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  • Article

    Charcot–Marie‐Tooth type 2A in vivo models: Current updates

    Authors
    Abati, Elena; Rizzuti, Mafalda; Anastasia, Alessia; Comi, Giacomo Pietro; Corti, Stefania; Rizzo, Federica
    Part of
    Journal of cellular and molecular medicine, 2024-05, Vol.28 (9), p.e18293-n/a
    Abstract
    • Charcot–Marie‐Tooth type 2A (CMT2A) is an inherited sensorimotor neuropathy associated with mutations within the Mitofusin 2 (MFN2) gene. These mutations impair normal mitochondrial functioning via different mechanisms, disturbing the equilibrium between mitochondrial fusion and fission, of mitophagy and mitochondrial axonal transport. Although CMT2A disease causes a significant disability, no resolutive treatment for CMT2A patients to date. In this context, reliable experimental models are essential to precisely dissect the molecular mechanisms of disease and to devise effective therapeutic strategies. The most commonly used models are either in vitro or in vivo, and among the latter murine models are by far the most versatile and popular. Here, we critically revised the most relevant literature focused on the experimental models, providing an update on the mammalian models of CMT2A developed to date. We highlighted the different phenotypic, histopathological and molecular characteristics, and their use in translational studies for bringing potential therapies from the bench to the bedside. In addition, we discussed limitations of these models and perspectives for future improvement.
    Subjects
    animal model; Animal models; Animals; Axonal transport; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - pathology; Charcot-Marie-Tooth Disease - therapy; Charcot–Marie‐Tooth type 2A; Congenital diseases; Disease Models, Animal; Fibroblasts; Genotype & phenotype; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Insects; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Dynamics - genetics; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mitofusin 2; Mitophagy; Molecular modelling; Morphology; Motility; mouse models; Mutation; Neuropathy; Review; Reviews; Sensorimotor system; Swimming; Zebrafish
  • Article

    PRUEBA 2A

    Authors
    ojsadminunicor UNICORDOBA; Érica Alexandra Martínez; Ernesto Forero
    Part of
    Revista MVZ Córdoba, 2024-04, Vol.20 (supl)
    Abstract
    • Lorem ipsum dolor sit amet, consectetuer adipiscing elit. Maecenas porttitor congue massa. Fusce posuere, magna sed pulvinar ultricies, purus lectus malesuada libero, sit amet commodo magna eros quis urna. Nunc viverra imperdiet enim. Fusce est. Vivamus a tellus. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Proin pharetra nonummy pede. Mauris et orci. Aenean nec lorem. In porttitor. Donec laoreet nonummy augue. Suspendisse dui purus, scelerisque at, vulputate vitae, pretium mattis, nunc. Mauris eget neque at sem venenatis eleifend. Ut nonummy.
    Subjects
    Prueba
  • Article

    Introduction of robotic pancreatoduodenectomy following phase 2a IDEAL guidelines

    Authors
    Mise, Yoshihiro; Miyashita, Mamiko; Yoshioka, Ryuji; Kawano, Fumihiro; Takeda, Yoshinori; Ichida, Hirofumi; Saiura, Akio
    Part of
    PloS one, 2024-05, Vol.19 (5), p.e0302848-e0302848
    Abstract
    • Robotic pancreatoduodenectomy (RPD) is a newly introduced procedure, which is still evolving and lacks standardization. An objective assessment is essential to investigate the feasibility of RPD. The current study aimed to assess our initial ten cases of RPD based on IDEAL (Idea, Development, Exploration, Assessment, and Long-term study) guidelines. This was a prospective phase 2a study following the IDEAL framework. Ten consecutive cases of RPD performed by two surgeons with expertise in open procedures at a single center were assigned to the study. With objective evaluation, each case was classified into four grades according to the achievements of the procedures. Errors observed in the previous case were used to inform the procedure in the next case. The surgical outcomes of the ten cases were reviewed. The median total operation time was 634 min (interquartile range [IQR], 594-668) with a median resection time of 363 min (IQR, 323-428) and reconstruction time of 123 min (IQR, 107-131). The achievement of the whole procedure was graded as A, "successful", in two patients. In two patients, reconstruction was performed with a mini-laparotomy due to extensive pneumoperitoneum, probably caused by insertion of a liver retractor from the xyphoid. Major postoperative complications occurred in two patients. One patient, in whom the jejunal limb was elevated through the Treitz ligament, had a bowel obstruction and needed to undergo re-laparotomy. RPD is feasible when performed by surgeons experienced in open procedures. Specific considerations are needed to safely introduce RPD.
    Subjects
    Adult; Aged; Biology and Life Sciences; Female; Gastrointestinal diseases; Humans; Liver; Male; Medical colleges; Medical research; Medicine and Health Sciences; Medicine, Experimental; Methods; Middle Aged; Operative Time; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - surgery; Pancreaticoduodenectomy; Pancreaticoduodenectomy - adverse effects; Pancreaticoduodenectomy - methods; People and Places; Practice guidelines (Medicine); Prospective Studies; Robotic surgery; Robotic Surgical Procedures - methods; Surgeons; Technology application; Treatment Outcome
  • Article

    The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction

    Authors
    Gao, Xiaopan; Wang, Bei; Zhu, Kaixiang; Wang, Linyue; Qin, Bo; Shang, Kun; Ding, Wei; Wang, Jianwei; Cui, Sheng
    Part of
    Nature communications, 2024-05, Vol.15 (1), p.4176-4176
    Abstract
    • SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A's ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.
    Subjects
    Actin; Actins - metabolism; Binding; Cryoelectron Microscopy; Crystallography; Crystallography, X-Ray; Electron microscopy; Enterovirus A, Human - genetics; Enterovirus A, Human - metabolism; Enterovirus Infections - metabolism; Enterovirus Infections - virology; Enteroviruses; Histone Methyltransferases; Histone-Lysine N-Methyltransferase - chemistry; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Human diseases; Humans; Interferometry; Models, Molecular; Molecular interactions; Molecular modelling; Protease; Protein Binding; Proteinase; Replication; Viral Proteins - chemistry; Viral Proteins - genetics; Viral Proteins - metabolism; Viral replication; Virus Replication; X-ray crystallography
  • Article

    Synaptic vesicle protein 2A mitigates parthanatos via apoptosis‐inducing factor in a rat model of pharmacoresistant epilepsy

    Authors
    Li, Chen; Wang, Ziqi; Ren, Mianmian; Ren, Siying; Wu, Guofeng; Wang, Likun
    Part of
    CNS neuroscience & therapeutics, 2024-05, Vol.30 (5), p.e14778-n/a
    Abstract
    • Aims Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure‐induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis‐inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF. Methods An intraperitoneal injection of lithium chloride‐pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF. Results Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ‐H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction. Significance SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE. This study showed that synaptic vesicle protein 2A, manipulated by lentivirus, acts as a neuroprotective target by blocking the parthanatos pathway via binding with apoptosis‐inducing factor, ultimately improving epileptic seizures in pharmacoresistant epilepsy rats.
    Subjects
    Alzheimer's disease; Animals; Anticonvulsants - pharmacology; Apoptosis; Apoptosis Inducing Factor - metabolism; Apoptosis-inducing factor; Biotechnology; Convulsions & seizures; Disease Models, Animal; Drug Resistant Epilepsy - drug therapy; Drug Resistant Epilepsy - metabolism; Epilepsy; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Lithium; Lithium chloride; Male; Medical research; Membrane Glycoproteins - metabolism; Nerve Tissue Proteins - metabolism; Nuclear transport; Original; parthanatos; pharmacoresistant epilepsy; Phenobarbital; Phenytoin; Pilocarpine; Poly(ADP-ribose) polymerase; Proteins; Rats; Rats, Sprague-Dawley; Seizures; Surveillance; synaptic vesicle protein 2A; Therapeutic targets
  • Article

    p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

    Authors
    Shanks, Hayley R C; Chen, Kewei; Reiman, Eric M; Blennow, Kaj; Cummings, Jeffrey L; Massa, Stephen M; Longo, Frank M; Börjesson-Hanson, Anne; Windisch, Manfred; Schmitz, Taylor W
    Part of
    Nature medicine, 2024-05
    Abstract
    • p75 neurotrophin receptor (p75 ) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75 with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75 with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .
  • Article

    Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma

    Authors
    Chen, Yijing; Zhang, Yan; Duo, Shi; Liu, Wen; Luo, Bing
    Part of
    Virus genes, 2024-05
    Abstract
    • O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers. However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC. The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.
  • Article

    The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity

    Authors
    Xuan, Yi-Fei; Lu, Shan; Ou, Ying-Jie; Bao, Xu-Bin; Huan, Xia-Juan; Song, Shan-Shan; Miao, Ze-Hong; Wang, Ying-Qing
    Part of
    Biochemical and biophysical research communications, 2024-07, Vol.716, p.150011-150011, Article 150011
    Abstract
    • Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.
      • MAT2A inhibitor and METTL3 inhibitor exert synergistic anti-tumor effect.
      • The combination is universally effective in cancer cells from several tissues.
      • The effect of combination is not limited by MTAP status.
      • The combination promotes apoptosis by downregulating m6A level and PI3K/AKT pathway.
    Subjects
    Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Combination therapy; Drug Synergism; Enzyme Inhibitors - pharmacology; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; m6A; MAT2A inhibitor; Methionine Adenosyltransferase - antagonists & inhibitors; Methionine Adenosyltransferase - genetics; Methionine Adenosyltransferase - metabolism; Methyltransferases - antagonists & inhibitors; Methyltransferases - metabolism; METTL3 inhibitor; Mice; Mice, Inbred BALB C; Mice, Nude; NSCLC; Xenograft Model Antitumor Assays
  • Article

    Recognition of antiepileptic brivaracetam by synaptic vesicle protein 2A

    Authors
    Liu, Shujin; Chao, Yulin; Zhou, Zixuan; Yang, Chuanhui; Zhu, Zhini; Wang, Yuwei; Qu, Qianhui
    Part of
    Cell discovery, 2024-05, Vol.10 (1), p.56-56
    Subjects
    Correspondence
  • Article

    How frequent the Landsat 8/9-Sentinel 2A/B virtual constellation observed the earth for continuous time series monitoring

    Authors
    Kai Jia; Umut Hasan; Hao Jiang; Boxiong Qin; Shuisen Chen; Dan Li; Chongyang Wang; Yue Deng; Jie Shen
    Part of
    International journal of applied earth observation and geoinformation, 2024-06, Vol.130, p.103899
    Abstract
    • The synergy of Landsat 8/9 and Sentinel 2A/B in the formation of a virtual constellation marked a significant advancement in high spatiotemporal time series monitoring. However, the presence of contaminations, including clouds, snow/ice, and shadows, had notably impacted the quality of image acquisition. The practical monitoring capacity of this constellation, particularly in terms of time scale, had not been exactly investigated. Therefore, this study proposed an evaluation method for the minimum time scale, accounting for the temporal discontinuity induced by contaminations. It was found that while the average revisit period of constellation was as short as 2.7 days, the effective period degraded to 5.5 days after the removal of contaminated observations. In considering continuous monitoring along with time series, the practical monitoring scale, referred to as the ideal period, was significantly longer than the effective period. Consequently, it was observed that roughly 80 % of global land (excluding Polar regions) could achieve a minimum time scale of only weekly monitoring. These findings underscored the potential overestimation of the practical capacities for the virtual constellation in previous knowledge, offering valuable insights for policymakers in determining the appropriate frequency and timing of satellite applications.
    Subjects
    Continuous time series; Landsat 8/9; Minimum time scale; Revisit period; Sentinel 2
  • Article

    Adenosine A[sub.2A] Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson’s Disease

    Authors
    Nunes, Ana Carla L; Carmo, Marta; Behrenswerth, Andrea; Canas, Paula M; Agostinho, Paula; Cunha, Rodrigo A
    Part of
    International journal of molecular sciences, 2024-05, Vol.25 (9)
    Abstract
    • Adenosine A[sub.2A] receptor (A[sub.2A]R) antagonists are the leading nondopaminergic therapy to manage Parkinson’s disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A[sub.2A]R antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP[sup.+] in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A[sub.2A]R antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP[sup.+] infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP[sup.+] infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A[sub.2A]R-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A[sub.2A]R antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.
    Subjects
    Adenosine; Ethylenediaminetetraacetic acid; Neurons; Pharmaceutical industry
  • Article

    Metabolism, Disposition, Excretion, and Potential Transporter Inhibition of 7–16, an Improving 5-HT[sub.2A] Receptor Antagonist and Inverse Agonist for Parkinson’s Disease

    Authors
    Hu, Zhengping; Wang, Wenyan; Yang, Huijie; Zhao, Fengjuan; Sha, Chunjie; Mi, Wei; Yin, Shuying; Wang, Hongbo; Tian, Jingwei; Ye, Liang
    Part of
    Molecules (Basel, Switzerland), 2024-05, Vol.29 (10)
    Subjects
    China; Control equipment industry; Diseases; Ethylenediaminetetraacetic acid; Liver; Massachusetts; Metabolites; United States
  • Article

    Efficacy, safety and tolerability of rozanolixizumab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a trial and open-label extension study

    Authors
    Querol, Luis; De Sèze, Jérôme; Dysgaard, Tina; Levine, Todd; Rao, T Hemanth; Rivner, Michael; Hartung, Hans-Peter; Kiessling, Peter; Shimizu, Saori; Marmol, Dominika; Bozorg, Ali; Colson, Anny-Odile; Massow, Ute; Eftimov, Filip; Bleecker, Jan De; Claeys, Kristl G; Debien, Elisa; Noordhout, Alain Maertens de; Sommer, Claudia; Garz, Katharina; Stettner, Mark; Schmidt, Jens; Fernández, Nuria Vidal; Gámez, Josep; Segura, Anna Canovas; Morales, Raúl Juntas; Hewamadduma, Channa; Haslam, Liam; Quarles, Brandy; Gable, Karissa; CIDP01 Study Investigators
    Part of
    Journal of neurology, neurosurgery and psychiatry, 2024-05, p.jnnp-2023-333112
    Abstract
    • BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management.MethodsCIDP01 (NCT03861481) was a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a study. Adults with definite or probable CIDP receiving subcutaneous or intravenous immunoglobulin maintenance therapy were randomised 1:1 to 12 once-weekly subcutaneous infusions of rozanolixizumab 10 mg/kg or placebo, stratified according to previous immunoglobulin administration route. Investigators administering treatment and assessing efficacy, and patients, were blinded. The primary outcome was a change from baseline (CFB) to day 85 in inflammatory Rasch-built Overall Disability Scale (iRODS) score. Eligible patients who completed CIDP01 entered the open-label extension CIDP04 (NCT04051944).ResultsIn CIDP01, between 26 March 2019 and 31 March 2021, 34 patients were randomised to rozanolixizumab or placebo (17 (50%) each). No significant difference in CFB to day 85 in iRODS centile score was observed between rozanolixizumab (least squares mean 2.0 (SE 3.2)) and placebo (3.4 (2.6); difference –1.5 (90% CI –7.5 to 4.5)). Overall, 14 (82%) patients receiving rozanolixizumab and 13 (76%) receiving placebo experienced a treatment-emergent adverse event during the treatment period. Across CIDP01 and CIDP04, rozanolixizumab was well tolerated over up to 614 days; no clinically meaningful efficacy results were seen. No deaths occurred.ConclusionsRozanolixizumab did not show efficacy in patients with CIDP in this study, although this could be due to a relatively high placebo stability rate. Rozanolixizumab was well tolerated over medium-to-long-term weekly use, with an acceptable safety profile.
    Subjects
    Antigens; Apheresis; Disease; FC RECEPTOR; Immunoglobulins; MOVEMENT DISORDERS; MYASTHENIA; Neuromuscular; Neuromuscular diseases; Patients; RANDOMISED TRIALS; Tuberculosis
  • Article

    Impact of Serotonergic 5HT[sub.1A] and 5HT[sub.2A] Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson’s Disease

    Authors
    Andrzejewski, Kryspin; Orłowska, Magdalena E; Zaremba, Małgorzata; Joniec-Maciejak, Ilona; Kaczyńska, Katarzyna
    Part of
    International journal of molecular sciences, 2024-04, Vol.25 (8)
    Abstract
    • In Parkinson’s disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT[sub.1A] and 5-HT[sub.2A] agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO[sub.2] in O[sub.2]) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO[sub.2] and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT[sub.1A]R agonist 8-OH-DPAT and 5-HT[sub.2A]R agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT[sub.2A]R agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.
    Subjects
    Ethylenediaminetetraacetic acid; Hypercapnia; Serotonin
  • Article

    Improvement of non-motor symptoms with NE3107 adjunctive to Carbidopa / Levodopa in patients with Parkinson`s disease: A Phase 2A, placebo-controlled study

    Authors
    Palumbo, J.; Reading, C.; Ahlem, C.; Osman, N.; Zhang, J.; Aldred, J.; Rodriguez, R.; Rivera-Rivera, E.; Isaacson, S.; Kumar, R.; Ellenbogen, A.; Lang, A.
    Part of
    Parkinsonism & related disorders, 2024-05, Vol.122
  • Article

    The Tomato Variety Affects the Survival of Shigella flexneri 2a in Fruit Pericarp

    Authors
    Henriquez, Tania; Guerra, Simona; Nerini, Marta; Purchase, Diane; Marvasi, Massimiliano
    Part of
    Pathogens (Basel), 2024-05, Vol.13 (5), p.379
    Abstract
    • The presence of enteric pathogens in produce can serve as a significant means of transmitting infections to consumers. Notably, tomatoes, as a type of produce, have been implicated in outbreaks caused by various human pathogens, such as enterica and pathogenic coli. However, the survival characteristics of spp. in tomatoes have not been thoroughly investigated. In this study, we assess the survival of 2a in two distinct varieties of post-harvested tomatoes. 2a was used to inoculate both regular-sized Vine tomatoes and cherry-type Mini Plum tomatoes. Our findings reveal no significant difference in survival in the pericarp of both varieties on day 2 post-inoculation. However, a significant disparity emerges on day 6, where all recovered colonies exclusively belong to the Mini Plum variety, with none associated with the Vine type. When was inoculated into the locular cavity (deep inoculation), no significant difference between varieties was observed. Additionally, we investigate the potential role of the SRL pathogenicity island (SRL PAI) in the survival and fitness of 2a in post-harvested tomatoes. Our results indicate that while the SRL PAI is not linked to the survival of the strains in tomato, it does impact their fitness. These findings underscore the variability in strains' survival capabilities depending on the tomato variety, highlighting the importance of understanding ecology beyond the human host and identifying molecular determinants influencing bacterial survival to mitigate the risk of future outbreaks. The significance of this data on persistence in fresh vegetables should not be underestimated, as even a small number of cells can pose a threat to the health of individuals.
    Subjects
    Bacterial infections; Drinking water; Drug resistance; E coli; Epidemics; Food; food safety; Fruits; Infections; Inoculation; Outbreaks; Pathogenicity; Pathogens; Pericarp; post-harvest tomato; Salmonella; Shigella; Shigella flexneri; Shigellosis; SRL pathogenicity island; Strains (organisms); Survival; Temperature; Tomatoes; vegetable
  • Article

    Targeting the adenosine A 2A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease

    Authors
    Zhao, Yan; Zhou, Yuan-Guo; Chen, Jiang-Fan
    Part of
    Chinese journal of traumatology, 2024-05, Vol.27 (3), p.125
    Abstract
    • Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors, called A and A receptors. The adenosine A receptor (A R) antagonists have been clinically pursued for the last 2 decades, leading to final approval of the istradefylline, an A R antagonist, for the treatment of OFF-Parkinson's disease (PD) patients. The approval paves the way to develop novel therapeutic methods for A R antagonists to address 2 major unmet medical needs in PD and traumatic brain injury (TBI), namely neuroprotection or improving cognition. In this review, we first consider the evidence for aberrantly increased adenosine signaling in PD and TBI and the sufficiency of the increased A R signaling to trigger neurotoxicity and cognitive impairment. We further discuss the increasing preclinical data on the reversal of cognitive deficits in PD and TBI by A R antagonists through control of degenerative proteins and synaptotoxicity, and on protection against TBI and PD pathologies by A R antagonists through control of neuroinflammation. Moreover, we provide the supporting evidence from multiple human prospective epidemiological studies which revealed an inverse relation between the consumption of caffeine and the risk of developing PD and cognitive decline in aging population and Alzheimer's disease patients. Collectively, the convergence of clinical, epidemiological and experimental evidence supports the validity of A R as a new therapeutic target and facilitates the design of A R antagonists in clinical trials for disease-modifying and cognitive benefit in PD and TBI patients.
    Subjects
    Adenosine A2 Receptor Antagonists - therapeutic use; Animals; Brain Injuries, Traumatic - complications; Brain Injuries, Traumatic - drug therapy; Cognition - drug effects; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - etiology; Cognitive Dysfunction - prevention & control; Humans; Neuroprotection; Neuroprotective Agents - therapeutic use; Parkinson Disease - complications; Parkinson Disease - drug therapy; Purines; Receptor, Adenosine A2A - metabolism; Receptor, Adenosine A2A - physiology
  • Conference proceeding

    Analysis of coastline changes using Sentinel 2A imagery in the coastal area of West Pandeglang, Banten

    Authors
    Huda Asshobirul; Panjaitan James Parlindungan; Agus Syamsul Bahri
    Part of
    BIO web of conferences, 2024, Vol.106, p.04007
    Abstract
    • Coastline changes on the west coast of the Pandeglang Regency are caused by hydrooceanographic parameters and human activities. These changes can be observed through remote sensing. This study aimed to identify and map these changes. The shoreline of the Sentinel 2A satellite image was extracted using the Tasseled Cap method. The shoreline was then calculated using the Digital Shoreline Analysis System (DSAS) method, and field data were collected using Ground Control Points (GCP). The analysis of shoreline changes indicated the dominance of abrasion over accretion. The most significant abrasion occurred in Sidamukti Village at a rate of 26.65 metres per year, while the largest accretion occurred in Sukajadi Village at a rate of 24.92 metres per year. A comparison of the categories of coastline changes can indicate areas that are susceptible to large waves. This information can be used to provide both experience and knowledge to the people of the Pandeglang Regency. The study of coastline changes is an important reference for the development of coastal areas, harbors, tourism, and cultivation.
  • Article

    Serine 3.39 and isoleucine 4.60 are key sites for 5-HT 2A R-mediated G s signaling

    Authors
    Xie, Lulu; Liu, Xiaoqian; Yao, Yishan; Tan, Bo; Su, Ruibin
    Part of
    FEBS letters, 2024-05
    Abstract
    • Certain amino acid sites of 5-HT R play crucial roles in interacting with various G proteins. Hallucinogens and non-hallucinogens both act on 5-HT R but mediate different pharmacological effects, possibly due to the coupling of different G proteins. Therefore, this study identified the binding sites of hallucinogens and non-hallucinogens with 5-HT R through molecular docking. We conducted site mutation to examine the impact of these sites on G proteins, in order to find out the sites that can distinguish the pharmacological effects of hallucinogens and non-hallucinogens. Our results indicate that I4.60A and S3.39A did not affect the ability of hallucinogens to activate G signaling, but significantly reduced G signaling activation by hallucinogens. These results suggest that S3.39 and I4.60 are important for the activation of G signaling by hallucinogens.
  • Article

    The Tomato Variety Affects the Survival of IShigella flexneri/I 2a in Fruit Pericarp

    Authors
    Henriquez, Tania; Guerra, Simona; Nerini, Marta; Purchase, Diane; Marvasi, Massimiliano
    Part of
    Pathogens (Basel), 2024-05, Vol.13 (5)
    Subjects
    Contamination; Developing countries; Dysentery; Health aspects; Tetracycline; Tetracyclines; Tomatoes
  • Article

    Structural Insights into Partial Activation of the Prototypic G Protein-Coupled Adenosine A 2A Receptor

    Authors
    Claff, Tobias; Mahardhika, Andhika B; Vaaßen, Victoria J; Schlegel, Jonathan G; Vielmuth, Christin; Weiße, Renato H; Sträter, Norbert; Müller, Christa E
    Part of
    ACS pharmacology & translational science, 2024-05, Vol.7 (5), p.1415
    Abstract
    • The adenosine A receptor (A AR) belongs to the rhodopsin-like G protein-coupled receptor (GPCR) family, which constitutes the largest class of GPCRs. Partial agonists show reduced efficacy as compared to physiological agonists and can even act as antagonists in the presence of a full agonist. Here, we determined an X-ray crystal structure of the partial A AR agonist 2-amino-6-[(1 -imidazol-2-ylmethyl)sulfanyl]-4- -hydroxyphenyl-3,5-pyridinedicarbonitrile (LUF5834) in complex with the A AR construct A -PSB2-bRIL, stabilized in its inactive conformation and being devoid of any mutations in the ligand binding pocket. The determined high-resolution structure (2.43 Å) resolved water networks and crucial binding pocket interactions. A direct hydrogen bond of the -hydroxy group of LUF5834 with T88 was observed, an amino acid that was mutated to alanine in the most frequently used A AR crystallization constructs thus preventing the discovery of its interactions in most of the previous A AR co-crystal structures. G protein dissociation studies confirmed partial agonistic activity of LUF5834 as compared to that of the full agonist -ethylcarboxamidoadenosine (NECA). In contrast to NECA, the partial agonist was still able to bind to the receptor construct locked in its inactive conformation by an S91 K mutation, although with an affinity lower than that at the native receptor. This could explain the compound's partial agonistic activity: while full A AR agonists bind exclusively to the active conformation, likely following conformational selection, partial agonists bind to active as well as inactive conformations, showing higher affinity for the active conformation. This might be a general mechanism of partial agonism also applicable to other GPCRs.
  • Article

    RETRACTION: "Okadaic acid promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells by inhibiting protein phosphatase 2A"

    Part of
    Journal of cellular biochemistry, 2024-05
    Abstract
    • J. Kong, D. Li, S. Zhang, H. Zhang, Y. Fu, B. Qian, C. Bei, S. Tan, X. Zhu, "Okadaic acid promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells by inhibiting protein phosphatase 2A," Journal of Cellular Biochemistry 122, no. 9 (2021): 993-1002, https://doi.org/10.1002/jcb.29629 The above article, published online on 6 January 2020 in Wiley Online Library (wileyonlinelibrary.com) has been retracted by agreement between the authors; the journal's Editor in Chief, Christian Behl; and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by third parties. During the investigation, several flaws and inconsistencies were found within the provided data. The authors admitted substantial mistakes during figure compilation for this manuscript. Thus, the conclusions of this article are considered invalid by the editors.
  • Article

    How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

    Authors
    Anna Wójcik; Aleksander Górny; Justyna Chwiejczak; Julita Młynarska; Jan Kościan; Karolina Szczerkowska; Anna Seroka; Maria Mitkowska; Maria Rybicka; Michał Obrębski
    Part of
    Journal of education, health and sport, 2024-05, Vol.71
    Abstract
    • Introduction and purpose: Parkinson’s disease (PD) is the second most common neurodegenerative disease, mainly characterized by motor impairment with symptoms including rigidity, bradykinesia, rest tremor and imbalance. It develops upon degeneration of dopaminergic neurons in the substantia nigra associated with neuroinflammatory process initiated by alpha-synuclein deposits. Although, levodopa replacement therapy is the gold-standard treatment, majority of the treated patients develop dyskinesia as the side effect, resulting from altered function of dopamine receptors. It is thought that the abnormal pulsate release of dopamine can be prevented by antagonism of adenosine 2A receptors (A2ARs). Aim of the study: This review aims to outline the action mechanism of A2AR antagonism on motor performance, and thus evaluate the suggested implications of coffee consumption in PD. Material and method: The involvement of A2ARs in the pathology and treatment of PD has been analyzed based on the findings of many published studies examining the effects of A2AR modulation. Results: Blockage of A2ARs enhances the action of dopamine via D2 receptors on striatopallidal neurons, decreasing their hyperactivity, and exerts neuroprotective effect, suppressing the neuroinflammation. Conclusions: Istradefylline, being the only approved A2AR antagonist, was able to reduce total cumulative dose of levodopa, improve motor control, alleviate postural abnormalities, and provide a reduction in daily ‘off’ time experienced by patients. Recent findings suggest the effects of drinking one cup of coffee are comparable with ones obtained by the newly introduced medication, presumably via shared action mechanism by A2AR inhibition.
    Subjects
    adenosine a2a receptor; dopamine; motor function; Parkinson's disease; striatal pathways
  • Article

    Two sisters diagnosed with familial paraganglioma syndrome type 1 (FPGL1) and multiple endocrine neoplasia type 2A (MEN2A)

    Authors
    Stawarz, Katarzyna; Durzynska, Monika; Galazka, Adam; Paszkowska, Monika; Bienkowska-Pluta, Karolina; Zwolinski, Jakub; Tysarowski, Andrzej; Kwiatkowska, Ewa; Podgorska, Agnieszka
    Part of
    World journal of surgical oncology, 2024-05, Vol.22 (1), p.139-139
    Abstract
    • BACKGROUNDIn clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence of two genetic diseases, even with partially common symptoms, remains unusual. Therefore, targeted next-generation sequencing (NGS), along with genetic consultation and imaging studies, is essential for every patient with confirmed paraganglioma. In this report, we present two sisters diagnosed with multiple endocrine neoplasia type 2 (MEN2A) and familial paraganglioma syndrome type 1 (FPGL1).CASE PRESENTATIONAfter presenting to the clinic with neck tumors persisting for several months, both patients underwent tumor removal procedures following imaging and laboratory studies. Pathological reports confirmed the diagnosis of paragangliomas. Subsequently, genetic testing, including NGS, revealed a mutation in the rearranged during transfection (RET) gene: the heterozygous change (c.2410G > A), (p.Val804Met), and a variant of the succinate dehydrogenase complex subunit D (SDHD) gene: (c.64 C > T), (p.Arg22Ter). Subsequently, thyroidectomy procedures were scheduled in both cases.CONCLUSIONTo the best of our knowledge, this is the first report presenting these two mutations in two related patients, resulting in distinctive genetic syndromes with similar manifestations. This underscores that although infrequent, multiple hereditary disorders may co-occur in the same individual.
    Subjects
    Case Report
  • Article

    Gene therapy with phosphodiesterases 2A and 4B ameliorates heart failure and arrhythmias by improving subcellular cAMP compartmentation

    Authors
    Pavlaki, Nikoleta; Froese, Alexander; Li, Wener; De Jong, Kirstie A; Geertz, Birgit; Subramanian, Hariharan; Mohagaonkar, Sanika; Luo, Xiaojing; Schubert, Mario; Wiegmann, Robert; Margaria, Jean Piero; Ghigo, Alessandra; Kämmerer, Susanne; Hirsch, Emilio; El-Armouche, Ali; Guan, Kaomei; Nikolaev, Viacheslav O
    Part of
    Cardiovascular research, 2024-05
    Abstract
    • Gene therapy with cardiac phosphodiesterases (PDEs) such as PDE4B has recently been described to effectively prevent heart failure in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload induced heart failure in mice by acting on and restoring altered cAMP compartmentalization in distinct subcellular microdomains. Heart failure was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3 or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentalization in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human induced pluripotent stem derived cardiomyocytes with the A2254 V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia. Our data indicate that gene therapy with phosphodiesterases can prevent heart failure including associated cardiac remodeling and arrhythmias by restoring altered cAMP compartmentalization in functionally relevant subcellular microdomains.
  • Article

    Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies

    Authors
    Youssef, Amir S; Ismail, Mohamed; Han, Kelong; Magee, Mindy; Nader, Ahmed
    Part of
    Infectious diseases and therapy, 2024-05
    Abstract
    • Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis. Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration-time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations. Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure. This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.
  • Article

    5-HT 1A and 5-HT 2A receptor effects on recognition memory, motor/exploratory behaviors, emotionality and regional dopamine transporter binding in the rat

    Authors
    Nikolaus, Susanne; Chao, Owen Y; Henke, Jan; Beu, Markus; Fazari, Benedetta; Almeida, Filipe Rodrigues; Abdel-Hafiz, Laila; Antke, Christina; Hautzel, Hubertus; Mamlins, Eduards; Müller, Hans-Wilhelm; Huston, Joseph P; von Gall, Charlotte; Giesel, Frederik L
    Part of
    Behavioural brain research, 2024-05, Vol.469, p.115051
    Abstract
    • Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT R agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT R agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[ I]iodophenyl)-nortropane ([ I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT R inhibition and 5-HT R activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.
  • Article

    Metabolism, Disposition, Excretion, and Potential Transporter Inhibition of 7-16, an Improving 5-HT 2A Receptor Antagonist and Inverse Agonist for Parkinson's Disease

    Authors
    Hu, Zhengping; Wang, Wenyan; Yang, Huijie; Zhao, Fengjuan; Sha, Chunjie; Mi, Wei; Yin, Shuying; Wang, Hongbo; Tian, Jingwei; Ye, Liang
    Part of
    Molecules (Basel, Switzerland), 2024-05, Vol.29 (10)
    Abstract
    • Compound 7-16 was designed and synthesized in our previous study and was identified as a more potential selective 5-HT receptor antagonist and inverse agonist for treating Parkinson's disease psychosis (PDP). Then, the metabolism, disposition, and excretion properties of 7-16 and its potential inhibition on transporters were investigated in this study to highlight advancements in the understanding of its therapeutic mechanisms. The results indicate that a total of 10 metabolites of 7-16/[ C]7-16 were identified and determined in five species of liver microsomes and in rats using UPLC-Q Exactive high-resolution mass spectrometry combined with radioanalysis. Metabolites formed in human liver microsomes could be covered by animal species. 7-16 is mainly metabolized through mono-oxidation (M470-2) and N-demethylation (M440), and the CYP3A4 isozyme was responsible for both metabolic reactions. Based on the excretion data in bile and urine, the absorption rate of 7-16 was at least 74.7%. 7-16 had weak inhibition on P-glycoprotein and no effect on the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 transporters. The comprehensive pharmacokinetic properties indicate that 7-16 deserves further development as a new treatment drug for PDP.
    Subjects
    Animals; Humans; Male; Microsomes, Liver - metabolism; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Rats; Serotonin 5-HT2 Receptor Agonists - pharmacology; Serotonin 5-HT2 Receptor Antagonists - pharmacology
  • Article

    Adenosine A 2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease

    Authors
    Nunes, Ana Carla L; Carmo, Marta; Behrenswerth, Andrea; Canas, Paula M; Agostinho, Paula; Cunha, Rodrigo A
    Part of
    International journal of molecular sciences, 2024-04, Vol.25 (9)
    Abstract
    • Adenosine A receptor (A R) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A R antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A R antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A R-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A R antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.
    Subjects
    Adenosine A2 Receptor Antagonists - pharmacology; Adenosine A2 Receptor Antagonists - therapeutic use; Animals; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Disease Models, Animal; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Male; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A - metabolism; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; Triazoles - pharmacology
  • Article

    Biochemical characterization of the Eya and PP2A-B55α interaction

    Authors
    Alderman, Christopher; Anderson, Ryan; Zhang, Lingdi; Hughes, Connor J.; Li, Xueni; Ebmeier, Chris; Wagley, Marisa E.; Ahn, Natalie G.; Ford, Heide L.; Zhao, Rui
    Part of
    The Journal of biological chemistry, 2024-05, p.107408-107408, Article 107408
    Abstract
    • The Eyes Absent (Eya) proteins were first identified as co-activators of the Six homeobox family of transcription factors and are critical in embryonic development. These proteins are also re-expressed in cancers after development is complete, where they drive tumor progression. We have previously shown that the Eya3 N-terminal domain (NTD) contains Ser/Thr phosphatase activity through an interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme, and that this interaction increases the half-life of Myc through pT58 dephosphorylation. Here we showed that Eya3 directly interacted with the NTD of Myc, recruiting PP2A-B55α to Myc. We also showed that Eya3 increased the Ser/Thr phosphatase activity of PP2A-B55α but not PP2A-B56α. Furthermore, we demonstrated that the NTD (∼250 amino acids) of Eya3 was completely disordered, and it used a 38-residue segment to interact with B55α. In addition, knockdown and phosphoproteomic analyses demonstrated that Eya3 and B55α affected highly similar phosphosite motifs with a preference for Ser/Thr followed by Pro, consistent with Eya3’s apparent Ser/Thr phosphatase activity being mediated through its interaction with PP2A-B55α. Intriguingly, mutating this Pro to other amino acids in a Myc peptide dramatically increased dephosphorylation by PP2A. Not surprisingly, MycP59A, a naturally occurring mutation hotspot in several cancers, enhanced Eya3-PP2A-B55α mediated dephosphorylation of pT58 on Myc, leading to increased Myc stability and cell proliferation, underscoring the critical role of this phosphosite in regulating Myc stability.
    Subjects
    cancer; Eya; Myc; phosphatase; Protein Phosphatase 2A (PP2A)

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