bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer's Disease: Prevention, Symptoms and Treatment
Authors: DiCarlo Marjorie L , Einstein George P , Tulp Orien L 
Published: November 2023

The gradual slowing down of memory is assumed to be a normal consequence of aging. When memory dysfunction begins to interfere with the performance of daily activities, then there is a great chance that Alzheimer's disease [AD] or some other form of dementia may be present. Because AD is a very devastating disease, people who suffer from it, including families and friends of the individual so affected, experience frustration, not to mention the stress and pain as the individual is stripped of their abilities and cognitive functions. As AD progresses, in 5 to 8% of the people who are diagnosed with it may suffer from symptoms such as depression, insomnia and even anorexia. In order to stage Alzheimer's disease, the discovery of biomarkers and validation are considered the key aspects to support the clinical diagnosis and provide discriminatory power between different stages of the disorder. Usually after other neurological tests have been performed and other medical issues have been ruled out, then the individual is tested for AD. Upon the death of the person with the disease, an MRI of the brain can usually confirm the diagnosis by means of protein accumulation in the way of clumps and plaque in the brain's gray matter. Even though there is no cure for AD, it has several risk factors that are out of a person's control such as genetics and age. Controlling and identifying risk factors, can help to preserve cognitive abilities even though there is no cure or effective treatment. This challenging disease poses a challenge for policy‐makers which includes, the level of funding and direction of federally funded research, as well as the cost pressures on Medicare and Medicaid for long‐term care. These challenges will continue to increase in intensity as demographics change, particularly with the aging of the current baby boomer generation.Support or Funding InformationSupported by Institutional Resources of USAT and Einstein Medical Institute
Ablation of Mitochondria Fusion Protein Mfn2 causes an Oxidative Stress Response and Eventual Neuronal Death in the Hippocampus and Cortex
Authors: Jiang Sirui , Wang Xinglong , Nandy Priya , Wang Chunyu , Torres Sandy , Siedlak Sandra L , Zhu Xiongwei 
Published: November 2023

Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer disease, and significant advances have recently been made in the understanding of the changes in morphology and distribution of neuronal mitochondria in this devastating disease. It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. It is clear that the mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelle. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the development of neurodegeneration. To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout Mfn2 in the hippocampus and cortex. Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the mfn2 KO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, cell cycle induction, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while cortical neuronal death was associated with fewer neurons and decreased cortical size, but no changes in neuronal density. Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many neurodegenerative changes and eventual neurodegeneration that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD.Support or Funding InformationThanks to the support of T32 NS077888, IIRG‐13‐284849, AARG‐16‐443584, R01 NS083385 and Dr. Robert M. Kohrman Memorial Fund.
Caffeine may affect apoptosis and autophagy activity to promote dopaminergic cells survival under the rotenone induced Parkinson disease model
Authors: Luo Chi‐Lun , Huang Yi‐Chieh , Huang Bin , Lu Tzongshi , Fu Yaw‐Syan 
Published: November 2023

Introduction and hypothesisParkinson's disease (PD) is the most common neurodegenerative movement disorder caused by the loss of dopaminergic neurons in midbrain. Rotenone is a natural toxic compound extracted from Fabaceae plants and widely used as insecticide and pesticide. Rotenone is highly lipophilic and readily crosses the blood–brain barrier to impair oxidative phosphorylation in mitochondria and that may lead to dopaminergic neuron loss. In this study we investigated the protective effects of caffeine on the rotenone‐induced neurotoxicity of PD models.MethodsTwo dopaminergic cell lines, SH‐SY5Y cells and PC12 cells, were pretreated with caffeine (0~100μM) for 30mins and followed by treatment with rotenone (0~10μM) for 8hr~24hr respectively. The cell survival rate, proliferation, morphology were analysis by flow cytometry, ELISA, Cell Counting Kit‐8(CCK‐8), and histology studies. Cell apoptosis/necrosis were analyzed by Annexin V/PI staining using flow cytometry. The expressions of apoptosis and autophagy related proteins were analyzed by western blotting.ResultsBoth dopaminergic cell lines treated with 10nM rotenone for 8hr may decrease the mitochondrial activity of around 60%. Caffeine treatments (0–100μM) had rarely toxic effect on both dopaminergic cell lines but could promote autophagy. When cells pretreated with caffeine (>10μM) for 30min and followed treated with 10nM rotenone for 8hr could significantly increase total cell numbers, but did not restored the mitochondrial activity. In addition, caffeine pretreatment (>10μM) could decrease the cell apoptotic ratio on rotenone‐induced neurotoxicity, but no effect on the necrosis ratio.ConclusionsOur study data suggested that caffeine treatment can affect autophagy and have protect effects to promote cell survival on rotenone‐induced neurotoxicity and to decline the apoptosis, but it do not influence necrosis.Support or Funding InformationKMU‐TP104E34, KMU‐NSYSU 105I001
The Use of Patient‐Oriented‐Problem‐Solving (POPS) in Pharmacology Exercises to Develop Simulated Scenes for Application during TBL
Authors: Hernandez Mark J , Foldy Samuel J , Abene Frank J , Lindsey Thomas J , Giannini John 
Published: November 2023

PurposeTeaching pharmacology with the use of pre‐recorded simulation scenes can be an effective, active‐learning pedagogy. To help teach basic pharmacology in a manner that can more easily integrate with clinical sciences, we have used simulated clinical scenarios. One unique approach involves a combination of simulation with exercises known as Patient‐Oriented Problem‐Solving (POPS) during Team Based Learning (TBL) sessions. POPS was developed in the 1980s as part of a movement to provide students with more problem‐solving sessions. Most recently, these exercises have been formatted so that they can be adapted to various course‐management software, with the objective that the POPS could be used by trainees in various health science professional programs (medicine, pharmacy, nursing, etc.), making them suitable for interprofessional education. Here, we describe a unique application of the cases in an educational setting using TBL where the episodes were re‐created with simulation and presented in the same order during the application exercises. This abstract describes the project and its outcomes.MethodsAccording to an AAMC report, simulation is any educational activity that utilizes simulative tools and methods in order to create learning opportunities. Our goal at the Alabama College of Osteopathic Medicine is to maximize pharmacology learning and bridge that knowledge with more clinical concepts using simulated scenes. The preparation of the simulated scenes involved both basic and clinical faculty along with the active participation of third year medical student‐fellows who recorded the episodes. The episodes were then presented during the application exercises of TBL sessions delivered to first‐year and second‐year medical students. After each scene, there was opportunity for group discussion followed by questions. Audience response software was used to capture the overall group responses. Student participation was recorded using TurningPoint and learning was later assessed through examination. A Likert scale was used to determine student satisfaction with the use of this method.ResultsThe incorporation of simulation helped bridge basic science and clinical sciences in a manner that made the group discussion more engaging. Our results indicate that more students were satisfied than dissatisfied with this method and more agreed that this was a valuable use of their time.ConclusionFaculty and student participation in these scenes was well‐received during the application exercises in TBL sessions. The educational approach described here encouraged discussion during the TBL session and promoted active learning, which led to successful outcomes and proved to be an efficient process.
Are Exon 11‐Associated Variants of the OPRM Gene Involved in Alcohol Reward?
Authors: Brown Taylor , Martinez Shani , Xu Jin , Pan Ying‐Xian , Rossi Grace 
Published: November 2023

Alcohol use remains a global problem with approximately 10–20% of chronic alcohol users becoming alcoholics. Despite severe consequences, alcohol continues to be a rewarding and highly addictive substance as other drugs of abuse. The opioid system has long been hypothesized to involve alcohol reward. Recent work in our laboratories has led to the generation of a knockout (KO) mouse model in which exon 11 (E11) of the mu opioid receptor gene (OPRM1) was disrupted. In E11‐KO mice, analgesia for several mu opioids, including M6G, fentanyl and heroin, was significantly reduced, while analgesic action for morphine and methadone was intact. Moreover, the analgesic action for a novel class of opioids, such as IBNtxA, that fails to produce the typical side effects associated with traditional opiates, was completely lost in E11‐KO mice. To investigate the role of E11‐associated variants in alcohol reward, we evaluated chronic alcohol self‐administration in wild‐type (WT) and E11 knockout (E11‐KO) mice using a two bottle choice paradigm. Total consumption was measured over a 30‐day period with escalating concentrations of alcohol (2–10%). Results showed E11‐KO mice drank significantly higher amounts of alcohol as compared to WT control mice, suggesting involvement of E11‐associated variants in the rewarding effects of alcohol. Although alcohol is presumed to have a very different mechanism of action than heroin, the physiological properties of reward might use a common E11 genetic map.Support or Funding InformationThis grant was funded in part by a Long Island University Monetary Grant.
Role of Phosphodiesterase 4D in Memory and Cognition
Authors: Zhang Chong , Xu Ying , Gurney Mark , O'Donnell James 
Published: November 2023

Inhibition of PDE4 has been proposed as a potential treatment for series of neuropsychological conditions including memory deficits. However, most centrally acting PDE4 inhibitors have accompanying tolerability issues such as emesis and diarrhea. Therefore, it is critical to elucidate the role of each subtype of PDE4 (namely PDE4A, B and D in the brain), so that unwanted adverse effects may be avoided. Using a selective PDE4D inhibitor, BPN14770, our data suggested that PDE4D might play a critical role in mediating behaviors related to memory and cognition. BPN14770 achieves its highly selective inhibition of PDE4D through allosteric binding to the phenylalanine, which is only present in the primates, in the UCR2 region of the enzyme. As a result, the compound inhibits human and mouse PDE4D with IC50s of 8 and 130 nM, respectively. In order to elucidate the involvement of PDE4D in the memory process in intact animals, we generated a “humanized” mouse line (PEDD) by mutating the mouse UCR2 tyrosine271 to phenylalanine. In the in vitro competition binding assay with 3H labeled rolipram, BPN14770 exhibited a preferred 2‐site binding mode with the PEDD but not the wild‐type mouse brain homogenate, suggesting that the compound may be able to bind with PDE4D with different affinities in the wild‐type and PEDD mouse brains. It was then demonstrated that in both the wild‐type and PEDD mice, BPN14770 were able to improve cognition, with the minimum effective doses of 1 and 0.01 mg/kg in the novel object recognition (NOR) test, respectively. However, such dose‐response shift was not present with rolipram, a non‐selective PDE4 inhibitor. These behavioral changes were supported by elevated brain cAMP levels in the mouse brain 1 hour after treatment, which showed a similar dose‐response shift between the wild‐type and PEDD mice. Moreover, BPN‐14770 enhanced the long‐term potential in hippocampal slices obtained from both the wild‐type and PEDD mice, with the minimum effective concentration of the latter being 10‐fold smaller. Neurochemical analyses of brain lysates from PEDD mice suggested that such behavioral changes may be due to altered synaptic function, especially in the post synapses, in the prefrontal cortex and hippocampus, as indicated by increased phosphorylation of synapsin and PSD95, as well as molecular targets downstream of cAMP, such as phosphorylation of CREB and BDNF. Taken together, our data suggested that PDE4D plays an indespensable role in regulation of memory and cognition.Support or Funding InformationThis work was supported by research grants from National Institute of Mental Health to Dr. M. E Gurney (No. R44MH091791).
Functional selectivity of GPCR‐directed drug action through location bias
Authors: Irannejad Roshanak 
Published: November 2023

G protein‐coupled receptors (GPCRs) are increasingly recognized to function at intracellular membranes as well as the plasma membrane. We showed previously that the β2‐adrenergic GPCR promotes cyclic AMP (cAMP) signal generation by activating the heterotrimeric G protein, Gs, both from the plasma membrane and after ligand‐induced delivery of receptors to endosomes. We show here that the homologous β1‐adrenergic receptor mediates a second phase of intracellular Gs‐cAMP signaling from the Golgi apparatus rather than endosomes. The Golgi‐derived activation mechanism utilizes a pre‐existing receptor pool, contrasting with endosome‐localized activation that utilizes receptors internalized from the plasma membrane, thereby requiring ligands to access the Golgi‐localized pool separately from receptors. We show that epinephrine, a hydrophilic endogenous ligand, activates the Golgi‐localized receptor pool after facilitated transport requiring extraneuronal monoamine transporter (EMT/OCT3), conferring Golgi‐localized activation that is selectively inhibited by corticosterone. We also show that clinically relevant drugs differentially access the Golgi receptor pool according to hydrophobicity, presumably through passive diffusion across membranes, and that β‐blocker drugs presently used in the clinic differ significantly in their ability to inhibit Golgi relative to plasma membrane‐localized receptor activation. These results fundamentally expand the present understanding of intracellular GPCR activation, and reveal a remarkable distinction in the cellular signaling properties of closely homologous adrenoceptor subtypes based on location. We propose the principle of ‘location bias’ as a discrete cellular scheme for discriminating the signaling properties of related GPCRs when activated by endogenous ligands, and to impose functional selectivity on receptor‐mediated drug action.Support or Funding InformationK99HL122508
PAR1 and p38 MAPK Regulation of Endothelial Pro‐inflammatory Responses
Authors: Rada Cara , Grimsey Neil , Canto Isabel , Trejo JoAnn 
Published: November 2023

Endothelial cells line the lumen of blood vessels and create a semi‐permeable barrier that is disrupted during vascular inflammation resulting in increased permeability, tissue edema, and subsequent organ failure. Endothelial dysfunction also results in cytokine production and leukocyte recruitment. Thrombin, a coagulant protease, is generated during tissue injury and inflammation and triggers inflammatory responses including endothelial barrier disruption and cytokine production through activation of protease‐activated receptor‐1 (PAR1), a G protein‐coupled receptor. We recently discovered that thrombin activation of PAR1 stimulates p38 MAPK activation through a non‐canonical pathway mediated by TAB1 to promote endothelial permeability. PAR1‐induced p38 activation has been linked to vascular inflammation; however, the mechanism as to how p38 may be integrated into major signaling pathways that promote endothelial inflammatory responses is not known. We found that thrombin‐stimulated p38 functions independent of the classic RhoA activation and MLC phosphorylation pathways but how p38 controls endothelial inflammatory responses is not known. We found that thrombin‐stimulated p38 signals through activation of MAPKAPK2 (MK2), which mediates phosphorylation of HSP27. Interestingly, thrombin/PAR1 activation of MK2 is dependent on p38 MAPK and results in differential phosphorylation of HSP27. The mechanisms by which the p38‐MK2‐HSP27 signaling pathway regulates endothelial pro‐inflammatory responses will be further investigated.Support or Funding InformationT32 Pharmacological Sciences Training Grant (NIGMS T32 GM007752)
Adhesion G Protein‐Coupled Receptor Activation by Novel Small Molecule Modulators
Authors: Stoveken Hannah Marie , Smrcka Alan V , Tall Gregory G. 
Published: November 2023

Adhesion G protein‐coupled receptors (aGPCRs) are constitutively cleaved during biosynthesis into two‐part receptors that remain non‐covalently bound at the plasma membrane. Self‐cleavage occurs within the GPCR Autoproteolysis Inducing (GAIN) domain, a unit of the large extracellular domain (ECDs), which is closely apposed to the 7‐transmembrane (7TM) domain. The auto‐cleavage generates a tethered agonist that remains concealed within the hydrophobic GAIN domain core. We demonstrated that operative dissociation of the ECD of the aGPCR GPR56 / ADGRG1 resulted in enhanced G protein 13 activation kinetics and that the proposed tethered agonist region is both necessary and sufficient to activate the 7TM. Proposed aGPCR ligands are primarily extracellular matrix (ECM) and anchored cell surface proteins. In vivo receptor activation likely requires cell‐movement mediated shear forces to dissociate the ECDs to permit receptor activation. Understanding the physiological roles these receptors play in development, immunity, and aberrantly in cancer growth and metastasis has been fettered by an inability to recapitulate authentic receptor pharmacology using dilute, soluble matrix proteins. We hypothesized, therefore, that small molecule modulators could be identified to activate or inhibit aGPCRs independent of protein ligand engagement of the ECD. Using the G13‐coupled GPR56 receptor with a truncated tethered agonist, we screened a 2,000 compound library using the Serum Response Element (SRE)‐luciferase gene reporter assay for compounds that functionally replicate the tethered agonist. From this pilot screen we identified two related classes of natural compounds that were capable of activating a subset of aGPCRs but did not active two Class A GPCRs that were tested. The most potent compound identified was a gedunin‐derivative, 3α‐acetoxydihydrodeoxygedunin, which activated the tethered agonist truncated GPR56 in two independent assay platforms with an EC50 of ~5 μM. By examining similar compounds, we were able to perform a structure‐activity relationship to narrow down functional groups that were essential for receptor activation. The aGPCR activators identified and characterized in our studies will serve as invaluable research tools to understand this unique‐class of GPCRs.Support or Funding InformationRO1GM120110 Mechanism of Adhesion GPCR Action
Chlorpromazine hydrochloride suppresses visceral hypersensitivity to colorectal distension in a rat model of irritable bowel syndrome
Authors: Asano Teita , Takenaga Mistuko 
Published: November 2023

Background and AimsIrritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic and recurrent abdominal pain and discomfort associated with altered bowel habits. Although IBS markedly reduces the patient's quality of life, pharmacological therapy has not been established. Visceral hypersensitivity plays an important role in pathogenesis of IBS. In the present study, we screened a compound library consisting of clinically used drugs for their ability to prevent visceral hypersensitivity to colorectal distension (CRD) in rats.MethodsVisceral sensitivity was monitored by the measurement of the electrical activity of the abdominal external oblique muscle in response to CRD (visceromotor response) in rats using a pressure‐volume control device, barostat. Two hundred nine clinically used drugs including bronchodilators, anticonvulsants, antibiotics, anti‐hypertensives and anti‐allergy drugs were selected for drug screen in rats. The drugs were screened for their ability to suppress visceral sensitivity to repeated CRD. Visceral hypersensitivity to CRD was induced by intra‐colonic administration of sodium butyrate in adulthood or 0.5% acetic acid administration in the early neonatal period.ResultsChlorpromazine, a typical antipsychotic drug, was identified as a compound that is able to suppress the visceromotor response to repetitive CRD. Oral administration of a 4 mg/kg of chlorpromazine restored visceral hypersensitivity to CRD induced by sodium butyrate or acetic acid to normal condition. This dose of chlorpromazine did not affect visceral sensitivity to CRD and colonic compliance in non‐stressed rats. We also found that quetiapine and risperidone (atyptical psychotic drugs) but not sulpiride and haloperidol (other typical psychotics drugs) suppressed butyrate‐induced colonic hypersensitivity. Chlorpromazine has antagonist action at dopamine D2 receptors and serotonin 2A (5‐HT2A) receptors. From analysis with selective antagonists, kentanserin (a 5‐HT2A receptor antagonist) but not L‐741,626 (a dopamine D2 receptor antagonist) suppressed colonic hypersensitivity induced by butyrate. Furthermore, a peripherally active 5‐HT2A agonist, AL‐34662 produced colonic hypersensitivity in normal rats.ConclusionsTaken together, our results suggest that chlorpromazine ameliorates visceral hypersensitivity to CRD through the inhibition of 5‐HT2A receptors. Then, the activation of 5‐HT2A receptors may be involved in the development of visceral hypersensitivity. 5‐HT2A receptors could be a molecular target for IBS treatment.Support or Funding InformationThis research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.