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Inhibition of the immunoproteasome LMP_(2) ameliorates ischemia/hypoxia-induced blood–brain barrier injury through the Wnt/β-catenin signalling pathway

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Military Medical Research 2022年第4期9卷 404-418页

作者： Xing-Yong Chen Shao-Fen Wan Nan-Nan Yao Ze-Jing Lin Yan-Guang Mao Xiao-Hua Yu Yin-Zhou Wang Department of Neurology Fujian Provincial HospitalShengli Clinical Medical College of Fujian Medical UniversityNo.134DongjieGulou DistrictFuzhou 350001China Fujian Academy of Medical Science Fuzhou 350o01China Key Testing Laboratory of Fujian Province Fuzhou 350001China.

Background:Disruption of the blood–brain barrier(BBB)after a stroke can lead to brain injury and neurological *** work confirmed the involvement of the immunoproteasome subunit of low molecular mass peptide 2(LMP2)in the pathophysiology of ischemia ***,the relationship between the immunoproteasome LMP2 and the BBB remains ***:Adult male Sprague–Dawley rats were subjected to transient middle cerebral artery occlusion/reperfusion(MCAO/R).Three days before MCAO,the rats were treated with lentivirus-mediated LMP2 shRNA preparations by stereotactical injection into the ipsilateral hemispheric *** rat brain microvascular endothelial cell(RBMVEC)line was exposed to oxygen–glucose deprivation/reperfusion(OGD/R)to mimic ischemic conditions in *** RNA interference-mediated knockdown of LMP2 orβ-catenin was analysed in vivo and in *** of the quantity of extravasated Evans blue(EB)and cerebral fluorescent angiography were performed to evaluate the integrity of the *** and Western blotting were employed to detect the expression of target *** migration was evaluated using a scratch migration *** results of immunofluorescence,Western blotting and cell migration were quantified using the software ImageJ(Version 1.53).Parametric data from different groups were compared using one-way ANOVA followed by the least significant difference(LSD)***:Cerebral ischemia led to lower levels of structural components of the BBB such as tight junction proteins[occludin,claudin-1 and zonula occludens(ZO-1)]in the MCAO/R group compared with the sham group(Pimmunoproteasome LMP2 restored the expression of these proteins,resulting in higher levels of occludin,claudin-1 and ZO-1 in the LMP2-shRNA group compared with the control-shRNA group(Pimmunoproteasome LMP2 contributed to higher microvascular density and decreased BBB perm

关键词： immunoproteasome Blood–brain barrier Wnt/β-catenin pathway Oxygen–glucose deprivation/reperfusion Cerebral ischemia

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The dichotomous role of immunoproteasome in cancer:Friend or foe?

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Acta Pharmaceutica Sinica B 2023年第5期13卷 1976-1989页

作者： Boya Chen Haiying Zhu Bo Yang Ji Cao Institute of Pharmacology and Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Cancer Center of Zhejiang University Hangzhou 310058China

immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex(MHC)-I *** from this primary function in antigen presentation,immunoproteasome is also responsible for the degradation of proteins,both unfolded proteins for the maintenance of protein homeostasis and tumor suppressor proteins contributing to tumor *** altered expression of immunoproteasome is frequently observed in cancers;however,its expression levels and effects vary among different cancer types exhibiting antagonistic roles in tumor *** review focuses on the dichotomous role of immunoproteasome in different cancer types,as well as summarizes the current progression in immunoproteasome activators and *** targeting immunoproteasome may be a beneficial therapeutic intervention in cancer treatment and understanding the role of immunoproteasome in cancers will provide a significant therapeutic insight for the prevention and treatment of cancers.

关键词： immunoproteasome Ubiquitin—proteasome system Antigenic peptides Proteolysis Cancer Immunotherapy Proteasome inhibitor Targeted therapy

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The role of proteasomes in tumorigenesis

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Genes & Diseases 2024年第4期11卷 155-169页

作者： Xiangyi Zhou Ruqing Xu Yue Wu Li Zhou Tingxiu Xiang Department of Oncology The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this *** proteasome 2os is a concentric circle structure with twoαrings and twoβrings *** proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ*** proteasome can degrade misfolded,excess proteins tomaintain *** the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their *** can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug ***-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer *** addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple *** and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and ***,proteasome inhibitors are not much effective due to their tolerance and singleness in other ***,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

关键词： Bortezomib Cancer therapy immunoproteasome Multiplemyeloma Proteasome 20S Proteasome inhibitor Thymoproteasom

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Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo

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Translational Neurodegeneration 2018年第1期7卷 175-186页

作者： Ming-Shu Mo Gui-Hua Li Cong-Cong Sun Shu-Xuan Huang Lei Wei Li-Min Zhang Miao-Miao Zhou Zhuo-Hua Wu Wen-Yuan Guo Xin-Ling Yang Chao-Jun Chen Shao-Gang Qu Jian-Xing He Ping-Yi Xu Department of Neurology First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120GuangdongChina Department of Neurology Qilu Hospital of Shandong UniversityJinan 250012ShandongChina Department of Neurology First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080GuangdongChina Department of Neurology Second Affiliated Hospital of Xinjiang Medical UniversityUrumchi 830011XinjiangChina Clinic Brain Center Guangzhou Hospital of Integrated Traditional and Western MedicineGuangzhou 510800GuangdongChina Department of Blood Transfusion Fifth Affiliated Hospital Southern Medical UniversityGuangzhou 510900GuangdongChina Department of Thoracic Surgery First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120Guangdong China

Background:Abnormal expression of major histocompatibility complex class I(MHC-I)is increased in dopaminergic(DA)neurons in the substantia nigra(SN)in Parkinson’s disease(PD).Low-molecular-mass protein 7(β5i)is a proteolytic subunit of the immunoproteasome that regulates protein degradation and the MHC pathway in immune ***:In this study,we investigated the role of β5i in DA neurons using a 6-hydroxydopamine(6-OHDA)model in vitro and ***:We showed that 6-OHDA upregulatedβ5i expression in DA neurons in a concentration-and time-dependent *** and downregulation ofβ5i induced the expression of glucose-regulated protein(Bip)and exacerbated 6-OHDA neurotoxicity in DA *** inhibition of β5i further promoted the activation of Caspase 3-related pathways induced by 6-OHDA.β5i also activated transporter associated with antigen processing 1(TAP1)and promoted MHC-I expression on DA ***:Taken together,our data suggest that β5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.

关键词： Parkinson’s disease 6-hydroxydopamine immunoproteasome TAP1

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Mallory-Denk body pathogenesis revisited

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World Journal of Hepatology 2010年第8期2卷 295-301页

作者： Samuel W French Fawzia Bardag-Gorce Barbara A French Joan Oliva Department of Pathology Harbor-UCLA Medical Center

This editorial reviews the recent evidence showing that Mallory-Denk bodies(MDBs)form in hepatocytes as the result of a drug-induced shift from the 26s proteasome formation to the immunoproteasome *** shift is the result of changes in gene expression induced in promoter activation,which is induced by the IFNγ and TNFa signaling *** activates TLR 2 and 4 *** TLR signaling pathway stimulates both the induction of a cytokine proinflammatory response and an up regulation of growth *** MDB-forming hepatocytes proliferate as a result of the increase in growth factor expression by the MDBforming cells,which selectively proliferate in response to drug *** of these mechanisms are induced by drug toxicity,and are prevented by feeding the methyl donors SAMe and betaine,supporting the epigenetic response of MDB formation.

关键词： Toll-like receptor Proinflammatory Methyl donors Epigenetic processes Drug toxicity 26s Proteasome immunoproteasome

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Proteasomal adaptations to FDA-approved proteasome inhibitors:a potential mechanism for drug resistance?

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Cancer Drug Resistance 2021年第3期4卷 634-645页

作者： Kyung Bo Kim Department of Pharmaceutics College of PharmacyUniversity of KentuckyLexingtonKY 40536-0596USA

With proteasome inhibitors(PIs)becoming clinically available since 2003,outcomes for patients with multiple myeloma(MM)have dramatically changed,improving quality of life and *** the impressive treatment success,however,almost all MM patients who initially respond to these PIs eventually develop ***,a portion of MM patients is inherently unresponsive to the *** mechanistic investigations identified several non-proteasomal signaling pathways suspected to be linked to the PI resistance,for which several excellent reviews are currently *** the other hand,it is still unclear how cancer cells under high PI environments adapt to spare proteasome activity essential for survival and proliferation regardless of cancer evolution *** review outlines current progress towards understanding the proteasomal adaptations of cells in response to PI treatment to maintain necessary proteasome activity.A better understanding of cellular proteasomal changes in response to the PIs could provide a rationale to develop new therapeutics that could be used to overcome resistance to existing PI drugs.

关键词： Constitutive proteasome immunoproteasome carfilzomib bortezomib drug resistance

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