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Science China Chemistry 2025年第1期 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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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

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

Analysis of receptor-ligand binding by photoaffinity cross-linking

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Science China Chemistry 2014年第2期57卷 232-242页

作者： XU Bin WU Ling department of Biochemistry and Center for drug discovery Virginia TechBlacksburgVA 24061USA

Photoaffinity cross-linking is a fast developing technology for biomolecular interactions,including receptor-ligand *** chemical mechanisms of the most commonly used photoactivatable probes and their respective photochemistry are *** review focuses on the expanding utilities of this technology as a result of recent advances in the(i)identification of receptor contact sites,(ii)monitoring ligand-induced receptor conformational changes,(iii)identification of global binding surfaces,(iv)binding mode analysis using bifunctional photo-probes,(v)application of biosynthetic photo-probes,and(vi)examples of novel target discovery using this *** and future potential of this approach are also discussed.

关键词： photoaffinity cross-linking receptor-ligand interaction photoscanning bifunctional photo-probe biosynthetic photo-probe novel receptor discovery

Dual PPAR delta/gamma agonist offer therapeutic potential for Alzheimer's disease

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Neural Regeneration Research 2024年第6期19卷 1175-1176页

作者： Ian Steinke Meenakshi Singh Rajesh Amin department of drug discovery and Development Auburn UniversityAuburn AlabamaALUSA

The increasing incidence of Alzheimer's disease(AD)in the aging population,indicates the critical need for the development of novel targeted molecular therapies for ameliorating AD ***,clinical and preclinical evidence demonstrates that peroxisomal proliferator activating receptors(PPAR)agonists regulate energy and lipid homeostasis in models of diabetes,as well as improve spatial memory in animal models of AD(Khan et al.,2019).

关键词： Alzheimer clinical homeostasis

A Therapeutic Sheep in Metastatic Wolf’s Clothing: Trojan Horse Approach for Cancer Brain Metastases Treatment

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Nano-Micro Letters 2022年第7期14卷 140-156页

作者： Hai-jun Liu Mingming Wang Shanshan Shi Xiangxiang Hu Peisheng Xu department of drug discovery and Biomedical Sciences College of PharmacyUniversity of South CarolinaColumbiaSC 29208USA

Early-stage brain metastasis of breast cancer(BMBC), due to the existence of an intact blood–brain barrier(BBB), is one of the deadliest neurologic complications. To improve the efficacy of chemotherapy for BMBC, a Trojan horse strategy-based nanocarrier has been developed by integrating the cell membrane of a brain-homing cancer cell and a polymeric drug depot. With the camouflage of a MDA-MB-231/Br cell membrane, doxorubicin-loaded poly(D, L-lactic-co-glycolic acid) nanoparticle(DOX-PLGA@CM) shows enhanced cellular uptake and boosted killing potency for MDA-MB-231/Br cells. Furthermore, DOX-PLGA@CM is equipped with naturally selected molecules for BBB penetration, as evidenced by its boosted capacity in entering the brain of both healthy and early-stage BMBC mouse models. Consequently, DOX-PLGA@CM effectively reaches the metastatic tumor lesions in the brain, slows down cancer progression, reduces tumor burden, and extends the survival time for the BMBC ***, the simplicity and easy scale-up of the design opens a new window for the treatment of BMBC and other brain metastatic cancers.

关键词： Trojan horse Brain metastasis Blood-brain barrier Cell membrane Nanomedicine

The inhibition of Typhonium flagelliforme Lodd. Blume leaf extract on COX-2 expression of Wi Dr colon cancer cells

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Asian Pacific Journal of Tropical Biomedicine 2016年第3期6卷 251-255页

作者： Agustina Setiawati Handika Immanuel Mery Tri Utami department of drug Design and discovery Faculty of Pharmacy Sanata Dharma University

Objective: To determine the inhibition activity of Typhonium flagelliforme Lodd. Blume(T. flagelliforme) leaf extract on cyclooxygenase 2(COX-2) expression of colon cancer ***: T. flagelliforme leaf extract was prepared to macerate in ethyl acetate. In vitro anticancer activity was assayed by MTT method on Wi Dr colon cancer cells. This study applied apoptosis induction assay to investigate the mechanism of cell death using double staining method. COX-2 expression was stained by ***: T. flagelliforme showed anticancer activity and induced apoptosis on Wi Dr cells through inhibition of COX-2 expression with IC5070 mg/m ***: This study showed that T. flagelliforme is a promising chemopreventive agent for colon cancer through COX-2 inhibition.

关键词： Typhonium flagelliforme Colon cancer WiDr Cyclooxygenase 2

Highly Aromatic Norditerpenoid Heterodimers and Monomers from Trigonostemon fragilis

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Engineering 2024年第7期38卷 144-154页

作者： Jun-Su Zhou Long Cheng Yuan Gao Zhan-Peng Ge Bin Zhou Jing-Ya Li Jin-Xin Zhao Jian-Min Yue State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China

Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon *** 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical *** 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization ***(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid *** by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,*** structures were characterized using a combined ***,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.

关键词： Norditerpenoid heterodimer Trigonostemon fragilis Euphorbiaceae Trigofragiloid Structural revision Adenosine triphosphate-citrate lyase(ACLY) inhibitory activity

A new age in understanding adult hippocampal neurogenesis in Alzheimer’s disease

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Neural Regeneration Research 2022年第12期17卷 2615-2618页

作者： Maya A.Hanspal Sébastien Gillotin MRL London discovery MSDLondon Bioscience Innovation CentreLondonUK

Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout *** rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem *** causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been *** is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in *** it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this *** this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s *** outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s *** particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.

关键词： adult hippocampal neurogenesis Alzheimer’s disease cognition human tissue induced pluripotent stem cell mouse models neurodegeneration therapeutics tractable target

Harnessing generative AI to decode enzyme catalysis and evolution for enhanced engineering

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National Science Review 2023年第12期10卷 13-25页

作者： Wen Jun Xie Arieh Warshel department of Medicinal Chemistry Center for Natural Products Drug Discovery and DevelopmentGenetics InstituteUniversity of Florida department of Chemistry University of Southern California

Enzymes, as paramount protein catalysts, occupy a central role in fostering remarkable progress across numerous fields. However, the intricacy of sequence-function relationships continues to obscure our grasp of enzyme behaviors and curtails our capabilities in rational enzyme engineering. Generative artificial intelligence(AI), known for its proficiency in handling intricate data distributions, holds the potential to offer novel perspectives in enzyme research. Generative models could discern elusive patterns within the vast sequence space and uncover new functional enzyme sequences. This review highlights the recent advancements in employing generative AI for enzyme sequence analysis. We delve into the impact of generative AI in predicting mutation effects on enzyme fitness, catalytic activity and stability, rationalizing the laboratory evolution of de novo enzymes, and decoding protein sequence semantics and their application in enzyme engineering. Notably, the prediction of catalytic activity and stability of enzymes using natural protein sequences serves as a vital link, indicating how enzyme catalysis shapes enzyme evolution. Overall,we foresee that the integration of generative AI into enzyme studies will remarkably enhance our knowledge of enzymes and expedite the creation of superior biocatalysts.

关键词： generative AI mutation effects evolution–catalysis relationship enzyme engineering enzyme evolution