Natural Products and Bioprospecting最新文献

Two pairs of undescribed alkaloid enantiomers, (+)-/(−)-ormohenins A (1) and B (2), were isolated from the seeds of Ormosia henryi Prain, along with four undescribed alkaloids (3, 4, 7 and 8) and seven known ones (5, 6, 9–13). Compounds 1–6 belong to the ormosanine-type alkaloids, compounds 7, 9, and 11 are of the lupinine-type, compounds 8 and 10 are classified as anagyrine-type alkaloids, 12 and 13 are cytisine-type alkaloids. The chemical structures of 1–13 were elucidated through comprehensive NMR and MS data analyses. Furthermore, the racemates (±)-1 and (±)-2 were successfully resolved into their respective optically pure enantiomers using a chiral HPLC system. The absolute configurations of compounds 1–3 were determined using single-crystal X-ray diffraction and corroborated by DFT calculations of specific rotations. The absolute configurations of 4, 7, and 8 were assigned by the experimental electronic circular dichroism (ECD) with those predicted using TDDFT calculations. Compound 12 exhibited significant acetylcholinesterase (AChE) inhibitory activity with the IC₅₀ value of 6.581 ± 1.203 μM. The neuroprotective effects of these compounds against Aβ_25-35 induced cell damage in PC12 cells were investigated, and compounds 3, 9, and 12 exhibited significant neuroprotective effects against Aβ_25-35 induced PC12 cell damage, with the EC₅₀ values of 7.99–15.49 μM, respectively.

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Modern pharmacology has found that both Realgar and Coptis chinensis can induce apoptosis in tumor cells, and traditional Chinese medicine theory suggests the possibility of combining the two, however, the specific mechanisms involved have not been elucidated. This study investigated the therapeutic mechanism of the Realgar-Coptis chinensis drug pair (RCCD) against hepatocellular carcinoma (HCC) by identifying its key active compounds and targets. Through integrated LC–MS analysis, transcriptomics, network pharmacology, and bioinformatics, we identified the mechanism of action, key bioactive compounds, and core targets. Molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST) validated the binding affinity between key compounds and core targets. TIMER2.0 database was used to analyze the relationship between the core targets and HCC. H22 tumor xenograft mouse model and immunohistochemistry and pathology analyses were performed to validate the antitumor efficacy of the active compounds. RCCD has a high degree of selectivity of lipid metabolism pathway, 4-Methylumbelliferone (4-MU) was the key active compound with strong binding activity to the core target fatty acid synthase (FAS), and 4-MU down-regulated the expression of FASN in tumor tissues and induced apoptosis in HCC cells. In addition, as a hyaluronan synthase (HAS2/3) inhibitor, 4-MU interfered with the HA-dependent tumor microenvironment and fibrosis process by inhibiting HAS2/3. Thus, 4-MU may inhibit tumor progression by inhibiting FAS and HAS2/3. 4-MU extracted from RCCD exerts anti-HCC effects by modulating the activities of FAS and HAS2/3, thereby reprogramming lipid metabolism and regulating hyaluronan synthesis.

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Background

Depression promotes breast cancer progression. Given the lack of specific targets for depression-associated breast cancer, there are currently no therapeutic drugs for this type of breast cancer.

Methods

Transcriptomic analysis was conducted to identify and functionally annotate genes with differential expression in breast cancer patients exhibiting depressive symptoms. Subsequently, Mendelian randomization was employed to investigate the causal associations between these pivotal genes and breast cancer, thereby validating their potential roles as therapeutic targets. Furthermore, molecular docking techniques were utilized to screen for candidate compounds that may exert therapeutic effects on depression-associated breast cancer. The efficacy of the selected compounds was further assessed using both in vitro cellular experiments and in vivo animal models.

Results

We identified IL-8 as a key gene involved in depression-mediated breast cancer progression using transcriptomics. Mendelian randomized analysis suggested that high IL-8 expression promoted breast cancer progression. Further studies demonstrated that IL-8 mediated the breast cancer-promoting effect of depression through the receptor CXCR2. Evidence from both in vitro and in vivo experiments indicates that senkyunolide H may exert its therapeutic effect by regulating CXCR2, thereby counteracting the protumor effects associated with depression in breast cancer.

Conclusion

Depression activates CXCR2-mediated breast cancer cell proliferation through IL-8, and senkyunolide H regulates CXCR2 and inhibits its ability to block the cancer-promoting effects of depression, ultimately inhibiting the growth of breast cancer in the context of depression.

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Tuberculosis (TB) is a leading infectious disease killer and one of the major causes of deaths worldwide. Although TB is a curable and preventable disease, in 2023, approximately 10.8 million people fell ill with TB and there were an estimated 1.25 million of deaths worldwide. Despite some research progress for new drug candidates, drug repurposing, and new regimens, there is still an urgent need for the new medicins to treat TB, especially due to the growing cases of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug resistance is a challenging obstacle to TB care and prevention globally, making TB harder and longer to treat, often with poorer outcomes for patients. The Actinomycetota encompass Gram-positive bacteria that produce a milieu of bioactive metabolites, including antibiotics, antiproliferative drugs, immunosuppressive agents, and other important medical molecules. Actinomycetota have a special place in the therapeutic arsenal to fight TB, as rifamycins, aminoglycosides, and cycloserine are derived from Streptomyces species, one of the most important genera in this phylum. Furthermore, hundreds of antimycobacterial metabolites have been isolated from Actinomycetota and can serve as effective drugs or useful agents for the discovery of new lead compounds to combat TB. The present review covers more than 171 isolated substances as potential antimycobacterial agents discovered between the years 1972 to 2024. Among the most potent compounds, with MIC in the submicromolar range, steffimycins, ilamycins/rufomycins, nosiheptide, actinomycins, lassomycin and boromycin are the most promising compounds. These compounds represent highly promising candidates for development of new antitubercular drugs. Additionally, some of these substances also demonstrated activity against resistant Mycobacterium tuberculosis (Mtb) strains, which is particularly relevant given the difficulty of treating MDR and XDR strains. Thus, actinobacteria have played and continue to play an important role in fight TB, remaining a promising source of antibiotic metabolites. Their unique metabolic diversity enables the production of metabolites with innovative mechanisms of action, making them a strategic reservoir for discovering therapies against untreatable forms of the disease.

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Natural product tanshinone I exhibits weak potency and poor drug-like properties, which have restricted its clinical development as an anticancer agent. Herein, twenty novel tanshinone I-pyridinium salt derivatives and a pyridinium salt precursor were designed and synthesized, and their antitumor activities were evaluated. Among these tanshinone I-pyridinium salts, compound a4, bearing a 4-bromobenzoylmethyl substituent at the N-1 position of the pyridine ring, showed the most potent cytotoxicity against breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and prostate cancer (22RV1) cell lines, with IC₅₀ values of 1.40–1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC₅₀ of 9.24 ± 0.20 μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, a4 significantly downregulates the expression of the immune checkpoint protein PD-L1, indicating its potential to activate tumor immunity. These findings demonstrate that tanshinone I-pyridinium salt derivative a4 is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents.

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The extraction of anticancer agents from medicinal plants represents a highly promising research frontier. Ginkgetin, a natural biflavone, is one of the effective pharmacological components of Ginkgo biloba leaves (GBLs). This natural product exhibits significant anti-cancer efficacy against a variety of cancer cells in vitro and demonstrates a potent inhibitory impact on tumor growth in vivo without severe toxicity. Additionally, ginkgetin synergizes with chemotherapy drugs or adjuvant therapies to potentiate antitumor effects and reduce side effects. These compelling findings underscore Ginkgetin's potential as a promising candidate for novel anti-cancer therapeutics. Therefore, this review systematically summarizes the remarkable anticancer effects of ginkgetin and elucidates its multifaceted anticancer mechanisms, including inducing cell cycle arrest, triggering programmed cell death, and preventing invasion and angiogenesis. From a molecular mechanism perspective, ginkgetin exerts anti-cancer activity by modulating critical signaling pathways (e.g. JAK/STAT, Wnt/β-catenin, AKT/GSK-3β, MAPKs, and estrogen receptor pathways) and regulating microRNA expression levels. Furthermore, target identification, research limitations, future directions, and application prospects are comprehensively outlined, aiming to facilitate the clinical translation of ginkgetin.

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