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Role of copper in central nervous system physiology and pathology

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Neural Regeneration Research 2025年第4期20卷 1058-1068页

作者： Martina Locatelli Cinthia Farina Institute of experimental Neurology Division of NeuroscienceIstituto di Ricovero e Cura a Carattere Scientifico(IRCCS)San Raffaele Scientific InstituteMilanItaly Vita-Salute San Raffaele University MilanItaly

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous *** copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple *** review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper ***,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

关键词： astrocytes central nervous system copper cuprizone multiple sclerosis myelin neurodegenerative disorders

Small heat shock protein B8:from cell functions to its involvement in diseases and potential therapeutic applications

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Neural Regeneration Research 2025年第10期20卷 2872-2886页

作者： Marta Chierichetti Riccardo Cristofani Valeria Crippa Veronica Ferrari Marta Cozzi Elena Casarotto Paola Pramaggiore Laura Cornaggia Guglielmo Patelli Ali Mohamed Margherita Piccolella Mariarita Galbiati Paola Rusmini Barbara Tedesco Angelo Poletti Laboratory of experimental Biology Dipartimento di Scienze Farmacologiche e Biomolecolari“Rodolfo Paoletti”(DiSFeB)Universitàdegli Studi di MilanoMilanItaly

Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock ***8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and ***8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective *** line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and *** cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under ***,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar *** note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other *** is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial *** review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its ***-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.

关键词： aggregation autophagy cancer chaperone chaperone-assisted selective autophagy cognitive impairment HSPB8 neuroinflammation neuromuscular diseases therapy

RhoA and Cdc42 in T cells:Are they targetable for T cell-mediated inflammatory diseases?

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Precision Clinical Medicine 2021年第1期4卷 56-61页

作者： Fukun Guo division of experimental hematology and Cancer Biology Children’s Hospital Medical CenterCincinnatiOH 45229USA

Many inflammatory diseases are not curable,necessitating a better understanding of their pathobiology that may help identify novel biological *** and Cdc42 of Rho family small GTPases regulate a variety of cellular functions such as actin cytoskeletal organization,cell adhesion,migration,proliferation,and *** characterization of mouse models of conditional gene knockout of RhoA and Cdc42 has revealed their physiological and cell type-specific roles in a number of cell *** T lymphocytes,which play an important role in the pathogenesis of most,if not all,of the inflammatory diseases,we and others have investigated the effects of T cell-specific knockout of RhoA and Cdc42 on T cell development in the thymus,peripheral T cell homeostasis,activation,and differentiation to effector and regulatory T cells,and on T cell-mediated allergic airway inflammation and *** we highlight the phenotypes resulting from RhoA and Cdc42 deletion in T cells and discuss whether pharmacological targeting of RhoA and Cdc42 is feasible in treating asthma that is driven by allergic airway inflammation and colitis.

关键词： RhoA Cdc42 T cells allergic airway inflammation colitis

Targeted cytokine delivery:cell therapy to remodel the pre-metastatic niche

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Signal Transduction and Targeted Therapy 2021年第8期6卷 2278-2279页

作者： Michael A.Morgan Lucas Lange Axel Schambach Institute of experimental hematology Hannover Medical SchoolHannoverGermany REBIRTH Research Center for Translational Regenerative Medicine Hannover Medical SchoolHannoverGermany division of hematology/Oncology Boston Children’s HospitalHarvard Medical SchoolBostonMAUSA

Tumor metastases present an often difficult to treat therapeutic challenge for cancer patients and their *** recent paper by the Kaplan group(Kaczanowska et al.)exploited the natural capacity of monocytes or a subset of monocytes to migrate to tumor sites and pre-metastatic niches to deliver IL-12 in a novel anticancer approach designed to stimulate local immune responses.1 This raises the possibility to simultaneously fight cancer on at least two critical fronts,(1)elimination of the primary tumor and(2)inhibition of newly developing pre-metastatic lesions.

关键词： metastatic cytokine migrate

Sphingosine signaling and atherogenesis

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Acta Pharmacologica Sinica 2004年第7期25卷 3-8页

作者： Jacob HANSEN-SCHWARTZ,Lars EDVINSSON Department of Clinical experimental Research Glostrup University Hospital Glostrup Denmark division of experimental Vascular Research Institute of Medicine Lund University Sweden

Sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger toregulate cell proliferation and survival, and extracellularly, as a ligand for a group of G protein-coupled receptors(GPCRs) named the endothelial differentiation gene (EDG) family. Five closely related GPCRs of EDG family(EDG1, EDG3, EDG5, EDG6, and EDG8) have recently been identified as high-affinity S1P receptors. Thesereceptors are coupled via Gi, Gq, G12/13, and Rho. The signaling pathways are linked to vascular cell migration,proliferation, apoptosis, intracellular Ca2+ mobilization, and expression of adhesion molecules. The formation of anatherosclerotic lesion occurs through activation of cellular events that include monocyte adhesion to the endothe-lium and vascular smooth muscle cell (VSMC) migration and proliferation. Thus, S1P signaling may play animportant role in the pathogenesis of atherosclerotic vascular disease. This review highlights S1P signalling invascular cells and its involvement in the formation of atherosclerotic lesions.

关键词： sphingosine 1-phosphate sphingosine kinase sphingosine-1-phosphate receptors endothelium myocardium smooth muscle arteriosclerosis

The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer

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Chinese Journal of Cancer 2012年第7期31卷 327-334页

作者： Amaury G. Dumont Sarah N.Dumont Jonathan C. Trent Department of experimental Pediatrics University of Texas-MD Anderson Cancer CenterHouston Texas United States division of hematology and Oncology University of Miami-Sylvester Comprehensive Cancer CenterMiami Florida United States

The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast can

关键词：肿瘤患者乳腺癌突变转基因小鼠肌动蛋白细胞骨架磷脂酰肌醇-3 信号通路乳腺肿瘤

Parthenolide:a novel pharmacological approach to promote nerve regeneration

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Neural Regeneration Research 2016年第10期11卷 1566-1567页

作者： Heike Diekmann Dietmar Fischer division of experimental Neurology Department of NeurologyHeinrich-Heine-University

Traumatic axonal lesions disrupt the connections between neurons and their targets, leading to loss of motoric and sensory functions. Although lesioned peripheral nerves can principally regenerate, the rate of recovery depends on the mode and severity of the respective injury （Grinsell and Keating, 2014）. While injuries close to the innervation site have good chances of recovery, long distance regeneration is particularly problematic due to relatively slow axonal growth rates, which even under favorable conditions do not normally exceed 1-2 mm per day （Sunderland, 1947）.

关键词： BDNF NGF

Base editing: a novel cure for severe combined immunodeficiency

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4433-4435页

作者： Teng-Cheong Ha Michael Morgan Axel Schambach Institute of experimental hematology Hannover Medical SchoolHannover30625Germany REBIRTH Research Center for Translational Regenerative Medicine Hannover Medical SchoolHannover30625Germany division of hematology/Oncology Boston Children’s HospitalHarvard Medical SchoolBostonMA02115USA

In a recent Cell article,McAuley,Kohn et *** proof-of-principle of a promising gene therapy(GT)approach to correct the underlying genetic defect responsible for CD3δ-deficient severe combined immunodeficiency(SCID)using a CRISPR-Cas9-derived adenine-base-editor(ABE).1 This ground-breaking and important study could impact future GTs for monogenic diseases by providing novel tailored therapeutic options(Fig.1).

关键词： immunodeficiency al. diseases

Skeletal muscle-directed gene therapy: hijacking the fusogenic properties of muscle cells

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4428-4430页

作者： Hildegard Buning Michael Morgan Axel Schambach Institute of experimental hematology Hannover Medical SchoolHannover30625Germany REBIRTH Research Center for Translational Regenerative Medicine Hannover Medical SchoolHannover30625Germany division of hematology/Oncology Boston Children’s HospitalHarvard Medical SchoolBostonMA02115USA

A recent study published in Cell by the Millay lab reports on an elegant strategy to expand the repertoire of lentiviral(LV)vectors from being the main delivery tool for ex vivo gene therapy to an in vivo applicable viral vector that specifically transduces skeletal muscle.1 This very significant advance may result in novel therapeutics for patients suffering from various skeletal muscle diseases.

关键词： skeletal directed muscle