Article
Neurosciences
Henry S. Lange, Joshua D. Vardigan, Christopher E. Cannon, Vanita Puri, Darrell A. Henze, Jason M. Uslaner
Summary: Alzheimer's disease is a profoundly debilitating neurodegenerative disorder, and Compound 24 has shown potential therapeutic effects in non-human primates, reducing behavioral disturbances and enhancing cognitive function.
Article
Chemistry, Medicinal
Rory A. Capstick, David Whomble, Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, Changho Han
Summary: The lack of suitable tool compounds has restricted the in vivo understanding of M5 receptor biology. In this article, the authors present their ongoing efforts to develop next-generation M5 antagonists with improved clearance profiles.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Douglas L. Orsi, Andrew S. Felts, Alice L. Rodriguez, Paige N. Vinson, Hyekyung P. Cho, Sichen Chang, Anna L. Blobaum, Colleen M. Niswender, Jeffrey Conn, Carrie K. Jones, Craig W. Lindsley, Changho Han
Summary: This Letter describes the ongoing effort to improve the clearance of selective M5 antagonists, reporting the replacement of the previously disclosed piperidine amide with a pyrrolidine amide core. The compounds in this series showed good potency, subtype selectivity, and moderate to low clearance profiles. Interestingly, the SAR for this series diverged from previous efforts.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Neurosciences
Eva Dolejsi, Eszter Szanti-Pinter, Nikolai Chetverikov, Dominik Nelic, Alena Randakova, Vladimir Dolezal, Eva Kudova, Jan Jakubik
Summary: The study revealed that membrane cholesterol can modulate the function of muscarinic receptors, with different steroidal compounds showing varying affinity for the receptors. Corticosterone and progesterone were found to allosterically modulate receptor function under physiological conditions.
Review
Biochemistry & Molecular Biology
Ewa Szczurowska, Eszter Szanti-Pinter, Alena Randakova, Jan Jakubik, Eva Kudova
Summary: Muscarinic acetylcholine receptors are membrane receptors involved in various physiological processes, and dysfunction of their signaling is associated with internal diseases and psychiatric/neurologic conditions. Steroidal compounds, besides their genomic effects, can also modulate membrane proteins including muscarinic acetylcholine receptors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Prashant Donthamsetti, David B. Konrad, Belinda Hetzler, Zhu Fu, Dirk Trauner, Ehud Y. Isacoff
Summary: G protein-coupled receptors (GPCRs) are common drug discovery targets, but the complexity of in vivo receptor activation has hindered drug development. Photopharmacology offers the potential to control drug action using light. Recent advances include a photoswitchable allosteric agonist that selectively activates receptors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Medicine, Research & Experimental
Seungkirl Ahn, Harm Maarsingh, Julia K. L. Walker, Samuel Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
Summary: This article investigates the potential of β2AR-selective positive allosteric modulators (PAMs) in the treatment of asthma and other obstructive respiratory diseases. The results demonstrate that these PAMs can enhance the binding and downstream signaling of β2-agonists to β2ARs in guinea pigs and humans, thereby promoting bronchodilation and protection.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Clinical Neurology
Mackenzie Smith, Bright Arthur, Jakub Cikowski, Calista Holt, Sonia Gonzalez, Nicole M. Fisher, Sheryl Anne D. Vermudez, Craig W. Lindsley, Colleen M. Niswender, Rocco G. Gogliotti
Summary: Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG-binding protein 2 (MeCP2). Transcriptional profiling in RTT patients identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. M-1 positive allosteric modulators (PAMs) may represent a new class of RTT therapeutics.
Article
Chemistry, Multidisciplinary
Almudena Barbero-Castillo, Fabio Riefolo, Carlo Matera, Sara Caldas-Martinez, Pedro Mateos-Aparicio, Julia F. Weinert, Aida Garrido-Charles, Enrique Claro, Maria V. Sanchez-Vives, Pau Gorostiza
Summary: Being able to control neural activity is crucial in both basic neuroscience research and clinical neurology. Different methods exist for spatiotemporal controlled neuromodulation, including light-mediated control like optogenetics. A drug-based light-mediated approach using a photoswitchable muscarinic agonist has been shown to transform cortical activity patterns without requiring genetic manipulation.
Review
Immunology
Namrita Halder, Girdhari Lal
Summary: Neurological and immunological signals interact to maintain homeostasis in the body. The cholinergic system plays a crucial role in neuroimmune communication, regulating immune response. Various molecules of the neuronal and non-neuronal cholinergic system interact to modulate inflammation and immunity.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Tehila Mizrachi, Oshrit Marsha, Karen Brusin, Yael Ben-David, Ganesh A. Thakur, Adi Vaknin-Dembinsky, Millet Treinin, Talma Brenner
Summary: GAT107, an ago-PAM of alpha 7 nAChR, can significantly reduce disease severity and neuroinflammation in EAE by activating the receptor, leading to decreased pro-inflammatory cytokine production and increased anti-inflammatory cytokine IL-10. It also alters the expression of immune cell markers and directly activates alpha 7 nAChR in immune cells of MS patients and healthy donors.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Clinical Neurology
Charlotte Bakker, Tim Tasker, Jan Liptrot, Ellen P. Hart, Erica S. Klaassen, Robert Jan Doll, Giles A. Brown, Alastair Brown, Miles Congreve, Malcolm Weir, Fiona H. Marshall, David M. Cross, Geert Jan Groeneveld, Pradeep J. Nathan
Summary: The study demonstrated that HTL0018318 was well-tolerated and safe at multiple doses of 15-35mg. It showed pro-cognitive effects on short-term memory and learning, supporting its development for cognitive dysfunction in AD and DLB.
ALZHEIMERS RESEARCH & THERAPY
(2021)
Article
Multidisciplinary Sciences
Jia Duan, Peiyu Xu, Huibing Zhang, Xiaodong Luan, Jiaqi Yang, Xinheng He, Chunyou Mao, Dan-Dan Shen, Yujie Ji, Xi Cheng, Hualiang Jiang, Yi Jiang, Shuyang Zhang, Yan Zhang, H. Eric Xu
Summary: This study presents cryo-EM structures of follicle stimulating hormone receptor (FSHR) in active and inactive states, providing insights into the molecular basis of FSH and small allosteric agonist-mediated FSHR activation. The findings have important implications for the treatment of infertility and in vitro fertilization.
NATURE COMMUNICATIONS
(2023)
Article
Neurosciences
Laura B. Teal, Michael Bubser, Edith Duncan, Robert W. Gould, Craig W. Lindsley, Carrie K. Jones
Summary: Recent evidence suggests that inhibition of the M5 muscarinic acetylcholine receptor (mAChR) may provide a novel non-opioid mechanism for the treatment of opioid use disorder (OUD). In this study, the effects of the M5 negative allosteric modulator (NAM) VU6008667 on oxycodone self-administration and reinstatement behaviors were evaluated. The results showed that VU6008667 decreased oxycodone self-administration and attenuated cue-induced reinstatement of lever pressing, while having minimal effects on other behaviors.
Review
Pharmacology & Pharmacy
Huong T. M. Nguyen, Emma T. van der Westhuizen, Christopher J. Langmead, Andrew B. Tobin, Patrick M. Sexton, Arthur Christopoulos, Celine Valant
Summary: This review focuses on the drug discovery of M-1 receptor for the treatment of Alzheimer's disease and schizophrenia. Despite some progress, only a few drugs have reached clinical trials due to cholinergic adverse effects.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Physiology
Ke Cao, Ye Liu, Ningning Liang, Xia Shen, Rui Li, Huiyong Yin, Leihong Xiang
Summary: The study found that acne patients have higher levels of saturated fatty acids and monounsaturated fatty acids in facial sebum, while the levels of polyunsaturated fatty acids are lower in the chin area. Male patients also had lower levels of docosahexaenoic acid in circulating erythrocytes. Female patients had more severe sebum abnormalities and chin-specific fatty acid profiles, consistent with higher acne incidences in male adults. Serum levels of insulin-like growth factor 1 were only positively correlated with saturated fatty acids and monounsaturated fatty acids in facial sebum in male patients.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Nutrition & Dietetics
Suhong Zhao, Yanan Tian, Shanjie Wang, Fan Yang, Junyan Xu, Zhifeng Qin, Xinxin Liu, Muhua Cao, Peng Zhao, Guohua Zhang, Zhuozhong Wang, Yiying Zhang, Yidan Wang, Kaiyang Lin, Shaohong Fang, Zhao Wang, Tianshu Han, Maoyi Tian, Huiyong Yin, Jinwei Tian, Bo Yu
Summary: This study found that plasma levels of certain gut microbiota-derived metabolites are associated with major adverse cardiovascular events (MACEs) in patients with ST-segment elevation myocardial infarction (STEMI). Higher levels of PAGln, IS, DCA, TML, and TMAO are significantly correlated with MACEs, suggesting that these metabolites may serve as useful prognostic markers for STEMI patients.
AMERICAN JOURNAL OF CLINICAL NUTRITION
(2023)
Letter
Cardiac & Cardiovascular Systems
Guizhu Liu, Qian Liu, Naifu Wan, Xia Shen, Hui Cui, Cheng Dong, Xu Zhang, Huiyong Yin, Jian Wang, Colin D. Funk, Ying Yu
Article
Biochemistry & Molecular Biology
Shumeng Hao, Sulin Zhang, Jialin Ye, Lifan Chen, Yan Wang, Siyu Pei, Qingchen Zhu, Jing Xu, Yongzhen Tao, Neng Zhou, Huiyong Yin, Cai-Wen Duan, Chaoming Mao, Mingyue Zheng, Yichuan Xiao
Summary: Obesity is associated with elevated fatty acid beta-oxidation (FAO) and CD4(+) T cell hyperactivation, leading to enhanced induction of inflammation. The FAO rate-limiting enzyme Cpt1a stabilizes mitochondrial E3 ubiquitin ligase Goliath, promoting glycolysis and hyperactivation of CD4(+) T cells in obesity. Inhibiting the FAO-glycolysis metabolic axis with the Goliath inhibitor DC-Gonib32 reduces inflammation in obese mice.
Review
Cardiac & Cardiovascular Systems
Jian Zhang, Yunyun Guo, Xiangkai Zhao, Jiaojiao Pang, Chang Pan, Jiali Wang, Shujian Wei, Xiao Yu, Cheng Zhang, Yuguo Chen, Huiyong Yin, Feng Xu
Summary: The inactivating ALDH2 rs671 polymorphism is associated with increased risk of cardiovascular diseases. ALDH2 can also modulate risk factors associated with atherosclerosis through non-enzymatic pathways.
NATURE REVIEWS CARDIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Hope Woods, Dominic L. Schiano, Jonathan I. Aguirre, Kaitlyn V. Ledwitch, Eli F. McDonald, Markus Voehler, Jens Meiler, Clara T. Schoeder
Summary: This study investigates the impact of in-frame deletion mutations on protein structure and function, and proposes a computational method using AlphaFold2 and RosettaRelax for prediction and classification of deletion mutants. The results demonstrate the effectiveness of this method, especially when using a metric combining pLDDT values and Rosetta DDG for classifying tolerated deletion mutations.
Article
Biochemical Research Methods
Brennica Marlow, Georg Kuenze, Jens Meiler, Julia Koehler Leman
Summary: Lipid molecules, such as cholesterol, interact with integral membrane proteins (IMP) in a different way compared to drug-like molecules. The RosettaCholesterol protocol, developed in this study, improves the sampling and scoring of native poses of protein-cholesterol complexes. It also quantifies the specificity of cholesterol binding sites, providing a basis for further experimental validation and modeling.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Chak Kwong Cheng, Huanyu Ding, Minchun Jiang, Huiyong Yin, Maik Gollasch, Yu Huang
Summary: Perivascular adipose tissue (PVAT) refers to the aggregate of adipose tissue surrounding the vasculature, exhibiting the phenotypes of white, beige and brown adipocytes. PVAT is actively involved in the regulation of reactive oxygen species (ROS) homeostasis and inflammation in the vascular system. The phenotype-genotype of PVAT varies in different regions of the vasculature and plays a role in cardiovascular pathogenesis. Treatments targeting PVAT may provide new therapeutic insights for cardiovascular diseases.
Article
Endocrinology & Metabolism
Xiangfeng Chen, Bin Wu, XiaoRong Shen, Xin Wang, Ping Ping, Maohua Miao, Ningning Liang, Huiyong Yin, Huijuan Shi, Jun Qian, Tiancheng Zhang
Summary: This study aimed to investigate the effects of PUFA-derived metabolites in seminal plasma on male fertility and evaluate the potential of PUFA as a biomarker for normozoospermic male infertility. Semen samples were collected from 564 men, and the levels of PUFA-derived metabolites were analyzed. The results showed significant differences in the concentrations of certain metabolites between fertile and infertile men with normozoospermia and oligoasthenozoospermia. The metabolites 7(R)-MaR1, 11,12-DHET, 17(S)-HDHA, LXA5, and PGJ2 were identified as potential diagnostic biomarkers for infertility in normozoospermic men.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Oncology
Arnaldo Marin, Abdullah Al Mamun, Hima Patel, Hiroaki Akamatsu, Dan Ye, Dhivya R. Sudhan, Lisa Eli, Katherine Marcelain, Benjamin P. Brown, Jens Meiler, Carlos L. Arteaga, Ariella B. Hanker
Summary: This study reveals the driver function of acquired HER2 mutations in resistance to HER2 tyrosine kinase inhibitors, and provides a potential treatment strategy to overcome this resistance.
Article
Biochemistry & Molecular Biology
Hannes Junker, Jens Meiler, Clara T. Schoeder
Summary: Recent studies have shown that G protein-coupled receptors (GPCRs) can adopt various conformations that coexist in equilibrium, with the apo state possessing high entropy. The formation of a ligand-GPCR-transducer complex comes at the cost of reduced conformational space and increased entropy. This study suggests that the conservation of binding partners, their affinity, and the rigidity of binding sites are important factors in balancing the energetic cost of intra- and extracellular binding events in GPCR signal transduction.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
D. Sala, F. Engelberger, H. S. Mchaourab, J. Meiler
Summary: Many proteins switch among different structures to exert their function, and understanding these conformational ensembles is crucial for unraveling key mechanistic aspects of protein function. Experimental determination of these structures is limited by cost, time, and technical challenges, but the machine-learning technology AlphaFold has shown promising accuracy in predicting the three-dimensional structure of monomeric proteins. However, AlphaFold typically represents a single conformational state with minimal structural heterogeneity, leading to the development of pipelines to expand the diversity or bias the prediction towards desired conformational states. In this study, we analyze the functionality, limitations, and future directions of these pipelines.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Biographical-Item
Biochemistry & Molecular Biology
Sean S. Davies, Joshua P. Fessel, Ginger L. Milne, Kevin Moore, Huiyong Yin
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Article
Rheumatology
Ming Wang, Rui Li, Han Qi, Lei Pang, Lingling Cui, Zhen Liu, Jie Lu, Rong Wang, Shuhui Hu, Ningning Liang, Yongzhen Tao, Nicola Dalbeth, Tony R. Merriman, Robert Terkeltaub, Huiyong Yin, Changgui Li
Summary: The study aims to discover differential metabolites and pathways underlying infrequent and frequent gout flares using metabolomics and establish a predictive model by machine learning algorithms. The results show that systematic metabolic alterations underlie infrequent and frequent gout flares, and distinct profiles are associated with differences in gout flare frequencies. The predictive model based on selected metabolites from metabolomics can differentiate infrequent and frequent gout flares.
ARTHRITIS & RHEUMATOLOGY
(2023)
Article
Cell Biology
Yunguang Li, Shijie Tang, Xiaohan Shi, Jingwen Lv, Xueyuan Wu, Yehan Zhang, Huan Wang, Juan He, Yiqin Zhu, Yi Ju, Yajuan Zhang, Shiwei Guo, Weiwei Yang, Huiyong Yin, Luonan Chen, Dong Gao, Gang Jin
Summary: This study investigates the metabolic characteristics of pancreatic ductal adenocarcinomas (PDAC) and identifies two subtypes based on glucose and lipid metabolism levels. Glucomet-PDAC, characterized by high glucose metabolism, exhibits higher chemotherapy resistance and worse prognosis compared to lipomet-PDAC with high lipid metabolism. The study reveals the role of the GLUT1/ALDOB/G6PD axis in inducing chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Inhibition of GLUT1 or G6PD enhances chemotherapy response in glucomet-PDAC.
CELL REPORTS MEDICINE
(2023)