Article
Neurosciences
Victoria Gomez-Murcia, Kevin Carvalho, Bryan Thiroux, Raphaelle Caillierez, Melanie Besegher, Nicolas Sergeant, Luc Buee, Emile Faivre, David Blum
Summary: Due to the complexity of Alzheimer's disease, it is of interest to find multitarget approaches that can mitigate multiple pathogenic mechanisms. In this study, the potential of Doxycycline (Dox), a second-generation tetracycline, in the APP/PS1 mouse model of amyloidogenesis was evaluated. The results showed that Dox moderately improved spatial memory in APP/PS1 mice without major effect on amyloid lesions. The study also found that Dox enhanced the amyloid-dependent upregulation of neuroinflammatory markers. Overall, chronic Dox delivery did not provide significant pathophysiological improvements in the APP/PS1 mouse model.
Article
Biochemistry & Molecular Biology
Joonhong Jun, Jihyun Baek, Songyi Yang, Hyungwoo Moon, Hyejin Kim, Hyunwook Cho, Jung-Mi Hah
Summary: In this study, a series of JNK3 inhibitors were synthesized and one compound exhibited excellent performance in terms of JNK3 inhibition and neuroprotective effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Engineering, Biomedical
Nelda Antonovaite, Lianne A. Hulshof, Christiaan F. M. Huffels, Elly M. Hol, Wytse J. Wadman, Davide Iannuzzi
Summary: Evidence of altered tissue mechanics in neurodegeneration is increasing, especially in Alzheimer's disease. Viscoelastic differences have been found in the brain tissue of APP/PS1 mice compared to wild-type mice, with regions in the hippocampus showing increased stiffness and viscous dissipation. Despite overall mechanical heterogeneity, local alterations in stiffness were not observed at the cellular scale around the plaques.
JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS
(2021)
Article
Chemistry, Medicinal
Joonhong Jun, Jihyun Baek, Dahyun Kang, Hyungwoo Moon, Hyejin Kim, Hyunwook Cho, Jung-Mi Hah
Summary: In this study, a series of JNK3 inhibitors based on the tetrahydrocyclopenta[d]imidazole scaffold were synthesized and evaluated. The results showed that these compounds exhibited higher JNK3 inhibitory effects and isoform selectivity compared to previously developed inhibitors. Compound 22b, in particular, showed excellent inhibitory activity and could be a potential starting point for the preclinical optimization of novel JNK3 inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Immunology
Jiawei Zhang, Yaling Zheng, Yao Zhao, Yaxuan Zhang, Yu Liu, Fang Ma, Xiuzhe Wang, Jianliang Fu
Summary: Andrographolide can significantly alleviate cognitive impairments, reduce amyloid-β deposition, inhibit microglial activation, and decrease the secretion of proinflammatory factors in APP/PS1 mice. Furthermore, transcriptome sequencing analysis revealed that Andro could significantly decrease the expression of various genes associated with inflammation in APP/PS1 mice, which was further validated by qRT-PCR. Our results suggest that Andro might be a potential therapeutic drug for AD by regulating neuroinflammation.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Geriatrics & Gerontology
Liangyun Liu, Jianing Cao, Chujun Huang, Erdong Yuan, Jiaoyan Ren
Summary: Cognitive impairment is a major clinical feature in AD patients, but research suggests peripheral organs may also play a role in AD pathology. Studies on aged APP/PS1 mice show increased inflammation response and decreased anti-oxidative capacity in peripheral organs, highlighting the need for a more comprehensive approach to studying AD.
EXPERIMENTAL GERONTOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Min-Yi Wu, Wen-Jun Zou, Daehoon Lee, Lin Mei, Wen-Cheng Xiong
Summary: Sarcopenia, characterized by muscle mass and strength/function loss, is associated with neurodegenerative diseases like Alzheimer's disease (AD). The underlying mechanisms for their associations are not well understood. The APP gene encodes amyloid precursor protein (APP), enriched at neuromuscular junction (NMJ) and synapses in the central nervous system (CNS). This review highlights the physiological functions of APP and its family members and the pathological roles of Swedish mutant APP (APP(swe)) in muscles and NMJ, providing insights into neuromuscular diseases and AD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Henrique Correia Campos, Deidiane Elisa Ribeiro, Debora Hashiguchi, Talita Glaser, Milena da Silva Milanis, Christiane Gimenes, Deborah Suchecki, Ricardo Mario Arida, Henning Ulrich, Beatriz Monteiro Longo
Summary: The aim of this study was to investigate the effects of resistance exercise on preventing and recovering from AD-related neuropathological conditions in APP/PS1 mice. The results showed that 4 weeks of resistance exercise improved locomotor activity and memory in APP/PS1 mice, and reduced A beta plaques and systemic inflammation. These findings suggest that resistance exercise plays a role in alleviating AD symptoms and can be an effective complementary treatment for AD.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Neurosciences
Yee Fun Lee, Lavender Lariviere, Alyssa N. Russ, Sang-Zin Choi, Brian J. Bacskai, Ksenia V. Kastanenka
Summary: The study demonstrated that the novel multimodal therapeutic NB-02 could reverse and prevent the neuropathophysiological processes of Alzheimer's disease in an animal model, including reducing amyloid plaque deposition, restoring neuronal function, and regulating neuroinflammation responses.
Article
Biochemistry & Molecular Biology
Yafei Zheng, Qingqing Xu, Qihao Jin, Yao Du, Junjie Yan, Hongchang Gao, Hong Zheng
Summary: In this study, the urinary and faecal metabolic profiles in APP/PS1 mice were investigated, revealing disrupted metabolic phenotypes and potential biomarkers at earlier stage of AD.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Clinical Neurology
Hector M. Estevez-Silva, German Cuesto, Ninovska Romero, Jose Miguel Brito-Armas, Abraham Acevedo-Arozena, Angel Acebes, Daniel J. Marcellino
Summary: Sigma-1 receptor agonists ACR16 and PRE-084 have been shown to promote the formation of new synapses and dendritic spines in vitro, while also exhibiting neuroprotective effects against oxidative stress and excitotoxicity. In an APP/PS1 mouse model, ACR16 improved spatial learning and memory deficits through activation of the PI3K/Akt pathway.
Article
Clinical Neurology
Shang Wang, Taiyang Zhu, Wanyan Ni, Chao Zhou, Hui Zhou, Li Lin, Yuting Hu, Xiaoyu Sun, Jingjing Han, Yan Zhou, Guoliang Jin, Jie Zu, Hongjuan Shi, Xingxing Yang, Zuohui Zhang, Fang Hua
Summary: This study investigates the role of early activation of Toll-like receptor 3 (TLR3) in the pathophysiological process of Alzheimer's disease (AD). The results showed that the early activation of TLR3 attenuated neuronal loss and neurobehavioral dysfunction in a mouse model of AD. This could be attributed to its role in A beta clearance, the inhibition of glial cells, and the regulation of neuroinflammation in the hippocampus.
ALZHEIMERS RESEARCH & THERAPY
(2023)
Article
Geriatrics & Gerontology
Arnold M. Salazar, Amanda M. Leisgang, Andrew A. Ortiz, Andrew S. Murtishaw, Jefferson W. Kinney
Summary: The study demonstrates altered GABAergic signaling in an amyloid model of AD, with changes in GABA-related targets associated with disease-related memory and learning deficits.
NEUROBIOLOGY OF AGING
(2021)
Article
Neurosciences
Guohua Li, Yu Wang, Fang Cao, Dawei Wang, Limin Zhou, Yanwu Jin
Summary: The study revealed that SEVO exposure significantly impaired spatial reference memory, sensorimotor, and cognitive function in mice. Mechanistically, SEVO induced the formation of NLRP3 inflammasome, leading to neurodegeneration.
FRONTIERS IN NEUROSCIENCE
(2021)
Article
Immunology
Xiaolei Wu, Qi Shen, Haocai Chang, Junyu Li, Da Xing
Summary: This study demonstrated that photobiomodulation therapy (PBMT) effectively promotes adult hippocampal neurogenesis (AHN) and reverses cognitive deficits in AD mouse models by upregulating expression of interferon-gamma (IFN-γ) and interleukin-10 (IL-10) in non-parenchymal CD4(+) T cells through the JAK2/STAT4/STAT5 signaling pathway.
JOURNAL OF NEUROINFLAMMATION
(2022)
Article
Chemistry, Medicinal
Shuang Mei, Su Jiang, Yuting Wang, Han Jing, Peng Yang, Miao-Miao Niu, Jindong Li, Kai Yuan, Yan Zhang
Summary: This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Hyeonjun Lee, Ju Yeon Lee, Hyunsoo Jang, Hye Young Cho, Minhee Kang, Sang Hyun Bae, Suin Kim, Eunji Kim, Jaebong Jang, Jin Young Kim, Young Ho Jeon
Summary: By using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, we identified new chemical moieties that bind to the target sites of the protein of interest, allowing for reversible binding and protein degradation. This method has the potential to expand the application of PROTAC technology.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Bingsi Wang, Mingxu Ma, Yusen Dai, Pengfei Yu, Liang Ye, Wenyan Wang, Chunjie Sha, Huijie Yang, Yingjie Yang, Yunjing Zhu, Lin Dong, Shujuan Wei, Linlin Wang, Jingwei Tian, Hongbo Wang
Summary: Breast cancer is a common malignant tumor in women, and drug resistance remains a clinical challenge. In this study, a novel compound, G-5b, was developed with potent antagonistic and degradation activities comparable to the current drug fulvestrant. G-5b also showed improved stability and solubility. Mechanistically, G-5b engages the proteasome pathway to degrade ER, inhibiting the ER signaling pathway and inducing apoptosis and cell cycle arrest. In animal models, G-5b exhibited superior pharmacokinetics and pharmacodynamics properties. Overall, G-5b is a promising long-acting SERD worthy of further investigation and optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Michal Sulik, Diana Fontinha, Dietmar Steverding, Szymon Sobczak, Michal Antoszczak, Miguel Prudencio, Adam Huczynski
Summary: This study describes the synthesis of the first-in-class ivermectin derivatives obtained through derivatization of the C13 position, along with the unexpected rearrangement of the macrolide ring. These derivatives show potential for antiparasitic activity and are important for the development of new antiparasitic agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Jun Liu, Qiu-Xian Chen, Wen-Fu Wu, Dong Wang, Si -Yu Zhao, Jia-Hao Li, Yi-Qun Chang, Shao-Gao Zeng, Jia-Yi Hu, Yu-Jie Li, Jia-Xin Du, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai -Bo Zhou, Yong-Heng Wang, Jian Zou, Ping-Hua Sun
Summary: A new anti-infective drug strategy has been discovered to attenuate virulence and modulate inflammation caused by drug-resistant Pseudomonas aeruginosa infections. Compound 5f inhibits biofilm formation, macrophage migration, and inflammatory response induced by P. aeruginosa, showing potential as a novel candidate against drug-resistant infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Liuzeng Chen, Ke Wang, Lingyun Wang, Wei Wang, Lifan Wang, Jia Li, Xiaohan Liu, Mengya Wang, Banfeng Ruan
Summary: In this study, a series of novel anti-inflammatory compounds were designed and synthesized based on the natural product pterostilbene skeleton. Among them, compound 8 showed the highest activity and exhibited its effects through inhibition of pro-inflammatory cytokines by blocking the NF-KB/MAPK signaling pathway. Compound 8 also demonstrated a good relieving effect on acute colitis in mice and showed good safety in acute toxicity experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Si-Min Liang, Gui-Bin Liang, Hui-Ling Wang, Hong Jiang, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
Summary: A series of novel multi-target antitumor agents were designed, synthesized, and evaluated. Some compounds exhibited significant antitumor activity and one compound showed excellent efficacy, limited toxicity, and low resistance. Further mechanism studies revealed that the compound exerted antitumor effects through multiple pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)