Pharmacological Reports最新文献

{"title":"Psilocybin and the glutamatergic pathway: implications for the treatment of neuropsychiatric diseases.","authors":"Izabela Szpręgiel, Agnieszka Bysiek","doi":"10.1007/s43440-024-00660-y","DOIUrl":"10.1007/s43440-024-00660-y","url":null,"abstract":"<p><p>In recent decades, psilocybin has gained attention as a potential drug for several mental disorders. Clinical and preclinical studies have provided evidence that psilocybin can be used as a fast-acting antidepressant. However, the exact mechanisms of action of psilocybin have not been clearly defined. Data show that psilocybin as an agonist of 5-HT2A receptors located in cortical pyramidal cells exerted a significant effect on glutamate (GLU) extracellular levels in both the frontal cortex and hippocampus. Increased GLU release from pyramidal cells in the prefrontal cortex results in increased activity of γ-aminobutyric acid (GABA)ergic interneurons and, consequently, increased release of the GABA neurotransmitter. It seems that this mechanism appears to promote the antidepressant effects of psilocybin. By interacting with the glutamatergic pathway, psilocybin seems to participate also in the process of neuroplasticity. Therefore, the aim of this mini-review is to discuss the available literature data indicating the impact of psilocybin on glutamatergic neurotransmission and its therapeutic effects in the treatment of depression and other diseases of the nervous system.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1297-1304"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472213","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":"Obesity-related drug transporter expression alterations in human liver and kidneys.","authors":"Katarzyna Kosicka-Noworzyń, Aleksandra Romaniuk-Drapała, Yi-Hua Sheng, Christine Yohn, Luigi Brunetti, Leonid Kagan","doi":"10.1007/s43440-024-00665-7","DOIUrl":"10.1007/s43440-024-00665-7","url":null,"abstract":"<p><strong>Background: </strong>Pathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug's PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters.</p><p><strong>Methods: </strong>Human liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25 kg/m²) and the study group (overweight/obese subjects; BMI ≥ 25 kg/m²). Real-time quantitative PCR was performed for the analysis of 84 drug transporters.</p><p><strong>Results: </strong>Our results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1.</p><p><strong>Conclusions: </strong>The observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1429-1442"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472212","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":"mGlu4R, mGlu7R, and mGlu8R allosteric modulation for treating acute and chronic neurodegenerative disorders.","authors":"Helena Domin, Grzegorz Burnat","doi":"10.1007/s43440-024-00657-7","DOIUrl":"10.1007/s43440-024-00657-7","url":null,"abstract":"<p><p>Neuroprotection, defined as safeguarding neurons from damage and death by inhibiting diverse pathological mechanisms, continues to be a promising approach for managing a range of central nervous system (CNS) disorders, including acute conditions such as ischemic stroke and traumatic brain injury (TBI) and chronic neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). These pathophysiological conditions involve excessive glutamatergic (Glu) transmission activity, which can lead to excitotoxicity. Inhibiting this excessive Glu transmission has been proposed as a potential therapeutic strategy for treating the CNS disorders mentioned. In particular, ligands of G protein-coupled receptors (GPCRs), including metabotropic glutamatergic receptors (mGluRs), have been recognized as promising options for inhibiting excessive Glu transmission. This review discusses the complex interactions of mGlu receptors with their subtypes, including the formation of homo- and heterodimers, which may vary in function and pharmacology depending on their protomer composition. Understanding these intricate details of mGlu receptor structure and function enhances researchers' ability to develop targeted pharmacological interventions, potentially offering new therapeutic avenues for neurological and psychiatric disorders. This review also summarizes the current knowledge of the neuroprotective potential of ligands targeting group III mGluRs in preclinical cellular (in vitro) and animal (in vivo) models of ischemic stroke, TBI, PD, AD, and MS. In recent years, experiments have shown that compounds, especially those activating mGlu4 or mGlu7 receptors, exhibit protective effects in experimental ischemia models. The discovery of allosteric ligands for specific mGluR subtypes has led to reports suggesting that group III mGluRs may be promising targets for neuroprotective therapy in PD (mGlu4R), TBI (mGlu7R), and MS (mGlu8R).</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1219-1241"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351790","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":"Synergistic effect of antibiotics, α-linolenic acid and solvent type against Staphylococcus aureus biofilm formation.","authors":"Karolina Knap, Konrad Kwiecień, Dorota Ochońska, Katarzyna Reczyńska-Kolman, Elżbieta Pamuła, Monika Brzychczy-Włoch","doi":"10.1007/s43440-024-00669-3","DOIUrl":"10.1007/s43440-024-00669-3","url":null,"abstract":"<p><strong>Background: </strong>A promising approach to the treatment of bacterial infections involves inhibiting the quorum sensing (QS) mechanism to prevent the formation and growth of bacterial biofilm. While antibiotics are used to kill remaining bacteria, QS inhibitors (QSIs) allow for antibiotic doses to be reduced. This study focuses on evaluating the synergy between gentamicin sulphate (GEN), tobramycin (TOB), or azithromycin (AZM) with linolenic acid (LNA) against the formation of an early Staphylococcus aureus biofilm.</p><p><strong>Methods: </strong>Minimum biofilm inhibitory concentration (MBIC) was determined using the resazurin reduction assay for all antibiotics and LNA. The reduction of biofilm mass was assessed using the crystal violet (CV) assay. We have also evaluated the effect of dimethyl sulfoxide with TWEEN (DMSO_T) on early biofilm formation. Synergy was determined by metabolic activity assay and fractional biofilm inhibitory concentration (FBIC).</p><p><strong>Results: </strong>DMSO_T at a concentration of 1% enhanced early biofilm formation, but also decreased the doses of antibiotic needed to reduce the biofilm by up to 8 times. Adding LNA at a concentration of 32 µg/ml or 64 µg/ml allowed up to a 32-fold reduction of antibiotic doses for GEN and TOB and a 4-fold reduction for AZM.</p><p><strong>Conclusions: </strong>LNA's use in combination with various antibiotics could reduce their doses and help fight drug-resistant bacteria in the biofilm.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1456-1469"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522564","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":"Targeting glucocorticoid receptor signaling pathway for treatment of stress-related brain disorders.","authors":"Tansu Göver, Michal Slezak","doi":"10.1007/s43440-024-00654-w","DOIUrl":"10.1007/s43440-024-00654-w","url":null,"abstract":"<p><p>The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in governing stress-related disorders such as major depressive disorder (MDD), anxiety, and post-traumatic stress disorder. Chronic stress or early life trauma, known risk factors of disease, alter HPA axis activity and pattern of glucocorticoid (GC) secretion. These changes have consequences for physiological processes controlled by glucocorticoid receptor (GR) signaling, such as immune response and metabolism. In the brain, the aberrant GR signaling translates to altered behavior, making the GR pathway a viable target for therapies of stress-related disorders. One of the crucial elements of the pathway is FKBP5, a regulator of GR sensitivity and feedback control within the HPA axis, in which genetic variants were shown to moderate the risk of developing psychiatric conditions. The difficulty in targeting the GR-FKBP5 pathway stems from tailoring the intervention to specific brain regions and cell types, in the context of personalized genetic variations in GR and GR-associated genes, like FKBP5. The development of selective inhibitors, antagonists, and approaches based on targeted protein degradation offer insights into mechanistic aspects of disease and pave the way for improved therapy. These strategies can be employed either independently or in conjunction with conventional medications. Concomitant advancements in personalized drug screening (e.g. in vitro models exploiting induced pluripotent stem cells, iPSCs) bring the potential for optimization of therapy aiming to rescue central deficits originating from the HPA imbalance. In this mini-review, we discuss potential therapeutic strategies targeting GR signaling in stress-related disorders, with a focus on personalized approaches and advancements in drug development.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1333-1345"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366183","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":"Interactions between metabotropic glutamate and CB1 receptors: implications for mood, cognition, and synaptic signaling based on data from mGluR and CB1R-targeting drugs.","authors":"Katarzyna Stachowicz","doi":"10.1007/s43440-024-00612-6","DOIUrl":"10.1007/s43440-024-00612-6","url":null,"abstract":"<p><p>Metabotropic glutamate receptors (mGluRs) are part of the G protein-coupled receptors (GPCRs) family. They are coupled to G_αq (group I) or G_i/o (groups II and III) proteins, which result in the generation of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP₃) or the inhibition of adenylyl cyclase, respectively. mGluRs have been implicated in anxiety, depression, learning, and synaptic plasticity. Similarly, CB1 cannabinoid receptors (CB1Rs), also GPCRs, play roles in cognitive function and mood regulation through G_αi/o-mediated inhibition of adenylyl cyclase. Both mGluRs and CB1Rs exhibit surface labeling and undergo endocytosis. Given the similar cellular distribution and mechanisms of action, this review complies with fundamental data on the potential interactions and mutual regulation of mGluRs and CB1Rs in the context of depression, anxiety, and cognition, providing pioneering insights into their interplay.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1286-1296"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470113","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":"Fiber photometry in neuroscience research: principles, applications, and future directions.","authors":"Michal Kielbinski, Joanna Bernacka","doi":"10.1007/s43440-024-00646-w","DOIUrl":"10.1007/s43440-024-00646-w","url":null,"abstract":"<p><p>In recent years, fluorescent sensors are enjoying a surge of popularity in the field of neuroscience. Through the development of novel genetically encoded sensors as well as improved methods of detection and analysis, fluorescent sensing has risen as a new major technique in neuroscience alongside molecular, electrophysiological, and imaging methods, opening up new avenues for research. Combined with multiphoton microscopy and fiber photometry, these sensors offer unique advantages in terms of cellular specificity, access to multiple targets - from calcium dynamics to neurotransmitter release to intracellular processes - as well as high capability for in vivo interrogation of neurobiological mechanisms underpinning behavior. Here, we provide a brief overview of the method, present examples of its integration with other tools in recent studies ranging from cellular to systems neuroscience, and discuss some of its principles and limitations, with the aim of introducing new potential users to this rapidly developing and potent technique.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1242-1255"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133444","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":"ONC206, an imipridone derivative, demonstrates anti-colorectal cancer activity against stem/progenitor cells in 3D cell cultures and in patient-derived organoids.","authors":"Alissar Monzer, Fatima Ghamlouche, Kevork Wakimian, Farah Ballout, Samar Al Bitar, Amani Yehya, Mariam Kanso, Nour Saheb, Ayman Tawil, Samer Doughan, Maher Hussein, Deborah Mukherji, Walid Faraj, Joshua E Allen, Varun V Prabhu, Tamara Abou-Antoun, Hala Gali-Muhtasib, Wassim Abou-Kheir","doi":"10.1007/s43440-024-00676-4","DOIUrl":"https://doi.org/10.1007/s43440-024-00676-4","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains one of the most frequently diagnosed and life-threatening malignancies worldwide. CRC's high recurrence rates and drug resistance have been correlated with a subpopulation of dormant slowly dividing cells termed CRC stem cells (CCSCs). Consequently, there is a pressing need to identify novel therapeutics that can effectively and specifically target CCSCs. Imipridones are promising structurally related anticancer molecules that showed efficacy in several solid and hematological preclinical models and phase I/II/III clinical trials. This study mainly aimed to assess the potential anticancer effects of ONC206, an imipridone derivative, on CRC three-dimensional in vitro culture systems using HCT116 and HT29 cells. Importantly, the study aimed at using CRC patient-derived organoids (PDOs) to test the potential therapeutic effect of ONC206.</p><p><strong>Methods: </strong>Two-dimensional cell proliferation, viability, migration, and invasion assays were used to assess the effects of ONC206 on two colorectal cancer cell lines, HCT116 and HT29, in vitro. Immunofluorescence imaging, flow cytometry, and western blot analysis were also performed to investigate the mechanism of action of this drug. Sphere formation assay and CRC PDOs were employed to evaluate the effect of ONC206 on CRC cells in a 3D setting and specifically its potency in targeting the CRC stem/progenitor subpopulation of cells.</p><p><strong>Results: </strong>Our results showed that ONC206 was more potent than its parental molecule ONC201 in inhibiting the proliferation and viability of HCT116 and HT29 cells. Moreover, ONC206 significantly reduced the migration and invasion indices of CRC cells. These effects were accompanied by an increase in reactive oxygen species (ROS) production, sub-G1 phase accumulation, and apoptosis in HCT116 and HT29 cells. Furthermore, ONC206 significantly inhibited the 3D colonospheres growth and self-renewal ability of CCSCs more potently than ONC201, which was associated with a decrease in the expression of CSC-related markers. Lastly, ONC206 significantly reduced the growth of organoids derived from CRC patients.</p><p><strong>Conclusion: </strong>Collectively, our findings demonstrate that ONC206 is an effective anticancer molecule capable of targeting CCSCs, which may represent a novel therapeutic strategy that can overcome CRC resistance and recurrence.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648138","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":"Progress in the study of anti-tumor effects and mechanisms of vitexin.","authors":"Qiming Yang, Rui Huan, Defeng Meng, Junwei Qi, Lei Xia","doi":"10.1007/s43440-024-00664-8","DOIUrl":"https://doi.org/10.1007/s43440-024-00664-8","url":null,"abstract":"<p><p>Vitexin (apigenin-8-C-beta-D-glucopyranoside) is a natural flavonoid derivative with anti-cancer, antioxidant, anti-inflammatory, antihypertensive, anti-asthma, anti-epilepsy, and other therapeutic effects. It is extracted from pearl millet, hawthorn, pigeon bean, mung bean, and other medicinal plants. Vitexin has received widespread attention because of its significant anti-tumor effect. It induces apoptosis and anti-tumor angiogenesis, inhibits tumor cell migration and invasion, regulates tumor cell autophagy and immunity, and increases patient sensitivity to radiotherapy and chemotherapy. It has a significant anti-tumor effect on breast, prostate, liver, cervical, and colon cancers, gliomas, and other malignant tumors. This review demonstrates the latest research progress on the anti-tumor effects and potential mechanisms of vitexin. It summarizes its anti-tumor mechanism to provide new theoretical support and reference for cancer treatment.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546682","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":"Effects of puerarin on gait disturbance in a 6-hydroxydopamine mouse model of Parkinson's disease.","authors":"Na-Hyun Kim, Yukiori Goto, Young-A Lee","doi":"10.1007/s43440-024-00673-7","DOIUrl":"https://doi.org/10.1007/s43440-024-00673-7","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a neurodegenerative disorder caused by dopamine (DA) neuronal dysfunction. Although DA agonists and N-methyl-D-aspartate receptor (NMDAR) antagonists are used to treat PD, chronic use causes severe side effects. Puerarin (PUE) is a natural bioactive compound that affects the DA system; however, its effect on PD-associated motor functions is unknown. Therefore, we investigated whether PUE treatment in a 6-hydroxydopamine (6-OHDA) PD mouse model affects motor dysfunction.</p><p><strong>Methods: </strong>Adult male ICR mice received unilateral 6-OHDA microinfusion into the right medial forebrain bundle. After a 2-week recovery period, PUE (20 or 50 mg/kg) or the vehicle (saline, VEH) was administered intraperitoneally once daily for 21 days. Motor dysfunction was assessed using the locomotion, gait cycle, and rotation tests. Local field potentials (LFPs) were measured in the substantia nigra compacta (SNc), striatum (STR), subthalamic nucleus (STN), and primary motor cortex.</p><p><strong>Results: </strong>6-OHDA-lesioned PD mice showed increased gait cycle disturbance and unidirectional rotation. PUE treatment ameliorated the gait cycle disturbance, but not unidirectional rotation of PD mice. These effects differed with DA agonist treatment (which improved PD symptoms) and NMDAR antagonist treatment (which aggravated PD symptoms). Moreover, locomotion was increased only in NMDAR antagonist treatment. PUE treatment induced no changes in the attenuated LFP of the beta wave in the STR and STN, and SNc-STN delta-wave coherence was shown in PD animals.</p><p><strong>Conclusions: </strong>This study suggests that PUE is a beneficial co-therapeutic agent for alleviating gait cycle disturbance in PD symptoms.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522563","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}