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Transient receptor potential channels and calcium dysregulation: a pathogenic duo in Parkinson's disease

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Neural Regeneration Research 2025年第3期20卷 808-810页

作者： Iqira Saeed Linlin Ma Griffith Institute for Drug discovery Griffith UniversityNathanBrisbaneQLDAustralia School of Environment and Science Griffith University NathanBrisbaneQLDAustralia

Parkinson's disease(PD) has a complex and multifactorial pathophysiology. Various studies, conducted both in pre-clinical models and PD patients, have reported a link between the disruption of calcium(Ca^(2+)) homeostasis and the subsequent development of PD. Ca^(2+) regulation is crucial for neuronal survival, differentiation,exocytosis at synapses,gene transcription,and proliferation.

关键词： homeostasis clinical subsequent

Breaking new ground in photocatalysis: lutetium texaphyrin as a trigger for pyroptosis through biomolecular photoredox reactions

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Science China Chemistry 2025年第1期68卷 1-2页

作者： Qihang Ding Mengrong He Meijia Gu Department of Chemistry Korea University Department of Ultrasound Medicine Union Hospital Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Combinatorial Biosynthesis and Drug discovery (MOE) School of Pharmaceutical Sciences Wuhan University

Malignant neoplasms consistently pose a significant threat to global public health [1,2]. In recent years, immunotherapy has demonstrated remarkable clinical success; however, its efficacy is limited by the scarcity of immune cell infiltration within tumor microenvironments. Cell pyroptosis, a gasdermin-mediated process characterized by cellular swelling,rupture, and the release of intracellular contents such as IL-1β, IL-18, ATP, HMGB1, plays a crucial role in this context[3,4].

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The role of organic electron donors in the initiation of BHAS base-induced coupling reactions between haloarenes and arenes

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Science China Chemistry 2019年第11期62卷 1425-1438页

作者： Andrew J.Smith Darren L.Poole John A.Murphy Department of Pure and Applied Chemistry University of StrathclydeStrathclydeGlasgow G11XLUnited Kingdom flexible discovery unit GlaxoSmithKline Medicines Research CentreStevenageSG12NYUnited Kingdom

Coupling reactions between haloarenes and arenes(including heteroarenes)that are conducted without added transition metals but in the presence of KOtBu or NaOtBu,have been a topic of great interest since their discovery in *** organic structures act as additives that assist these *** additives are converted into organic electron donors by the butoxide base and this leads to initiation of the coupling reactions,which proceed by radical chain *** review provides an overview of the initiation stages of these reactions.

关键词： organic electron donor potassium tert-butoxide electron transfer base-promoted homolytic aromatic substitution(BHAS) coupling benzyne

Promoting remyelination for the treatment of multiple sclerosis:opportunities and challenges

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Neuroscience Bulletin 2013年第2期29卷 144-154页

作者： Yueting Zhang Taylor B.Guo Hongtao Lu Neuroimmunology discovery Performance unit GlaxoSmithKline Research and Development Center

Multiple sclerosis （MS） is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

关键词： multiple sclerosis myelination neurodegeneration oligodendrocytes disease progression disease modifying therapy drug target animal models

Anew wave of innovations within the DNA damagee response

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4548-4573页

作者： Qi Li Wenyuan Qian Yang Zhang Lihong Hu Shuhui Chen Yuanfeng Xia Domestic discovery Service unit WuXi AppTec200131 ShanghaiChina

Genome instability has been identified as one of the enabling hallmarks in *** damage response(DDR)network is responsible for maintenance of genome integrity in *** cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress,targeting DDR processes could induce excessive DNA damages(or unrepaired DNA)that eventually lead to cell ***(ADP-ribose)polymerase(PARP)inhibitors have brought impressive benefit to patients with breast cancer gene(BRCA)mutation or homologous recombination deficiency(HRD),which proves the concept of synthetic lethality in cancer ***,the other two scenarios of DDR inhibitor application,replication stress and combination with chemo-or radio-therapy,are under active clinical *** this review,we revisited the progress of DDR targeting therapy beyond the launched firstgeneration PARP *** generation PARP1 selective inhibitors,which could maintain the efficacy while mitigating side effects,may diversify the application scenarios of PARP inhibitor in *** with unavoidable on-mechanism toxicities,several small molecules targeting DNA damage checkpoints(gatekeepers)have shown great promise in preliminary clinical results,which may warrant further *** addition,inhibitors for other DNA repair pathways(caretakers)are also under active preclinical or clinical *** these progresses and efforts,we envision that a new wave of innovations within DDR has come of age.

关键词： damage eventually maintain

Spinal cord injury regenerative therapy development:integration of design of experiments

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Neural Regeneration Research 2025年第9期20卷 2571-2573页

作者： Yuji Okano Hideyuki Okano Yoshitaka Kase Division of CNS Regeneration and Drug discovery International Center for Brain Science(ICBS)Fujita Health UniversityKutsukake-ChoToyoake-ShiAichiJapan Department of Extended Intelligence for Medicine The Ishii-Ishibashi LaboratoryKeio University School of MedicineShinanomachiShinjuku-KuTokyoJapan Keio University Regenerative Medicine Research Center Kawasaki-kuKawasaki-shiJapan

Spinal cord injury(SCI)can cause motor and sensory paralysis,and autonomic nervous system disorders including malfunction of urination and defecation,thereby significantly impairing the quality of *** continue to explo re new stem cell strategies for the treatment of paralysis by transpla nting human induced pluripotent stem cell-derived neural ste m/progenitor cells(hiPSCNS/PCs)into spinal cord injured tissues.

关键词： Spinal paralysis injury

Recent advances in the culture-independent discovery of natural products using metagenomic approaches

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Chinese Journal of Natural Medicines 2024年第2期22卷 100-111页

作者： SHEN Yiping LIU Nan WANG Zongqiang Laboratory of Microbial Drug discovery China Pharmaceutical UniversityNanjing 211198China

Natural products derived from bacterial sources have long been pivotal in the discovery of drug ***,the cultivation of only about 1%of bacteria in laboratory settings has left a significant portion of biosynthetic diversity hidden within the genomes of uncultured *** in sequencing technologies now enable the exploration of genetic material from these metagenomes through culture-independent *** approach involves extracting genetic sequences from environmental DNA and applying a hybrid methodology that combines functional screening,sequence tag-based homology screening,and bioinformatic-assisted chemical *** this process,numerous valuable natural products have been identified and synthesized from previously uncharted metagenomic *** paper provides an overview of the recent advancements in the utilization of culture-independent techniques for the discovery of novel biosynthetic gene clusters and bioactive small molecules within metagenomic libraries.

关键词： Metagenomics Culture-independent approach Natural product Functional screening Sequence tag-based homology screening Syn-BNP

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

Targeting cancer stem cells in drug discovery: Current state and future perspectives

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World Journal of Stem Cells 2019年第7期11卷 398-420页

作者： Fang-Yu Du Qi-Fan Zhou Wen-Jiao Sun Guo-Liang Chen Key Laboratory of Structure-Based Drug Design and discovery of Ministry of Education Shenyang Pharmaceutical University

In recent decades,cancer stem cells(CSCs)have been increasingly identified in many ***-related signaling pathways and their functions provide new strategies for treating *** aberrant activation of related signaling pathways(e.g.,Wnt,Notch,and Hedgehog pathways)has been linked to multiple types of malignant tumors,which makes these pathways attractive targets for cancer *** display many characteristic features,such as self-renewal,differentiation,high tumorigenicity,and drug ***,there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication,survival,and *** crosstalk occurs among different signaling pathways and potentially leads to compensatory ***,multitarget inhibitors will be one of the main methods to overcome the drug resistance of *** small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials,and some inhibitors,such as vismodegib,sonidegib,and glasdegib,have been *** cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo *** signal transducers and activators of transcription 3(STAT3)inhibitor BBI608 is being evaluated in a phase III trial for a variety of *** derivatives of BBI608 are the main focus of STAT3 inhibitor development,which is another strategy for CSC *** addition to the potential pharmacological inhibitors targeting CSCrelated signaling pathways,other methods of targeting CSCs are available,such as nano-drug delivery systems,mitochondrion targeting,autophagy,hyperthermia,immunotherapy,and CSC microenvironment *** addition,we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.

关键词： Cancer stem cells Cancer stem cell-related signaling pathways Nano-drug delivery system Immunotherapy Mitochondrion Cancer stem cell