Journal of Natural Medicines最新文献

Ovarian cancer (OC) is the most common malignant gynecologic tumor, with the highest mortality rate among female reproductive system cancers. Resistance to chemotherapy drugs, which often develops after long-term use, is a major cause of treatment failure. In recent years, traditional Chinese medicine has been widely used in the treatment of tumor for their advantages in improving the efficacy of chemotherapy and alleviating the toxic side effects. Tenacissoside G (Tsd-G), as one of the main active ingredients of Marsdenia tenacissima, exhibits anti-tumor effects. However, its impact on ovarian cancer is not well understood. To assess the role and mechanism of Tsd-G in reversing paclitaxel (PTX) resistance, the reversal fold of Tsd-G in combination with PTX on OC PTX-resistant (A2780/T) cells was determined using CCK-8 assay. The apoptosis level and migration ability of A2780/T cells after 24 h treatment with Tsd-G and PTX were assessed by Hoechst 33,342, flow cytometry, and wound healing assay. Western Blot and Src overexpression plasmid were used to explore the relationship between Src and PTX resistance. The relationship between Src expression and human OC was analyzed by gene expression database. The effect of Tsd-G on P-gp activity was detected by flow cytometry. Western blot and RT-PCR experiments were performed to detect the differences in mRNA and protein expression of Src/PTN/P-gp signaling axis to validate the mechanism of Tsd-G in reversing the resistance to PTX in ovarian cancer. The results showed that Tsd-G reverses PTX resistance in ovarian cancer cells by regulating cell proliferation, cell cycle, inducing apoptosis, and inhibiting migration. The mechanism might associate with the inhibition of Src expression and phosphorylation activation, which in turn inhibits the expression and activity of downstream PTN and P-gp. This study provides a new idea for the treatment of PTX-resistant OC patients and provides theoretical support for revealing the anti-ovarian cancer active ingredients in Marsdenia tenacissima.

Pseudomonas aeruginosa is an opportunistic human pathogen that causes a wide range of infections. The increasing multidrug-resistance of P. aeruginosa poses a critical challenge for medical care. P. aeruginosa employs virulence factors and biofilms to establish infections in humans and protect itself from environmental stress or antibiotics. These factors are regulated by a quorum sensing mechanism involving multiple regulatory systems that act interdependently through signaling molecules. Therefore, interference with quorum sensing systems can suppress the pathogenicity of P. aeruginosa. In this study, quorum sensing inhibitors were explored from secondary metabolites derived from 111 strains of actinomycetes by targeting the las system, which is thought to be upstream of the quorum sensing cascade in P. aeruginosa. As a result, reumycin was isolated from the culture broth of Streptomyces sp. TPMA0082. Reumycin, a molecule containing a pyrimidotriazine ring, inhibited the binding of the autoinducer to the LasR receptor in the las system, thereby suppressing the production of P. aeruginosa virulence factors, including pyocyanin, rhamnolipids, elastase, motility, and biofilms, without affecting bacterial growth. Toxoflavin, a reumycin derivative with a methyl group at the N1 position, exhibited strong antibacterial activity. Fervenulin, a reumycin derivative with a methyl group at the N8 position, had a negative impact on the logarithmic growth phase of the bacteria and exhibited lower inhibitory activity against virulence factor production compared to reumycin. These findings suggest that the position and number of methyl groups attached to the pyrimidotriazine structure significantly influence its biological activity, exerting distinct effects on quorum sensing inhibition and antibacterial activity.

Fuzi is a generic term for various processed products of the lateral roots of Aconitum carmichaelii Debeaux, with a long history of medicinal use including hypoglycemic, anti-inflammatory, and immunity-enhancing. However, the toxicity of Fuzi limits its widespread use. Different processing methods have been used to minimize toxicity and improve the medicinal properties of Fuzi. Three processed Fuzi products were prepared according to Chinese Pharmacopoeia and their chemical compositions were qualitatively and quantitatively analysed using UPLC-MS. The toxicity, antioxidant properties and bioactivity changes were assessed in Caenorhabditis elegans. A total of 99 compounds were preliminarily identified, and a subsequent multivariate analysis showed significant differences among the different processed products in terms of chemical compositions. The processing led to a significant loss of alkaloids, decrease in the contents of total polyphenols and flavonoids, and a decrease in antioxidant capacity while increasing the total polysaccharide and uronic acid contents in Yan Fuzi and Hei Shunpian as well as the content of monoester diterpenoid alkaloids in Hei Shunpian and Bai Fupian. Furthermore, the processed products prevented cold stress in C. elegans. In conclusion, processing altered the composition and reduced the toxicity of Fuzi and led to differences in the pharmacological activities of different processed Fuzi products. These results provide a theoretical basis for the in-depth pharmacological study and application of processed products of Fuzi.

In this study, a lipid disorder Alzheimer's disease (AD) model was developed with high-fat diet and D-galactose injected intraperitoneally (HFD & D-gal) to evaluate the activities of Buyang Huanwu Decoction (BYHWD) compared with donepezil hydrochloride. The learning and memory abilities of BYHWD were evaluated by Morris water maze test (MWM). The lipid levels in serum, histopathology, and immunohistochemistry of hyperphosphorylated tau protein in hippocampal neurons were conducted to prove the therapy effects of BYHWD. After the identification of constituents absorbed into the brain using LC-MS, UPLC-TQ-MS was employed to analyze endogenous lipid metabolites in the hippocampi of mice. Based on the validated differential markers identified through lipidomics analysis, we further substantiated potential therapeutic pathway of BYHWD through the application of molecular docking technology. The mechanism underlying BYHWD was subsequently confirmed by palmitic acid-injured HT22 cells. The results showed that BYHWD significantly improved the cognitive deficits and regulated the lipid levels of HFD & D-gal mice. BYHWD also protected the neuronal cell condition of hippocampal neurons, increased the density of dendritic spines, and reduced the expression of P-tau. Lipidomics revealed that 41 differential lipid metabolites were retuned after BYHWD administration, and this change may be related to the PPARγ pathway. Calycosin-7-glucoside showed good interaction with PPARγ in vivo composition analysis. Calycosin-7-glucoside increased the mRNA expression levels of lipid metabolism-related enzymes and PPARγ, as well as the expression of PPARγ protein in vitro study. BYHWD activated the PPARγ pathway to induce peroxisome proliferation and regulated lipid metabolism disorders in the AD mice brain.

Actinomycetes have produced a variety of bioactive secondary metabolites; however, discovering new actinobacterial natural products using conventional approaches has become increasingly challenging. Meanwhile, genomic studies of actinomycetes have revealed that numerous secondary metabolite biosynthetic gene clusters (SM-BGCs) remain untapped. Thus, utilizing these secondary metabolic pathways is expected to facilitate the discovery of new actinomycetes-derived natural products. In this review, I primarily describe our research on the utilization of these untapped actinobacterial SM-BGCs and the discovery of new secondary metabolites. First, I introduce our studies on the activation of silent SM-BGCs through the co-cultivation of various actinomycetes with mycolic acid-containing bacteria (MACB), which led to the identification of 20 actinobacterial secondary metabolites, including 16 new compounds. In the latter part, I describe our recent findings on arsenic-related secondary metabolism, which has been overlooked in model actinomycetes, including the identification of a novel organoarsenic natural product, and the elucidation of its unique biosynthetic strategy, which is independent of S-adenosylmethionine (SAM)-dependent enzymes.

Chronic pancreatitis (CP) is a progressive disease characterized by injury on pancreatic acinar cells (PACs), ongoing fibrosis, and gradual loss of exocrine and endocrine functions. Sphingosine kinase 1 (SK1) expression is elevated in injured PACs, and its metabolite sphingosine-1-phosphate (S1P) promotes the activation of pancreatic stellate cell (PSC) through autophagy and pyroptosis. Chaihu Guizhi Ganjiang Decoction (CGGD), a traditional Chinese medicine is widely used in the clinical treatment of digestive diseases. However, whether CCGD affects the SK1/S1P axis and relieves pancreatic damage through this pathway remains unknown. In this study, CP rats were treated with CGGD, individually or in combination with S1P and SKI-178 for four weeks to assess the effect of CGGD on pancreatic injury, fibrosis, autophagy and pyroptosis. The results showed that SK1, S1P and S1PR2 levels were increased in the pancreatic tissues of CP rats, while CGGD reduced these levels. Treatment with S1P exacerbated histological damage, promoted fibrosis, accelerated autophagy, and induced pyroptosis. Conversely, SKI-178 suppressed these effects. Notably, CGGD mitigated histological damage, decreased serum amylase and lipase levels, and alleviated pancreatic fibrosis induced by S1P. Furthermore, CGGD downregulated autophagy and pyroptosis induced by S1P, exhibiting an effect comparable to SKI-178 in CP. In conclusion, CGGD ameliorates pancreatic damage by reducing fibrosis, inhibiting autophagy, and suppressing pyroptosis through the SK1/S1P axis.

Background: Berberine (BBR), an isoquinoline alkaloid from Coptidis Rhizoma, possesses powerful activities against diverse human malignancies, including non-small cell lung cancer (NSCLC). Nevertheless, the underlying anti-tumor mechanisms of BBR in NSCLC remain poorly understood.

Methods: NSCLC cells were cultured and treated with various doses (0, 15, 30, and 45 μM) of BBR for 48 h. Cell viability, proliferation, apoptosis, migration, and invasion were detected using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. Cell division cycle-associated protein 5 (CDCA5) and Cyclin A2 (CCNA2) mRNA level and protein level were measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot assays. After STRING databases prediction, the possible interaction between CDCA5 and CCNA2 was identified using Co-Immunoprecipitation (IP) assays. The biological role of BBR treatment on NSCLC tumor growth was assessed using the xenograft tumor model in vivo.

Results: BBR treatment blocked NSCLC cell proliferation, migration, invasion, and promoted apoptosis. CDCA5 and CCNA2 levels were increased in NSCLC tissues, whereas their expression was decreased in BBR-induced NSCLC cells. CDCA5 or CCNA2 overexpression might attenuate the inhibitory role of BBR on NSCLC cell malignant behaviors. CDCA5 interacted with CCNA2 to regulate its expression in NSCLC cells. BBR administration blocked NSCLC xenograft growth in vivo.

Conclusion: BBR hindered NSCLC cell malignant progression partly by modulating CDCA5 and CCNA2, providing a promising therapeutic target for NSCLC treatment.

Ten glycosidic compounds (1-10), including two novel amide glycosides and one new phenylpropanoid glycoside, were isolated from the fruits of Piper longum L. These novel compounds were identified as (E)-N-feruloylpiperidine 4'-O-β-d-glucopyranosyl-(1 → 4)-β-d-glucopyranoside (1), (E)-N-p-coumaroylpiperidine 4'-O-β-d-glucopyranosyl-(1 → 4)-β-d-glucopyranoside (2), and (E)-cinnamyl alcohol 9-O-β-d-glucopyranosyl-(1 → 4)-α-l-rhamnose-(1 → 6)-β-d-glucopyranoside (3) by detailed spectroscopic and spectrometric techniques. Acid hydrolysis was employed to determine the glycosidic linkages, facilitating the structural elucidation of these compounds. The anti-inflammatory activities of all isolated compounds were assessed, and the results demonstrated that compounds 8 and 9 exhibited moderate inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.