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：Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade (ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified; some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration (FDA) for clinical treatment. However, limited responses and immune-related adverse events (irAEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.  

    Hongying YE, Weijie LIAO, Jiongli PAN, Yin SHI, Qingqing WANG

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  • Review

    Abstract：Skeletal muscle dysfunction is a common extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with decreased quality-of-life and survival in patients. The autophagy lysosome pathway is one of the proteolytic systems that significantly affect skeletal muscle structure and function. Intriguingly, both promoting and inhibiting autophagy have been observed to improve COPD skeletal muscle dysfunction, yet the mechanism is unclear. This paper first reviewed the effects of macroautophagy and mitophagy on the structure and function of skeletal muscle in COPD, and then explored the mechanism of autophagy mediating the dysfunction of skeletal muscle in COPD. The results showed that macroautophagy- and mitophagy-related proteins were significantly increased in COPD skeletal muscle. Promoting macroautophagy in COPD improves myogenesis and replication capacity of muscle satellite cells, while inhibiting macroautophagy in COPD myotubes increases their diameters. Mitophagy helps to maintain mitochondrial homeostasis by removing impaired mitochondria in COPD. Autophagy is a promising target for improving COPD skeletal muscle dysfunction, and further research should be conducted to elucidate the specific mechanisms by which autophagy mediates COPD skeletal muscle dysfunction, with the aim of enhancing our understanding in this field.  

    Xiaoyu HAN, Peijun LI, Meiling JIANG, Yuanyuan CAO, Yingqi WANG, Linhong JIANG, Xiaodan LIU, Weibing WU

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  • Research Article

    Abstract：Immune thrombocytopenia (ITP) is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury. ITP has complicated immunopathological mechanisms that need further elucidation. It is well known that the costimulatory molecules OX40 ligand (OX40L) and OX40 play essential roles in the immunological mechanisms of autoimmune diseases. Previously, we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells (PBMCs) of ITP patients. In our present study, OX40L-induced follicular helper T (Tfh) cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator (ICOS), programmed cell death protein-1 (PD-1), and cluster of differentiation 40 ligand (CD40L) in vitro. Moreover, aberrant OX40L‒OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo, inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model, which might accelerate the progression of ITP. Additionally, signal transduction through the OX40L‒OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor (TRAF)‒nuclear factor-κB (NF-κB) and Janus kinase (JAK)‒signal transducer and activator of transcription (STAT) signaling pathways. Overall, OX40L‒OX40 signaling is proposed as a potential novel therapeutic target for ITP.  

    Ziyin YANG, Lei HAI, Xiaoyu CHEN, Siwen WU, Yan LV, Dawei CUI, Jue XIE

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  • Research Article

    Abstract：Loss-of-function variants of low-density lipoprotein receptor-related protein 5 (LRP5) can lead to reduced bone formation, culminating in diminished bone mass. Our previous study reported transcription factor osterix (SP7)‍-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration. However, the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown. In this study, we used mice with a conditional knockout (cKO) of LRP5 in mature osteoblasts, which presented decreased osteogenesis. The in vitro experimental results showed that SP7 could promote LRP5 expression, thereby upregulating the osteogenic markers such as alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), and β‍-catenin (P<0.05). For the in vivo experiment, the SP7 overexpression virus was injected into a bone defect model of LRP5 cKO mice, resulting in increased bone mineral density (BMD) (P<0.001) and volumetric density (bone volume (BV)/total volume (TV)) (P<0.001), and decreased trabecular separation (Tb.‍Sp) (P<0.05). These data suggested that SP7 could ameliorate bone defect healing in LRP5 cKO mice. Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.  

    Yue XI, Qifeng JIANG, Wei DAI, Chaozhen CHEN, Yang WANG, Xiaoyan MIAO, Kaichen LAI, Zhiwei JIANG, Guoli YANG, Ying WANG

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  • Research Article

    Abstract：Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.  

    Quanmin KANG, Fang LE, Xiayuan XU, Lifang CHEN, Shi ZHENG, Lijun LOU, Nan JIANG, Ruimin ZHAO, Yuanyuan ZHOU, Juan SHEN, Minhao HU, Ning WANG, Qiongxiao HUANG, Fan JIN

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  • Research Article

    Abstract：Ulcerative colitis (UC) is an inflammatory condition of the intestine, resulting from an increase in oxidative stress and pro-inflammatory mediators. In this study, the extract of endophytic bacterium Rhizobium aegyptiacum was prepared for the first time using liquid chromatography-mass spectrometry (LC-MS). In addition, also for the first time, the protective potential of R. aegyptiacum was revealed using an in vivo rat model of UC. The animals were grouped into four categories: normal control (group I), R. aegyptiacum (group II), acetic acid (AA)‍-induced UC (group III), and R. aegyptiacum-treated AA-induced UC (group IV). In group IV, R. aegyptiacum was administered at 0.2 mg/kg daily for one week before and two weeks after the induction of UC. After sacrificing the rats on the last day of the experiment, colon tissues were collected and subjected to histological, immunohistochemical, and biochemical investigations. There was a remarkable improvement in the histological findings of the colon tissues in group IV, as revealed by hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, and periodic acid-Schiff (PAS) staining. Normal mucosal surfaces covered with a straight, intact, and thin brush border were revealed. Goblet cells appeared magenta in color, and there was a significant decrease in the distribution of collagen fibers in the mucosa and submucosal connective tissues. All these findings were comparable to the respective characteristics of the control group. Regarding cyclooxygenase-2 (COX-2) immunostaining, a weak immune reaction was shown in most cells. Moreover, the colon tissues were examined using a scanning electron microscope, which confirmed the results of histological assessment. A regular polygonal unit pattern was seen with crypt orifices of different sizes and numerous goblet cells. Furthermore, the levels of catalase (CAT), myeloperoxidase (MPO), nitric oxide (NO), interleukin-6 (IL-6), and interlukin-1β (IL-1β) were determined in the colonic tissues of the different groups using colorimetric assay and enzyme-linked immunosorbent assay (ELISA). In comparison with group III, group IV exhibited a significant rise (P<0.05) in the CAT level but a substantial decline (P<0.05) in the NO, MPO, and inflammatory cytokine (IL-6 and IL-1β) levels. Based on reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the tumor necrosis factor-‍α (TNF-‍α) gene expression was upregulated in group III, which was significantly downregulated (P<0.05) by treatment with R. aegyptiacum in group IV. On the contrary, the heme oxygenase-1 (HO-1) gene was substantially upregulated in group IV. Our findings imply that the oral consumption of R. aegyptiacum ameliorates AA-induced UC in rats by restoring and reestablishing the mucosal integrity, in addition to its anti-oxidant and anti-inflammatory effects. Accordingly, R. aegyptiacum is potentially effective and beneficial in human UC therapy, which needs to be further investigated in future work.  

    Engy ELEKHNAWY, Duaa ELIWA, Sebaey MAHGOUB, Sameh MAGDELDIN, Ehssan MOGLAD, Sarah IBRAHIM, Asmaa Ramadan AZZAM, Rehab AHMED, Walaa A. NEGM

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  • Erratum

    Abstract：The original version of this article (Yang et al., 2023) unfortunately contained a mistake. In Acknowledgments, the funding information for the Zhejiang Provincial Natural Science Foundation of China (No. LBY21H160001) was wrong. The correct funding should be the Zhejiang Health Science and Technology Project (No. 2022KY682), China.  

    Qiuhui YANG, Yeqin FU, Jiaxuan WANG, Hongjian YANG, Xiping ZHANG

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