bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antinociceptive and Gastrointestinal Effects of Mu/Kappa Opioid Mixtures in Rats
Authors: Minervini Vanessa , Osteicoechea Daniela C , France Charles P 
Published: June 2021

Prescription opioids (mu receptor agonists) are commonly used to treat moderate to severe pain despite well‐documented adverse effects (e.g., constipation, abuse). Kappa opioid receptor agonists also have antinociceptive and adverse effects but might be useful for treating pain in drug mixtures. The use of smaller doses in mixtures might reduce or avoid adverse effects that occur with larger doses of either drug given alone. This study evaluated the kappa opioid receptor agonist spiradoline, the mu opioid receptor agonist morphine, and spiradoline:morphine mixtures (in 3:1, 1:1, 1:3, and 1:10 ratios) for their effects on antinociception and gastrointestinal (GI) motility to test the hypothesis that mixtures selectively enhance antinociceptive effects. Tail withdrawal latency from 50°C water was used to assay antinociception in one group of 8 male Sprague Dawley rats, and fecal output (count) was used to assay GI motility in another group of 8 male Sprague Dawley rats. Drugs were given i.p., with tests separated by at least 5 days. Spiradoline (3.2–32 mg/kg) and morphine (1.78–17.8 mg/kg) dose‐dependently increased tail withdrawal latency to a maximum of 20 sec; morphine (1–10 mg/kg) dose‐dependently decreased fecal count from 12 to less than 2 pellets. Spiradoline:morphine in 3:1 and 1:1 ratios had additive antinociceptive effects. The potency of morphine for antinociceptive effects was increased by spiradoline:morphine in 1:3 and 1:10 ratios (greater than predicted additivity). Conversely, in no instances was the potency of morphine increased for effects on GI motility. The potency of morphine to inhibit GI motility was either unchanged (e.g., 1:10) or decreased (e.g., 3:1) by spiradoline:morphine mixtures. Overall, spiradoline:morphine mixtures selectively reduce the dose of morphine needed to produce antinociceptive (therapeutic) effects. It remains to be determined whether spiradoline:morphine mixtures have other adverse effects (abuse, respiratory depression, and dysphoria) and whether interactions between spiradoline and morphine on these outcomes might be related to the ratio of each drug in mixtures.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The effects of intermittent dietary supplementation with fish oil on high fat diet‐induced enhanced sensitivity to the behavioral effects of dopaminergic drugs
Authors: Beltran Nina Marie , Hernandez‐Casner Caroline , Serafine Katherine 
Published: June 2021

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat laboratory chow are more sensitive than rats eating standard chow to the behavioral effects of the dopamine receptor D2/D3 receptor agonist quinpirole. Specifically, quinpirole induces yawning in rats, and quinpirole‐induced yawning is enhanced in rats eating high fat chow as compared to rats eating standard chow. Daily dietary supplementation with 20% (w/w) fish oil prevents this high fat diet‐induced effect; however, for beneficial effects of fish oil in humans, doctors recommend that patients take fish oil only 2–3 times a week. To test the hypothesis that intermittent (e.g., 2/7 days per week) dietary supplementation with fish oil prevents high fat diet‐induced effects (e.g., weight gain and enhanced sensitivity to the behavioral effects of dopaminergic drugs) rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2/7 days per week) dietary fish oil supplementation were tested once weekly with quinpirole (0.0032–0.32 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole. That is, the quinpirole‐induced yawning dose‐response curve was shifted significantly to the left for rats eating high fat chow as compared to rats eating standard chow. Intermittent access to fish oil prevented this effect, since quinpirole‐induced yawning was not different among rats eating standard chow and rats eating high fat chow supplemented with fish oil. Future experiments will examine other dopaminergic drugs (e.g., cocaine) and will focus on understanding the mechanism by which fish oil produces these beneficial effects, by examining the specific omega‐3 polyunsaturated fatty acids found in fish oil.Support or Funding InformationA portion of this project was supported by R25 GM069621.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Attenuation of dementia by AS605240‐PI3K inhibitor in ICV‐STZ induced sporadic Alzheimer's disease rat model
Authors: Alluri Ramesh , Sivamallikarjuna Reddy A , Supriya Reddy G , Banu Nafiza 
Published: June 2021

Sporadic Alzheimer's disease is an age allied neurological and psychiatric disorder branded by impaired energy metabolism. Oxidative stress and neuro‐inflammation are associated in pathophysiology of sporadic type of dementia. The quest for chemical entities able to kerb the action of the PI3K/AKT/mTOR pathway is evolving as a potential therapeutic stratagem for its treatment and/or prevention.The Intra‐cerebroventricular (ICV) administration of streptozotocin prompts behavioural and biochemical changes resembling those in sporadic type of Alzheimer's patients. The current study was intended to investigate the effects of chronic pre‐treatment with Phosphoinositide 3‐kinase(PI3K)inhibitor AS605240 on cognitive dysfunction and oxidative stress markers in intracerebroventricular (ICV) streptozotocin‐treated albino rats.Treatment with AS605240 orally was done on a daily basis for a period of 21 days, 1 hr prior to ICV‐STZ injection using stereotaxy and evaluated for cognitive function tests and biochemical parameters.AS605240 when given orally on a daily basis for a period of 21 days significantly improved STZ‐induced cognitive impairment. Besides, improving cognitive dysfunction, AS605240, reduced elevated nitrite levels, and restored reduced glutathione and superoxide dismutase levels, Lipid peroxidation and total Protein content.Taken together, these results demonstrate that PI3K inhibitor AS605240 can be helpful in treatment of sporadic Alzheimer's Disease.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of Chronic Cadmium Exposure on Chemotherapy Sensitivity in Breast Cancer Cells
Authors: Manabat Candice , Bloomfield Mathew , Louie Maggie C 
Published: June 2021

Breast cancer is a leading cause of cancer‐related mortality among women in the United States. Exposure to environmental carcinogens, such as cadmium, has been shown to increase the risk of breast cancer. While humans are only exposed to cadmium at minute quantities through diet and cigarette smoke, it tends to bioaccumulate in the body. Epidemiological studies have shown that patients with breast cancer tend to have higher levels of cadmium in comparison to healthy patients. Previous findings from our lab indicate that breast cancer cells chronically exposed to low levels of cadmium (MCF7‐Cd) had altered gene expression profiles and higher rates of cell growth, migration, and invasion compared to the parental cells (MCF7). Despite evidence suggesting chronic cadmium exposure promotes breast cancer progression, its effect on therapeutic response is largely unknown. Here we evaluate the effects of chronic cadmium exposure on the ability of breast cancer cells to response to different classes of cancer therapeutics—antiestrogens (tamoxifen and endoxifen), taxanes (cabazitaxel and docetaxel), an anthracycline (doxorubicin), and an antimetabolite (gemcitabine). Our results suggest that cells chronically exposed to cadmium (MCF7‐Cd7 and ‐Cd12) did not show a differential response to antiestrogens, doxorubicin, or gemcitabine. Interestingly, MCF7‐Cd7 and ‐Cd12 cells did exhibit decreased response to the taxanes in comparison to the parent MCF7 cells (GI50 of 11.34 nM and 15.12 nM, respectively, vs. GI50 of 4.04 nM) suggesting that chronic cadmium exposure contributes to the development of taxane resistance. Analysis at the protein level indicate that 1 nM of cabazitaxel or docetaxel was sufficient to induce PARP cleavage—a signal of apoptosis— in MCF7 cells, while PARP cleavage was not evident in MCF7‐Cd7 and ‐Cd12 cells until 5 and 10 nM, respectively. Consistent with this finding, the expression of p53 and p21 were concordantly increased in response to 1 nM of cabazitaxel or docetaxel in MCF7 cells, but expression did not increase in the cadmium‐adapted cells until a higher taxane concentration. Collectively, this data strongly suggest that chronic cadmium exposure may contribute to the development of resistance to taxane‐induced apoptosis, and does not alter sensitivity to the other cancer drugs. Further work is necessary to understand the mechanism of this drug resistance and the potential implications in the treatment of breast cancer.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lung Fibroblasts Modulate Human Breast Cancer Cell Sensitivity to Chemotherapy and Autophagy Inhibition in a 3‐Dimensional Organotypic Co‐Culture Model
Authors: Regan Daniel , Gustafson Daniel 
Published: June 2021

Fibroblasts are one cell type present in the tumor microenvironment (TME) which have been linked to several tumor growth and metastasis promoting activities. Recent data suggest that the molecular mechanisms underlying these metastasis‐promoting effects of the TME share significant overlap with those which mediate therapeutic resistance. Despite this, very few studies have evaluated the contributions of stromal cells on potential extrinsic mechanisms of cancer chemo‐resistance. Periostin (POSTN) is an extracellular matrix protein whose expression by lung fibroblasts has been shown to promote metastatic colonization and induction of a cancer stem cell (CSC) phenotype in a mouse model of breast cancer metastasis. However, the potential effects of lung fibroblasts (LFs) and POSTN in mediating tumor cell survival and chemoresistance in human breast cancer cells (BCCs) has not been evaluated. Therefore, we evaluated the effects of primary human LFs and recombinant POSTN on human BCC sensitivity to doxorubicin (DOX) and pharmacological inhibition of autophagy utilizing a modified 3D organotypic co‐culture model. Initial screening of a panel of six human breast cancer cell lines demonstrated that while rPOSTN induced BCC survival/proliferation under low‐serum conditions, it had no effect on BCC resistance to the autophagy inhibitor chloroquine (CQ). However, compared to standard 2‐D monolayer culture, 3D culture of either human BCCs or LFs alone induced resistance of both LFs and triple‐negative breast cancer (TNBC) cell lines to autophagy inhibition with CQ. Interestingly, the addition of primary human LFs into this 3D co‐culture system re‐sensitized TNBC cell lines to CQ, to a degree similar to that observed in standard 2‐D mono‐culture. In contrast, DOX sensitivity was not altered by 3D mono‐culture of any of the human BCC lines screened, while the addition of LFs induced DOX‐resistance in the luminal, ER+ cell line, T47D. These results suggest that the effect of lung fibroblasts on human BCC sensitivity to chloroquine and doxorubicin may be dependent on breast cancer molecular subtype and provide evidence for lung fibroblast‐mediated regulation of autophagy in human BCCs.Support or Funding InformationThe authors would like to acknowledge the following sources of funding support: NIH‐NCI K01ODO22982 (DP Regan) and NIH‐NCI 1R01CA190170 (DL Gustafson).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Structural insights into mitochondrial EndoG in response to oxidative stress
Authors: Yuan Hanna S. , Lin Jason L. J. , Chu Woei‐Chyn 
Published: June 2021

Endonuclease G (EndoG) is an evolutionarily conserved mitochondrial protein that degrades chromosomal DNA during apoptosis. In mitochondria, EndoG also processes DNA and participates in mitochondrial DNA metabolism. EndoG‐deficient mice have high levels of mitochondria reactive oxygen species (ROS) and develop heart and mental diseases, showing that the EndoG defect is linked to mitochondrial dysfunction and oxidative stress‐linked diseases. However, it remained unclear how EndoG degrades DNA as a homodimer and why EndoG's function is linked to ROS levels in mitochondria. We reported the crystal structures of the C. elegans EndoG homologue, CPS‐6, in complex with single‐stranded DNA at a resolution of 2.3 Å. Two separate DNA strands are bound at the bba‐metal motifs in the homodimer with their nucleobases pointing away from the enzyme, explaining why CPS‐6 degrades DNA without sequence specificity. We also showed that under oxidative stress, homodimeric EndoG becomes oxidized and converts to monomers with a diminished endonuclease activity. High ROS levels are thus linked to mitochondrial dysfunction by repressing EndoG's activity. Modulation of EndoG dimer conformation and endonuclease activity could present an avenue for prevention and treatment of the diseases resulted from oxidative stresses.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intercellular Communication by Gap Junctions in the Cranial Neural Crest
Authors: Taneyhill Lisa 
Published: June 2021

Cell‐cell interactions and communication are critical for several fundamental biological processes that underscore vertebrate development, including cell migration and the formation of multicellular tissues. Much of the patterning that occurs during vertebrate embryogenesis is accomplished by neural crest cells, which are initially stationary but acquire the capacity to migrate through the epithelial‐to‐mesenchymal transition (EMT). Once motile, neural crest cells must communicate and interact with one another and with other cells, later differentiating to become sensory neurons and glia, the craniofacial cartilage and skeleton, portions of the heart, and skin pigment cells. The molecular basis by which neural crest cells establish intercellular communication during their initial formation and migration, however, is still not known. One unexplored means of such intercellular communication is through gap junctions that permit the passage of small molecules between connected cells. Gap junctions are comprised of Connexin proteins, of which Connexin 43 (Cx43) is the most abundant, with modulation of Cx43 previously shown to impact the formation of neural crest cell derivatives. Notably, mutations in Cx43 lead to oculodentodigital dysplasia, a disease characterized, in part, by craniofacial defects. To delineate a function for Cx43, and gap junctions, in cranial neural crest cell development, we first characterized the spatio‐temporal expression pattern of Cx43, noting it in premigratory neural crest cells, during EMT, and in fully migratory neural crest cells. Given this expression pattern, we next performed molecular and chemical perturbation assays to respectively alter Cx43 and gap junction function in neural crest cells. Our live imaging experiments reveal the presence of functional gap junctions in premigratory neural crest cells in vivo and in migratory neural crest cells cultured ex vivo. Moreover, gap junctions within the migratory neural crest cell population depend on Cx43 to properly transfer dye between cells. In keeping with this finding, chemical inhibition of general gap junction function, but not formation, abrogates neural crest cell EMT and/or migration in a reversible manner. Depletion of Cx43 from premigratory neural crest cells in vivo alters the expression of some neural crest cell markers but, interestingly, does not overtly affect EMT. These studies will decipher the roles of Cx43 and gap junctions in cranial neural crest cell EMT and migration, providing insight into the significance of intercellular communication during these key processes that are required for the formation of the vertebrate embryo.Support or Funding InformationThis research is supported by NIH R01DE024217 and American Cancer Society RSG‐15‐023‐01‐CSM grants.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Can Cellular Labile Iron Pool be Considered Solely a Pro‐oxidant Species in Cells?
Authors: Damasceno Fernando Cruvinel , Toledo José Carlos , Condeles André Luis , Lopes Angélica Kodama Bueno , Facci Rômulo Rodrigues , Linares Edlaine , Truzzi Daniela Ramos , Augusto Ohara 
Published: June 2021

The ubiquitous cellular labile iron pool (LIP) is often associated with the production of the highly reactive species hydroxyl radical, which forms through redox reaction with hydrogen peroxide. Several studies indicate that LIP‐dependent hydroxyl radical production causes cellular damage through oxidation of biomolecules. Although LIP's interaction with hydrogen peroxide and its effects are well established, the interaction of LIP and peroxynitrite, and it's effects are not yet understood. Does peroxynitrite, a potent oxidant species known to interact with transition metals, act as an oxidant species in cells just like hydrogen peroxide? In murine macrophage cells we observed that removal of LIP with membrane‐permeable iron chelators attenuates peroxynitrite‐dependent oxidation and nitrosation of fluorescent probes in both normal and oxidative stress conditions which is in stark contrast to H2O2‐dependent oxidation. These results could not be reproduced in cell‐free systems indicating that the chelator‐enhancing effect on peroxynitrite‐dependent modifications of the probes depend on cells constituents, presumably including LIP, that reacts with these chelators. It is also observed that neither free nor ferrous‐complexed chelators stimulated intracellular or extracellular nitrosative and oxidative processes. These results indicates that LIP is a competitive cellular target for peroxynitrite and its derived oxidants, and thereby reduces oxidative processes, which may change the current view of LIP as a cellular source of pro‐oxidant iron.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Utilizing live‐cell imaging in Drosophila cells to identify stressors that induce protein misfolding
Authors: Choi Annette , Hrizo Stacy , Buckley Martin 
Published: June 2021

Proteins drive many of the biological processes in cells. To do this, they fold into complex 3D structures that are integral for their functionality. Notably, various environmental and chemical stressors can disrupt protein folding and thus disable the functions of proteins, threatening the livelihood of cells. To mitigate this stress, organisms initiate the highly‐conserved heat shock stress response. In eukaryotes, the master heat shock activator heat shock factor (HSF) is rapidly recruited to the Hsp70 heat shock protein genes and triggers the recruitment of additional co‐activator proteins that facilitate gene expression. This leads to the production of heat shock proteins that function as molecular chaperones to promote refolding of proteins, prevent aggregation and increase protein degradation pathways. Notably, activation of the heat shock response pathway, can be visualized by measuring GFP‐tagged HSF binding to the heat shock protein genes in living Drosophila salivary gland nuclei. Our lab is currently using this technique to identify novel compounds that induce the heat shock response pathway. Our pioneering experiments have shown that diamide and hydrogen peroxide, two chemicals known to cause protein misfolding and activation of the heat shock response pathway, trigger the recruitment of GFP‐HSF to the Hsp70 loci in living salivary gland cells to a similar level as HS stress. In addition, to our surprise, high levels of Dithiothreitol (DTT, 100 mM), a chemical known to cause protein misfolding and activation of the unfolded protein response pathway (UPR), results in the recruitment of GFP‐HSF to the Hsp70 gene loci. Here we describe experiments to further explore a possible dose dependent activation of HSF by DTT.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Expression of Microtubule Associated Protein Tau (MAPT) in Saccharomyces cerevisiae to Determine the Effects of N‐terminal Acetylation
Authors: Anderson Jess Lynn , Holmes William 
Published: June 2021

Protein aggregates, which can result in cellular toxicity, are found in the brains of people afflicted with neurodegenerative diseases. One of the proteins found to aggregate is the Microtubule Associated Protein Tau, a protein that stabilizes microtubules in neuronal cells. Based on its amino acid sequence, Tau is predicted to be N‐terminally acetylated by the acetyltransferase complex NatA, which is responsible for the acetylation of 50% of the proteome in yeast and humans. Loss of NatA activity results in a variety of pleiotropic detrimental phenotypes, suggesting that acetylation is a crucial modification for many proteins. The first 10 amino acids of Tau have previously been demonstrated to play a role in aggregation, but the specific role of N‐terminal acetylation has yet to be determined. Without the presence of NatA – and therefore without acetylation – Tau may be more prone to aggregation and toxicity. By expressing Tau in yeast strains with and without the presence of NatA, the possible effects of acetylation or lack thereof can be determined by examining protein expression and aggregation within the cells by various methods including SDS‐PAGE, SDD‐AGE, and visualization of GFP‐tagged Tau via microscopy.Support or Funding InformationThis work was made possible by an Early Career Development Award through RI‐INBRE (2P20GM103430) and by Dr. William Holmes.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.