The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A’s phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A’s canonical function. We demonstrate that PDE3A’s H840, Q975, Q1001, and F1004 residues—as well as I105 in SLFN12—are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.
Oxidative stress has been proven to play a critical role in the pathogenesis of neuronal injury. As a novel adipocytokine, omentin is produced by visceral adipose with insulin sensitizing effects and has been revealed to possess anti-inflammatory effects. However, the possible effect of omentin on oxidative stress remains unknown. The present study aimed to detect the potential protective effect of omentin against hydrogen peroxide (H 2 O 2 )-induced cytotoxicity of PC12 cells. The results showed that no cytotoxic effect was shown in PC12 cells co-cultured with omentin alone at a concentration of 50-1000 ng/mL. The CCK8 and TUNEL assays suggested that omentin could remarkably attenuate apoptosis induced by 100 lM H 2 O 2 . The PCR and western blotting showed that the expression levels of Bax was significantly inhibited by omentin via the upregulation of miR-128-3p at its 3 0 -UTR. Taken together, these results indicated that omentin protects PC12 cells against H 2 O 2 -induced apoptosis, and further studies need to be conducted before utilization in the clinic for the treatment of neurodegenerative diseases.
ObjectivesOlfactory disorder is one of the sensory features that reflects a decline in cognitive function. However, olfactory changes and the discernibility of smell testing in the aging population have yet to be fully elucidated. Therefore, this study aimed to examine the effectiveness of the Chinese Smell Identification Test (CSIT) in distinguishing individuals with cognitive decline from those with normal aging and to determine whether the patients with MCI and AD show changes in their olfactory identification abilities.MethodsThis cross-sectional study included eligible participants aged over 50 years between October 2019 and December 2021. The participants were divided into three groups: individuals with mild cognitive impairment (MCI), individuals with Alzheimer's disease (AD), and cognitively normal controls (NCs). All participants were assessed using neuropsychiatric scales, the Activity of Daily Living scale, and the 16-odor cognitive state test (CSIT) test. The test scores and the severity of olfactory impairment were also recorded for each participant.ResultsIn total, 366 eligible participants were recruited, including 188 participants with MCI, 42 patients with AD, and 136 NCs. Patients with MCI achieved a mean CSIT score of 13.06 ± 2.05, while patients with AD achieved a mean score of 11.38 ± 3.25. These scores were significantly lower than those of the NC group (14.6 ± 1.57; P < 0.001). An analysis showed that 19.9% of NCs exhibited mild olfactory impairment, while 52.7% of patients with MCI and 69% of patients with AD exhibited mild to severe olfactory impairment. The CSIT score was positively correlated with the MoCA and MMSE scores. The CIST score and the severity of olfactory impairment were identified as robust indicators for MCI and AD, even after adjusting for age, gender, and level of education. Age and educational level were identified as two important confounding factors that influence cognitive function. However, no significant interactive effects were observed between these confounders and CIST scores in determining the risk of MCI. The area under the ROC curve (AUC) generated from the ROC analysis was 0.738 and 0.813 in distinguishing patients with MCI and patients with AD from NCs based on the CIST scores, respectively. The optimal cutoff for distinguishing MCI from NCs was 13, and for distinguishing AD from NCs was 11. The AUC for distinguishing AD from MCI was 0.62.ConclusionsThe olfactory identification function is frequently affected in patients with MCI and patients with AD. CSIT is a beneficial tool for the early screening of cognitive impairment among elderly patients with cognitive or memory issues.
The synthetic approach to the core framework of daphniglaucin-type Daphniphyllum alkaloids is described herein. The B-C ring was constructed via a Rh-catalyzed [3+2] cycloaddition. Continuous quaternary centers were installed through [3+2] cycloaddition and alkylation. The attempt to build the A-D ring motif using dipolar cycloaddition of azomethine ylides was extensively investigated.
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