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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

Gene therapy for spinal muscular atrophy:perspectives on the possibility of optimizing SMN1 delivery to correct all neurological and systemic perturbations

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Neural Regeneration Research 2025年第7期20卷 2011-2012页

作者： Sharon J.Brown Rafael J.Yáñez-Muñoz Heidi R.Fuller School of Pharmacy and Bioengineering Keele UniversityKeeleUK Wolfson center for Inherited Neuromuscular disease TORCH BuildingRJAH Orthopaedic HospitalOswestryUK *** Center of Gene and Cell TherapyDepartment of Biological SciencesSchool of Life Sciences and the EnvironmentRoyal Holloway University of LondonEghamUK

Spinal muscular atrophy(SMA)is a genetic condition that results in selective lower motor neuron loss with concomitant muscle weakness and *** genetic cause of SMA was understood in 1995 when loss or impairment of the survival motor neuron 1(SMN1)gene was identified as the main contributing factor(Lefebvre et al.,1995).This,in combination with the discovery that humans have a“back-up”gene,SMN2,which can produce low levels(approximately 10%)of the full-length functional SMN protein,has led to the generation of SMA-specific gene *** was traditionally classified according to age of symptom onset and developmental milestones achieved,with life expectancy and severity varying between ***,SMN2 copy number is used as a proxy for the prediction of disease severity,with higher SMN2 copy number typically being associated with reduced severity of SMA,although this relationship is not absolute:some individuals with low SMN2 copy number have less severe SMA phenotypes and vice ***,the etiology of SMA is further complicated by other factors,such as non-typical nucleotide variants and SMN2-independent modifiers of disease severity.

关键词： atrophy traditionally absolute

Therapeutic potential of exercise-hormone irisin in Alzheimer's disease

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Neural Regeneration Research 2025年第6期20卷 1555-1564页

作者： Eunhee Kim Rudolph ETanzi Se Hoon Choi Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative DiseaseDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolCharlestownMAUSA McCance center for Brain Health Massachusetts General HospitalBostonMAUSA

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type Ⅲ domain-containing protein 5(FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.

关键词： Alzheimer's disease exercise fibronectin typeⅢdomain-containing protein 5(FNDC5) irisin

Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability

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World Journal of Gastroenterology 2016年第45期22卷 10024-10037页

作者： Hao-Jun Shi Chen Jin De-Liang Fu Department of pancreatic Surgery Pancreatic Disease Institute Huashan Hospital Fudan University

AIM To identify predictors for synchronous liver metastasis from resectable pancreatic ductal adenocarcinoma(PDAC) and assess unresectability of synchronous liver *** Retrospective records of PDAC patients with synchronous liver metastasis who underwent simultaneous resections of primary PDAC and synchronous liver metastasis, or palliative surgical bypass, were collected from 2007 to 2015. A series of pre-operative clinical parameters, including tumor markers and inflammation-based indices, were analyzed by logistic regression to figure out predictive factors and assess unresectability of synchronous liver metastasis. Cox regression was used to identify prognostic factors in liver-metastasized PDAC patients after surgery, with intention to validate their conformance to the indications of simultaneous resections and palliative surgical bypass. Survival of patients from different groups were analyzed by the Kaplan-Meier method. Intra- and post-operative courses were compared, including complications. PDAC patients with no distant metastases who underwent curative resection served as the control *** CA125 > 38 U/mL(OR = 12.397, 95%CI: 5.468-28.105, P 62 U/mL(OR = 5.181, 95%CI: 1.612-16.665, P = 0.006) and age > 62 years(OR = 3.921, 95%CI: 1.217-12.632, P = 0.022) correlated with unresectability of synchronous liver metastasis, both of which also indicated a worse long-term outcome of liver-metastasized PDAC patients after surgery. After the simultaneous resections, patients with postoperatively elevated serum CA125 levels had shorter survival than those with post-operatively reduced serum CA125 levels(7.7 mo vs 16.3 mo, P = 0.013). The survival of liver-metastasized PDAC patients who underwent the simultaneous resections was similar to that of non-metastasized PDAC patients who underwent cu

关键词： CA125 pancreatic ductal adenocarcinoma Liver metastasis Unresectability Prognosis

Is routine drainage necessary after pancreaticoduodenectomy?

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World Journal of Gastroenterology 2014年第25期20卷 8110-8118页

作者： Qiang Wang Yong-Jian Jiang Ji Li Feng Yang Yang Di Lie Yao Chen Jin De-Liang Fu Department of pancreatic Surgery Pancreatic Disease InstituteHuashan Hospital Affiliated with Fudan University

With the development of imaging technology and surgical techniques, pancreatic resections to treat pancreatic tumors, ampulla tumors, and other pancreatic diseases have increased. pancreaticoduodenectomy, one type of pancreatic resection, is a complex surgery with the loss of pancreatic integrity and various anastomoses. Complications after pancreaticoduodenectomy such as pancreatic fistulas and anastomosis leakage are common and significantly associated with patient outcomes. pancreatic fistula is one of the most important postoperative complications; this condition can cause intraperitoneal hemorrhage, septic shock, or even death. An effective way has not yet been found to avoid the occurrence of pancreatic fistula. In most medical centers, the frequency of pancreatic fistula has remained between 9% and 13%. The early detection and routine drainage of anastomotic fistulas, pancreatic fistulas, bleeding, or other intra-abdominal fluid collections after pancreatic resections are considered as important and effective ways to reduce postoperative complications and the mortality rate. However, many recent studies have argued that routine drainage after abdominal operations, including pancreaticoduodenectomies, does not affect the incidence of postoperative complications. Although inserting drains after pancreatic resectionscontinues to be a routine procedure, its necessity remains controversial. This article reviews studies of the advantages and disadvantages of routine drainage after pancreaticoduodenectomy and discusses the necessity of this procedure.

关键词： pancreaticoduodenectomy Drainage Suction Fistula Postoperative complications Intra-abdominal infections

Metabolic reprogramming: a new option for the treatment of spinal cord injury

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Neural Regeneration Research 2025年第4期20卷 1042-1057页

作者： Jiangjie Chen Jinyang Chen Chao Yu Kaishun Xia Biao Yang Ronghao Wang Yi Li Kesi Shi Yuang Zhang Haibin Xu Xuesong Zhang Jingkai Wang Qixin Chen Chengzhen Liang Department of Orthopedics The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina Orthopedics Research Institute of Zhejiang University Zhejiang UniversityHangzhouZhejiang ProvinceChina Key Laboratory of Motor System disease Research and Precision Therapy of Zhejiang Province HangzhouZhejiang ProvinceChina Clinical Research center of Motor System disease of Zhejiang Province HangzhouZhejiang ProvinceChina Qiandongnan Prefecture People’s Hospital KailiGuizhou ProvinceChina Department of Orthopedics Fourth Medical CenterChinese PLA General HospitalBeijingChina

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they *** the ongoing development of various therapies for spinal cord injuries,their effectiveness remains ***,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic *** this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic *** spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic ***,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial *** metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of *** rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell *** available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord *** further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

关键词： axons glycolysis metabolic reprogramming metabolism mitochondria neural regeneration neuroprotection oxidative phosphorylation spinal cord injury therapy

Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

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Neural Regeneration Research 2025年第1期20卷 6-20页

作者： Xiu-Yun Zhao De-En Xu Ming-Lei Wu Ji-Chuan Liu Zi-Ling Shi Quan-Hong Ma Department of Neurology and Clinical Research center of Neurological disease the Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina Institute of Neuroscience&Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-diseases Soochow UniversitySuzhouJiangsu ProvinceChina Department of Neurology Jiangnan University Medical CenterWuxiJiangsu ProvinceChina

The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular *** reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and *** this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular *** also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative *** summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve *** review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

关键词： autophagy endoplasmic reticulum endoplasmic reticulum autophagy endoplasmic reticulum quality control system endoplasmic reticulum receptors endoplasmic reticulum-associated degradation neurodegeneration neurodegenerative disease selective autophagy unfolded protein response

Current status and progress of pancreatic cancer in China

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World Journal of Gastroenterology 2015年第26期21卷 7988-8003页

作者： Quan-Jun Lin Feng Yang Chen Jin De-Liang Fu Department of pancreatic Surgery Pancreatic Disease InstituteHuashan HospitalShanghai Medical CollegeFudan University

Cancer is currently one of the most important public health problems in the *** cancer is a fatal disease with poor *** in most other countries,the health burden of pancreatic cancer in China is increasing,with annual mortality rates almost equal to incidence *** increasing trend of pancreatic cancer incidence is more significant in the rural areas than in the urban *** diagnoses and deaths of pancreatic cancer in China are now beyond the number of cases in the United *** 2012 estimates that cases in China account for 19.45%(65727/337872) of all newly diagnosed pancreatic cancer and 19.27%(63662/330391) of all deaths from pancreatic cancer *** population's growing socioeconomic status contributes to the rapid increase of China's proportional contribution to global ***,we present an overview of control programs for pancreatic cancer in China focusing on prevention,early diagnosis and *** addition,we describe key epidemiological,demographic,and socioeconomic differences between China and developed *** including no nationwide screening program for pancreatic cancer,delay in early detection resulting in a late stage at presentation,lack of awareness of pancreatic cancer in the Chinese population,and low investment compared with other cancer types by government have led to backwardness in China's pancreatic cancer diagnosis and ***,we suggest measures to improve health outcomes of pancreatic cancer patients in China.

关键词： pancreatic cancer Incidence Diagnosis Treatment

Accuracy of routine multidetector computed tomography to identify arterial variants in patients scheduled for pancreaticoduodenectomy

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World Journal of Gastroenterology 2015年第3期21卷 969-976页

作者： Feng Yang Yang Di Ji Li Xiao-Yi Wang Lie Yao Si-Jie Hao Yong-Jian Jiang Chen Jin De-Liang Fu Department of pancreatic Surgery Pancreatic Disease InstituteHuashan HospitalShanghai Medical CollegeFudan University

AIM:To assess the efficacy of cross-sectional multidetector computed tomography(MDCT) imaging without arterialreconstruction to identify aberrant right hepatic artery(RHA) and celiac artery stenosis(CAS) in patients scheduled for ***:Patients with peri-ampullary and pancreatic head tumors who underwent routine preoperative MDCT and subsequent computed tomography(CT) angiography(CTA),conventional angiography or pancreaticoduodenectomy between September 2007 and August 2013 were *** analysis of imaging data was undertaken using CTA,conventional angiographic and surgical findings as the reference *** accuracy,sensitivity,specificity,positive predictive value(PPV) and negative predictive value(NPV) of MDCT in evaluation of aberrant RHA and CAS were ***:A group of 458 patients met the inclusion criteria of this study to detect aberrant RHA,and 181 cases were included to identify ***-four(11.8%) patients were confirmed to have aberrant RHA,while 12(6.6%) patients with CAS were *** yielded an accuracy of 98.5%,sensitivity of 96.3% and specificity of 98.8% in the detection of aberrant *** sensitivity,specificity,PPV and NPV of MDCT for detecting CAS were 58.3%,98.2%,70% and 97.1%,***:Routine MDCT is recommended such that surgeons and radiologists be alerted to the importance of arterial variants on preoperative CT scans in patients scheduled for pancreaticoduodenectomy.

关键词： pancreaticoduodenectomy Aberrant hepatic artery Ce