Editors-in-Chief

Shu-Min DUAN

Zhi-Hong LIU

ISSN 1673-1581

CN 33-1356/Q

Published by

Zhejiang University Press

2022 JIF 4.7

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  • Review

    Abstract：Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.  

    Suya ZHENG, Ye CHEN, Zhipeng ZHU, Nan LI, Chunyu HE, H. Phillip KOEFFLER, Xin HAN, Qichun WEI, Liang XU

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  • Review

    Abstract：Lymph node metastasis (LNM) is a crucial risk factor influencing an unfavorable prognosis in specific cancers. Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets. Nevertheless, the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments. Preclinical models, in this context, serve as the conduit connecting fundamental theories to clinical outcomes. In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms. Using various experimental animals, including mice, diverse methods, such as carcinogen-induced tumorigenesis, tumor cell line or human tumor transplantation, genetic engineering, and humanization, have been used effectively to construct numerous models for tumor LNM. Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis. Transplantation models, using human tumor cell lines or patient-derived tumors, offer a research platform closely mirroring the histology and clinical behavior of human tumors. Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment. Humanized models are used to overcome barriers between human and murine immune systems. Beyond mouse models, various other animal models have unique advantages and limitations, all contributing to exploring LNM. This review summarizes existing in vitro and animal preclinical models, identifies current bottlenecks in preclinical research, and offers an outlook on forthcoming preclinical models.  

    Liya WEI, Zizhan LI, Niannian ZHONG, Leiming CAO, Guangrui WANG, Yao XIAO, Bo CAI, Bing LIU, Linlin BU

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  • Review

    Abstract：Citrus, which has been consumed internationally for a long time, is widely used as a health food. Citrus and its active components exert significant effects on oxidative stress and lipid metabolism, which are closely associated with female reproductive health. Studies suggest that citrus-derived compounds may alleviate oxidative stress by activating signaling pathways such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Sirtuin 1 (SIRT1), and improve lipid metabolism through the activation of pathways such as peroxisome proliferator-activated receptor α (PPARα). This review focuses on the effects of Citrus on oxidative stress and lipid metabolism, aiming to provide new insights for promoting female reproductive health; however, further work is needed to elucidate the mechanisms involved and validate the therapeutic potential of Citrus’s bioactive components in clinical settings.  

    Yiyan YANG, Jue ZHOU

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  • Research Article

    Abstract：Periodontitis is a common oral disease caused by bacteria coupled with an excessive host immune response. Stem cell therapy can be a promising treatment strategy for periodontitis, but the relevant mechanism is complicated. This study aimed to explore the therapeutic potential of mitochondria from human embryonic stem cell-derived mesenchymal stem cells (hESC-MSCs) for the treatment of periodontitis. The gingival tissues of periodontitis patients are characterized by abnormal mitochondrial structure. Human gingival fibroblasts (HGFs) were exposed to 5 μg/mL lipopolysaccharide (LPS) for 24 h to establish a cell injury model. When treated with hESC-MSCs or mitochondria derived from hESC-MSCs, HGFs showed reduced expression of inflammatory genes, increased adenosine triphosphate (ATP) level, decreased reactive oxygen species (ROS) production, and enhanced mitochondrial function compared to the control. The average efficiency of isolated mitochondrial transfer by hESC-MSCs was determined to be 8.93%. Besides, a therapy of local mitochondrial injection in mice with LPS-induced periodontitis showed a reduction in inflammatory gene expression, as well as an increase in both the mitochondrial number and the aspect ratio in gingival tissues. In conclusion, our results indicate that mitochondria derived from hESC-MSCs can reduce the inflammatory response and improve mitochondrial function in HGFs, suggesting that the transfer of mitochondria between hESC-MSCs and HGFs serves as a potential mechanism underlying the therapeutic effect of stem cells.  

    Bicong GAO, Chenlu SHEN, Kejia LV, Xuehui LI, Yongting ZHANG, Fan SHI, Hongyan DIAO, Hua YAO

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  • Research Article

    Abstract：ObjectiveThe use of stem cells is a promising strategy for seizure treatment owing to their unique characteristics. We investigated the role of endothelial progenitor cells (EPCs) in a pentylenetetrazole (PTZ)‍-induced rat seizure model. A selected panel of long noncoding RNAs (lncRNAs), which maintain an elaborate balance in brain neural regulatory networks as well as the autophagy pathway, was also targeted.MethodsThe impact of intravenously administered EPCs on PTZ-induced kindling in rats was evaluated by measuring the expression of neuronal damage markers, neurotrophic factors, and relevant lncRNA genes. Rat behavior was assessed using Y-maze test and open field test (OFT).ResultsEPCs mitigated seizure-associated neurological damage and reversed PTZ-induced working memory and locomotor activity deficits, as evidenced by improved performance in the Y-maze test and OFT. EPC treatment reversed the downregulation of the expression of the lncRNAs Evf2, Pnky, Dlx1, APF, HOTAIR, and FLJ11812. EPCs also boosted vascular endothelial growth factor (VEGF) expression. The ameliorative effect achieved by EPCs was comparable to that produced by valproate.ConclusionsThese findings indicate that EPCs ameliorate kindling epileptic seizures and their associated abnormalities and that the effect of EPCs may be mediated via the upregulation of certain regulatory lncRNAs.  

    Shimaa O. ALI, Nancy N. SHAHIN, Marwa M. SAFAR, Sherine M. RIZK

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  • Correspondence

    Abstract：解淀粉芽孢杆菌（Bacillus amyloliquefaciens LX-6）因具有中性蛋白酶活性，在豆粕（soybean meal, SBM）发酵中具有较大应用潜力。本研究通过核糖体工程及培养基优化技术，提高解淀粉芽孢杆菌LX-6的中性蛋白酶活性。首先，利用核糖体工程技术从306个自发利福平抗性（Rif r）突变株中筛选出突变株5r-10。与野生型（WT）菌株LX-6相比，突变株的中性蛋白酶活性提高了38.45%。研究发现，突变株编码RNA聚合酶β亚基的rpoB基因在第469个氨基酸位点发生谷氨酸→精氨酸（glutamic acid→arginine，Glu→Arg）的突变；在形态上与WT菌株LX-6相比，突变株5r-10的细胞表面更光滑且鞭毛更少。随后，在摇瓶实验中，我们采用基于响应面方法的单因素实验和Box-Behnken设计，对菌株产中性蛋白酶培养基成分进行了优化。在最佳浓度的乳糖、酪蛋白和氯化钙（CaCl2）培养条件下，突变株5r-10的中性蛋白酶活性最高可以达到(3470.67±23.17) U/mL，是WT菌株LX-6在原始培养基中产生的中性蛋白酶活性的1.49倍。此外，与WT菌株LX-6相比，突变株5r-10在固体发酵过程中对SBM中大分子抗原蛋白的降解更快，即与LX-6发酵相比，经突变株5r-10发酵后，SBM中大豆球蛋白和β-伴大豆球蛋白的降解率显著增加。  

    Yifan ZHU, Xinyi HUANG, Tao HAN, Jiteng WANG, Xiaoping YU, Zheng MA

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