Xanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known. The effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope. Mechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity. Collectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC.

Ten new epipolythiodioxopiperazine (ETP) alkaloids, named corallomycetellains A–J (1–10), along with one known analogue, haematocin (11), were isolated from the fungi Corallomycetella repens HDN23-0007. Their structures, including absolute configurations, were established by comprehensive spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1–2 represent the first two examples of aranotin-type ETPs possessing an aromatic indole moiety. Compounds 2–4 all featured a unique C2-methyl disulfide substituent, whereas compound 4 additionally possessed a C2′-oxomethyl group. In in vitro cytotoxicity assays, compounds 7–10, which contained α–α′ polysulfide bridges, exhibited strong anticancer activity, with IC₅₀ values ranging from 1.1 to 9.3 μM.

Background: Alcoholic dementia (AlD) is a severe neurological disorder with no effective treatment. Development of pan-phosphodiesterase-4 (PDE4) inhibitors for clinical treatment of neurological conditions has been hampered by emetic side effects primarily mediated by PDE4D, one of the four subtypes of PDE4. Although PDE4A was shown to be upregulated by chronic alcohol exposure, its therapeutic relevance to AlD remains unclear. Methods: A stable mouse model of AlD was established in 3-month-old 3xTg-AD mice using a free-choice two-bottle protocol (25% alcohol) for 19 weeks. Mice received either rolipram injections for 3 weeks or PDE4A knockdown for 6 weeks. Cognitive function was assessed using the Morris water maze, novel object recognition, and Y-maze tests. Hippocampal neuropathology—including Aβ deposition, synaptic integrity, Tau phosphorylation (at Ser214/Ser404), and neuronal apoptosis—was evaluated by immunofluorescence or immunohistochemistry. Changes in key proteins of the cAMP/PKA/CREB signaling pathway were analyzed by Western blotting. Results: This study demonstrated that selectively targeting PDE4A rescued cognitive and neuropathological deficits in a validated mouse model of AlD. Behavioral tests showed that PDE4A knockdown significantly improved spatial memory and cognition in the Morris water maze, novel object recognition, and the Y maze in the AlD mice. Pathological analysis revealed that PDE4A knockdown reduced amyloid-beta (Aβ) deposition and phosphorylated Tau levels. Furthermore, it restored synaptic integrity, as evidenced by the upregulation of PSD95 and Synaptophysin, enhanced dendritic complexity, and increased spine density, while also exerting neuroprotective effects by suppressing neuronal apoptosis in AlD mice. Mechanistically, the therapeutic benefits of PDE4A knockdown were mediated through the reactivation of the critically impaired cAMP/PKA/CREB signaling pathway, leading to elevated cAMP levels, increased PKA activity, and enhanced phosphorylation of CREB. Conclusion: Our findings established PDE4A as one of the key AlD pathological drivers and identified its selective inhibition as a novel and promising therapeutic strategy for AlD, offering a viable approach to circumvent the adverse effects associated with broad-spectrum PDE4 inhibition.

Tubulin tyrosine ligase-like enzyme-12 (TTLL-12), belonging to the TTLL family, holds a crucial position in posttranslational tubulin modifications implicated in cancer development, making it a potential target for anti-tumor therapy. However, the precise mechanisms of TTLL12 in HCC remain inadequately elucidated. In this study, we found markedly elevated expression of TTLL12 in HCC tissues compared to their adjacent normal counterparts, which is strongly linked to an unfavorable prognosis. Functional assays demonstrated that knockdown of TTLL12 significantly suppressed HCC cell proliferation, whereas overexpression of TTLL12 promoted oncogenic behaviors. In vivo models further confirmed that TTLL12 enhances tumor growth, as indicated by larger tumors in TTLL12-overexpressing cells compared to vector controls. Mechanistically, TTLL12 suppressed ubiquitin-proteasome-mediated degradation of eEF1A1 via competing with Bood POZ-containing gene type 2 (BPOZ-2), which typically recruits eEF1A1 to CULLIN (CUL3), and ultimately results in an enhancement of cancer cell proliferation. Our analyses underscore the oncogenic potential of TTLL12 in hepatocarcinogenesis by safeguarding eEF1A1 from BPOZ-2- mediated degradation, introducing a novel therapeutic target for combating HCC.