Efficient Isolation and Structure Analysis of (+)-Ranuncoside, a Unique Tricyclic Spiroacetal Glycoside, from Christmas Rose (Helleborus niger L.)

The use of medicinal herbs as remedies reaches back to the Stone Age, and their importance as a source of drugs has continuously increased since then. Herbal ingredients can serve as active pharmaceuticals themselves or as lead substances for the development of synthetic pharmaceuticals with less toxicity, higher effectiveness or with new properties. To date, only 6% of the ∼600,000 plants on earth have been tested pharmacologically. Among these, the medicinal plant Helleborus niger L. (Christmas rose) is especially promising because its leaves contain ( + )-ranuncoside 1, characterized by a spiroacetal ring system, a motif which is responsible for the biological activity of a multitude of natural products. Structure-activity relationship studies of ( + )-ranuncoside 1 are lacking and no synthesis of 1 has been described yet. Therefore, we developed a protocol for the rapid and efficient isolation of 1 from the leaves of cultivated Christmas rose. Crystals of high purity were obtained that enabled us to study the stereochemistry of 1 by NMR spectroscopy in solution for the first time. The spiro configuration, the absolute stereochemistry, and the geometry of all three rings was then confirmed by x-ray structure analysis. Our data will enable future structure-activity relationship studies to assess the potential of 1 as a lead substance for the development of novel antibiotics and anticancer agents.

A Network Pharmacology Perspective Investigation of the Pharmacological Mechanisms of the Herbal Drug FDY003 in Gastric Cancer

Gastric cancer (GC) is one of the most common and deadly malignant tumors worldwide. While the application of herbal drugs for GC treatment is increasing, the multicompound–multitarget pharmacological mechanisms involved are yet to be elucidated. By adopting a network pharmacology strategy, we investigated the properties of the anticancer herbal drug FDY003 against GC. We found that FDY003 reduced the viability of human GC cells and enhanced their chemosensitivity. We also identified 8 active phytochemical compounds in FDY003 that target 70 GC-associated genes and proteins. Gene ontology (GO) enrichment analysis suggested that the targets of FDY003 are involved in various cellular processes, such as cellular proliferation, survival, and death. We further identified various major FDY003 target GC-associated pathways, including PIK3-Akt, MAPK, Ras, HIF-1, ErbB, and p53 pathways. Taken together, the overall analysis presents insight at the systems level into the pharmacological activity of FDY003 against GC.

Evaluation on Intestinal Permeability of Phlorotannins Using Caco-2 Cell Monolayers

Among the phlorotannins of seaweed polyphenols, eckols which have a dibenzodioxin linkage are known to have various physiological functions. The purpose of this study was to investigate the intestinal epithelial absorption of eckols using Caco-2 cell monolayers of the small intestinal membrane model. Each compound permeated from the apical (AP) side to the basolateral (BL) side in the monolayers was identified and quantitated by liquid chromatography-mass spectrometry with electrospray ionization. In the transport assays using five types of eckols (eckol, fucofuroeckol A, phlorofucofuroeckol A, dieckol, and 8,8'-bieckol), only the monomeric eckol showed limited transepithelial absorption with relatively small apparent permeability values (0.30 ± 0.04 × 10−8 cm/s). Analyzing the Hanks’ balanced salt solution in the receiver on the BL side showed that phloroglucinol was detected in all experimental sections using eckols, and it's concentration increased with time over the course of the incubation. The other molecules corresponding to the unconjugated and conjugated metabolites of eckols were not detected in the AP and BL sides through the assays. These results suggest that eckols, including monomeric eckol, may be decomposed into phloroglucinol in the intestinal epithelium and the resulting phloroglucinol permeates to the BL side.

Chrysoeriol Enhances Melanogenesis in B16F10 Cells Through the Modulation of the MAPK, AKT, PKA, and Wnt/β-Catenin Signaling Pathways

Chrysoeriol is a 3′-O-methoxy flavone, chemically a derivative of luteolin, which is commonly found across the plant kingdom. Chrysoeriol is of great scientific interest because of its promising anti-inflammatory, anti-cancer, antioxidative, anti-lipase, anti-xanthin oxidase, and antimicrobial activities against multidrug-resistant (MDR) bacterial pathogens; however, its effects on melanogenesis have not yet been elucidated. Here, we report a novel effect of chrysoeriol on melanogenesis in B16F10 cells. Chrysoeriol treatment significantly increased the expression of the melanogenic enzymes tyrosinase (TRY), tyrosinase-related protein-1 (TRP-1), and TRP-2 and upregulated the expression of microphthalmia-associated transcription factor (MITF) in a concentration-dependent manner. Furthermore, chrysoeriol suppressed the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in a concentration-dependent manner. In addition, chrysoeriol treatment increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK)-3β, β-catenin, and protein kinase A (PKA) and decreased the production of β-catenin, which is involved in the transcriptional activation of MITF in melanogenesis. Finally, the structure–activity relationship (SAR) of chrysoeriol and its derivatives, including luteolin and apigenin, with regard to their melanin inhibitory activity was also investigated; we identified the significance of the 4′-OH group and C-3′ methoxylation in melanogenesis. Together, these findings indicate that chrysoeriol promotes melanogenesis in B16F10 cells by upregulating the expression of melanogenic enzymes through the MAPK, phosphatidylinositol 3-kinase (PI3K)/AKT, PKA, and Wnt/β-catenin signaling pathways; thus, chrysoeriol may be used as a cosmetic ingredient to promote melanogenesis or as a therapeutic agent against hypopigmentation disorders.

Charantoside L, A New Cucurbitane-Type Glycoside from Momordica charantia L. with α-Glucosidase Inhibitory Activities

A new cucurbitane-type glycoside (1) and two known compounds (2-3) were isolated from the ethanol extract of the fruits of Momordica charantia L. Their chemical structures were determined as (19 S,23 E)-5 β­,19-epoxy-19-methoxycucurbita-6,23-diene-3 β,25-diol 3 -O-β-D-allopyranoside (1), goyaglycoside d (2), and (19 S,23 E)-5 β,19-epoxy-19-methoxycucurbita-6,23-diene-3 β,25-diol (3) on the basis of the extensive spectroscopic methods, including 1D, 2D NMR, HRESIMS, and in comparison with the reported data. Compounds 1 to 3 were evaluated for α-glucosidase inhibitory effects. Compounds 1 and 2 showed anti α-glucosidase activity with IC50 values of 134.12 ± 11.20 and 163.17 ± 13.71 µM, respectively, compared with the positive control, acarbose, IC50 160.99 ± 14.30 μM. Compounds 2 and 3 were first isolated from plant M. charantia growing in Vietnam.

Isolation of Antimalarial Agents From Indonesian Medicinal Plants: Swietenia mahagoni and Pluchea indica

Malaria is a neglected tropical disease that still demands serious efforts to tackle successfully, including the need for new antimalarial lead compounds to combat drug-resistant Plasmodium. Intensive phytochemical and pharmacological investigation into the Indonesian medicinal plants Swietenia mahagoni and Pluchea indica successfully revealed 5 constituents. Antimalarial bioassays indicated 34,5-tri- O-caffeoylquinic acid (4) to be the most active against Plasmodium falciparum 3D7 and Dd2 strains with IC50 values of 8.2 and 8.8 µM, respectively. No cytotoxicity was observed against Human Embryonic Kidney cells at a concentration of 40 µM.

Dihydrobenzofurans and Propynylthiophenes From the Roots of Eupatorium heterophyllum

Seven new dihydrobenzofurans and 2 new propynyl thiophenes were isolated from the roots of Eupatorium heterophyllum together with 13 known compounds. The compounds were characterized using spectroscopic methods including 2D NMR, infrared, and mass spectrometric techniques. Aerial parts of this plant have been known to contain various sesquiterpenoids and displayed high chemical diversity (several compounds isolated and/or identified) among their chemical constituents depending on the collection site. Nevertheless, we found that the chemical diversity in the roots was lower than in the aerial parts.

Discrimination of 11 Malaysian Durian Cultivars Based on Sulfur-Containing Volatiles and Esters Using Multivariate Data Analysis

There are reports documenting the volatile oils of several durian cultivars in Malaysia. However, there is limited information on the rapid discrimination of the durian cultivars based on the composition of the total volatiles and individual volatile compounds. Thus, the present work aims to discriminate 11 Malaysian durian cultivars based on their volatile compositions using multivariate data analysis. Sulfur-containing volatiles are the major volatiles in D175 (Udang Merah), D88 (Darling), D13 (Golden Bun), DXO (D24 Special), D17 (Green Bamboo), D2 (Dato Nina), and D168 (Hajah Hasmah) durian cultivars, while esters are predominant in D99 (Kop Kecil), D24 (Bukit Merah), and D160 (Musang Queen) durian cultivars. D197 (Musang King) cultivar has an almost equal composition of sulfur-containing volatiles and esters. In the ester predominated volatile durian oil, ethyl 2-methylbutanoate and propyl 2-methylbutanoate are the major volatile compounds, while the durian cultivars with predominant sulfur-containing volatiles mainly contain diethyl disulfide, diethyl trisulfide, and 3,5-dimethyl-1,2,4-trithiolane. The durian cultivars were clustered into 8 clusters using principal component analysis, with 3 clusters consisting of 2 cultivars, and with the remaining cultivars clustered individually. The highly sought-after durian cultivars, D160 and D197, were clustered into one. Hierarchal clustering analysis identified the distinct compounds which discriminate every durian cultivar.

A new Butenolide Derivative from the Brown Alga Sargassum micracanthum

A new butenolide derivative (1), along with three known compounds (2-4) were isolated from the MeOH extract of brown alga Sargassum micracanthum. The structures of 1 to 4 were determined by the analyses of 1D and 2D NMR and mass spectroscopic data. The known compounds (2-4) were identified as (5 E,10 Z)-6,10,14-trimethylpentadeca-5,10-dien-2,12-dione (2), (5 E,9 E)-6,10,14-trimethylpentadeca-5,9-dien-2,12-dione (3), and (-)-loliolide (4) by comparing with their published spectroscopic data. The antioxidant activities of compounds 1 to 4 were evaluated based on using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities. Compounds 1 to 4 were inactive at the concentration of 200 μM.

Rubusoside Reduces Blood Glucose and Inhibits Oxidative Stress by Activating the AMPK Signaling Pathway in Type 2 Diabetes Mellitus Mice

The current study aimed at investigating the therapeutic effects of rubusoside on type 2 diabetes mellitus (T2DM) mice models as an alternative hypoglycemic candidate drug. T2DM mice models were established with a combination of streptozotocin (STZ) intraperitoneal injection and high-fat diet. After 10 weeks of rubusoside intragastric administration (100, 200 mg/kg/day) to the mice, the body weight, fasting blood glucose, glucose tolerance, and blood lipids were measured. The liver protein expression levels of p-AMPK, GLUT2, GLUT4 and total antioxidant capacity were also investigated. After 10 weeks of rubusoside administration, the levels of blood glucose and lipids were decreased in T2DM mice. Compared with the model group, rubusoside administration significantly decreased the liver mass-to-body weight ratio, upregulated p-AMPK and GLUT4, and downregulated GLUT2 expression levels in the liver. Activities of superoxide dismutase (SOD), catalase (CAT), and gluathione peroxidase (GSH-Px) were increased, and the concentration of malondialdehyde (MDA) was decreased to reduce oxidative stress in the liver. Liver hematoxylin and eosin (H&E) pathological analysis also showed that rubusoside had a protective effect on T2DM mice liver. These results demonstrate that rubusoside could be used as an anti-diabetic candidate drug, and that its hypoglycemic mechanism might be related to the activation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) to modulate the expression of GLUT2 and GLUT4. Finally, rubusoside could also increase total antioxidant capacity to protect the liver from oxidative stress.