Pseudotaxus chienii
, the only species in the genus
Pseudotaxus
, is closely related to
Taxus
genus. Whether
P. chienii
can produce paclitaxel has long remained controversial. Here, we present a chromosome-level, haplotype-resolved genome of
P. chienii
, with each haplotype ( ~ 15.4 Gb) exhibiting high continuity and completeness. We identify a structurally conserved yet physically dispersed genomic region, termed the Taxane Biosynthetic Archipelago (TBA), containing three biosynthetic gene clusters and collinear core genes essential for taxane biosynthesis. Integrative transcriptomic, metabolite, and heterologous enzymatic analyses reveal that while
P. chienii
retains a largely conserved genomic architecture associated with paclitaxel biosynthesis, its terminal pathway shows severe functional degradation and may have largely lost the functional capacity for paclitaxel production. Concurrently, it exhibits significant accumulation of taxinine J. This study provides an evolutionary framework for interpreting the long-standing debate on paclitaxel production beyond
Taxus
, and understanding the evolutionary decay of complex specialized pathways.
Huan Wang, Hai-Dong Chen, Ya-Ping Sun et al.· Nature Communications· 0 citations
Background Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common malignancy globally, with tumor uncontrolled angiogenesis being major causes of therapeutic failure and patient death. Isoalantolactone (IATL), a natural compound, exhibits antioxidant, anti-inflammatory, anti-proliferative, and anti-tumor properties. However, its role in inhibiting tumor angiogenesis in pancreatic cancer and the underlying mechanisms remain unclear. This study aims to investigate the anti-angiogenic effects of IATL in PDAC and elucidate the associated molecular pathways. Methods In vitro experiments were performed using PDAC cell lines (Panc02, PANC-1, and SW 1990) and HUVECs. In vivo studies were conducted using an orthotopic pancreatic cancer model in C57BL/6 mice. Cell viability, wound-healing, tube formation, in vivo imaging system analysis, laser speckle contrast imaging, immunohistochemistry, immunofluorescence, RT-qPCR, ELISA, and Western blot assays were used to evaluate the effects of IATL on tumor growth, angiogenesis, and inflammatory responses. Molecular docking and cellular thermal shift assay were performed to assess the interaction between IATL and NLRP3. Results IATL significantly inhibited the proliferation and migration of Panc02, PANC-1, and SW1990 cells. In the orthotopic pancreatic cancer model, IATL dose-dependently suppressed tumor growth, as evidenced by reduced IVIS fluorescence signals and tumor volume. IATL also markedly inhibited angiogenesis, as shown by reduced HUVECs migration and tube formation, decreased tumor blood perfusion detected by laser speckle imaging, and downregulated CD34 and VEGFA expression both in vivo and in vitro. Network pharmacology, molecular docking, and cellular thermal shift assay identified NLRP3 as a direct target of IATL. Mechanistically, IATL suppressed NLRP3 inflammasome activation, reduced ASC speck formation, inhibited the NLRP3/IL-1β signaling axis, and decreased the expression of inflammatory cytokines, including IL-6, TNF-α, IL-1β, and IL-18. NLRP3 knockdown mimicked the effects of IATL, whereas NLRP3 overexpression partially reversed its anti-tumor, anti-angiogenic, and anti-inflammatory effects, further supporting the target specificity of IATL. Conclusion IATL functions as a novel NLRP3 pathway inhibitor, suppressing angiogenesis through anti-inflammatory mechanisms, thereby effectively inhibiting PDAC progression. These findings suggest that IATL holds potential as a therapeutic agent for pancreatic cancer.
Ying Zhang, Changquan Liu, Shengjiang Liu et al.· Frontiers in Pharmacology· 0 citations
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