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Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes

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中华医学杂志(英文版) 2024年第7期137卷 791-805页

作者： Cui Daxin Feng Xingrong Lei Siman Zhang Hongmei Hu Wanxin Yang Shanshan Yu Xiaoqian Su Zhiguang molecular medicine Research Center and department of Endocrinology and Metabolism West China Hospital Sichuan University Chengdu Sichuan 610041 China State Key Laboratory of Biotherapy Clinical translational Innovation Center

Pancreatic β-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing β-cells and hence restoring insulin production are gaining attention in translational diabetes research, and β-cell replenishment has been the main focus for diabetes treatment. Significant findings in β-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate β-cells. In this review, we summarize current knowledge on the mechanisms implicated in β-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to β-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting β-cell proliferation, inducing non-β-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for β-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous β-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

关键词： Pancreatic β-cell regeneration Diabetes Insulin Dedifferentiation Transdifferentiation Stem cell

Phosphodiesterase 9 localization in cytoplasm and nucleus:the gateway to selective targeting in neuroprotection?

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Neural Regeneration Research 2025年第6期20卷 1701-1702页

作者： Giovanni Ribaudo Matteo Giannangeli Margrate Anyanwu Alessandra Gianoncelli department of molecular and translational medicine University of BresciaBresciaItaly

The umbrella term"neurodege ne rative disorders"(NDDs) refers to several conditions characterized by a progressive loss of structure and function of cells belonging to the nervous system.Such diseases affect more than 50million people worldwide.Neurodegenerative disorders are characterized by sundry factors and pathophysiological mechanisms that a re challenging to be fully profiled.Many of these rely on cell signaling pathways to preserve homeostasis,involving second messengers such as cyclic adenosine monophosphate (cAMP)and cyclic guanosine 3',5'-monophosphate(cGMP).Their ability to control the duration and amplitude of the signaling cascade is given by the presence of several common and uncommon effectors.Protein kinases A and G (PKA and PKG),phosphodiesterases (PDEs),and scaffold proteins are among them.

关键词： gateway homeostasis preserve

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Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease

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Research 2024年第1期6卷 687-706页

作者： Qianqian Huang Chaoqing Jiang Xue Xia Yufan Wang Chenxing Yan Xiaorong Wang Ting Lei Xiaotong Yang Wenqin Yang Guo Cheng Huile Gao Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry West China School of PharmacySichuan UniversityChengdu 610041P.R.China Laboratory of molecular translational medicine Center for Translational MedicineKey Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University)Ministry of EducationDepartment of PediatricsWest China Second University HospitalSichuan UniversityChengdu 610041P.R.China

Inflammatory responses,manifested in excessive oxidative stress and microglia overactivation,together with metal ion-triggered amyloid-beta(Aβ)deposition,are critical hallmarks of Alzheimer’s disease(AD).The intricate pathogenesis causes severe impairment of neurons,which,in turn,exacerbates Aβaggregation and facilitates AD progression.Herein,multifunctional melanin-like metal ion chelators and neuroinflammation regulators(named PDA@K)were constructed for targeted treatment of AD.In this platform,intrinsically bioactive material polydopamine nanoparticles(PDA)with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide,endowing the system with the capacity of enhanced pathological blood–brain barrier(BBB)crossing and lesion site accumulation via Aβhitchhiking.In vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβand were able to hitch a ride on Aβto achieve increased pathological BBB crossing.The engineered PDA@K effectively mitigated Aβaggregate and alleviated neuroinflammation.

关键词： oxidative aggregation chelating

Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases

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Neural Regeneration Research 2024年第6期19卷 1291-1298页

作者： Qi Jia Jin Li Xiaofeng Guo Yi Li You Wu Yuliang Peng Zongping Fang Xijing Zhang department of Anesthesiology and Perioperative medicine and department of Intensive Care Unit Xijing Hospital The Fourth Military Medical University department of Critical Care medicine translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People's Hospital School of Medicine Tongji University

Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins. Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis, while providing nutrients and support for cell survival. Chaperone-mediated autophagy activity can be detected in almost all cells, including neurons. Owing to the extreme sensitivity of neurons to their environmental changes, maintaining neuronal homeostasis is critical for neuronal growth and survival. Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases. It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction. Under certain conditions, regulation of chaperone-mediated autophagy activity attenuates neurotoxicity. In this paper, we review the changes in chaperone-mediated autophagy in neurodegenerative diseases, brain injury, glioma, and autoimmune diseases. We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases.

关键词： chaperone-mediated autophagy neurodegenerative disease neuronal homeostasis neuroprotection

Cell-type resolved transcriptomic approaches for dissecting selective vulnerability in neurodgeneration

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Neural Regeneration Research 2024年第7期19卷 1411-1413页

作者： Caleb A.Wood Nicholas M.Tran department of Neuroscience Baylor College of MedicineHoustonTXUSA department of molecular and Human Genetics Baylor College of MedicineHoustonTXUSA

A common feature among neurodegenerative conditions is that ce rtain neuronal populations are selectively vulnerable to loss(Fu et al.,2018).By corollary,other neurons are selectively resilient,suggesting they may possess unique features that support their survival.U nderstanding the basis of neuronal resilience or vulnerability would provide a logical strategy to identify factors that could be targeted therapeutically.

关键词： selective targeted

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The dual role of striatal interneurons: circuit modulation and trophic support for the basal ganglia

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Neural Regeneration Research 2024年第6期19卷 1277-1283页

作者： Elliot Wegman Marlena Wosiski-Kuhn Yu Luo department of molecular and Cellular Biosciences University of Cincinnati 2. Department of Emergency Medicine at the School of Medicine University of Cincinnati Neuroscience Graduate Program University of Cincinnati

Striatal interneurons play a key role in modulating striatal-dependent behaviors, including motor activity and reward and emotional processing. Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson’s or Huntington’s disease. This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions. In addition to direct circuit modulation, striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood. We discuss this interesting and novel role of striatal interneurons, with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.

关键词： cholinergic dopamine GABAergic interneuron levodopa-induced dyskinesia parvalbumin sonic hedgehog striatum trophic factor

CD9 role in proliferation, rejuvenation, and therapeutic applications

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Genes & Diseases 2024年第3期11卷 95-97页

作者： Sai Priyanka Kodam Neda Baghban Mujib Ullah Institutefor Immunityand Transplantation Stem Cell Biology and Regenerative MedicineSchool of MedicineMolecular Medicine Department of MedicineStanford UniversityPaloAltoCA94304USA

The CD9 gene,also known as the Tspan29 gene,codes for a protein called CD9,which is a member of the tetraspanin family of transmembrane proteins.^(1) The CD9 protein is involved in various cellular processes,including cell proliferation,differentiation,adhesion,and migration.^(1,2) CD9 has also been found to play a role in the regulation of stem cell proliferation and differentiation.

关键词： migration. therapeutic CD9

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 sickness.Autophagy plays a critical role in ischemic brain injury,but its role in hypo-baric hypoxia(HH)remains unknown.Here 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 damage.The autophagic agonist rapamycin only promotes the initiation of autophagy.By proteome analysis,a screen showed that protein dynamin2(DNM2)potentially regulates autophagic flux.Overexpression of DNM2 significantly increased the formation of autolysosomes,thus maintaining autophagic flux in combination with rapamycin.Furthermore,the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure.These 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

Self-assembly of tau fragments as a key pathologic event in tauopathies

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Neural Regeneration Research 2024年第12期19卷 2565-2566页

作者： Ly Thi Huong Luu Le Jung Hoon Lee Min Jae Lee department of Biochemistry and molecular Biology Seoul National University College of MedicineSeoulKorea

Tau protein is encoded by the microtubuleassociated protein tau(MAPT)gene and stabilizes microtubules in the neurons.Tau has unique biophysical properties that make it both highly water-soluble and positively charged.Although tau is an intrinsically disordered protein lacking defined secondary structures,it can acquire highly organized-sheet structures and stack into a filamentous inclusion such as a paired helical filament(PHF).

关键词： tau pathologic assembly

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