Journal of Natural Medicines最新文献

Aconitum japonicum, native to the mountainous regions of Japan, is a toxic perennial plant widely recognized for its therapeutic potential. Despite its pharmacological importance, the complete biosynthetic pathway of diterpene alkaloids, bioactive compounds with significant pharmaceutical implications and derived from Aconitum species, remains elusive. In this study, leveraging high-throughput metabolome and transcriptome analyses, we conducted a comprehensive investigation using four tissues of A. japonicum, including leaf, mother root, daughter root, and rootlet. By integrating these multi-omics datasets, we achieved a holistic insight into the gene expression patterns and metabolite profiles intricately linked with diterpene alkaloid biosynthesis. Our findings unveil potential regulatory networks and pinpoint key candidate genes pivotal in diterpene alkaloid synthesis. Through comparative analyses across tissues, we delineate tissue-specific variations in gene expression and metabolite accumulation, shedding light on the spatial regulation of these biosynthetic pathways within the plant. Furthermore, this study contributes to a deeper understanding of the molecular mechanisms dictating the production of diterpene alkaloids in A. japonicum. Besides advancing our knowledge of plant secondary metabolism in A. japonicum, this study also provides a high-quality multi-omics resource for future studies aimed at functionally characterizing the target genes involved in different metabolic processes.

Seishinrenshiin (SRI), a Kampo formula, is often used for frequent urination. Nelumbo Seed, a crude-drug component of SRI was reported to inhibit bladder smooth muscle contraction using excised rat bladder tissues. However, the active ingredients of Nelumbo Seed have not yet been identified. In this study, we investigated the active ingredients of Nelumbo Seed that inhibit bladder smooth muscle contraction. We obtained liquid chromatography/mass spectrometry profiles of extracts prepared from five types of Nelumbo Seed materials from different production areas and evaluated their inhibitory effects on excised rat bladder smooth muscle contraction. Analysis of these data using orthogonal projections to latent structures revealed neferine (Nef) as the compound with the highest variable influence on projection. Among the Nelumbo Seed materials processed using different methods, the Nef content was the highest in 'Sekirenshi', when embryo and pericarp were not removed at all. We determined the effects of administering Nelumbo Seed extracts with different Nef content on frequent-urination model rats. The Nef content in rat plasma was the highest when the Sekirenshi extract was administered, but Nef was not detected when seed embryos were removed. In this model, administration of the Nelumbo Seed extract improved the maximum bladder contraction pressure and bladder contraction interval, albeit not significantly. In particular, Sekirenshi tended to reduce the maximum bladder contraction pressure compared to other Nelumbo Seed. Our results indicate that although Nef in Nelumbo Seed does not clearly improve frequent urination, it might contribute to the improvement of urination disorder.

Four new oxepin and dihydrobenzofuran derivatives, saccoxepins A-C (1-3) and saccobenzofurin A (4), along with one known compound, bauhinoxepin A (5), were isolated from the roots of Bauhinia saccocalyx. The structures were elucidated by extensive analysis of spectroscopic data in combination with ECD analysis. The EtOAc extract exhibited significant NO inhibition (94.4 ± 0.35%, 50 μg/mL), and saccoxepin A and bauhinoxepin A demonstrated strong NO suppression, with IC₅₀ values of 49.35 µM and 30.28 µM, respectively, alongside notable antioxidant activity. Saccoxepin A and bauhinoxepin A selectively reduced interleukin-6 (IL-6) levels, while bauhinoxepin A slightly lowered tumor necrosis factor-alpha (TNF-α) at a low dose. Furthermore, bauhinoxepin A exhibited cytotoxicity against HCT-116 cells, with an IC₅₀ of 8.88 µM. These findings suggest that the roots of B. saccocalyx possess potent antioxidant, anti-inflammatory, and anticancer activities, supporting its traditional medicinal applications and highlighting its potential as a source of therapeutic agents.

Immature Evodia fruits are used in herbal medicine for their analgesic properties; however, determining the appropriate time for harvesting these fruits remains challenging. Here, we investigated the growth characteristics and optimal timing for collecting the immature fruits of three Evodia species-E. rutaecarpa (Juss.) Benth., E. officinalis Dode, and E. hupehensis Dode-cultivated at the Tanegashima Division of the Research Center for Medicinal Plant Resources, Japan. Evodiamine and rutaecarpine content in the three species were measured across different collection seasons, and the relationship between time elapsed from the start of flowering and the levels of these active ingredients was determined. We found that the optimal time to collect the immature fruits of E. officinalis for use in herbal medicine was 2 weeks after flowering, when the fruit was heavier, contained more active ingredients, and had not yet dehisced. E. rutaecarpa fruits were heavier, contained more active ingredients, and retained their color (orange) until 3 weeks post-flowering. This suggests that the optimal collection time varied among species. Overall, E. rutaecarpa was the most suitable species for cultivation in Japan for use in herbal medicines because its optimal collection time was easier to determine, and its pericarp and seeds did not separate during drying. Therefore, to efficiently harvest Evodia fruits, cultivation methods should be optimized to leverage the specific growth characteristics of each species, with particular emphasis on accurately determining the optimal harvest time.

Leptomonines A and B, two novel rare benzyltetrahydroisoquinoline N-oxides, were isolated from the aerial parts of Leptopyrum fumarioides (L.) Reichenb. collected in Tuv province, Mongolia. Their chemical structures, absolute configurations, and conformations were established by 2D-NMR and CD spectral analyses. Leptomonine A (1) can suppress TNF-α production and COX-2 expression in LPS-stimulated RAW 267.4 cells. This compound at a concentration of 100 µM significantly reduced the TNF-α and COX-2 levels by 36.43% and 47.10%, respectively, compared with the negative control. Moreover, leptomonine B (2) remarkably lowers COX-2 levels at the highest concentration. The docking simulations were conducted with the COX-2 enzyme and revealed the binding ability of leptomonine A (1) and leptomonine B (2) with binding energies of - 9.03 and - 8.96 kcal/mol, respectively. The interactions of these alkaloids with the targets were mainly with the hydrophobic and hydrophilic sites, which are quite similar to rofecoxib. Phytochemical investigation revealed the diversity and novelty of the natural isoquinoline alkaloids in Leptopyrum fumarioides. Two new benzyltetrahydroisoquinoline N-oxides were identified as the bioactive constituents of Leptopyrum fumarioides by assessing its anti-inflammatory effects. The findings provide scientific justification to support the traditional application of Leptopyrum fumarioides for treating liver diseases associated with inflammation.

The genus Salvia is a well-established source of biologically active compounds with beneficial health effects. In this study, we aimed to isolate and structurally characterize novel compounds from Salvia grandifolia and evaluate their cytotoxic activity against human promyelocytic leukemia (HL-60) and cervical cancer (HeLa) cell lines. Three new rearranged abietane-type diterpenes, grandifolins A-C (1-3) and a new abietane diterpene, grandifolin D (4), were isolated from the roots of Salvia grandifolia, along with 12 known compounds (5-16). Their structures were determined by combining extensive ¹H and ¹³C spectroscopy, X-ray crystallography, and electronic circular dichroism spectra (ECD). The skeletons of 1-3 had a rearranged structure with a 6/6/5 ring from an abietane-type diterpene. A plausible biosynthetic pathway for the rearranged skeleton was also proposed. Many of the isolated compounds showed weak cytotoxicity against HeLa or HL-60 cell lines.

Two new abietane-type diterpenoids, 6β-(3-furoyloxy)ferruginol (1) and 6-chloro-6,7-dehydroferruginol (2), were isolated from the roots of Euonymus hamiltonianus along with five known diterpenoids (3-7). Their structures were characterized using various spectroscopic analysis including HRMS, 1D and 2D NMR, and ECD analysis. All isolated compounds (1-7) were evaluated for their cytotoxic activity against human colon cancer cell line, HCT116, and it was found to exhibit moderate cytotoxic activity with IC₅₀ values ranging from 4.5 to 22.9 μM. Among the isolated compounds, montbretol (4) displayed the most cytotoxic activity (IC₅₀ = 4.50 ± 0.29 μM) against HCT116 human colon cancer cells than the other isolated compounds.

The search for a potent α-glucosidase inhibitor from the fungus Biscogniauxia capnodes SWUF15-40 yielded eighteen compounds. A comprehensive analysis from NMR and MS data revealed three new α-pyrones, biscogniapyrones A-C (1-3), two new isocoumarins (5 and 6), and thirteen known compounds. The configurations were assigned from calculated ¹³C NMR chemical shifts and ECD spectra, together with ¹H NMR analysis of Mosher esters. Several compounds exhibited effective inhibitory activity against α-glucosidase with IC₅₀ values in the range of 0.041-0.257 mM, which are lower than the positive control, acarbose (IC₅₀ 0.713 mM). The proposed non-competitive mode of inhibition was deduced from Lineweaver-Burk plots together with K_m and V_max values. In silico dockings of the strongest inhibitor, compound 3 were studied. Three out of the five determined allosteric sites of the enzyme model were favorable, with closed free binding energies of roughly - 4.00 kcal/mol. The binding interactions observed between 3 and amino acids in the pocket sites were hydrogen bonding and hydrophobic interactions. These findings, therefore, provide opportunities for drug development processes to be carried out.

Silent information regulator 5 (SIRT5) is the fifth member of the sirtuin family, which is mainly expressed in mitochondrial matrix. SIRT5 plays a key role in metabolism and antioxidant responses, and is an important regulator for maintaining intracellular homeostasis. Given its involvement in multiple cellular processes, dysregulation of SIRT5 activity is associated with a variety of diseases. This review explores the structural characteristics of SIRT5 that influence its substrate specificity, highlights recent research advances, and summarizes its four key enzymatic activities along with their corresponding substrates in disease contexts. We also discuss the natural products that modulate SIRT5 activity and identify potential targets of SIRT5 through virtual docking, which may provide new therapeutic avenues. Although the mechanism of SIRT5 in diseases needs to be further elucidated and deglutathionylation activities are still at an early stage, targeting SIRT5 and its substrates holds significant promise for the development of novel therapeutics.

Boletus bicolor is a kind of wild edible boletus, which is widely distributed in China. We have isolated the protein D1 from B. bicolor, and found that protein D1 has a significant inhibitory effect on the growth and proliferation of lung cancer A549 cells both in vitro and in vivo. In this paper, we found that miR-34a plays an important role in inhibiting the proliferation of A549 cells. miR-34a is the functional target of protein D1 against A549 cells. Protein D1 induces the positive feedback regulation of miR-34a and p53, which further regulates downstream Bcl-2 and CDK6, and inhibits the proliferation of A549 cells.