bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alaskan Blueberries and Cranberries Restore Glucose Uptake in a Type 2 Diabetes Model
Authors: Collin Aline L , Dunlap Kriya L , Kuhn Thomas B 
Published: November 2023

Insulin increases glucose uptake in skeletal muscle cells and adipose tissue by stimulating the recruitment of the glucose transporter 4 (Glut4) to plasma membranes from a pool of storage vesicles. Type II diabetes (T2D) is characterized by an inability to clear blood glucose in response to insulin due to an impairment of Glut4 recruitment and/or function. A persistent, systemic inflammatory and oxidative stress (IOS) is key to the impairment of insulin‐stimulated glucose uptake. Diets high in saturated fatty acids promote insulin resistance mediated by IOS and a disruption of sphingolipid metabolism. T2D incidence has reached epidemic proportions in the US population and worldwide and is strongly associated with obesity. Although the incidence of obesity in Alaska Natives is higher compared to rest of the US population, incidence of T2D is considerably less, which is largely attributed to their subsistence diet rich in Alaska berry fruits.The objective of this study is to demonstrate whether botanical extracts of wild berries endemic to Alaska harbor the potency to protect or restore insulin‐stimulated glucose uptake utilizing a cellular model of T2D.Acute insulin exposure of adipocytes and myotubes stimulates a rapid recruitment of Glut4 (glucose transporter 4) to plasma membranes thereby increasing glucose uptake. Cells under control conditions (0.1 mg/ml BSA) responded to increasing concentrations of insulin (100 nM and 200 nM) with an increase in glucose uptake (100 nM: 1.80 +0.43 %, n=8, *p<0.05 and 200 nM: 2.23 + 0.42 %, n=8, *p<0.01) utilizing 2‐NBD‐glucose (2‐(N‐(7‐Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)Amino)‐2‐Deoxyglucose, a fluorescent glucose reporter). In sharp contrast, pretreatment of cells with 0.75 mM palmitate (saturated C16 fatty acid adsorbed onto BSA) for 18 h significantly abolished insulin‐stimulated glucose uptake (100 nM insulin in palmitate treated cells compared to 100 nM insulin and control p<0.05). Cells pretreated with palmitate and increasing concentrations of insulin (100 nM and 200 nM) did not show a significant difference (100 nM: 1.59 +0.12 %, n=8, and 200 nM: 2.05 + 0.18 %, n=8).Conclusively, persistent presence of palmitate impairs insulin‐mediated glucose transport and plasma membrane recruitment of Glut4. Supplementation of adipocytes or skeletal myotubes with Alaskan berry botanicals (crude extracts, total anthocyanins, total proanthocyanidins) prior to addition of palmitate partially restored insulin‐stimulated glucose uptake.Support or Funding InformationResearch was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Numbers UL1GM118991, TL4GM118992, or RL5GM118990.Research was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103395.
Garden cress (Lepidium sativum L.) Seed Oil: Alternative Source for ALA
Authors: Shetty Umesha Shankara , Akhilender Naidu K. 
Published: November 2023

Garden cress (Lepidium sativum L.) is an edible, herb belonging to Cruciferae family. The seeds of garden cress claimed to possess medicinal properties (galactogogue, diuretic, demulcent, aphrodisiac, carminative and emmenagogue). Garden cress seeds contain 21–24 % oil. Garden cress seed oil(GCO) nutritionally enrich with Alpha‐linolenic acid (30–34%), Antioxidants (Tocopherols‐1799 mg/kg oil, Phenolics‐124 mg GAE/kg of oil) and Phytosterols (14.33 mg/g) and it is also relatively stable oil due to the presence these minor molecules. Despite its great medicinal and nutritional value, garden cress has not received the attention it deserves. The United Nation Organization's. FAO has classified Cress is one of the underutilized or neglected crop among age old crops. If these neglected crops not paid attention, they may be extinct near future.The present study was part of Ph.D. thesis, the objective of thesis was aimed to explore & utilize the garden cress seed oil as a new source of health oil. Garden cress oil extracted from seeds and charterized for physicochemical properties, toxicants, safety and nutritional evaluations. It is also demonstrated utilization of GCO by using edible oil blending and microencapsulation technologies for successful application in foods system.Our research findings show that GCO is free from of any unusual fatty acid, it has good natural antioxidants with potential radical scavenging activity. Rats fed with GCO observed there are no significant changes in food intake, body weight gain, organ weights, clinical enzymes, histological changes in vital organs. GCO significantly modulated fatty acid and lipid profile. ALA from GCO and its blended oil was well absorbed, accumulated and metabolized to LCPUFAs (n‐6/n‐3 PUFA ratio of 2.3 to 2.6. and in native oils 50.2–157). By feeding rats with GCO significantly increased the tocopherols levels (12.2–21.6 %) and activity of antioxidant enzymes, and also significantly lowered platelet aggregation by increasing n‐3 PUFA levels in platelets and decreasing proaggregatroy prostaglandin thromboxane and prostacyclin.GCO was microencapsuled with Whey protein by using spray drying technique. Microencapsulation offered good oxidative protection during storage and also during baking, when GCO microcapsules incorporated in the cookies. These studies clearly indicated that GCO has potential qualities to become alternative source of omega‐3 PUFA for vegetarians. Some of the above findings were published food & nutrition journals, unpublished data will be discussed during the conference.
Influence of Omega‐3 Fatty Acids Intake on Human Responsiveness to Ambient Air Pollution Exposure
Authors: Shen Wan , Samet James , Diaz‐Sanchez David , Tong Haiyan 
Published: November 2023

Exposure to air pollution, including particulate matter and gaseous pollutants, is associated with respiratory and cardiovascular morbidity, such as vascular dysfunction, high blood pressure, cardiac dysrhythmia, and impaired pulmonary function. Eicosapentaenoic acid (20:5, n‐3; EPA) and docosahexaenoic acid (22:6, n‐3; DHA) are the primary beneficial omega‐3 fatty acids found in seafood and fish oil. Dietary consumption of EPA and DHA has been shown to confer protection to the cardiovascular system. This registered and IRB approved panel study is designed to investigate the relationship between dietary consumption of EPA and DHA and ambient air pollution‐induced adverse cardiovascular and pulmonary responses. Cardiovascular and pulmonary indices in healthy 25–55 year‐old subjects consuming at least 3 g/week of EPA and DHA from supplements and dietary sources for a period of 6 months prior to enrollment (High Group) will be compared to a control group (Low Group) with an intake of no more than 1 pill/month of fish oil supplement and 1 serving (4–6 oz)/month of ocean fish/shellfish during the previous 6 months prior to enrollment. Subjects will undergo a battery of tests over 5 2‐day sessions at the U.S. Environmental Protection Agency Human Studies Facility, with each 7 or more days apart. The following endpoints will be measured: blood pressure, heart rate variability, blood fatty acid levels, endothelial cell function, retinal microvascular diameter, and spirometry. Subjects will wear GPS and activity monitors overnight during visits in order to permit a quantitative assessment of individual exposure to pollutants measured using area air quality monitoring stations and satellite imaging data. We hypothesize that dietary consumption of EPA and DHA influences adverse cardiopulmonary responses to ambient air pollution exposure.Support or Funding InformationU.S. Environmental Protection Agency
Overexpression of MCPIP1 attenuates IL‐6‐induced vascular smooth muscle cell migration by suppressing IL‐6‐stimulated STAT3 signaling
Authors: Chang Yingzi 
Published: November 2023

Vascular injury‐induced inflammation is the initial step of angioplasty‐associated vascular restenosis. As a major pro‐inflammatory cytokine, interleukin‐6 (IL‐6)‐induced motogenic effects on vascular smooth muscle cells is considered as the major contributor. Attenuation of vascular injury‐induced neointima thickening was observed by blocking STAT3 tyrosine phosphorylation, a key component of IL‐6 signaling. MCPIP1 (monocyte chemotactic protein [MCP]–induced protein 1; also known as ZC3H12A), an immune response modifier expressed in mice macrophage in response to inflammatory stimulation, plays a negative role in the process of inflammation. Our previous in vivo results revealed that MCPIP1 expression levels are increased following balloon‐catheter‐induced rat carotid injury at 3, 7 and 14 days. Our current study was designed to test if upregulation of MCPIP1 plays a negative role in injury‐induced vascular stenosis by suppressing IL‐6‐induced vascular smooth muscle migration. Using subcultured (passages 5–9) smooth muscle cells isolated from rat aortae, we found that: 1) Overexpression of wild‐type MCPIP1 abolished IL‐6‐induced smooth muscle cell migration; 2) expression of wild‐type MCPIP1 reduced IL‐6‐induced STAT3 phosphorylation but not the expression level of total STAT3. The aforementioned results suggest that the upregulation of MCPIP1 may serve as a negative regulator in vascular injury‐induced stenosis by inhibition of IL‐6 signaling and subsequent induction of smooth muscle cell migration.Support or Funding InformationA.T. Still University Warner's grant
Latest reference genome rat strain‐specific variants provide new insight into human diseases
Authors: Tutaj Monika , Smith Jennifer R , De Pons Jeffrey L , Laulederkind Stanley J , Tutaj Marek A , Hayman G Thomas , Wang Shur‐Jen , Petri Victoria , Dwinell Melinda R , Shimoyama Mary E 
Published: November 2023

Popularization of DNA sequencing technologies and increasing amount of data generated by researchers demand efficient methods to search and analyze sequence data. As part of a large corpus of genomic, genetic, phenotype and disease data, the Rat Genome Database (RGD) provides information about strain‐specific variants, including copy number variations, single nucleotide variants (SNVs), indels and mutations, generated from whole genome sequencing (WGS) of rat strains used as models for a variety of common human diseases. These variants were originally analyzed against previous rat genomic assemblies (RGSC 3.4 and RGSC 5.0). To bring this up to date, RGD is re‐analyzing available rat strain whole‐genome sequences using the newest version of the rat reference assembly (RGSC 6.0, released in 2014). Difficulties with correct variant identification and developing reliable calling algorithms require extensive validation. To accomplish this, we are developing an analysis pipeline which utilizes state‐of‐the‐art tools for variant calling and effect prediction. In addition, we are expanding our current search tools to include the ability to use the combination of a variant position in the genome with the functional annotations assigned to RGD genes and strains. The combination of improved variant data and disease, phenotype, pathway, function and chemical interaction information will help researchers find appropriate models for disease research and drug testing.Support or Funding InformationThe National Heart, Lung, and Blood Institute of the National Institutes of Health, Grant #R01HL064541
The sigma‐1 receptor modulates methamphetamine‐dysregulated dopamine neurotransmission
Authors: Sambo Danielle , Lin Min , Richardson Ben , Jagnarine Darin , Madhurt Shetty , Owens Anthony , Febo Marcelo , Henry Keith , Daws Lynette , Bruijnzeel Adriaan , Khoshbouei Habibeh 
Published: November 2023

Dopamine neurotransmission is highly compromised by psychostimulants such as methamphetamine, a substrate for the dopamine transporter (DAT). The mechanistic aspects of methamphetamine's interactions with DAT are well understood; however, little is known about the molecular actions of methamphetamine once it enters dopaminergic neurons. Methamphetamine is also known to interact with the sigma‐1 receptor (σ1R), an inter‐organelle signaling modulator located at the endoplasmic reticulum. Using complimentary experimental strategies we have identified a novel mechanism for σ1R regulation of dopamine neurotransmission in response to methamphetamine. Single neuron physiology revealed that treatment with the selective σ1R agonist PRE‐084 prevented methamphetamine‐induced, DAT‐mediated increases in the spontaneous firing activity of dopamine neurons. In addition, σ1R activation reduces methamphetamine‐induced DAT‐mediated currents, which have previously been linked to the actions of methamphetamine. Simultaneous patch‐clamp and amperometry and in vivo chronoamperomtry revealed σ1R agonist treatment decreased methamphetamine‐stimulated dopamine efflux without affecting basal dopamine neurotransmission. In vivo studies indicate that σ1R agonist treatment decreased methamphetamine‐stimulation of acute psychomotor responses, motivated behavior as measured by conditioned place preference, and methamphetamine‐induced reductions in reward thresholds as measured by intracranial self‐stimulation. Notably, this study revealed that the σ1R interacts with DAT. This interaction provides evidence for a functional link between endoplasmic reticulum and plasma membrane via a Ca2+‐dependent mechanism. Broadly, these data provide evidence for σ1R regulation of dopamine neurotransmission and the potential therapeutic use of drugs that target the σ1R for the treatment of methamphetamine addiction.Support or Funding InformationDA026947, NS071122, OD020026, DA026947S1, University of Florida McKnight Brain Institute Fellowship
Systemic Oxytocin Attenuates Methylphenidate Self‐Administration and Potentiates Its Effects on Dopamine in the Nucleus Accumbens Shell in Rats
Authors: Tanda Gianluigi , Rohn Matthew C.H. , Newman Amy H. , Coggiano Mark , Zanettini Claudio , Katz Jonathan L. , Leggio Lorenzo , Lee Mary R. 
Published: November 2023

Clinical and preclinical reports have shown that the hypothalamic neurohormone oxytocin plays a role in social bonding, a behavior that is also controlled by the neurotransmitter dopamine. Dopamine also plays an important role in both natural and pathologic behaviors related to reward and reinforcement, including substance use disorders. Dopamine is especially relevant for psychostimulant used is orders, and early reports have shown that oxytocin treatments might interfere with psychostimulant behavioral effects. Several recent studies have focused on oxytocin effects in models of reward or drug abuse in order to understand whether this neuropeptide interferes with pathological compulsive behaviors. Thus, oxytocin has been tested as a potential therapy for alcohol and psychostimulant use disorders. In the present study, the effects of oxytocin were assessed in Sprague‐Dawley rats: 1) trained to self‐administer methylphenidate intravenously (1 mg/kg, fixed ratio 5) during single daily 1‐hr sessions, 2) implanted with microdialysis probes to assess methylphenidate(0.1–1 mg/kg, i.v.) effects on extracellular levels of dopamine in the nucleus accumbens, a brain area related to reward and reinforced behavior, and 3)placed in infrared activity monitors to measure behavioral activation.Injections of oxytocin (0.1–2mg/kg, i.p.) 10 min before the sessions dose‐dependently decreased maximal self‐administration of methylphenidate (0.03–1.0 mg/kg/injection, i.v.). Though, oxytocin (0.2–2 mg/kg, i.p.) had little to no significant effects on extracellular levels of dopamine in the accumbens shell, oxytocin dose‐dependently enhanced the dopamine levels stimulated by intravenous methylphenidate (0.1–1 mg/kg, i.v.). Notably, this enhancement of dopamine levels did not result in stimulation of behavioral activities at levels higher than those produced by methylphenidate alone.The present results suggest that oxytocin attenuates the psychostimulant‐like reinforcing effects of methylphenidate, likely acting through altered dopamine neurotransmission in the terminals of the mesolimbic system. Thus, these results confirm and extend the potential translational therapeutic value of oxytocin for psychostimulant use disorders.Support or Funding InformationResearch Funded by:NIDA‐IRP, NIH/DHHS; Bench‐to‐Bedside Grant by the OBSSR/NIH; Intramural Grant ZIAAA000218‐01 (CPN Section) DICBR/NIAAA/NIH/DHHS.
Roles for Type‐2 Cannabinoid Receptors in the Retrieval and Retention of Fear Memory in Mice
Authors: Duphare Chandni , Li Yong , Kim Jimok 
Published: November 2023

Demand for medical marijuana is rising, but psychotropic harm is the major problem for its clinical use. Harnessing only beneficial effects of cannabis is critical for its therapeutic application, but has been difficult because only one type of cannabinoid receptor—CB1R—is known to be expressed in the brain and mediate both beneficial and detrimental effects of cannabis. Recent discoveries of type‐2 cannabinoid receptors (CB2Rs) in the brain challenge the status of CB1Rs as the only cannabinoid receptor in the nervous system, and require the determination of medical benefits, if any, of CB2Rs. CB2R knockout mice display reduction in fear memory, suggesting that CB2Rs might have therapeutic potential for fear memory management. We hypothesize that pharmacological blockade of CB2Rs might modulate aversive fear memory in mice. First, the effect of CB2R blockade on fear memory retrieval was tested. C57BL/6J mice were injected with the CB2R antagonist SR144528 (1 mg/kg; i.p.) or vehicle once a day for 2 weeks. After the drug treatment, the mice were fear‐conditioned with foot shocks and tones. Contextual and cued fear memory was assayed from freezing behavior 24 hours after the conditioning. SR144528 had little effect on the retrieval of contextual or cued fear memory. Second, the effect of CB2R blockade on fear memory retention was examined. Drug‐naive C57BL/6J mice were fear‐conditioned, and then, daily treated with SR144528 (1 mg/kg; i.p.) or vehicle for 1 week. After the 1‐week treatment, the mice were tested for fear memory. The post‐conditioning treatment with SR144528 increased cued, but not contextual, fear memory. In summary, our data indicate that pharmacological blockade of CB2Rs after, but not before, adverse experience elevates the retention of hippocampus‐independent fear memory. Unveiling more detailed roles of CB2Rs in modulating fear memory will provide insights into the cannabinoid‐mediated treatment of aversive memory in conflict‐affect individuals.Support or Funding InformationThis work was supported by the Medical Scholars Program of Medical College of Georgia, Augusta University.
Improving Cellular Uptake and Endosomal Targeting of Neurokinin 1 Receptor Antagonists
Authors: Veldhuis Nicholas A , Mai Quynh N , Conner Josh N , Graham Bim , Halls Michelle , Lieu TinaMarie , Bunnett Nigel W 
Published: November 2023

IntroG protein‐coupled receptors (GPCRs) are cell‐surface sensors that control most pathophysiological processes. Following stimulation, many activated receptors redistribute to endosomes and evidence suggests that endosome‐localized receptors generate signals that are distinct from cell surface signaling outputs. Importantly, these endosomal signals underlie physiologically relevant cellular processes. We have recently observed that Substance P‐mediated endosomal signalling from the Neurokinin 1 Receptor (NK1R) is associated with central pain transmission and hence, the selective inhibition of NK1R within endosomes could be therapeutically advantageous.Methods and ResultsWe have synthesized a series of membrane anchored drug conjugates including Cyanine‐5 fluorophore conjugated to spantide (Span‐Cy5), cholestanol (Cy5‐Chol), spantide and cholestanol (Cy5‐Span‐Chol), or a PEG‐ethyl ester control (Cy5‐EE). Cellular uptake, membrane association and ligand‐receptor interactions were determined by live cell confocal microscopy and fluorescence correlation spectroscopy. Biological activity of these constructs was determined by ERK functional assays. These data demonstrate that cholestanol membrane anchors enhance cellular uptake, membrane‐localized drug concentrations and endosomal distribution of fluorescently labelled, lipid‐conjugated compounds. Furthermore, these compounds can interact with the NK1R and demonstrate improved analgesic potential in pre‐clinical pain models, relative to their non‐targeted counterparts.Support or Funding InformationFunding support for the National Health and Medical Research Institute and the ARC Centre of Excellence for Bio‐Nano Science and Technology
Regulation of the Sigma‐1 Receptor Quaternary Structure by Ligand Binding
Authors: Hong W. Conrad 
Published: November 2023

Since the initial proposal of sigma receptors four decades ago, extensive studies have shown that the sigma‐1 receptor (σ1R) is a unique membrane protein that may serve as a molecular chaperone. In earlier attempts to purify sigma receptors from native tissues using [3H](+)SKF10047 or [3H]azido‐DTG as affinity ligands, the labeled protein complexes appeared to be > 150 kDa under non‐denaturing conditions. Recent breakthrough on the crystal structure of σ1R revealed a homotrimer, with each protomer containing a single transmembrane domain and a cytoplasmic ligand‐binding domain. Whether ligand binding can affect the quaternary structure of σ1R has not been fully investigated. We devised a novel biochemical method to examine the multimeric status of σ1R. Epitope‐tagged σ1R from transfected cells was solubilized using mild detergents, electrophoretically separated under non‐denaturing conditions, and detected by immunoblotting. The majority of σ1R appeared as high molecular weight (MW) bands (apparent MW > 132 kDa), suggesting a high‐order quaternary organization of multimers. Pretreatment with σ1R agonists, such as (+)‐pentazocine and DTG, decreased σ1R high‐MW bands, while increased σ1R lower‐MW bands that were presumably dimers and monomers. Conversely, pretreatment with σ1R antagonists, such as BD1063 and haloperidol, exhibited opposite effects on σ1R multimerization. These results demonstrate that the quaternary structure of σ1R is regulated by binding of agonists or antagonists in a distinct manner. As σ1R has been shown to alter the function of various membrane proteins through dynamic interactions, we hypothesize that σ1R agonists promote the formation of σ1R monomers and facilitate their modulation of interacting partners.Support or Funding InformationButler University Faculty Startup Fund and Holcomb Research Award.