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Hydrogen sulfide reduces oxidative stress in Huntington's disease via Nrf2

Neural Regeneration Research 2025年第6期20卷 1776-1788页

作者： Zige Jiang Dexiang Liu Tingting Li Chengcheng Gai Danqing Xin Yijing Zhao Yan Song Yahong Cheng Tong Li Zhen Wang Department of Physiology School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanShandong ProvinceChina Department of medical Psychology and Ethics School of Basic Medicine SciencesCheeloo College of MedicineShandong UniversityJinanShandong ProvinceChina Department of Neurosurgery Surgery Qingdao Municipal HospitalQingdaoShandong ProvinceChina

The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.

关键词： apoptosis cystathionine-β-synthase nuclear factor erythroid 2-related factor 2 Huntington's disease hydrogen sulfide mitochondrion neuroplasticity oxidative stress quinolinic acid reactive oxygen species

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CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system

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Neural Regeneration Research 2025年第8期20卷 2420-2432页

作者： Lin Yin Yalan Xu Jie Mu Yu Leng Lei Ma Yu Zheng Ruizhi Li Yin Wang Peifeng Li Hai Zhu Dong Wang Jing Li Institute for Translational Medicine The Affiliated Hospital of Qingdao UniversityMedical CollegeQingdao UniversityQingdaoShandong ProvinceChina School of Basic Medicine Qingdao UniversityQingdaoShandong ProvinceChina college of Life Sciences and School of PharmacyMedical CollegeQingdao UniversityQingdaoShandong ProvinceChina Department of Urology Qingdao Municipal Hospital Affiliated to Qingdao UniversityQingdaoShandong ProvinceChina

The protein connector enhancer of kinase suppressor of Ras 2(CNKSR2),present in both the postsynaptic density and cytoplasm of neurons,is a scaffolding protein with several protein-binding *** of the CNKSR2 gene have been implicated in neurodevelopmental disorders,particularly intellectual disability,although the precise mechanism involved has not yet been fully *** has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane,thereby influencing synaptic signaling and the morphogenesis of dendritic ***,the function of CNKSR2 in the cytoplasm remains to be *** this study,we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of *** a combination of bioinformatic analysis and cytological experiments,we found that the CNKSR2 interactors were significantly enriched in the proteome of the *** also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker *** colocalization analysis confirmed the centrosomal localization of *** we downregulated CNKSR2 expression in mouse neuroblastoma cells(Neuro 2A),we observed significant changes in the expression of numerous centrosomal *** manipulation also affected centrosome-related functions,including cell size and shape,cell proliferation,and ***,we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum *** findings establish a connection between CNKSR2 and the centrosome,and offer new insights into the underlying mechanisms of neurodevelopmental disorders.

关键词： autism spectrum disorder centrosome CNKSR2 intellectual disability interactome mass spectrometry microtubule neurodevelopmental disease protein complexes protein-protein interactions

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Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondrial metabolism in immune thrombocytopenia

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Cellular & Molecular Immunology 2022年第7期19卷 764-776页

作者： Yu Hou Jie Xie Shuwen Wang Daqi Li Lingjun Wang Haoyi Wang Xiaofei Ni Shaoqiu Leng Guosheng Li Ming Hou Jun Peng Department of Hematology Qilu HospitalCheeloo College of MedicineShandong UniversityJinanChina shandong Provincial Key Laboratory of Immunohematology Qilu HospitalCheeloo College of MedicineShandong UniversityJinanChina Jinan Central Hospital Cheeloo College of MedicineShandong UniversityJinanChina Leading Research Group of Scientific Innovation Department of Science and Technology of Shandong ProvinceQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina Advanced medical Research Institute Shandong UniversityJinanChina

Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive *** metabolic changes in MDSCs exert a direct immunological influence on their suppressive *** previous study demonstrated that high-dose dexamethasone(HD-DXM)corrected the functional impairment of MDSCs in immune thrombocytopenia(ITP);however,the MDSC population was not restored in nonresponders,and the mechanism remained *** this study,altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders,accompanied by decreased levels of carnitine palmitoyltransferase-1(CPT-1),a rate-limiting enzyme in fatty acid oxidation(FAO).Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM *** also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor(GR),which can translocate into mitochondria to regulate the transcription of mitochondrial DNA(mtDNA)as well as the level of oxidative *** was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine ***,by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs,we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with *** conclusion,our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.

关键词： immune thrombocytopenia myeloid-derived suppressor cell HD-DXM glucocorticoid receptor

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Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2021年第6期16卷 1044-1051页

作者： Zi-Qi Shao Shan-Shan Dou Jun-Ge Zhu Hui-Qing Wang Chun-Mei Wang Bao-Hua Cheng Bo Bai cheeloo college of Medicine Shandong UniversityJinanShandong ProvinceChina Neurobiology Institute Jining Medical UniversityJiningShandong ProvinceChina

Apelin-13 is a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor,and it may be neuroprotective against cerebral ischemia ***,the precise mechanisms of the effects of apelin-13 remain to be *** investigate the effects of apelin-13 on apoptosis and autophagy in models of cerebral ischemia/reperfusion injury,a rat model was established by middle cerebral artery ***-13(50μg/kg)was injected into the right ventricle as a *** addition,an SH-SY5Y cell model was established by oxygen-glucose deprivation/reperfusion,with cells first cultured in sugar-free medium with 95%N2 and 5%CO2 for 4 hours and then cultured in a normal environment with sugar-containing medium for 5 *** SH-SY5Y cell model was treated with 10-7 M apelin-13 for 5 *** showed that apelin-13 protected against cerebral ischemia/reperfusion ***-13 treatment alleviated neuronal apoptosis by increasing the ratio of Bcl-2/Bax and significantly decreasing cleaved caspase-3 *** addition,apelin-13 significantly inhibited excessive autophagy by regulating the expression of LC3B,p62,and ***,the expression of Bcl-2 and the phosphatidylinositol-3-kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR)pathway was markedly *** LY294002(20μM)and rapamycin(500 nM),which are inhibitors of the PI3K/Akt/mTOR pathway,significantly attenuated the inhibition of autophagy and apoptosis caused by *** conclusion,the findings of the present study suggest that Bcl-2 upregulation and mTOR signaling pathway activation lead to the inhibition of apoptosis and excessive *** effects are involved in apelin-13-induced neuroprotection against cerebral ischemia/reperfusion injury,both in vivo and in *** study was approved by the Animal Ethical and Welfare Committee of Jining medical university,China(approval No.2018-JS-001)in February 2018.

关键词： central nervous system brain brain injury factor pathways apoptosis autophagy neuroprotection regeneration

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The delivery of miR-21a-5p by extracellular vesicles induces microglial polarization via the STAT3 pathway following hypoxia-ischemia in neonatal mice

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Neural Regeneration Research 2022年第10期17卷 2238-2246页

作者： Dan-Qing Xin Yi-Jing Zhao Ting-Ting Li Hong-Fei Ke Cheng-Cheng Gai Xiao-Fan Guo Wen-Qiang Chen De-Xiang Liu Zhen Wang Department of Physiology School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanShandong ProvinceChina Department of Neurology Loma Linda University HealthLoma LindaCAUSA Department of Cardiology Qilu HospitalCheeloo College of MedicineShandong UniversityJinanShandong ProvinceChina Department of medical Psychology and Ethics School of Basic Medicine SciencesCheeloo College of MedicineShandong UniversityJinanShandong ProvinceChina

Extracellular vesicles(EVs)from mesenchymal stromal cells(MSCs)have previously been shown to protect against brain injury caused by hypoxia-ischemia(HI).The neuroprotective effects have been found to relate to the anti-inflammatory effects of ***,the underlying mechanisms have not previously been *** this study,we induced oxygen-glucose deprivation in BV-2 cells(a microglia cell line),which mimics HI in vitro,and found that treatment with MSCs-EVs increased the cell *** treatment was also found to reduce the expression of pro-inflammatory cytokines,induce the polarization of microglia towards the M2 phenotype,and suppress the phosphorylation of selective signal transducer and activator of transcription 3(STAT3)in the *** results were also obtained in vivo using neonatal mice with induced *** investigated the potential role of miR-21a-5p in mediating these effects,as it is the most highly expressed miRNA in MSCs-EVs and interacts with the STAT3 *** found that treatment with MSCs-EVs increased the levels of miR-21a-5p in BV-2 cells,which had been lowered following oxygen-glucose *** the level of miR-21a-5p in the MSCs-EVs was reduced,the effects on microglial polarization and STAT3 phosphorylation were reduced,for both the in vitro and in vivo HI *** results indicate that MSCs-EVs attenuate HI brain injury in neonatal mice by shuttling miR-21a-5p,which induces microglial M2 polarization by targeting STAT3.

关键词： extracellular vesicles hypoxia-ischemia mesenchymal stromal cells microglia miR-21a-5p neuroinflammation oxygen-glucose deprivation STAT3

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Diagnostic value of amygdala volume on structural magnetic resonance imaging in Alzheimer’s disease

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World Journal of Clinical Cases 2021年第18期9卷 4627-4636页

作者： De-Wei Wang Shou-Luan Ding Xian-Li Bian Shi-Yue Zhou Hui Yang Ping Wang Department of Neurology The Second HospitalCheeloo College of MedicineShandong UniversityJinan 250033Shandong ProvinceChina Center for Evidence-Based Medicine Institute of Medical SciencesThe Second HospitalCheeloo College of MedicineShandong UniversityJinan 250033Shandong ProvinceChina cheeloo college of Medicine Shandong UniversityJinan 250012Shandong ProvinceChina

BACKGROUND The main clinical manifestation of Alzheimer’s disease(AD)is memory loss,which can be accompanied by neuropsychiatric symptoms at different stages of the *** is closely related to emotion and *** To evaluate the diagnostic value of amygdala on structural magnetic resonance imaging(sMRI)for *** In this study,22 patients with AD and 26 controls were *** amygdala volumes were measured by sMRI and analyzed using an automatic analysis *** The bilateral amygdala volumes of AD patients were significantly lower than those of the controls and were positively correlated with the hippocampal *** operating characteristic curve analyses showed that the sensitivity of the left and right amygdala volumes in diagnosing AD was 80.8%and 88.5%,*** analyses showed that amygdala atrophy was more serious in AD patients with neuropsychiatric symptoms,which mainly included irritability(22.73%),sleep difficulties(22.73%),apathy(18.18%),and hallucination(13.64%).CONCLUSION Amygdala volumes measured by sMRI can be used to diagnose AD,and amygdala atrophy is more serious in patients with neuropsychiatric symptoms.

关键词： Alzheimer’s disease Amygdala Structural magnetic resonance imaging Neuropsychiatric symptoms

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Anti-inflammatory mechanism of rhein in treating asthma based on network pharmacology

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Journal of Traditional Chinese Medicine 2022年第2期42卷 296-303页

作者： FENG Junfang CHEN Ou WANG Yibiao Department of Pediatrics the Second HospitalCheeloo College of MedicineShandong UniversityJinan 250033China School of Nursing Cheeloo College of MedicineShandong UniversityJinan 250012China

OBJECTIVE:To predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma by using network pharmacology,and to further explore its potential mechanism in ***:The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),and the rhein-target network was constructed with Cytoscape 3.7.1 *** Genbank and Drugbank databases were used to collect and screen asthma targets,and the rhein-target-disease interaction network was constructed.A target protein-protein interaction(PPI)network was constructed using the STRING database to screen key ***,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis was used to identify biological processes and signaling *** anti-asthmatic effects of rhein were tested in vitro,and the expression levels of proteins in the mitogen-activated protein kinase/nuclear factor kappa-B(MAPK/NF-κB)signaling pathway were assessed by western blot ***:Altogether,83 targets of rhein were screened in the relevant databases,989 targets of asthma were obtained in the National Center for Biotechnology Information(NCBI)GENE *** network analysis and KEGG pathway enrichment analysis predicted that rhein could regulate the epidermal active growth factor receptor(EGFR),mitogen-activated protein kinase 14(MAPK14),tumour necrosis factor receptor superfamily member 1A(TNFRSF1A),receptor tyrosineprotein kinase erb B-2(ERBB2),and other signaling ***,we selected the MAPK signaling pathway to determine the anti-inflammatory effects of ***,further in vitro experiments demonstrated that rhein was shown to inhibit HBE cells ***:The anti-inflammatory mechanism of rhein in the treatment of asthma may be related to EGFR,MAPK14,TNFRSF1A and ERBB2 as well as their signaling *** prevent the exacerbation of asthma,instead of targeting a

关键词： asthma rhein anti-inflammatory agents pharmacology drug development

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Near-perfect replication on amorphous alloys through active force modulation based on machine learning/neural network parameter prediction

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Science China(Physics,Mechanics & Astronomy) 2025年第1期Mechanics & Astronomy) .卷 181-191页

作者： Senkuan Meng Zheng Wang Ruisong Zhu Ruijie Liu Jiang Ma Lina Hu Weihua Wang Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials (Ministry of Education) School of Materials Science and Engineering Shandong University college of Mechatronics and Control Engineering Shenzhen University Songshan Lake Materials Laboratory Institute of Physics Chinese Academy of Sciences

As a microforming technique, micro/nano-structural replication possesses advantages of high precision and efficiency. With the remarkable superplasticity in the supercooled liquid region, amorphous alloys or metallic glasses(MGs) are regarded as ideal materials for miniature fabrication. However, due to the intrinsic metastable nature of supercooled liquids, the design of imprinting processes for MGs poses a challenge. In the past, process parameters have largely relied on trial-and-error *** this work, a low-frequency active force modulation system is employed to apply a stable, precise, and real-time feedback stress field for imprinting of MG samples. Low-frequency vibrations can facilitate the filling of microstructures on the template surface by reducing the effective viscosity of the supercooled liquid. With the dataset composed of orthogonal experiments, a machine learning strategy based on back-propagation(BP) neural networks was utilized to construct a 3D parameter space for temperature, stress, and time, and to predict the corresponding filling ratio. Furthermore, the optimal combination of imprinting process parameters was identified, and its filling ratio was experimentally validated to reach as high as 0.94. The near-perfect replication of microstructures confirms the superiority of the active force modulation system and the data-driven strategy of machine learning-assisted parameter design. At the same time, this one-step microforming process provides a new approach to addressing the accuracy-cost trade-off dilemma in precision manufacturing.

关键词： metallic glass amorphous alloy microforming imprinting machine learning

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Immunotherapy combined with antiangiogenic agents in patients with advanced malignant pleural mesothelioma: A case report

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World Journal of Clinical Cases 2022年第23期10卷 8284-8290页

作者： Tian-Tian Xuan Guang-Yi Li Si-Bo Meng Zhan-Mei Wang Lin-Li Qu Department of medical Oncology Qilu Hospital(Qingdao)Cheeloo College of MedicineShandong UniversityQingdao 266035Shandong ProvinceChina Department of Respiratory Qilu Hospital(Qingdao)Cheeloo College of MedicineShandong UniversityQingdao 266035Shandong ProvinceChina

BACKGROUND Malignant pleural mesothelioma has limited therapeutic options and a poor outcome. Antiangiogenic agents might increase the efficacy of immunotherapy as second-line treatment of advanced-stage *** SUMMARY A patient with stage ⅢB pleural mesothelioma received second-line treatment with a combination of pembrolizumab, bevacizumab and chemotherapy following standard chemotherapy under the guidance of second-generation sequencing. He achieved a partial response after four cycles of treatment with progression-free survival of 5 mo. Pembrolizumab was suspended due to grade 2 immunerelated pneumonia, which was resolved by oral ***, disease progression was observed after immunotherapy rechallenge and anlotinib therapy. The patient had disease progression, multiorgan dysfuntion and died suddenly in October *** The combination of immune checkpoint inhibitor, anti-angiogenic agents and chemotherapy showed effective response for advanced pleural mesothelioma, but with adverse reactions.

关键词： Pleural mesothelioma Immune checkpoint inhibitor Next-generation Sequencing Immunerelated pneumonia Immunotherapy rechallenge Case report

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Regenerative antibacterial hydrogels from medicinal molecule for diabetic wound repair

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Bioactive Materials 2023年第7期25卷 541-554页

作者： Chunxiao Chai Pengfei Zhang Lin Ma Qi Fan Zhicheng Liu Xiang Cheng Yunpeng Zhao Weiwei Li Jingcheng Hao Key Laboratory of Colloid and Interface Chemistry(shandong university) Ministry of EducationJinan250100PR China Department of Orthopaedic Surgery Qilu HospitalCheeloo College of MedicineShandong UniversityJinan250012PR China cheeloo college of Medicine Shandong UniversityJinan250012PR China Department of Pathology Qilu HospitalCheeloo College of MedicineShandong UniversityJinan250012PR China Laboratory of Basic medical Sciences Qilu HospitalCheeloo College of MedicineShandong UniversityJinan250012PR China

Hydrogel products for chronic diabetic wounds,a serious and prevalent complication of diabetes,show limited effects on disability and remain ***,improvements in the usage of pharmaceutical molecule in the hydrogels are highly desirable to increase the therapeutic effect of *** this study,thioctic acid(a common medicine molecule in diabetes treatment)is used for preparing regenerative antibacterial hydrogels(RAH)which contains in situ synthesized silver nanoparticles(AgNPs).The RAH shows regenerative,self-healing and injectable ability,because of the reversible hydrogen and coordination *** good regenerative capacity,RAH can be stored as powder to avoid the water loss and facilitate storage *** to the antioxidant properties of thioctic acid,the RAH can decrease the oxidative damage and retain cell proliferation *** to the in situ synthesized AgNPs,the RAH also exhibits extraordinary antimicrobial capacities against MDR *** of these superiorities enable RAH to be a promising therapy for chronic diabetic wounds.

关键词： Diabetic wound healing Antibacterial hydrogel Thioctic acid Antioxidant Regeneration

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