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Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52

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Journal of Pharmaceutical Analysis 2024年第1期14卷 86-99页

作者： Shengyou Li Xue Gao Yi Zheng Yujie Yang Jianbo Gao Dan Geng Lingli Guo Teng Ma Yiming Hao Bin Wei Liangliang Huang Yitao Wei Bing Xia Zhuojing Luo Jinghui Huang Department of Orthopedics Xijing HospitalFourth Military Medical UniversityXi'an710032China

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

关键词： Ferroptosis UBA52 Ferroportin Ubiquitination Hydralazine Peripheral nerve injury

Translocation of telomerase reverse transcriptase coincided with ATP release in postnatal cochlear supporting cells

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Neural Regeneration Research 2024年第5期19卷 1119-1125页

作者： Yukai Zhang Keyong Tian Wei Wei Wenjuan Mi Fei Lu Zhenzhen Liu Qingwen Zhu Xinyu Zhang Panling Geng Jianhua Qiu Yongli Song Dingjun Zha Department of Otolaryngology Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina

The spontaneous bursts of electrical activity in the developing auditory system are derived from the periodic release of adenosine triphosphate(ATP)by supporting cells in the Kölliker’s ***,the mechanisms responsible for initiating spontaneous ATP release have not been *** previous study revealed that telomerase reverse transcriptase(TERT)is expressed in the basilar membrane during the first postnatal *** role in cochlear development remains *** this study,we investigated the expression and role of TERT in postnatal cochlea supporting *** results revealed that in postnatal cochlear Kölliker’s organ supporting cells,TERT shifts from the nucleus into the cytoplasm over *** found that the TERT translocation tendency in postnatal cochlear supporting cells in vitro coincided with that observed in *** analysis showed that TERT in the cytoplasm was mainly located in mitochondria in the absence of oxidative stress or apoptosis,suggesting that TERT in mitochondria plays roles other than antioxidant or anti-apoptotic *** observed increased ATP synthesis,release and activation of purine signaling systems in supporting cells during the first 10 postnatal *** phenomenon that TERT translocation coincided with changes in ATP synthesis,release and activation of the purine signaling system in postnatal cochlear supporting cells suggested that TERT may be involved in regulating ATP release and activation of the purine signaling *** study provides a new research direction for exploring the spontaneous electrical activity of the cochlea during the early postnatal period.

关键词： apoptosis ATP release Ca2+transients cochlea mitochondrial function reactive oxygen species spontaneous electrical activity supporting cells

ADAR1 Inhibits Macrophage Apoptosis and Alleviates Sepsis-induced Liver Injury Through miR-122/BCL2A1 Signaling

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Journal of Clinical and Translational Hepatology 2024年第2期12卷 134-150页

作者： Shanshou Liu Jiangang Xie Chujun Duan Xiaojun Zhao Zhusheng Feng Zheng Dai Xu Luo Yu Li Minghe Yang Ran Zhuang Junjie Li Wen Yin Emergency Department Xijing HospitalFourth Military Medical UniversityXi’anShaanxiChina Emergency Department Tangdu HospitalFourth Military Medical UniversityXi’anShaanxiChina Third Student Brigade School of Basic Medical ScienceFourth Military Medical UniversityXi’anShaanxiChina Department of Immunology Fourth Military Medical UniversityXi’anShaanxiChina

apoptosis plays regulatory roles in the pathogenesis of immunosuppression and organ *** previously reported that adenosine deaminases acting on RNA-1(ADAR1)reduced intestinal and splenic inflammatory damage during ***,the roles and mechanism of ADAR1 in sepsis-induced liver injury remain ***:We performed transcriptome and single-cell RNA sequencing of peripheral blood mononuclear cells(PBMCs)from patients with sepsis to investigate the effects of ADAR1 on immune cell *** also employed a cecal ligation and puncture(CLP)sepsis mouse model to evaluate the roles of ADAR1 in sepsisinduced liver ***,we treated murine RAW 264.7 macrophages with lipopolysaccharide to explore the underlying ADAR1-mediated mechanisms in ***:PBMCs from patients with sepsis had obvious apoptotic morphological ***-cell RNA sequencing indicated that apoptosis-related pathways were enriched in monocytes,with significantly elevated ADAR1 and BCL2A1 expression in severe ***-induced septic mice had aggravated liver injury and Kupffer cell apoptosis that were largely alleviated by ADAR1 ***1 directly bound to premiR-122 to modulate miR-122 ***-122 was an upstream regulator of ***,ADAR1 also reduced macrophage apoptosis in mice with CLP-induced sepsis through the miR-122/BCL2A1 signaling pathway and protected against sepsis-induced liver ***:The findings show that ADAR1 alleviates macrophage apoptosis and sepsis-induced liver damage through the miR-122/BCL2A1 signaling *** study provides novel insights into the development of therapeutic interventions in sepsis.

关键词： Sepsis Macrophage ADAR1 microRNA122 BCL2A1 Apoptosis

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice

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Neuroscience Bulletin 2024年第1期40卷 35-49页

作者： Shuhui Dai Yuan Feng Chuanhao Lu Hongchen Zhang Wenke Ma Wenyu Xie Xiuquan Wu Peng Luo Lei Zhang Fei Fei Zhou Fei Xia Li Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi'an 710000China National Translational Science Center for Molecular Medicine and Department of Cell Biology Fourth Military Medical UniversityXi'an 710000China Department of Neurosurgery The Central Hospital of BaojiBaoji 721000China Department of Ophthalmology Xijing HospitalFourth Military Medical UniversityXi'an 710000China

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude *** plays a critical role in ischemic brain injury,but its role in hypo-baric hypoxia(HH)remains *** we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain,and is partially responsible for HH-induced oxidative stress,neuronal loss,and brain *** autophagic agonist rapamycin only promotes the initiation of *** proteome analysis,a screen showed that protein dynamin2(DNM2)potentially regulates autophagic *** of DNM2 significantly increased the formation of autolysosomes,thus maintaining autophagic flux in combination with ***,the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH *** results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

关键词： Autophagy-Proteomics Oxidative stress Hypobaric hypoxia-Brain injury

IGF2BPs as novel m^(6)A readers:Diverse roles in regulating cancer cell biological functions,hypoxia adaptation,metabolism,and immunosuppressive tumor microenvironment

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Genes & Diseases 2024年第2期11卷 890-920页

作者： Meiqi Duan Haiyang Liu Shasha Xu Zhi Yang Fusheng Zhang Guang Wang Yutian Wang Shan Zhao Xiaofeng Jiang Department of General Surgery The Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoning 110032China Department of Gastroendoscopy The Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoning 110032China Department of Rheumatology and Immunology The First Affiliated Hospital of China Medical UniversityShenyangLiaoning 110002China

m^(6)A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role in cancer progression by regulating biological ***-like growth factor 2 mRNA-binding proteins(IGF2BP)are newly identified m^(6)A‘readers’.They belong to a family of RNA-binding proteins,which bind to the m^(6)A sites on different RNA sequences and stabilize them to promote cancer *** this review,we summarize the mechanisms by which different upstream factors regulate IGF2BP in *** current literature analyzed here reveals that the IGF2BP family proteins promote cancer cell proliferation,survival,and chemoresistance,inhibit apoptosis,and are also associated with cancer glycolysis,angiogenesis,and the immune response in the tumor ***,with the discovery of their role as‘readers’of m^(6)A and the characteristic re-expression of IGF2BPs in cancers,it is important to elucidate their mechanism of action in the immunosuppressive tumor *** also describe in detail the regulatory and interaction network of the IGF2BP family in downstream target RNAs and discuss their potential clinical applications as diagnostic and prognostic markers,as well as recent advances in IGF2BP biology and associated therapeutic value.

关键词： Cancer IGF2BP Immunosuppressive TME m^(6)A Molecular mechanism Therapy

Establishment of NaLuF_(4):15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy

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International Journal of Minerals,Metallurgy and Materials 2024年第3期31卷 599-610页

作者： Yi Tian Zhiguang Fu Xiaosheng Zhu Chunjing Zhan Jinwei Hu Li Fan Chaojun Song Qian Yang Yu Wang Mei Shi Department of Radiation Oncology Xijing HospitalThe Fourth Military Medical UniversityXi’an 710032China Department of Oncology Air Force Medical CenterPLAThe Fourth Military Medical UniversityBeijing 100142China Department of Tumor Radiotherapy Air Force Medical CenterPLAThe Fourth Military Medical UniversityBeijing 100142China Department of Gastroenterology Air Force Hospital of Southern Theater CommandGuangzhou 510062China Department of Pharmaceutical Chemistry and Analysis School of PharmacyThe Fourth Military Medical UniversityXi’an 710032China School of Life Sciences Northwestern Polytechnical UniversityXi’an 710072China Institue of Materia Medica School of PharmacyThe Fourth Military Medical UniversityXi’an 710032China

X-ray excited photodynamic therapy(X-PDT)is the bravo answer of photodynamic therapy(PDT)for deep-seated tumors,as it employs X-ray as the irradiation source to overcome the limitation of light penetration ***,high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT *** address this issue,this work employed a classic-al co-precipitation reaction to synthesize NaLuF_(4):15%Tb^(3+)(NLF)with an average particle size of(23.48±0.91)nm,which was then coupled with the photosensitizer merocyanine 540(MC540)to form the X-PDT system NLF-MC540 with high production of singlet *** system could induce antitumor efficacy to about 24%in relative low dose X-ray irradiation range(0.1-0.3 Gy).In vivo,when NLF-MC540 irradiated by 0.1 Gy X-ray,the tumor inhibition percentage reached 89.5%±5.7%.The therapeutic mechanism of low dose X-PDT was found.A significant increase of neutrophils in serum was found on the third day after *** immunohistochemical staining of tumor sections,the Ly6G^(+),CD8^(+),and CD11c^(+)cells infiltrated in the tumor microenvironment were *** the bilat-eral tumor model,the NLF-MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor ***-tected by enzyme linked immunosorbent assay(ELISA),two cytokines IFN-γand TNF-αin serum were upregulated 7 and 6 times than negative control,*** by enzyme linked immune spot assay(ELISPOT),the number of immune cells attributable to the IFN-γand TNF-αlevels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group,***,it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells,stimulate the secretion of cy-tokines(especially IFN-γand TNF-α),activate antitumor immunity,and finally inhibit colon tumor growth.

关键词： X-ray excited photodynamic therapy singlet oxygen low dose X-Ray irradiation efficient antitumor therapy anti-tumor immunity

Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway

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Neural Regeneration Research 2024年第1期19卷 180-189页

作者： Zhihao Zhang Zhiwen Song Liang Luo Zhijie Zhu Xiaoshuang Zuo Cheng Ju Xuankang Wang Yangguang Ma Tingyu Wu Zhou Yao Jie Zhou Beiyu Chen Tan Ding Zhe Wang Xueyu Hu Department of Orthopedics Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina

Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury *** cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous *** proteins are thus candidate targets for spinal cord injury *** previous studies demonstrated that 810 nm photo biomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model ***,the specific mechanism and potential targets involved remain to be *** this study,to investigate the therapeutic effect of photo biomodulation,we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm~2 for 50 minutes once a day for 7 consecutive *** found that photobiomodulation greatly restored motor function in mice and down regulated chondroitin sulfate proteoglycan expression in the injured spinal *** analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury,and versican,a type of proteoglycan,was one of the most markedly changed *** staining showed that after spinal cord injury,versican was present in astrocytes in spinal cord *** expression of versican in primary astrocytes cultured in vitro increased after inflammation induction,whereas photobiomodulation inhibited the expression of ve ***,we found that the increased levels of p-Smad3,p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204,(E)-SIS3,and SB *** suggests that Sma d 3/Sox9 and MAP K/Sox9 pathways may be involved in the effects of photobiomodulatio

关键词： chondroitin sulfate proteoglycans Erk MAPK P38 photobiomodulation principal component analysis Smad3 Sox9 spinal cord injury versican

Promising prognostic value of ATP binding cassette transporters and their correlation with tumor-infiltrating immune cells in lung adenocarcinoma

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Genes & Diseases 2024年第5期11卷 91-93页

作者： Linzi Wei Qian Yu Xueying Yang Department of Thoracic Surgery The Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoning 110032China

Lung cancer(LC)is a prevalent and fatal malignancy,with high incidence and mortality rates.1 ATP binding cassette(ABC)transporters,a superfamily of integral membrane proteins,use ATP hydrolysis to facilitate substrate transport across cellular membranes.2 The pivotal role of ABC transporters in tumorigenesis was initially established by Mochida,3 who demonstrated that the loss of ABCB1 suppresses intestinal polyp formation and tumor progression in *** investigations have reported correlations between ABC transporters and the tumor microenvironment and cancer immunotherapy response,suggesting their modulatory effects on tumor progression and immunotherapy.

关键词： mortality adenocarcinoma Lung

A new era of mutation rate analyses: Concepts and methods

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Zoological Research 2024年第4期45卷 767-780页

作者： Kun Wu Danqi Qin Yang Qian Haoxuan Liu Center for Evolutionary&Organismal Biology and the fourth Affiliated hospital of Zhejiang university Zhejiang University School of MedicineHangzhouZhejiang 310058China

The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable *** advances in high-throughput sequencing and analytical methodologies have profoundly transformed our understanding in this domain,ushering in an unprecedented era of mutation rate *** paper aims to provide a comprehensive overview of the key concepts and methodologies frequently employed in the study of mutation *** examines various types of mutations,explores the evolutionary dynamics and associated theories,and synthesizes both classical and contemporary ***,this review comprehensively explores recent advances in understanding germline and somatic mutations in animals and offers an overview of experimental methodologies,mutational patterns,molecular mechanisms,and driving forces influencing variations in mutation rates across species and ***,it proposes several potential research directions and pressing questions for future investigations.

关键词： Mutation rate Somatic mutations Germline mutations Animal