Search Results (17)

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is the most significant cause of cancer-related death globally, with limited treatment options, including surgical resection, liver transplantation, ablation, chemoembolization, immunotherapy, and radiation. Angelica keiskei, a plant that is rich in chalcones and flavonoids, has demonstrated interesting anticancer properties. This study assesses the pharmacological effects of Angelica keiskei extract on HepG2 cells in order to investigate its efficacy as a therapeutic intervention for HCC. Using in vitro cell culture models, HepG2 cells were treated with different doses of the extract, and its cytotoxic and apoptotic effects were studied. GC-MS analysis revealed the presence of several bioactive compounds, including DDMP, which are likely involved in the observed effects. The MTT assay revealed a considerable, dose-dependent reduction in cell viability, with higher dosages causing notable morphological alterations. An antibody apoptotic array indicated significant changes in apoptotic proteins, specifically IGFBP1, BAD, and Bid. Cluster heatmaps, volcano plots, STRING analysis, Voom-mean variance trends, Glimma plots, and PCA were used to obtain an understanding of the molecular interactions involved. These results suggest that Angelica keiskei extract can cause apoptosis in HepG2 cells, with DDMP appearing as a potentially significant contributor. However, more experimental validation is required to determine the precise molecular mechanisms driving these favorable effects and their clinical implications in HCC. Full article

The screening of a small library of Japanese herbal tea extracts revealed significant anti-glycation activity in the leaves of Angelica keiskei. LC-MS analysis led to the identification of twenty compounds in this herb tea, including seven flavonoids, five phenylpropanoids, and eight coumarin derivatives, based on their chromatographic behavior and fragmentation patterns. Further LC-MS analysis of the methanol-eluted fraction after incubation with methylglyoxal (MGO) was performed on the reaction mixture, revealing quercetin 3-O-glucoside to be a key compound contributing to the anti-glycation activity of the leaves. Full article

Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba’s compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = −8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = −7.84 kcal/mol; Ki = 7.96µM). From ashitaba’s compounds, it was found that 4′-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3′-carboxymethyl-4,2′-dihydroxy-4′-methoxychalcone have low ΔG of below −6 kcal/mol. The lowest ΔG value was found in 3′-carboxymethyl-4,2′-dihydroxy-4′-methoxy chalcone with a ΔG of −6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = −5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = −6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity. Full article

The ‘Lilly of the Valley’ species, Convallaria, is renowned for its fragrant white flowers and distinctive fresh and green floral scent, attributed to a rich composition of volatile organic compounds (VOCs). However, the molecular mechanisms underlying the biosynthesis of this floral scent remain poorly understood due to a lack of transcriptomic data. In this study, we conducted the first comparative transcriptome analysis of C. keiskei, encompassing the leaf, flower, and root tissues. Our aim was to investigate the terpene synthase (TPS) genes and differential gene expression (DEG) patterns associated with essential oil biosynthesis. Through de novo assembly, we generated a substantial number of unigenes, with the highest count in the root (146,550), followed by the flower (116,434) and the leaf (72,044). Among the identified unigenes, we focused on fifteen putative ckTPS genes, which are involved in the synthesis of mono- and sesquiterpenes, the key aromatic compounds responsible for the essential oil biosynthesis in C. keiskei. The expression of these genes was validated using quantitative PCR analysis. Both DEG and qPCR analyses revealed the presence of ckTPS genes in the flower transcriptome, responsible for the synthesis of various compounds such as geraniol, germacrene, kaurene, linalool, nerolidol, trans-ocimene and valencene. The leaf transcriptome exhibited genes related to the biosynthesis of kaurene and trans-ocimene. In the root, the identified unigenes were associated with synthesizing kaurene, trans-ocimene and valencene. Both analyses indicated that the genes involved in mono- and sesquiterpene biosynthesis are more highly expressed in the flower compared to the leaf and root. This comprehensive study provides valuable resources for future investigations aiming to unravel the essential oil-biosynthesis-related genes in the Convallaria genus. Full article

Angelica keiskei Koidzumi (A. keiskei) is used as a traditional medicine, anti-aging agent, and health food, as well as to restore vitality. Xanthoangelol (xanol), a prenylated chalcone, is the predominant constituent of A. keiskei. Oral squamous cell carcinoma (OSCC), the most common malignancy, has a high proliferation rate and frequent metastasis. However, it is unknown whether xanol has anti-OSCC effects on apoptosis, autophagy, and necroptosis. In the present study, we purified xanol from A. keiskei and demonstrated that it suppressed cell proliferation and induced cytotoxicity in human OSCC. Xanol triggered apoptotic cell death by regulating apoptotic machinery molecules but inhibited necroptotic cell death by dephosphorylating the necroptotic machinery molecules RIP1, RIP3, and MLKL in human OSCC. We also found that xanol inhibited the PI3K/AKT/mTOR/p70S6K pathway and induced autophagosome formation by enhancing beclin-1 and LC3 expression levels and reducing p62 expression levels. Furthermore, we showed that xanol prevented the metastatic phenotypes of human OSCC by inhibiting migration and invasion via the reduction of MMP13 and VEGF. Finally, we demonstrated that xanol exerted anticancer effects on tumorigenicity associated with its transformed properties. Taken together, these findings demonstrate the anticancer effects and biological mechanism of action of xanol as an effective phytomedicine for human OSCC. Full article

Angelica keiskei is a perennial plant, belonging to the Apiaceae family and originating from Japan. This plant has been reported to act as a diuretic, analeptic, antidiabetic, hypertensive, tumor, galactagogue, and laxative. The mechanism of action of A. keiskei is not known, but previous studies have suggested that it may act as an antioxidant. In this work, we used Drosophila melanogaster to evaluate the impact of A. keiskei on lifespan and healthspan and its potential anti-aging mechanism by conducting multiple assays on three fly strains: w¹¹¹⁸, chico, and JIV. We observed that the extract extended lifespan and improved healthspan in a sex- and strain-dependent manner. A. keiskei extended lifespan and improved reproductive fitness in female flies and either had no effect or decreased survival and physical performance in males. The extract protected against the superoxide generator paraquat in both sexes. These sex-specific effects suggest that A. keiskei may act through age-specific pathways such as the insulin and insulin-like growth factor signaling (IIS) pathways. Upon examination, we found that the increased survival of A. keiskei-fed females was dependent on the presence of the insulin receptor substrate chico, supporting the role of IIS in the action of A. keiskei. Full article

Flavonoids are easily destroyed and their activity lost during gastrointestinal digestion. Protein-based nanocomplexes, a delivery system that promotes nutrient stability and bioactivity, have received increasing attention in recent years. This study investigated the stability, inhibitory activity against α-glucosidase and interaction mechanisms of protein-based nanocomplexes combining whey protein isolate (WPI), soybean protein isolate (SPI) and bovine serum albumin (BSA) with flavonoids (F) from A. keiskei using spectrophotometry, fluorescence spectra and molecular docking approaches. The results show that the flavonoid content of WPI-F (23.17 ± 0.86 mg/g) was higher than those of SPI-F (19.41 ± 0.56 mg/g) and BSA-F (20.15 ± 0.62 mg/g) after simulated digestion in vitro. Furthermore, the inhibition rate of WPI-F (23.63 ± 0.02%) against α-glucosidase was also better than those of SPI-F (18.56 ± 0.02%) and BSA-F (21.62 ± 0.02%). The inhibition rate of WPI-F increased to nearly double that of F alone (12.43 ± 0.02%) (p < 0.05). Molecular docking results indicated that the protein-flavonoids (P-F) binding occurs primarily through hydrophobic forces, hydrogen bonds and ionic bonds. Thermodynamic analysis (ΔH > 0, ΔS > 0) indicated that the P-F interactions are predominantly hydrophobic forces. In addition, the absolute value of ΔG for WPI-F is greater (−30.22 ± 2.69 kJ mol⁻¹), indicating that WPI-F releases more heat energy when synthesized and is more conducive to combination. This paper serves as a valuable reference for the stability and bioactivity of flavonoids from A. keiskei. Full article

Angelica keiskei contains a variety of bioactive compounds including chalcone, coumarin, and phytochemicals, endowing it with pharmacological effects such as lipid-lowering activity, antitumor activity, liver protection, and nerve protection. This study aims to study the hypoglycemic and hypolipidemic effects of the flavonoid-rich extract from Angelica keiskei (FEAK) in an effort to exploit new applications of FEAK and increase its commercial value. In this paper, flavonoid compounds in Angelica keiskei were extracted using 50% ethanol, and the contents of the flavonoid compounds were analyzed by UPLC-MS/MS. Then, the hypoglycemic and hypolipidemic activities of the FEAK were investigated through in vitro enzyme activity and cell experiments as well as establishing in vivo zebrafish and Caenorhabditis elegans (C. elegans) models. The UPLC-MS/MS results show that the major flavonoid compounds in the FEAK were aureusidin, xanthoangelol, kaempferol, luteolin, and quercetin. The inhibitory rates of the FEAK on the activity of α-amylase and cholesterol esterase were 57.13% and 72.11%, respectively. In cell lipid-lowering experiments, the FEAK significantly reduced the total cholesterol (TC) and total triglyceride (TG) levels in a dose-dependent manner, with 150 μg/mL of FEAK decreasing the intracellular levels of TC and TG by 33.86% and 27.89%, respectively. The fluorescence intensity of the FEAK group was 68.12% higher than that of the control group, indicating that the FEAK exhibited hypoglycemic effects. When the concentration of the FEAK reached 500 μg/mL, the hypoglycemic effect on zebrafish reached up to 57.7%, and the average fluorescence intensity of C. elegans in the FEAK group was 17% lower than that of the control group. The results indicate that the FEAK had hypoglycemic and hypolipidemic activities. The findings of this study provide theoretical references for the high-value utilization of Angelica keiskei and the development of natural functional food with hypoglycemic and hypolipidemic activities. Full article

The genus Convallaria (Asparagaceae) comprises three herbaceous perennial species that are widely distributed in the understory of temperate deciduous forests in the Northern Hemisphere. Although Convallaria species have high medicinal and horticultural values, studies related to the phylogenetic analysis of this genus are few. In the present study, we assembled and reported five complete chloroplast (cp) sequences of three Convallaria species (two of C. keiskei Miq., two of C. majalis L., and one of C. montana Raf.) using Illumina paired-end sequencing data. The cp genomes were highly similar in overall size (161,365–162,972 bp), and all consisted of a pair of inverted repeats (IR) regions (29,140–29,486 bp) separated by a large single-copy (LSC) (85,183–85,521 bp) and a small single-copy (SSC) region (17,877–18,502 bp). Each cp genome contained the same 113 unique genes, including 78 protein-coding genes, 30 transfer RNA genes, and 4 ribosomal RNA genes. Gene content, gene order, AT content and IR/SC boundary structure were nearly identical among all of the Convallaria cp genomes. However, their lengths varied due to contraction/expansion at the IR/LSC borders. Simple sequence repeat (SSR) analyses indicated that the richest SSRs are A/T mononucleotides. Three highly variable regions (petA-psbJ, psbI-trnS and ccsA-ndhD) were identified as valuable molecular markers. Phylogenetic analysis of the family Asparagaceae using 48 cp genome sequences supported the monophyly of Convallaria, which formed a sister clade to the genus Rohdea. Our study provides a robust phylogeny of the Asparagaceae family. The complete cp genome sequences will contribute to further studies in the molecular identification, genetic diversity, and phylogeny of Convallaria. Full article

Microbial transformation is an alternative method for structural modification. The current study aimed at application of microbial transformation for discovering new derivatives and investigating the structure-activity relationship of isobavachalcone (1), 4-hydroxyderricin (2), and xanthoangelol (3) isolated from the herb Angelica keiskei. In the initial screening process, 1–3 were incubated with microbes using a two-stage fermentation method and analyzed through TLC monitoring. The screening results showed that Rhizopus oryzae and Mucor hiemalis were able to transform 1 and 2, respectively. Additionally, M. hiemalis and Mortierella ramanniana var. angulispora were able to transform 3. Following scale-up fermentation, four new (4, 5, 7, and 10) and five known (6, 8, 9, 11, and 12) metabolites were produced. Cytotoxicity of all the compounds (1–12) was investigated using three human cancer cell lines including A375P, HT-29, and MCF-7 by MTT method. Meanwhile, the tyrosinase inhibitory activity of 1–12 was evaluated using l-tyrosine as a substrate. Overall, 1 and 3 displayed the highest cytotoxicity, and 5 and 7 exhibited the most potent tyrosinase inhibitory activity with relatively low cytotoxicity. This allowed us to postulate that the introduction of 4′-O-glucopyranosyl group led to the reduction in cytotoxicity and improvement in tyrosinase inhibitory activity. Full article

4-hydroxyderricin (4-HD), as a natural flavonoid compound derived from Angelica keiskei, has largely unknown inhibition and mechanisms on liver cancer. Herein, we investigated the inhibitory effects of 4-HD on hepatocellular carcinoma (HCC) cells and clarified the potential mechanisms by exploring apoptosis and cell cycle arrest mediated via the PI3K/AKT/mTOR signaling pathway. Our results show that 4-HD treatment dramatically decreased the survival rate and activities of HepG2 and Huh7 cells. The protein expressions of apoptosis-related genes significantly increased, while those related to the cell cycle were decreased by 4-HD. 4-HD also down-regulated PI3K, p-PI3K, p-AKT, and p-mTOR protein expression. Moreover, PI3K inhibitor (LY294002) enhanced the promoting effect of 4-HD on apoptosis and cell cycle arrest in HCC cells. Consequently, we demonstrate that 4-HD can suppress the proliferation of HCC cells by promoting the PI3K/AKT/mTOR signaling pathway mediated apoptosis and cell cycle arrest. Full article

Infertility, a couple’s inability to conceive after one year of unprotected regular intercourse, is an important issue in the world. The use of natural products in the treatment of infertility has been considered as a possible alternative to conventional therapies. The present study aimed to investigate the effects and the mechanisms of various natural products on infertility. We collected articles regarding infertility and natural products using the research databases PubMed and Google Scholar. Several natural products possess antioxidant properties and androgenic activities on productive factors and hormones. Antioxidants are the first defense barrier against free radicals produced by oxidative stress (OS). They remove reactive oxygen stress (ROS), reducing insulin resistance, total cholesterol, fat accumulation, and cancer growth. Moreover, various natural products increase endometrial receptivity and fertility ability showing androgenic activities on productive factors and hormones. For example, Angelica keiskei powder and Astragalus mongholicus extract showed anti-infertility efficacies in males and females, respectively. On the other hand, adverse effects and acute toxicity of natural products were also reported. Tripterygium glycoside decreased fertility ability both in males and females. Results indicate that management of infertility with natural products could be beneficial with further clinical trials to evaluate the safety and effect. Full article

Angelica keiskei sap is used as a blood-sugar reducer in Indonesia, however its molecular mechanism has not yet been explored. 4-hydroxyderricin (4-HD) is one of the major components extracted from A. keiskei sap. The aim of this work was to isolate 4-HD from the sap of A. keiskei planted in Lombok, Indonesia, and to study in silico and in vitro mechanisms against dipeptidyl peptidase-IV (DPP-IV). The dried sap was submitted to liquid–liquid extraction using solvents with different polarity. Further purification processing was conducted using gradient elution column chromatography. The isolated compound was a yellowish powder, m/z 339.2215 [M + H]⁺, which was confirmed as 4-HD. Sitagliptin, a DPP-IV inhibitor, was employed as the positive control for both the in silico and in vitro studies. It was indicated that 4-HD interacts with Glu²⁰⁶ and Phe³⁵⁷, important amino acid residues in the DPP-IV binding pocket. These interactions are similar to that of sitagliptin. The affinity of 4-HD (inhibition constant (Ki) = 3.99 μM) to DPP-IV is lower than that of sitagliptin (inhibition constant (Ki) = 0.17 μM). Furthermore, in vitro study showed that 4-HD inhibits DPP-IV (IC₅₀ = 81.44 μM) weaker than for sitagliptin (IC₅₀ = 0.87 μM). We concluded that 4- HD might have potential in inhibiting DPP-IV. However, by considering the polar interaction of sitagliptin with DPP-IV, a further structure modification of 4-HD, e.g., by introducing a polar moiety such as a hydroxyl group, might be needed to obtain stronger activity as a DPP-IV inhibitor. Full article

Ashitaba, Angelica keiskei Koidzumi (AK), as a traditional medicine in Korea, Japan, and China, has been known as an elixir of life having therapeutic potential. However, there is no scientific evidence to support that Ashitaba can enhance or maintain muscle strength. To find a new therapeutic agent from the medicinal plant, we evaluated the anti-myopathy effect of chalcones from ethanol extract of AK (EAK) in cellular and animal models of muscle atrophy. To examine anti-myopathy activity, EAK was treated into dexamethasone injected rats and muscle thickness and histopathological images were analyzed. Oral administration of EAK (250 or 500 mg/kg) alleviated muscle atrophic damages and down-regulated the mRNA levels of muscle-specific ubiquitin-E3 ligases. Among ten compounds isolated from EAK, 4-hydroxyderricin was the most effective principle in stimulating myogenesis of C2C12 myoblasts via activation of p38 mitogen-activated protein kinase (MAPK). In three cellular muscle atrophy models with C2C12 myoblasts damaged by dexamethasone or cancer cell-conditioned medium, 4-hydroxyderricin protected the myosin heavy chain (MHC) degradation through suppressing expressions of MAFbx, MuRF-1 and myostatin. These results suggest that the ethanol extract and its active principle, 4-hydroxyderricin from AK, can overcome the muscle atrophy through double mechanisms of decreasing muscle protein degradation and activating myoblast differentiation. Full article

Angelica keiskei Koidzumi (A. keiskei), as a Japanese edible herbal plant, enjoys a variety of biological activities due to the presence of numerous active compounds, especially flavonoids. This study aims for the optimization of ultrasound-assisted extraction (UAE) for flavonoids in A. keiskei and their antioxidant activity by using the response surface methodology (RSM). Single-factor experiments and a four-factor three-level Box–Behnken design (BBD) were performed to explore the effects of the following parameters on flavonoid extraction and antioxidant activity evaluation: ultrasonic temperature (X₁), ultrasonic time (X₂), ethanol concentration (X₃) and liquid–solid ratio (X₄). The optimum conditions of the combination of total flavonoid content (TFC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (DPPH-RSC) and ferric-reducing antioxidant power (FRAP) were as follows: X₁ = 80 °C, X₂ = 4 min, X₃ = 78%, X₄ = 35 mL/g, respectively. The experimental results provide a theoretical basis for the extensive utilization of A. keiskei and flavonoids extraction from A. keiskei as a potential source of antioxidants. Full article