Pharmacological Reports最新文献

{"title":"Psilocybin in pharmacotherapy of obsessive-compulsive disorder.","authors":"Maja Owe-Larsson, Katarzyna Kamińska, Barbara Buchalska, Dagmara Mirowska-Guzel, Agnieszka Cudnoch-Jędrzejewska","doi":"10.1007/s43440-024-00633-1","DOIUrl":"10.1007/s43440-024-00633-1","url":null,"abstract":"<p><p>Obsessive-compulsive disorder (OCD) is a chronic mental disease that affects approximately 2% of the population. Obsessions and compulsions are troublesome for patients and may disturb their everyday activities. The pathogenesis of this disease is still not fully elucidated, but dysfunctions of serotonin-, dopamine- and glutamate-mediated neurotransmission together with early maladaptive schemas seem of importance. Pharmacological treatment includes drugs affecting the serotoninergic, dopaminergic, and glutamatergic systems, such as selective serotonin reuptake inhibitors (SSRIs). Providing that up to 40% of patients with OCD are resistant to the currently available medications, there is a need for novel and effective therapies. Recent discoveries suggest that psilocybin, a non-physically addictive psychoactive substance, may ameliorate disease symptoms. When used in appropriate doses and under strict clinical control, psilocybin appears as a valuable treatment for OCD. This narrative article provides a thorough overview of OCD's etiology, current treatment options, and the emerging evidence supporting psilocybin's efficacy in managing OCD symptoms.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"911-925"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering the unique characteristics of different groups of 5-HT_5AR ligands with reference to their interaction with the target protein.","authors":"Szymon K Kordylewski, Ryszard Bugno, Andrzej J Bojarski, Sabina Podlewska","doi":"10.1007/s43440-024-00622-4","DOIUrl":"10.1007/s43440-024-00622-4","url":null,"abstract":"<p><strong>Background: </strong>The serotonin 5-HT_5A receptor has attracted much more research attention, due to the therapeutic potential of its ligands being increasingly recognized, and the possibilities that lie ahead of these findings. There is a growing body of evidence indicating that these ligands have procognitive, pro-social, and anti-depressant properties, which offers new avenues for the development of treatments that could address socially important conditions related to the malfunctioning of the central nervous system. The aim of our study was to unravel the molecular determinants for 5-HT_5AR ligands that govern their activity towards the receptor.</p><p><strong>Methods: </strong>In response to the need for identification of molecular determinants for 5-HT_5AR activity, we prepared a comprehensive collection of 5-HT_5AR ligands, carefully gathering literature and patent data. Leveraging molecular modeling techniques, such as pharmacophore hypothesis development, docking, and molecular dynamics simulations enables to gain valuable insights into the specific interactions of 5-HT_5AR ligand groups with the receptor.</p><p><strong>Results: </strong>The obtained comprehensive set of 2160 compounds was divided into dozens of subsets, and a pharmacophore model was developed for each group. The results from the docking and molecular dynamics simulations have enabled the identification of crucial ligand-protein interactions that are essential for the compound's activity towards 5-HT_5AR.</p><p><strong>Conclusions: </strong>The findings from the molecular modeling study provide valuable insights that can guide medicinal chemists in the development of new 5-HT_5AR ligands. Considering the pharmacological significance of these compounds, they have the potential to become impactful treatments for individuals and communities in the future. Understanding how different crystal/cryo-EM structures of 5-HT_5AR affect molecular modeling experiments could have major implications for future computational studies on this receptor.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1130-1146"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The possible pathogenesis of liver fibrosis: therapeutic potential of natural polyphenols.","authors":"Chengu Niu, Jing Zhang, Patrick I Okolo","doi":"10.1007/s43440-024-00638-w","DOIUrl":"10.1007/s43440-024-00638-w","url":null,"abstract":"<p><p>Liver fibrosis is the formation of a fibrous scar resulting from chronic liver injury, independently from etiology. Although many of the mechanical details remain unknown, activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Extracellular mechanisms such as apoptotic bodies, paracrine stimuli, inflammation, and oxidative stress are critical in activating HSCs. The potential for liver fibrosis to reverse after removing the causative agent has heightened interest in developing antifibrotic therapies. Polyphenols, the secondary plant metabolites, have gained attention because of their health-beneficial properties, including well-recognized antioxidant and anti-inflammatory activities, in the setting of liver fibrosis. In this review, we present an overview of the mechanisms underlying liver fibrosis with a specific focus on the activation of resident HSCs. We highlight the therapeutic potential and promising role of natural polyphenols to mitigate liver fibrosis pathogenesis, focusing on HSCs activation. We also discuss the translational gap from preclinical findings to clinical treatments involved in natural polyphenols in liver fibrosis.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"944-961"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced hippocampal TIAM2S expression alleviates cognitive deficits in Alzheimer's disease model mice.","authors":"Kuan-Chin Sung, Li-Yun Wang, Che-Chuan Wang, Chun-Hsien Chu, H Sunny Sun, Ya-Hsin Hsiao","doi":"10.1007/s43440-024-00623-3","DOIUrl":"10.1007/s43440-024-00623-3","url":null,"abstract":"<p><strong>Background: </strong>Dendritic spine dysfunction is a key feature of Alzheimer's disease (AD) pathogenesis. Human T-cell lymphoma invasion and metastasis 2 (TIAM2) is expressed in two isoforms, the full length (TIAM2L) and a short transcript (TIAM2S). Compared to TIAM2L protein, which is undetectable, TIAM2S protein is abundant in human brain tissue, especially the hippocampus, and can promote neurite outgrowth in our previous findings. However, whether enhanced hippocampal TIAM2S expression can alleviate cognitive deficits in Alzheimer's disease model mice remains unclear.</p><p><strong>Methods: </strong>We crossbred 3xTg-AD with TIAM2S mice to generate an AD mouse model that carries the human TIAM2S gene (3xTg-AD/TIAM2S mice). The Morris water maze and object location tests assessed hippocampus-dependent spatial memory. Lentiviral-driven shRNA or cDNA approaches were used to manipulate hippocampal TIAM2S expression. Golgi staining and Sholl analysis were utilized to measure neuronal dendrites and dendritic spines in the mouse hippocampi.</p><p><strong>Results: </strong>Compared to 3xTg-AD mice, 3xTg-AD/TIAM2S mice displayed improved cognitive functions. According to the hippocampus is one of the earliest affected brain regions by AD, we further injected TIAM2S shRNA or TIAM2S cDNA into mouse hippocampi to confirm whether manipulating hippocampal TIAM2S expression could affect AD-related cognitive functions. The results showed that the reduced hippocampal TIAM2S expression in 3xTg-AD/TIAM2S mice abolished the memory improvement effect, whereas increased hippocampal TIAM2S levels alleviated cognitive deficits in 3xTg-AD mice. Furthermore, we found that TIAM2S-mediated memory improvement was achieved by regulating dendritic plasticity.</p><p><strong>Conclusions: </strong>These results will provide new insights into connecting TIAM2S with AD and support the notion that TIAM2S should be investigated as potential AD therapeutic targets.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1032-1043"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress of propofol in alleviating cerebral ischemia/reperfusion injury.","authors":"Haijing Zheng, Xian Xiao, Yiming Han, Pengwei Wang, Lili Zang, Lilin Wang, Yinuo Zhao, Peijie Shi, Pengfei Yang, Chao Guo, Jintao Xue, Xinghua Zhao","doi":"10.1007/s43440-024-00620-6","DOIUrl":"10.1007/s43440-024-00620-6","url":null,"abstract":"<p><p>Ischemic stroke is a leading cause of adult disability and death worldwide. The primary treatment for cerebral ischemia patients is to restore blood supply to the ischemic region as quickly as possible. However, in most cases, more severe tissue damage occurs, which is known as cerebral ischemia/reperfusion (I/R) injury. The pathological mechanisms of brain I/R injury include mitochondrial dysfunction, oxidative stress, excitotoxicity, calcium overload, neuroinflammation, programmed cell death and others. Propofol (2,6-diisopropylphenol), a short-acting intravenous anesthetic, possesses not only sedative and hypnotic effects but also immunomodulatory and neuroprotective effects. Numerous studies have reported the protective properties of propofol during brain I/R injury. In this review, we summarize the potential protective mechanisms of propofol to provide insights for its better clinical application in alleviating cerebral I/R injury.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"962-980"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive update on the potential of curcumin to enhance chemosensitivity in colorectal cancer.","authors":"Mahdi Shadnoush, Mehrnaz Momenan, Veronique Seidel, Sascha Tierling, Nayeralsadat Fatemi, Ehsan Nazemalhosseini-Mojarad, Mohammad Tayefeh Norooz, Makan Cheraghpour","doi":"10.1007/s43440-024-00652-y","DOIUrl":"https://doi.org/10.1007/s43440-024-00652-y","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JG26 attenuates ADAM17 metalloproteinase-mediated ACE2 receptor processing and SARS-CoV-2 infection in vitro","authors":"Valentina Gentili, Silvia Beltrami, Doretta Cuffaro, Giorgia Cianci, Gloria Maini, Roberta Rizzo, Marco Macchia, Armando Rossello, Daria Bortolotti, Elisa Nuti","doi":"10.1007/s43440-024-00650-0","DOIUrl":"https://doi.org/10.1007/s43440-024-00650-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>ADAM17 is a metalloprotease implicated in the proteolysis of angiotensin-converting enzyme 2 (ACE2), known to play a critical role in the entry and spread of SARS-CoV-2. In this context, ADAM17 results as a potential novel target for controlling SARS-CoV-2 infection.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this study, we investigated the impact on ACE2 surface expression and the antiviral efficacy against SARS-CoV-2 infection of the selective ADAM17 inhibitor JG26 and its dimeric (compound <b>1</b>) and glycoconjugate (compound <b>2</b>) derivatives using Calu-3 human lung cells.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>None of the compounds exhibited cytotoxic effects on Calu-3 cells up to a concentration of 25 µM. Treatment with JG26 resulted in partial inhibition of both ACE2 receptor shedding and SARS-CoV-2 infection, followed by compound <b>1</b>.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>JG26, an ADAM17 inhibitor, demonstrated promising antiviral activity against SARS-CoV-2 infection, likely attributed to reduced sACE2 availability, thus limiting viral dissemination.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"12 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Group III metabotropic glutamate receptors: guardians against excitotoxicity in ischemic brain injury, with implications for neonatal contexts","authors":"Damian Mielecki, Elżbieta Salińska","doi":"10.1007/s43440-024-00651-z","DOIUrl":"https://doi.org/10.1007/s43440-024-00651-z","url":null,"abstract":"<p>The group III metabotropic glutamate receptors (mGluRs), comprising mGluR4, mGluR6, mGluR7, and mGluR8, offer neuroprotective potential in mitigating excitotoxicity during ischemic brain injury, particularly in neonatal contexts. They are G-protein coupled receptors that inhibit adenylyl cyclase and reduce neurotransmitter release, mainly located presynaptically and acting as autoreceptors. This review aims to examine the differential expression and function of group III mGluRs across various brain regions such as the cortex, hippocampus, and cerebellum, with a special focus on the neonatal stage of development. Glutamate excitotoxicity plays a crucial role in the pathophysiology of brain ischemia in neonates. While ionotropic glutamate receptors are traditional targets for neuroprotection, their direct inhibition often leads to severe side effects due to their critical roles in normal neurotransmission and synaptic plasticity. Group III mGluRs provide a more nuanced and potentially safer approach by modulating rather than blocking glutamatergic transmission. Their downstream signaling cascade results in the regulation of intracellular calcium levels, neuronal hyperpolarization, and reduced neurotransmitter release, effectively decreasing excitotoxic signaling without completely suppressing essential glutamatergic functions. Importantly, the neuroprotective effects of group III mGluRs extend beyond direct modulation of glutamate release influencing glial cell function, neuroinflammation, and oxidative stress, all of which contribute to secondary injury cascades in brain ischemia. This comprehensive analysis of group III mGluRs multifaceted neuroprotective potential provides valuable insights for developing novel therapeutic strategies to combat excitotoxicity in neonatal ischemic brain injury.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"15 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabotropic glutamate receptors—guardians and gatekeepers in neonatal hypoxic-ischemic brain injury","authors":"Damian Mielecki, Ewelina Bratek-Gerej, Elżbieta Salińska","doi":"10.1007/s43440-024-00653-x","DOIUrl":"https://doi.org/10.1007/s43440-024-00653-x","url":null,"abstract":"<p>Injury to the developing central nervous system resulting from perinatal hypoxia–ischemia (HI) is still a clinical challenge. The only approach currently available in clinical practice for severe cases of HI is therapeutic hypothermia, initiated shortly after birth and supported by medications to regulate blood pressure, control epileptic seizures, and dialysis to support kidney function. However, these treatments are not effective enough to significantly improve infant survival or prevent brain damage. The need to create a new effective therapy has focused attention on metabotropic glutamate receptors (mGluR), which control signaling pathways involved in HI-induced neurodegeneration. The complexity of mGluR actions, considering their localization and developmental changes, and the functions of each subtype in HI-evoked brain damage, combined with difficulties in the availability of safe and effective modulators, raises the question whether modulation of mGluRs with subtype-selective ligands can become a new treatment in neonatal HI. Addressing this question, this review presents the available information concerning the role of each of the eight receptor subtypes of the three mGluR groups (group I, II, and III). Data obtained from experiments performed on in vitro and in vivo neonatal HI models show the neuroprotective potential of group I mGluR antagonists, as well as group II and III agonists. The information collected in this work indicates that the neuroprotective effects of manipulating mGluR in experimental HI models, despite the need to create more safe and selective ligands for particular receptors, provide a chance to create new therapies for the sensitive brains of infants at risk.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"31 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JR-AB2-011 induces fast metabolic changes independent of mTOR complex 2 inhibition in human leukemia cells","authors":"Tereza Kořánová, Lukáš Dvořáček, Dana Grebeňová, Kateřina Kuželová","doi":"10.1007/s43440-024-00649-7","DOIUrl":"https://doi.org/10.1007/s43440-024-00649-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>The mechanistic target of rapamycin (mTOR) is a crucial regulator of cell metabolic activity. It forms part of several distinct protein complexes, particularly mTORC1 and mTORC2. The lack of specific inhibitors still hampers the attribution of mTOR functions to these complexes. JR-AB2-011 has been reported as a specific mTORC2 inhibitor preventing mTOR binding to RICTOR, a unique component of mTORC2. We aimed to describe the effects of JR-AB2-011 in leukemia/lymphoma cells, where the mTOR pathway is often aberrantly activated.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The impact of JR-AB2-011 on leukemia/lymphoma cell metabolism was analyzed using the Seahorse platform. AKT phosphorylation at Ser473 was used as a marker of mTORC2 activity. mTOR binding to RICTOR was assessed by co-immunoprecipitation. RICTOR-null cells were derived from the Karpas-299 cell line using CRISPR/Cas9 gene editing.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In leukemia/lymphoma cell lines, JR-AB2-011 induced a rapid drop in the cell respiration rate, which was variably compensated by an increased glycolytic rate. In contrast, an increase in the respiration rate due to JR-AB2-011 treatment was observed in primary leukemia cells. Unexpectedly, JR-AB2-011 did not affect AKT Ser473 phosphorylation. In addition, mTOR did not dissociate from RICTOR in cells treated with JR-AB2-011 under the experimental conditions used in this study. The effect of JR-AB2-011 on cell respiration was retained in RICTOR-null cells.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>JR-AB2-011 affects leukemia/lymphoma cell metabolism via a mechanism independent of mTORC2.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"2 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}