Article
Pharmacology & Pharmacy
Edijs Vavers, Liga Zvejniece, Maija Dambrova
Summary: In the past decade, sigma-1 receptor (Sig1R) has emerged as a promising target for the treatment of seizure disorders. Clinical trials are currently underway to test Sig1R ligands as therapies for drug-resistant seizures and other related conditions. However, the precise molecular mechanism by which Sig1R modulates seizures and the balance between excitation and inhibition pathways remain unclear.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Jing Li, Kenneth A. Satyshur, Lian-Wang Guo, Arnold E. Ruoho
Summary: Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones are widely present in mammalian cell membranes. Endogenous compounds that regulate the S1R play an important role in controlling S1R responses to cellular stress. This study investigated the interaction between S1R and sphingosine (SPH) and N,N'-dimethylsphingosine (DMS) in intact Retinal Pigment Epithelial cells (ARPE-19) and suggested that SPH and DMS are endogenous S1R agonists. Molecular docking analysis showed strong interactions between SPH/DMS and specific residues in the S1R, indicating a membrane bilayer pathway for SPH/DMS to access the S1R beta barrel. The enzymatic control of ceramide concentrations in intracellular membranes may dictate the availability of SPH and DMS to S1R and subsequently regulate S1R activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Jiaying Xiong, Tao Zhuang, Yurong Ma, Junyi Xu, Jiaqi Ye, Ru Ma, Shuang Zhang, Xin Liu, Bi-Feng Liu, Chao Hao, Guisen Zhang, Yin Chen
Summary: This study describes the optimization, synthesis, and pharmacological activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor antagonists and mu opioid receptor agonists. Compound 114 showed promising affinity and selectivity, with powerful dose-dependent analgesic effects and reduced opioid-like side effects compared to fentanyl. The pharmacokinetic properties of compound 114 were acceptable, suggesting its potential in treating neuropathic pain.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Giorgia Pellavio, Giacomo Rossino, Giulia Gastaldi, Daniela Rossi, Pasquale Linciano, Simona Collina, Umberto Laforenza
Summary: Sigma1 receptor (S1R) and aquaporins (AQP) are both important in oxidative stress, regulating the permeability of H2O2 to maintain the balance of reactive oxygen species within cells. S1R modulators can restore water permeability in heat-stressed cells and counteract the cell damage caused by oxidative stress.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Dasiel O. Borroto-Escuela, Alexander Lopez-Salas, Karolina Wydra, Marco Bartolini, Zilong Zhou, Malgorzata Frankowska, Agata Suder, Javier Benitez-Porres, Wilber Romero-Fernandez, Malgorzata Filip, Kjell Fuxe
Summary: Previous studies have shown that acute treatment with the monoamine stabilizer OSU-6162 can increase the density of accumbal shell D2R-Sigma1R and A2AR-D2R heteroreceptor complexes after cocaine self-administration. Low doses of A2AR agonist and Sigma1R ligand co-treatment significantly increased the density of A2AR-D2R heterocomplexes in the nucleus accumbens shell. However, these neurochemical effects did not affect cocaine self-administration, possibly due to increased release of ATP and adenosine in the nucleus accumbens shell during cocaine self-administration.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Medicine, Research & Experimental
Hidekazu Maruyama, Satoshi Sakai, Laurence Dewachter, Celine Dewachter, Benoit Rondelet, Robert Naeije, Masaki Ieda
Summary: This study found that the p38MAPK/DUSP1 negative feedback loop is impaired in pulmonary arterial hypertension (PAH), leading to excessive activation of p38MAPK and hyperplasia of PA-SMCs. The IP receptor agonist MRE-269 increases DUSP1 expression and inhibits p38MAPK-mediated PA-SMC proliferation. Further elucidation of the mechanism underlying reduced DUSP1 expression would be informative for PAH treatment.
Article
Cell Biology
Perry W. E. Spratt, Ryan P. D. Alexander, Roy Ben-Shalom, Atehsa Sahagun, Henry Kyoung, Caroline M. Keeshen, Stephan J. Sanders, Kevin J. Bender
Summary: The loss of Na(V)1.2 channels in pyramidal neurons leads to intrinsically hyperexcitable neurons, firing high-frequency bursts of action potentials despite reductions in AP size and speed. This cell-intrinsic mechanism may explain why loss-of-function variants in SCN2A gene paradoxically promote seizure.
Review
Endocrinology & Metabolism
Xin Zhao, Minghe Wang, Zhitong Wen, Zhihong Lu, Lijuan Cui, Chao Fu, Huan Xue, Yunfeng Liu, Yi Zhang
Summary: GLP-1 receptor agonists have been widely used in the treatment of type 2 diabetes due to their beneficial effects such as weight loss and protection of islet cells. Studies have shown that they have multiple biological effects on various tissues and organs, leading to potential applications in neuroprotection, cardiovascular protection, and metabolic regulation. The relationship between GLP-1RAs and tumorigenesis in patients with type 2 diabetes is also a subject of growing interest.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Chemistry, Medicinal
Guangsi Meng, Serdar Kuyucak
Summary: This study aims to improve the affinity and blocking capacity of mu-conotoxin KIIIA for Na(V)1.2 through computational studies. After molecular modeling and simulations on the Na(V)1.2-KIIIA complex, the S5R, S6D, and S13K mutations were identified as the most promising for additional contacts, which could enhance the affinity of KIIIA for Na(V)1.2 and enable complete blocking of the channel.
Article
Biochemistry & Molecular Biology
Lisa L. Wilson, Shainnel O. Eans, Insitar Ramadan-Siraj, Maria N. Modica, Giuseppe Romeo, Sebastiano Intagliata, Jay P. McLaughlin
Summary: SI 1/28 is an effective treatment for acute inflammatory pain and chronic neuropathy, without adverse effects at therapeutic doses. This supports the development of S1R antagonists as therapeutics for chronic pain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Seiji Watanabe, Mai Horiuchi, Yuri Murata, Okiru Komine, Noe Kawade, Akira Sobue, Koji Yamanaka
Summary: Organelle contact sites play a multifunctional role in maintaining cellular homeostasis. This study focuses on the mitochondria-associated membranes (MAM), a site where the endoplasmic reticulum (ER) is connected to the mitochondria, and its involvement in amyotrophic lateral sclerosis (ALS). The researchers found that a protein called ATAD3A, which accumulates at the MAM, is required for MAM maintenance and inhibits mitochondrial fragmentation. Targeting the interaction between sigma-1 receptor (a1R) and ATAD3A could be a promising therapeutic strategy for treating mitochondrial dysfunction in ALS.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Pharmacology & Pharmacy
Qiang Wu, Song Chen, Hanchen Zhu, Na Xu, Qianhua Yang, Wenbing Yao, Xiangdong Gao
Summary: This study focused on the characteristics and optimization of GLP-1 receptor endocytosis, using various methods to analyze the effects and screen potential agonists for treatment of type 2 diabetes mellitus. The results showed that endocytosis of GLP-1 receptor-mediated elimination was clathrin-dependent, and agonists biased towards the G protein pathway had less endocytosis. The identified analogue M4 showed prolonged hypoglycaemic activities and a long half-life, making it a potential lead compound for type 2 diabetes mellitus treatment.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Alba Vera-Zambrano, Maria Baena-Nuevo, Susanne Rinne, Marta Villegas-Esguevillas, Bianca Barreira, Gokcen Telli, Angela de Benito-Bueno, Antonio Blazquez Jose, Belen Climent, Francisco Perez-Vizcaino, Carmen Valenzuela, Niels Decher, Teresa Gonzalez, Angel Cogolludo
Summary: The study reveals that the chaperone sigma-1 receptor (S1R) plays a crucial role in modulating the expression and activity of KV1.5 channels, and may serve as a new pharmacological target for pathological conditions associated with KV1.5 channel dysfunction, such as pulmonary arterial hypertension and atrial fibrillation. S1R physically interacts with KV1.5 channels and can regulate their expression and function, with low concentrations of S1R increasing and high concentrations decreasing the activity of KV1.5 channels.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Behavioral Sciences
Parthena Martin, Tangui Maurice, Arnold Gammaitoni, Gail Farfel, Brooks Boyd, Bradley Galer
Summary: Fenfluramine is an effective anti-seizure medication for patients with Dravet syndrome. It acts as a serotonin releaser and positive modulator of the sigma-1 receptor. The study showed that Fenfluramine enhances the low-dose effects of neuro(active) steroids and involves the 5-HT1A and 5-HT2A receptors in memory function.
EPILEPSY & BEHAVIOR
(2022)
Article
Neurosciences
Yang Yu, Quentin K. Tsang, Josue Jaramillo-Polanco, Alan E. Lomax, Stephen J. Vanner, David E. Reed
Summary: Although lacking evidence, cannabis may be used as an adjunct or alternative to opioids. This study found that CB1R agonists can reduce colonic nociception in mice, while CB2R agonists do not have this effect. Combining CB1R and opioid agonists can alleviate pain responses and reduce side effects, which may help in reducing opioid dosage.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Psychiatry
Chunmei Wang, Wenjun Zhou, Yang He, Tiffany Yang, Pingwen Xu, Yongjie Yang, Xing Cai, Julia Wang, Hesong Liu, Meng Yu, Chen Liang, Tingting Yang, Hailan Liu, Makoto Fukuda, Qingchun Tong, Qi Wu, Zheng Sun, Yanlin He, Yong Xu
Summary: Sufficient feeding is essential for animals' survival, and the neurobiological processes regulating food seeking behavior have been partially understood, in which the AgRP -> PVT circuit is crucial for food seeking.
TRANSLATIONAL PSYCHIATRY
(2021)
Article
Biochemistry & Molecular Biology
Guobin Xia, Yong Han, Fantao Meng, Yanlin He, Dollada Srisai, Monica Farias, Minghao Dang, Richard D. Palmiter, Yong Xu, Qi Wu
Summary: The study reveals that chronic high-fat diet reduces GABAergic outputs from AgRP neurons to MC4R(dBNST) neurons, leading to severe mental dysregulation. By modulating GABA(A)R-alpha 5 and 5-HT3R within neurons, the diet-induced issues can be alleviated and weight can be reduced by suppressing food intake.
MOLECULAR PSYCHIATRY
(2021)
Article
Multidisciplinary Sciences
Guolian Ding, Xin Li, Xinguo Hou, Wenjun Zhou, Yingyun Gong, Fuqiang Liu, Yanlin He, Jia Song, Jing Wang, Paul Basil, Wenbo Li, Sichong Qian, Pradip Saha, Jinbang Wang, Chen Cui, Tingting Yang, Kexin Zou, Younghun Han, Christopher Amos, Yong Xu, Li Chen, Zheng Sun
Summary: The nuclear receptors REV-ERB-alpha and REV-ERB-beta in GABAergic neurons control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production, peaking at waking. This mechanism is crucial for understanding the extended dawn phenomenon in type 2 diabetes.
Article
Biochemistry & Molecular Biology
Yanlin He, Xing Cai, Hailan Liu, Krisitine M. Conde, Pingwen Xu, Yongxiang Li, Chunmei Wang, Meng Yu, Yang He, Hesong Liu, Chen Liang, Tingting Yang, Yongjie Yang, Kaifan Yu, Julia Wang, Rong Zheng, Feng Liu, Zheng Sun, Lora Heisler, Qi Wu, Qingchun Tong, Canjun Zhu, Gang Shu, Yong Xu
Summary: The translation discusses how obesity is primarily caused by consuming excessive calories beyond energetic requirements, while the underlying drivers have not been fully defined. The study found that activating specific neural pathways can regulate different types of feeding behavior, driven by either hunger or non-hunger cues.
MOLECULAR PSYCHIATRY
(2021)
Correction
Multidisciplinary Sciences
Guolian Ding, Xin Li, Xinguo Hou, Wenjun Zhou, Yingyun Gong, Fuqiang Liu, Yanlin He, Jia Song, Jing Wang, Paul Basil, Wenbo Li, Sichong Qian, Pradip Saha, Jinbang Wang, Chen Cui, Tingting Yang, Kexin Zou, Younghun Han, Christopher I. Amos, Yong Xu, Li Chen, Zheng Sun
Article
Multidisciplinary Sciences
Yong Han, Guobin Xia, Dollada Srisai, Fantao Meng, Yanlin He, Yali Ran, Yang He, Monica Farias, Giang Hoang, Istvan Toth, Marcelo O. Dietrich, Miao-Hsueh Chen, Yong Xu, Qi Wu
Summary: A subgroup of AgRP neurons regulate energy expenditure by targeting MC4R-expressing neurons in the dlDRN, which in turn innervate nearby serotonergic neurons. This neural circuit controls body weight bidirectionally mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat. Neuronal signaling plays a crucial role in regulating energy expenditure and body weight.
NATURE COMMUNICATIONS
(2021)
Article
Neurosciences
Zhaoyang Li, Wenhao Dong, Xinyuan Zhang, Jun-Mei Lu, Yan-Ai Mei, Changlong Hu
Summary: The study demonstrates that PKC activation inhibits Kv2.2 channel currents and alters their steady-state activation, showing that the function of Kv2.2 is dependent on its phosphorylation state. In cortical slices, PKC activation reduces the frequency of action potentials by regulating Kv2.2 channels.
NEUROSCIENCE BULLETIN
(2022)
Article
Neurosciences
Xing Cai, Hailan Liu, Bing Feng, Meng Yu, Yang He, Hesong Liu, Chen Liang, Yongjie Yang, Longlong Tu, Nan Zhang, Lina Wang, Na Yin, Junying Han, Zili Yan, Chunmei Wang, Pingwen Xu, Qi Wu, Qingchun Tong, Yanlin He, Yong Xu
Summary: The authors demonstrate that the effects of dopamine (DA) on serotonin (5-HT) neurons in a bidirectional manner regulate feeding behavior in mice. Activation of 5-HT neurons by DRD1 contributes to anorexia, which can be prevented by blocking DRD1. These findings provide insights into the interaction between DA and 5-HT neurons in the regulation of feeding behavior, which may be relevant to the pathophysiology of anorexia nervosa (AN).
NATURE NEUROSCIENCE
(2022)
Article
Neurosciences
Pengyu Zong, Jianlin Feng, Zhichao Yue, Yunfeng Li, Gongxiong Wu, Baonan Sun, Yanlin He, Barbara Miller, Albert S. Yu, Zhongping Su, Jia Xie, Yasuo Mori, Bing Hao, Lixia Yue
Summary: Enhanced excitotoxicity mediated by TRPM2-NMDAR coupling is identified as a novel mechanism underlying neuronal death in ischemic stroke, providing a potential therapeutic target.
Article
Anatomy & Morphology
Yumin Zhu, Xuefeng Zhang, Changlong Hu
Summary: Recent studies in mouse models have shown that the multi-cellular rosette structure of the adrenal zona glomerulosa (ZG) is crucial for aldosterone production by ZG cells. However, the rosette structure of human ZG has remained unclear. This study investigated the rosette structure of human adrenal with and without aldosterone-producing cell clusters (APCCs) and found that cells in APCCs form larger rosettes through enhanced adherens junctions. This study provides the first detailed characterization of the rosette structure of human adrenal ZG and suggests that the multi-cellular rosette structure may also be necessary for aldosterone production in APCCs.
JOURNAL OF ANATOMY
(2023)
Article
Biochemical Research Methods
Sudipa Maity, Meredith G. Mayer, Qingbo Shu, Hellmers Linh, Duran Bao, Robert Blair, Yanlin He, Christopher J. Lyon, Tony Y. Hu, Tracy Fischer, Jia Fan
Summary: Neurologic manifestations are common complications of COVID-19, but little is known about the neuropathogenesis of the disease. To understand its impact on the brain, researchers used mass-spectrometry-based proteomics to study cerebrospinal fluid (CSF) proteins from Rhesus Macaque and African Green Monkeys. The results showed significant differences between infected and uninfected monkeys, suggesting altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. Dysregulated CSF proteins were found to be associated with neurodegenerative disorders, hemostasis, and innate immune responses, indicating their potential role in neuroinflammatory responses following COVID-19.
MOLECULAR & CELLULAR PROTEOMICS
(2023)
Article
Multidisciplinary Sciences
Bing Feng, Hesong Liu, Ila Mishra, Clemens Duerrschmid, Peiyu Gao, Pingwen Xu, Chunmei Wang, Yanlin He
Summary: Asprosin, a recently discovered adipokine, activates AgRP neurons in the ARH through binding to Ptprd, and the SK channel plays a crucial role in mediating this effect. Deficiency or elevation of circulating asprosin affects the SK current in AgRPARH neurons, and deletion of SK3 blocks asprosin-induced activation of AgRPARH neurons and overeating.
Article
Oncology
Huoqiang Wang, Yi Li, Jiexi Han, Qin Lin, Long Zhao, Qiang Li, Juan Zhao, Haohao Li, Yiran Wang, Changlong Hu
Summary: This study aimed to develop a machine learning-based automatic analysis method for the diagnosis of early-stage lung cancer using PET/CT data. A retrospective cohort study was conducted using PET/CT data from 187 cases of lung cancer and 190 cases of benign pulmonary nodules. The performance of the machine learning-based PET/CT model was tested and validated in two separate cohorts.
FRONTIERS IN ONCOLOGY
(2023)
Article
Neurosciences
Yuqi Wang, Yuchen Zhang, Jiawei Hu, Chengfang Pan, Yiming Gao, Qingzhuo Liu, Wendong Xu, Lei Xue, Changlong Hu
Summary: Glucocorticoids rapidly activate Kv2.2 channels through non-genomic signaling pathways, suppress neuronal excitability, and inhibit synaptic transmission and plasticity.
NEUROBIOLOGY OF STRESS
(2024)
Article
Multidisciplinary Sciences
Yong Han, Guobin Xia, Yanlin He, Yang He, Monica Farias, Yong Xu, Qi Wu
Summary: This study identified a group of dopamine neurons located in the caudal ventral tegmental area that suppress food intake through enhanced satiation response by directly innervating DRD1-expressing neurons in the lateral parabrachial nucleus. Acute inhibition of these neurons before feeding bout termination significantly suppresses satiety and prolongs feeding, while activation of DRD1(LPBN) neurons inhibits feeding. Genetic deletion of Drd1 in LPBN leads to increased food intake and weight gain. Furthermore, DRD1(LPBN) signaling is crucial for methylphenidate-induced hypophagia.