Search

Abstract Background Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, exhibits promising anti-Alzheimer’s disease (AD) effects, but its underlying mechanisms remain inadequately investigated. This paper aims to identify potential targets and molecular mechanisms of DAU in AD treatment. Methods Network pharmacology and molecular docking simulation method were used to screen and focus core targets. Various transgenic Caenorhabditis elegans models were chosen to validate the anti-AD efficacy and mechanism of DAU. Results There are 66 potential DAU-AD target intersections identified from 100 DAU and 3036 AD-related targets. Subsequent protein-protein interaction (PPI) network analysis identified 16 core targets of DAU for anti-AD. PIK3CA, AKT1 and mTOR were predicted to be the central targets with the best connectivity through the analysis of “compound-target-biological process-pathway network”. Molecular docking revealed strong binding affinities between DAU and PIK3CA, AKT1, and mTOR. In vivo experiments demonstrated that DAU effectively reduced paralysis in AD nematodes caused by Aβ aggregation toxicity, downregulated expression of PIK3CA, AKT1, and mTOR homologues (age-1, akt-1, let-363), and upregulated expression of autophagy genes and the marker protein LGG-1. Simultaneously, DAU increased lysosomal content and enhanced degradation of the autophagy-related substrate protein P62. Thioflavin T（Th-T）staining experiment revealed that DAU decreased Aβ accumulation in AD nematodes. Further experiments also confirmed DAU’s protein scavenging activity in polyglutamine (polyQ) aggregation nematodes. Conclusion Collectively, the mechanism of DAU against AD may be related to the activation of the autophagy-lysosomal protein clearance pathway, which contributes to the decrease of Aβ aggregation and the restoration of protein homeostasis.

Abstract Background Body weight and its changes have been associated with cancer outcomes. However, the associations of short‐term peridiagnosis weight dynamics in standardized, clinically operational time frames with cancer survival remain largely unknown. This study aimed to screen for and evaluate the optimal indicator of short‐term peridiagnosis weight dynamics to predict overall survival (OS) in patients with cancer. Methods This multicentre cohort study prospectively collected data from 7460 patients pathologically diagnosed with cancer between 2013 and 2019. Body weight data were recorded 1 month before, at the time of and 1 month following diagnosis. By permuting different types (point value in kg, point height‐adjusted value in kg/m2, absolute change in kg or relative change in percentage) and time frames (prediagnosis, postdiagnosis or peridiagnosis), we generated 12 different weight‐related indicators and compared their prognostic performance using Harrell's C‐index, integrated discrimination improvement, continuous net reclassification improvement and time‐dependent C‐index. We analysed associations of peridiagnosis relative weight change (RWC) with OS using restricted cubic spine (RCS), Kaplan–Meier analysis and multivariable‐adjusted Cox regression models. Results The study enrolled 5012 males and 2448 females, with a median age of 59 years. During a median follow‐up of 37 months, 1026 deaths occurred. Peridiagnosis (1 month before diagnosis to 1 month following diagnosis) RWC showed higher prognostic performance (Harrell's C‐index = 0.601, 95% confidence interval [CI] = [0.583, 0.619]) than other types of indicators including body mass index (BMI), absolute weight change, absolute BMI change, prediagnosis RWC and postdiagnosis RWC in the study population (all P 10%, hazard ratio [HR] = 0.530, 95% CI = [0.413, 0.680]) and moderate (gain 5–10%, HR = 0.588, 95% CI = [0.422, 0.819]) weight gain groups were both associated with improved OS. In contrast, the moderate (loss 5–10%, HR = 1.219, 95% CI = [1.029, 1.443]) and significant (loss >10%, HR = 1.280, 95% CI = [1.095, 1.497]) weight loss groups were both associated with poorer OS. Conclusions The prognostic performance of peridiagnosis RWC is superior to other weight‐related indicators in patients with cancer. The findings underscore the importance of expanding the surveillance of body weight from at diagnosis to both past and future, and conducting it within clinically operational time frames, in order to identify and intervene with patients who are at risk of weight change‐related premature deaths.

The short flowering period of ornamental cherry trees is the main factor limiting their use in gardens. Determining the secondary flowering characteristics of ornamental cherry trees is required to prolong their flowering period. In this experiment, Cerasus subhirtella ‘Autumnalis’ was used as the experimental material. The phenological differences in their annual growth cycle were observed using the BBCH coding system. The cooling requirements of the flower buds were evaluated by the chilling hours model (temperature between 0 and 7.2 °C) and the Utah model. The expression of the core gene involved in bud dormancy regulation DAM (dormancy-associated MADS-box) from the completion of flower bud differentiation in one year until the following year was measured by performing real-time fluorescence-based quantitative PCR. The results showed that the flowering duration of C. subhirtella ‘Autumnalis’ from November to December was longer than that of C. yedoensis ‘Somei Yoshino’, which was from March to April. The progress from seed bud-break to flower bud opening took about 10 days for C. subhirtella ‘Autumnalis’, while the same stage for C. yedoensis ‘Somei Yoshino’ took around 20 days. Additionally, the flower buds of C. subhirtella ‘Autumnalis’ needed only the chilling temperature unit of 54.08 to satisfy the chilling requirement, while C. yedoensis ‘Somei Yoshino’ required a chilling temperature unit of 596.75. After the completion of flower bud differentiation, during low-temperature storage, the expression of DAM4 and DAM5 genes first increased and then decreased, whereas, the expression of the DAM6 gene continued to decrease, and the expression of DAM4, DAM5, and DAM6 in C. yedoensis ‘Somei Yoshino’ increased rapidly and was maintained at a high level. This showed that the upregulation of the expression of the DAM4, DAM5, and DAM6 genes can inhibit the flower bud germination of Cherry Blossom. The relative expression of the DAM gene of C. subhirtella ‘Autumnalis’ was significantly lower than that of the DAM gene of C. yedoensis ‘Somei Yoshino’ from the end of October to the beginning of December, leading to its secondary flowering in autumn. These results might elucidate why the flower buds of C. subhirtella ‘Autumnalis’ can break their internal dormancy and bloom in the autumn and then again in the following year. Our findings might provide a reference for conducting further studies on the mechanisms of secondary flowering and bud dormancy in cherries.

Flowering cherry (Cerasus sp.) are significant spring-blooming trees. However, the short blooming period and the rarity of early and late-flowering varieties limit their use in gardens in northern China. The experiment incorporated annually early-flowering species such as Cerasus discoidea, Cerasus pseudocerasus ‘Introtsa’, Cerasus dielsiana, Cerasus campanulata ‘Youkou’, Cerasus yedoensis ‘Somei-Yoshino’, and Cerasus spachiana f. ascendens, as well as twice-a-year flowering species like Cerasus subhirtella ‘Autumnalis’ and Cerasus subhirtella ‘Accolade’. We observed the timing of natural events and growth measurements for specific plants over a span of two years. This research involved a thorough examination of their ability to withstand cold temperatures, considering their physiological aspects. We examined the levels of nutrients and hormones in the flower buds at various stages of development in plants that bloom yearly and every two years. The findings indicated that C. subhirtella ‘Autumnalis’ is adaptable, offering the lengthiest autumn blooming phase lasting 54 days. The hierarchy of cold tolerance was as follows: C. pseudocerasus ‘Introtsa’ > C. discoidea > Cerasus × subhirtella ‘Autumnalis’ > C. dielsiana > C. ‘Youkou’. Furthermore, the soluble protein content in leaves increased before autumn flower buds’ sprout of twice-a-year flowering varieties but declined in C. yedoensis ‘Somei-Yoshino’ within the same time. We determined that changes in nutrient content significantly contribute to the autumn opening of C. subhirtella ‘Autumnalis’ robust short branch flower buds. During the final phase of flower bud development, the rise in trans-Zeatin-riboside (ZR) and indolacetic acid (IAA) promotes the initiation of the first flowering period in C. subhirtella ‘Autumnalis’ prior to its mandatory hibernation. The occurrence of secondary flowering involves a multifaceted regulatory process. These findings serve as valuable references for delving deeper into the mechanisms governing cherry blossom formation and secondary flowering.