounds therein. In our continuous study of other parts of this plant, the ability of the branch of Morus alba to inhibit α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), and advanced glycation end products (AGEs) formation was evaluated. Moreover, there are no previous studies that have performed enzyme kinetics and molecular docking analyses, along with assessments of peroxynitrite (ONOO⁻) inhibitory activities. Since the Morus alba branch exhibited favorable inhibitory effects, repeated column chromatography was performed to obtain eight compounds, including four flavonoids (1, 3, 6, 8), one arylbenzofuran (2), one stilbene (5), one Diels–Alder-type adduct (7), and one sterol (4). Among them, compounds 1–3 and 5–7 were mixed-type inhibitors of α-glucosidase, sharing the same catalytic residues with acarbose and the same allosteric sites with (Z)-3-bytylidenephthalide. On the other hand, kuwanon C (1) and oxyresveratrol (5) interacted with residues of the allosteric site (α3 and α6 helices) of PTP1B, indicating their use as non-competitive inhibitors. Interestingly, kuwanon G (7) directly bound the catalytic site, or interrupted the binding between the substrate and the active site, as a mixed-type inhibitor. Moreover, most of the compounds exhibited greater activity against AGE formation and ONOO⁻ than positive controls. The IC₅₀ values required to inhibit ONOO⁻ using compounds 1, 3, 5, 6, and 7 were reported for the first time, and range from 1.08 to 12.92 μM. Based on the structure–activity relationship, the presence of hydroxyl, resorcinol, and prenyl moieties was important in the prevention of diabetes’ pathological mechanisms, and these findings have been further supported by molecular docking analysis. These computational and experimental results will be useful in the development of therapeutic candidates to prevent/treat diabetes and its complications.

In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D₁R, D_2LR, D₃R, and D₄R). In hMAO-A inhibition, 1–3 showed mild effects (50% inhibitory concentration (IC₅₀): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC₅₀: 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC₅₀: 57.71 ± 2.12 μM) and 3 (IC₅₀: 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 1–3 as D₁R/D_2LR antagonists and D₃R/D₄R agonists. The half-maximum effective concentration (EC₅₀) of 1–3 on DA D₃R/D₄R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 1–3 inhibited 50% of the DA response on D₁R/D_2LR by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D₃R receptor and Asp115 and His414 at the D₄R receptor explain the high agonist effect. Likewise, Asp187 at D₁R and Asp114 at D_2LR play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 1–3 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D₁R/D_2LR antagonists and D₃R/D₄R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis.

Algae are unique natural products that can produce various types of biologically active compounds. The 70% ethanol extract of brown algae Sargassum macrocarpum collected from the East Sea of Korea inhibited human monoamine oxidases A and B enzymes (hMAO-A and hMAO-B) at a 50 μg/mL concentration. The bioassay-guided isolation was performed through solid-phase extraction and the Sepbox system followed by serial high-performance liquid chromatography on the reverse phase condition, resulting in the identification of two new monocyclic terpenoid lactones, sargassumins A and B (1 and 2). The planar structures of the compounds were determined by a combination of spectroscopic data. The absolute configurations were determined by the interpretation of circular dichroism data. Compound 1 exhibited mild hMAO-A inhibition (42.18 ± 2.68% at 200 μM) and docked computationally into the active site of hMAO-A (−8.48 kcal/mol). Although compound 2 could not be tested due to insufficient quantity, it docked better into hMAO-A (−9.72 kcal/mol). Therefore, the above results suggest that this type of monocyclic terpenoid lactone could be one of the potential lead compounds for the treatment of psychiatric or neurological diseases.

Traditional Chinese medicines (TCMs) have been a rich source of novel drug discovery, and Cassia seed is one of the common TCMs with numerous biological effects. Based on the existing reports on neuroprotection by Cassia seed extract, the present study aims to search possible pharmacological targets behind the neuroprotective effects of the Cassia seeds by evaluating the functional effect of specific Cassia compounds on various G-protein-coupled receptors. Among the four test compounds (cassiaside, rubrofusarin gentiobioside, aurantio-obtusin, and 2-hydroxyemodin 1-methylether), only aurantio-obtusin demonstrated a specific V_1AR antagonist effect (71.80 ± 6.0% inhibition at 100 µM) and yielded an IC₅₀ value of 67.70 ± 2.41 μM. A molecular docking study predicted an additional interaction of the hydroxyl group at C6 and a methoxy group at C7 of aurantio-obtusin with the Ser341 residue as functional for the observed antagonist effect. In the transient brain ischemia/reperfusion injury C57BL/6 mice model, aurantio-obtusin attenuated the latency time that was reduced in the bilateral common carotid artery occlusion (BCCAO) groups. Likewise, compared to neuronal damage in the BCCAO groups, treatment with aurantio-obtusin (10 mg/kg, p.o.) significantly reduced the severity of damage in medial cornu ammonis 1 (mCA1), dorsal CA1, and cortex regions. Overall, the findings of this study highlight V_1AR as a possible target of aurantio-obtusin for neuroprotection.

Natural flavone and isoflavone analogs such as 3′,4′,7-trihydroxyflavone (1), 3′,4′,7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer’s and Parkinson’s disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC₅₀ value: 7.57 ± 0.14 μM) and 3 as a competitive inhibitor of hMAO-B with an IC₅₀ value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD₄R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD₄R antagonist effect, respectively, for neuroprotection. The route of administration should be considered.

Sargassum is a large and diversified genus of marine brown algae that is distributed widely in tropical and subtropical areas. They have been used for centuries in Asian countries, and have demonstrated a variety of health advantages, including anti-cardiovascular disease, anti-osteoarthritis, anti-cancer, anti-inflammatory, antioxidant, and hypopigmentation effects. However, the putative anti-diabetic, anti-Alzheimer’s, and anti-Parkinson’s diseases activities of various Sargassum spp. have not been investigated and compared thoroughly. Thus, the purpose of this study was to examine the anti-diabetic, anti-Alzheimer’s, and anti-Parkinson’s diseases’ activities of ten Sargassum and one myagroides species collected off the Korean coast. In this study, we examined the inhibitory activity of 70% ethanolic extract of the Sargassum and myagroides species against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, peroxynitrite (ONOO^–), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), BACE1, MAO-A, and MAO-B. Among the Sargassum and myagroides species tested, S. hemiphyllum, S. filicinum, and S. miyabei showed potent PTP1B inhibitory activity (IC₅₀ values of 2.11, 1.87, and 6.49 μg/mL, respectively), α-glucosidase inhibitory activity (IC₅₀ values of 3.67, 2.30, and 11.12 μg/mL, respectively), and ONOO^– scavenging activity, with IC₅₀ values of 2.07, 4.49, and 2.46 μg/mL, respectively. Moreover, S. miyabei exhibited the highest BACE1 and BChE inhibitory activity, with IC₅₀ values of 3.38 and 39.76 μg/mL, respectively. The highest MAO-A inhibitory activity was seen in S. miyabei, S. serratifolium, and S. macrocarpum, with IC₅₀ values of 16.91, 12.46, and 14.02 μg/mL, respectively. Therefore, our findings showed that Sargassum species have health benefits and may be useful in treating diabetes and neurological disorders.