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The impact of lipids on the cancer—immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1488-1497页

作者： Mingming Zheng Wenxin Zhang Xi Chen Hongjie Guo Honghai Wu Yanjun Xu Qiaojun He Ling Ding Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of Medical Thoracic Oncology the Cancer Hospital of University of Chinese Academy of Sciences(Zhejiang Cancer Hospital)Chinese Academy of SciencesHangzhou 310022China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Cancer Center of Zhejiang University Hangzhou 310058China

Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the cancer—immunity cycle has also been gradually discovered.First,regarding antigen presentation,cholesterol prevents tumor antigens from being identified by antigen presenting cells.Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells,impairing antigen presentation to T cells.Prostaglandin E2(PGE2)reduce the accumulation of tumor-infiltrating dendritic cells.Regarding T-cell priming and activation,cholesterol destroys the structure of the T-cell receptor and reduces immunodetection.In contrast,cholesterol also promotes T-cell receptor clustering and relative signal transduction.PGE2 represses T-cell proliferation.Finally,regarding T-cell killing of cancer cells,PGE2 and cholesterol weaken granule-dependent cytotoxicity.Moreover,fatty acids,cholesterol,and PGE2 can improve the activity of immunosuppressive cells,increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines.Given the regulatory role of lipids in the cancer—immunity cycle,drugs that modulate fatty acids,cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy.These strategies have been studied in both preclinical and clinical studies.

关键词： Lipids Fatty acids Cholesterol Prostaglandin E2 Tumor immune escape Cancer—immunity cycle Immunotherapy Combination therapy

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Progesterone promotes neuronal differentiation of human umbilical cord mesenchymal stem cells in culture conditions that mimic the brain microenvironment

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Neural Regeneration Research 2012年第25期7卷 1925-1930页

作者： Xianying Wang Honghai Wu Gai Xue Yanning Hou Hebei Medical University Shijiazhuang 050017 Hebei Province China The Third Hospital of Hebei Medical University Shijiazhuang 050051 Hebei Province China Bethune Intemational Peace Hospital of Chinese PLA Shijiazhuang 050082 Hebei Province China

In this study, human umbilical cord mesenchymal stem cells from full-term neonates born by vagina delivery were cultured in medium containing 150 mg/mL of brain tissue extracts from Sprague-Dawley rats （to mimic the brain microenvironment）. Immunocytochemical analysis demonstrated that the cells differentiated into neuron-like cells. To evaluate the effects of progesterone as a neurosteroid on the neuronal differentiation of human umbilical cord mesenchymal stem cells, we cultured the cells in medium containing progesterone （0.1, 1, 10 pM） in addition to brain tissue extracts. Reverse transcription-PCR and flow cytometric analysis of neuron specific enolase-positive cells revealed that the percentages of these cells increased significantly following progesterone treatment, with the optimal progesterone concentration for neuron-like differentiation being 1 tJM. These results suggest that progesterone can enhance the neuronal differentiation of human umbilical cord mesenchymal stem cells in culture medium containing brain tissue extracts to mimic the brain microenvironment.

关键词： progesterone mesenchymal stem cells neuron differentiation brain tissue extracts neural regeneration

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Metabolic alteration of neuroactive steroids and protective effect of progesterone in Alzheimer's disease-like rats

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Neural Regeneration Research 2013年第30期8卷 2800-2810页

作者： Sha Liu Honghai Wu Gai Xue Xin Ma Jie wu Yabin Qin Yanning Hou Hebei Medical University Department of Pharmacy Bethune International Peace Hospital of Chinese PLA

A correlation between metabolic alterations of neuroactive steroids and Alzheimer’s disease remains unknown. In the present study, amyloid beta （Aβ） 25-35 （Aβ25-35） injected into the bilateral campus CA1 region significantly reduced learning and memory. At the biochemical level, hippocampal levels of pregnenolone were significantly reduced with Aβ25-35 treatment. Furthermore, progesterone was considerably decreased in the prefrontal cortex and hippocampus, and 17β-estradiol was signifi-cantly elevated. To our knowledge, this is the first report showing that Aβ25-35, a main etiological factor of Alzheimer’s disease, can alter the level and metabolism of neuroactive steroids in the prefrontal cortex and hippocampus, which are brain regions significantly involved in learning and memory. Aβ25-35 exposure also increased the expression of inflammatory mediators, tumor necrosis factor-αand interleukin-1β. However, subcutaneous injection of progesterone reversed the upregulation of tumor necrosis factor-αand interleukin-1βin a dose-dependent manner. Concomitant with improved cognitive abilities, progesterone blocked Aβ-mediated inflammation and increased the survival rate of hippocampal pyramidal cells. We thus hypothesize that Aβ-mediated cognitive deficits may occur via changes in neuroactive steroids. Moreover, our findings provide a possible therapeutic strategy for Alzheimer’s disease via neuroactive steroids, particularly progesterone.

关键词： neural regeneration neurodegenerative disease neuroactive steroids Alzheimer＇s disease pro-gesterone amyloid beta cognition neuroprotection neuroregeneration

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Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

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药学学报:英文版 2023年第6期13卷 2585-2600页

作者： Wenxin Zhang Xiaohui Pan Yanjun Xu Hongjie Guo Mingming Zheng Xi Chen Honghai Wu Fengming Luan Qiaojun He Ling Ding Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of Medical Thoracic Oncology the Cancer Hospital of University of Chinese Academy of Sciences(Zhejiang Cancer Hospital)Chinese Academy of SciencesHangzhou 310022China Department of Gastrointestinal Surgery Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310009China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Cancer Center of Zhejiang University Hangzhou 310058China

Mevalonate metabolism plays an important role in regulating tumor growth and progression;however,its role in immune evasion and immune checkpoint modulation remains unclear.Here,we found that non-small cell lung cancer(NSCLC)patients with higher plasma mevalonate response better to antiPD-(L)1 therapy,as indicated by prolonged progression-free survival and overall survival.Plasma mevalonate levels were positively correlated with programmed death ligand-1(PD-L1)expression in tumor tissues.In NSCLC cell lines and patient-derived cells,supplementation of mevalonate significantly upregulated the expression of PD-L1,whereas deprivation of mevalonate reduced PD-L1 expression.Mevalonate increased CD274 mRNA level but did not affect CD274 transcription.Further,we confirmed that mevalonate improved CD274 mRNA stability.Mevalonate promoted the affinity of the AU-rich elementbinding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA.By in vivo study,we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1,increased the infiltration of CD8^(+)T cells,and improved cytotoxic function of T cells.Collectively,our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody,and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

关键词： Metabolites Mevalonate PD-L1 mRNA stability HuR NSCLC Immune checkpoint blockade

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Exosomal circular RNAs inglioma:coexistenceof opportunitiesand challenges forapplication

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Chinese Medical Journal 2022年第13期135卷 1528-1530页

作者： Xiaoyong Chen Jinyuan Chen Yue Chen honghai You Yuanxiang Lin Zanyi wu Dezhi Kang Chenyu Ding Department of Neurosurgery Neurosurgical Research InstituteThe First Affiliated HospitalFujian Medical UniversityFuzhouFujianChina Department of Ophthalmology The First Affiliated HospitalFujian Medical UniversityFuzhouFujianChina The Graduate School of Fujian Medical University FuzhouFujianChina Fujian Provincial Key Laboratory of Precision Medicine for Cancer The First Affiliated HospitalFujan Medical UniversityFuzhouFujianChina Key Laboratory of Radiation Biology of Fujian Higher Education Instions The First Affiliated HospitalFujian Medical UniversitFuzhouFujianChina Fujian Provincial Insttutes of Brain Disorders and Brain Sciences FuzhouFujianChina Fujian Provincial Clinical Research Center for Neurological Diseases FuzhouFujianChina.

Glioma is the most common primary tumor in the central nervous system.With the help of intercellular communication,glioma cells have the ability to survive in the tumor microenvironment(TME)and make it more suitable.

关键词： glioma tumor circular

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SlMYB72 affects pollen development by regulating autophagy in tomato

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Horticulture Research 2023年第3期10卷 15-27页

作者： Mengbo wu Qiongdan Zhang Guanle wu Lu Zhang Xin Xu Xiaowei Hu Zehao Gong Yulin Chen Zhengguo Li honghai Li Wei Deng Key Laboratory of Plant Hormones and Development Regulation of Chongqing School of Life SciencesChongqing UniversityChongqing 400044China Center of Plant Functional Genomics Institute of Advanced Interdisciplinary StudiesChongqing University401331 ChongqingChina Department of Horticulture and Landscape Architecture Oklahoma State UniversityStillwaterOK 74078USA

The formation and development of pollen are among the most critical processes for reproduction and genetic diversity in the life cycle of f lowering plants.The present study found that SlMYB72 was highly expressed in the pollen and tapetum of tomato f lowers.Downregulation of SlMYB72 led to a decrease in the amounts of seeds due to abnormal pollen development compared with wild-type plants.Downregulation of SlMYB72 delayed tapetum degradation and inhibited autophagy in tomato anther.Overexpression of SlMYB72 led to abnormal pollen development and delayed tapetum degradation.Expression levels of some autophagy-related genes(ATGs)were decreased in SlMYB72 downregulated plants and increased in overexpression plants.SlMYB72 was directly bound to ACCAAC/ACCAAA motif of the SlATG7 promoter and activated its expression.Downregulation of SlATG7 inhibited the autophagy process and tapetum degradation,resulting in abnormal pollen development in tomatoes.These results indicated SlMYB72 affects the tapetum degradation and pollen development by transcriptional activation of SlATG7 and autophagy in tomato anther.The study expands the understanding of the regulation of autophagy by SlMYB72,uncovers the critical role that autophagy plays in pollen development,and provides potential candidate genes for the production of male-sterility in plants.

关键词： expression inhibited autophagy

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Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

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Neuroscience Bulletin 2016年第4期32卷 311-322页

作者： Meng Zhang Jia Liu Meng-Meng Zhou Honghai Wu Yanning Hou Yun-Feng Li Yuxin Yin Lemin Zheng Feng-Yu Liu Ming Yi You Wan Neuroscience Research Institute Peking UniversityBeiiing 100191 China Institute of Systems Biomedicine Peking UniversityBeijing 100191 China Department of Pharmacy Bethune International PeaceHospital Shijiazhuang Shijiazhuang 050082 China Department of New Drug Evaluation Beijing Institute ofPharmacology and Toxicology Beijing 100007 China Institute of Cardiovascular Sciences and Institute of SystemsBiomedicine and Key Laboratory of MolecularCardiovascular Sciences of the Ministry of Education PekingUniversity Beijing 100191 China Key Laboratory for Neuroscience Ministry of Education/National Health and Family Planning Commission School ofBasic Medical Sciences Peking University Beijing 100191China Department of Neurobiology School of Basic MedicalSciences Peking University Beijing 100191 China

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors （GABAARs）, which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-perfor mance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids （pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone） in the chronic stage of neuropathic pain （28 days after spared nerve injury） in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus （AP -3.0 mm, ML 4-3.0 mm, DV 6.0 mm） alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were sig- nificantly attenuated by the GABAAR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

关键词： Neurosteroids Translocator protein Sparednerve injury Thalamus GABAA receptors

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熨平板振动压实特性与摊铺密实度控制方法研究

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振动与冲击 2023年第23期42卷 167-174,191页

作者：罗清云吴平刘洪海贾洁长安大学道路施工技术与装备教育部重点实验室西安710064 内蒙古路桥集团有限责任公司呼和浩特010051

为控制摊铺密实度,针对摊铺机熨平板与铺层材料构成的振动压实系统,将铺层材料对振捣机构的作用力展开为傅里叶级数形式,并考虑振捣器惯性力,建立熨平板在振捣激励和振动激励作用下的振动模型;基于熨平板振动模型,研究了振动频率、压实... 详细信息

为控制摊铺密实度,针对摊铺机熨平板与铺层材料构成的振动压实系统,将铺层材料对振捣机构的作用力展开为傅里叶级数形式,并考虑振捣器惯性力,建立熨平板在振捣激励和振动激励作用下的振动模型;基于熨平板振动模型,研究了振动频率、压实系统固有频率、阻尼比对熨平板振幅影响,建立铺层材料密实度与熨平板振幅的关系模型,提出了铺层材料密实度控制方法,并通过试验验证。研究结果表明:基于振捣器与混合料周期接触分离的熨平板振动模型,得到的熨平板加速度频谱包含由振动频率、振捣频率及其二次谐波分量,仿真结果与现场试验一致;当摊铺材料为AC25,振动频率由10 Hz增至35 Hz,熨平板振幅增大,铺层材料密实度升高;通过调整熨平板振动频率,可实现铺层材料密实度控制,提升路面施工质量。

关键词：道路工程摊铺机熨平板振动模型振幅密实度

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厦门邻近海域海洋环境放射性水平及评价

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应用海洋学学报 2022年第3期41卷 443-453页

作者：崔守信张洪海门武中国海洋大学化学化工学院山东青岛266100 自然资源部第三海洋研究所、海洋放射性技术与环境安全评估实验室福建厦门361005 青岛海洋科学与技术国家实验室、海洋生态与环境科学功能实验室山东青岛266071

良好的环境质量是厦门成为一个宜居和滨海旅游城市的重要基石。自日本福岛核事故发生和福建省核电站陆续运行之后,厦门邻近海域潜在的核污染风险受到公众和管理部门的关注。本研究测定了2015年2月和8月厦门邻近海域海水和海洋沉积物中... 详细信息

良好的环境质量是厦门成为一个宜居和滨海旅游城市的重要基石。自日本福岛核事故发生和福建省核电站陆续运行之后,厦门邻近海域潜在的核污染风险受到公众和管理部门的关注。本研究测定了2015年2月和8月厦门邻近海域海水和海洋沉积物中主要放射性核素的含量水平,并据此评价了该海域的环境放射性质量状况。结果表明海水中总铀、^(90) Sr、^(226) Ra、^(137) Cs处于我国海洋放射性水平变化范围以内,无明显季节差异,其他放射性核素^(58) Co、^(60) Co、^(134) Cs、^(110m) Ag、^(59) Fe、^(54) Mn、^(65) Zn均未检出,海水中^(90) Sr和^(137) Cs的活度最大值远低于国家海水水质标准限值,海洋沉积物中放射性核素活度水平亦在我国海洋放射性水平变化范围以内。利用我国现有的海洋放射性环境质量评价方法对厦门邻近海域放射性质量状况进行分级评价得出其海水放射性质量为2级,海洋沉积物放射性环境质量为1级,均属于安全级别。研究结果表明2015年在厦门附近海域未观测到放射性污染现象。

关键词：海洋环境科学放射性污染环境质量环境评价厦门邻近海域

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基于熨平装置振动特性的摊铺密实度识别技术研究

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振动与冲击 2023年第14期42卷 237-244页

作者：罗清云刘洪海吴平史妍妮长安大学道路施工技术与装备教育部重点实验室西安710064 内蒙古路桥集团有限公司呼和浩特010051

为了检测摊铺层密实度,根据主副振捣器与铺层材料的接触情况,将熨平装置分为四种振动状态,建立了二自由度的振动模型;通过Newmark-β法对模型进行求解,分析了熨平装置质心位移幅值、加速度幅值与熨平板振动器频率、振捣频率、铺层材料... 详细信息

为了检测摊铺层密实度,根据主副振捣器与铺层材料的接触情况,将熨平装置分为四种振动状态,建立了二自由度的振动模型;通过Newmark-β法对模型进行求解,分析了熨平装置质心位移幅值、加速度幅值与熨平板振动器频率、振捣频率、铺层材料特性之间的关系,得出了熨平板加速度频谱图,并进行了相应的试验研究。研究结果表明:基于冲击接触模型得到的熨平装置加速度频谱图,包含了振动器频率、振捣频率及其谐波分量;在熨平装置加速度频谱中,振捣主频与熨平板振动器主频的幅值比随铺层密实度的增加而变大,通过振捣主频与熨平板振动器主频幅值比可实现摊铺密度的在线识别。研究结论可为检测摊铺密实度,提升路面施工质量提供参考。

关键词：道路工程摊铺机熨平装置冲击接触摊铺密实度频谱分析

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