bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of inflammation and genes associations with Prostate cancer risk.
Authors: ANDAVOLU RADHIKA GADE , Rodriguez Olivia , Shaaf Emon GADE 
Published: June 2021

The pathogenesis of cancer involves environmental factors in addition to hereditary factors. Recent studies have pointed to a potential role for inflammation in prostatic carcinogenesis and tumor progression. An important factor is the development of chronic inflammation in the prostate due to a number of potential causes including infections, dietary factors, hormonal changes and/or other unknown environmental exposures. In this study we investigated the possible association between single nucleotide polymorphisms in the interleukin IL‐1B (C>T), tumor necrosis factor (308G>A), RANTES‐403, GSTP1 exon 5 polymorphic site (Ile105àVal), PPARG (Pro12Ala) genes also two STR polymorphic marker GSTP1 (penta‐nucleotide repeat at promoter regions) and a pyrimidine‐rich penta‐nucleotide repeat length polymorphism, CD4‐1188 (TTTTC) and the risk for developing prostate cancer. Our study is comprised of 134 prostate cancer cases and age, gender and race matched 178 normal healthy controls. These genes are known to be important for inflammation of prostate and common allelic variants have been shown to have a biological effect. Hence, we searched for a possible association between SNP polymorphisms and STR polymorphic allele gene frequencies obtained in prostate cancer patients and compared with those of a normal control population, looking for allelic associations between any of these polymorphic loci and prostate cancer risk. Strong association between GSTP1, CD4, RANTES (p<0.001), a high variation in allelic frequency of mutant IL1B, TNF and PPARG (p=NS) and prostate cancer risk are observed. Genetic associations of disease and genetic variations in inflammatory genes are often relatively modest, it is likely that polymorphisms in multiple inflammatory genes cooperate in an additive or synergistic manner to impact disease risk Because genetic associations of disease and genetic variations in inflammatory genes are often relatively modest, it is likely that polymorphisms in multiple inflammatory genes cooperate in an additive or synergistic manner to impact disease risk. The possible role of inflammation and gene associations with prostate cancer risk will be discussed.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Toll‐like Receptor‐4 Activation Improves the Immunosuppressive Properties of Cancer Cells‐Derived Exosomes
Authors: Domenis Rossana , Marinò Daniele , Cifù Adriana , Fabris Martina , Niazi Kayvan R. , Soon‐Shiong Patrick , Curcio Francesco 
Published: June 2021

Tumor cells actively produce and release exosomes to promote tumor growth and progression. Upon the contact with target cells, exosomes alter phenotypic and functional features of recipients, reprogramming them into active contributors to metastasis and immunosuppression. Overexpression of Toll‐like receptor‐4 has been implicated in the development of several types of cancer, since its activation increase their tumorigenic potential of cancer cells.The purpose of this study is to investigate the immunosuppressive properties of cancer cell‐derived exosomes released upon TLR4 activation by LPS.Cancer cell lines (primary colon SW480, metastatic colon SW620, metastatic breast MDA‐MG‐231 and glioma U87) were treated with LPS (1μg/ml) for 24h and then cultured in exosome‐free medium for 48h. Exosomes were isolated from cells supernatants by polymer precipitation method (Exoquick), quantified by determining the activity of Acetyl‐CoA Esterase (Exocet test) and validated by exosome‐specific tetraspanins expression by western blot and flow cytometry analysis. The expression of immunosuppressive factors on exosomes surface was evaluated by flow cytometry and Multiplex ELISA. Exosomes immuneregulatory properties were assessed by in vitro functional assays on immune cell subpopulations isolated from healthy donor's blood.We demonstrated that the treatment with LPS enhances the immunosuppressive potential of cancer cells‐derived exosomes, although differences were observed depending on the origin of the tumor. The expression of TGFβ and MICA/B was increased on surface of exosomes released from LPS‐stimulated cells. Moreover, exosomes became able to inhibit the proliferation of activated CD3+ cells, increase T cells apoptosis and promote the conversion of CD4+ in regulatory T cells.Our data suggest that the activation of TLR4 contributes to tumor progression by promoting the release of more effective immunosuppressive exosomes, which allow tumor cells to escape immune surveillance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chemotherapeutic tolerability and Estrogen dose response in the B6;129‐Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model
Authors: Naden Jamie , Melton Michele , Bast Athena , Gardner Jermaine 
Published: June 2021

The B6;129‐Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) knockout mouse was developed by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL‐2, IL‐4, IL‐7, IL‐9 and IL‐15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. This model was developed to provide another immunodeficient option for the oncology and immunology fields. The literature supports better tolerability of DNA damaging oncology treatments for models that do not carry the SCID mutation. We have already reported in a white paper that the R2G2 mouse model is more tolerant of whole body radiation than a model with the SCID mutation. Herein we describe a study examining chemotherapeutic tolerability of common DNA damaging oncology drugs including 5‐fluorouracil (5‐FU), doxorubicin (Doxo), and cyclophosphamide (CTX) (n = 10 per group). 5‐FU was given at 30, 60 or 100 mg/kg, intraperitoneally, twice weekly for five weeks. Doxo was given at 2 or 5 mg/kg, intraperitoneally, once weekly for three weeks. CTX was given at 100 or 140 mg/kg intraperitoneally, once weekly for three weeks. The low dose was chosen based on the average dose used in immunodeficient mouse models and the high dose was chosen based on the average dose used in immunocompetent mouse models. This was done to determine if the R2G2 mouse model can tolerate higher doses of these chemotherapeutic agents compared to other immunodeficient mouse models. Results show that the R2G2 mouse model tolerates higher doses of these chemotherapeutic drugs than doses found in the literature for SCID models. Exogenous estrogen tolerance is another common concern in oncology research as some immunodeficient mouse models cannot tolerate the subcutaneous estrogen pellets, developing negative secondary effects resulting in removal from study. We performed an estrogen pellet dose response study using four doses of 60‐day release 17‐β estradiol pellets at 0.18, 0.36, 0.72, and 1.7 mg/pellet (n = 10 per group). R2G2 mice show dose dependent effects of estrogen on morbidity. These data will allow researchers to determine the optimal dose for use in the R2G2 model. In conclusion, these data support that the R2G2 mouse model may be a good alternative to SCID models when administering DNA damaging chemotherapies or when estrogen supplementation is required for xenograft growth.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Elucidation of self‐mediated enhancement of dopamine transport by the dopamine transporter which can be modulated by extracellular gate and N‐terminal residues
Authors: Henry L. Keith , Allen Michael Dean , Shetty Madhur , Cwikla Allison , Nies Isaac 
Published: June 2021

The dopamine (DA) and serotonin (5‐HT) transporters (DAT and SERT respectively) are members of the SLC6 family of neurotransmitter:sodium symporters (NSSs). DAT and SERT clear substrate from perisynaptic spaces by the generally accepted alternating access mechanism in which the transporters transition between outward‐facing and inward‐facing conformational states. This mechanism involves a sequential closing and opening of extracellular (EC) and intracellular (IC) gates along the permeation pathway. The EC and IC gates are almost exclusively composed of acidic and basic residues capable of interacting through salt bridge formation, closing the primary substrate binding site to the intracellular and extracellular milieus. Previously, we identified that the human SERT acidic/basic residue pair is critical for the recognition of 3,4‐methylenedioxymethamphetamine (MDMA) as a substrate. In contrast, mutations in the EC gate had no effect on 5‐HT recognition. Our current efforts focus on determining if the EC gate of the human DAT has similar mechanistic characteristics for substrate selectivity. While investigating that possibility, we identified a previously unreported phenomenon of self‐mediated enhancement of DA transport in hDAT expressing cells. In homologous competitive uptake experiments utilizing [3H]DA, a 200% to 300% increase in [3H]DA uptake is observed upon addition of micromolar concentrations of unlabeled DA. This enhancement is further modulated by the identity of the acidic EC gate residue. Substituting the Asp with the polar amino acid Asn (D476N) produces a 600% increase in [3H]DA uptake. Experiments utilizing heterologous competition with [3H]DA and the known hDAT substrates 1‐methyl‐4‐phenylpyridinium (MPP+), 4‐(4‐dimethylamino)phenyl‐1‐methylpyridinium(APP+) and tyramine indicate that the enhancement effect is not exclusive to DA nor is it observed with all DAT substrates. Notably, elimination of phosphorylation at N‐terminal residue Thr53 virtually eliminates the DA self‐enhancement phenotype. The apparent ability of DA to enhance its own uptake is consistent with reports proposing a second substrate binding site (S2) that can act as a trigger for release of substrate from the primary DA binding site (S1). However, the presence of this S2 site remains controversial. Continued investigation of this phenomenon may provide insight into molecular determinants on both the substrate and transporter that are important for substrate identification and translocation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
D2 Autoreceptor Signaling is Depressed by Neurotensin Released from Discrete Inputs to Midbrain Dopamine Neurons.
Authors: Tschumi Christopher W. , Beckstead Michael J. 
Published: June 2021

Midbrain dopamine neurons play physiological roles in many processes including reward learning and motivated behavior. Neurotensin (NT) is a neuropeptide which acutely modulates midbrain dopamine neuron excitability through multiple mechanisms, including a decrease in dopamine D2 autoreceptor‐mediated inhibition. While there are dense neurotensinergic inputs to the midbrain that arise from many different brain regions, most studies to date have relied on exogenous application of NT and NT ligands to determine physiological consequences of NT signaling. As such, the mechanisms involved in release and signaling of endogenous NT from different sources are poorly understood. Here we used transgenic mice that express channelrhodopsin in neurons that also either express NT or the dopamine transporter. We then combined patch clamp electrophysiology of dopamine neurons in midbrain slices with blue light stimulation to specifically activate either neurotensinergic or dopamine neurons (respectively). We found that low frequency stimulation of dopamine neurons alone was sufficient to induce long‐term depression (LTD) of D2 autoreceptor inhibitory postsynaptic currents (IPSCs) and that this LTD could be blocked by either chelation of calcium in the patched cell or by preincubating the slice with a non‐selective NT type 1 and 2 receptor antagonist. It is believed that dopamine neurons do not synthesize NT, but rather take up NT via internalization of NT receptors. Consistent with this, in mice that expressed channelrhodopsin in neurotensinergic neurons, blue light did not cause a channelrhodopsin‐mediated excitation of dopamine neurons. However, low frequency stimulation of neurotensinergic neurons did result in a depression of D2‐IPSCs (though to a lesser extent than stimulation of dopamine neurons) and this depression was blocked by preincubating the slice with a non‐selective NT type 1 and 2 receptor antagonist. Together, these results suggest that neurotensin could be released either by dopamine neurons themselves to act as a retrograde messenger or released by non‐dopaminergic neurons to act as an anterograde messenger, and in both cases can cause LTD of D2 autoreceptor signaling. These findings are the first steps in defining the circuit‐specific NT‐induced plasticity which regulates dopamine neuron activity.Support or Funding InformationThis work was supported by National Institute on Drug Abuse Grant R01 DA32701 (M.J.B.), as well as funds from the Presbyterian Health Foundation and the Oklahoma Center for Adult Stem Cell Research.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 Mu‐Delta Opioid Receptor Heterodimer Promotes Acute and Chronic Morphine Induced Dependence/Withdrawal in Mice
Authors: Nguyen Paul , Keresztes Attila , Olson Keith , Hruby Victor , Streicher John M. 
Published: June 2021

Opioid drugs like morphine are the gold standard for treating acute and chronic pain, but induce detrimental side effects such as tolerance and dependence. It has been suggested that the mu‐delta opioid receptor heterodimer (MDOR) transduces some of these side effects and that heterodimer targeted drugs could be a solution to weaken these side effects. We have thus created an MDOR selective antagonist called D24M. We evaluated D24M in vitro, and found a ~100 fold selectivity for the MDOR over the monomers. Similarly, we performed hot water tail‐flick experiments in mice in the presence of various doses of D24M against CYM51010 and Deltorphin‐2 (MDOR selective agonist), and DAMGO (MOR monomer selective agonist), and found that D24M potently (A50=2–7.8 nmol) blocked MDOR activity with no activity against the MOR monomer up to 10 nmol. To test the ability of D24M to lessen acute or chronic morphine‐induced dependence and withdrawal, we established acute (4 hr) and chronic (4 day) morphine dependence models, with 1 nmol D24M or vehicle injected 5 minutes prior to naloxone precipitation of withdrawal. We found that D24M strongly reduced jumping behavior in dependent mice in both the acutely and chronically models; further confirming that the MDOR promotes withdrawal behavior, and that D24M could possibly be a promising drug candidate for opioid dependence and withdrawal. These discoveries will further determine the role of the MDOR in vivo, and provide a novel tool that could greatly impact opioid heterodimer research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of Swimming Exercise in Combination with non‐Steroidal Anti‐Inflammatory Drugs on Inflammatory Nociception in Rats
Authors: Alsalem Mohammad , Altarifi Ahmad , Kalha Zain , Alzoubi Abdallah , Alfaqih Mahmoud , Kana'an Saddam 
Published: June 2021

Pain is a growing health problem with increasing prevalence and burden worldwide. Major approaches for pain control include pharmacological and non‐pharmacological interventions. Pharmacological treatment is achieved by the use of analgesics, such as non‐steroidal anti‐inflammatory drugs (NSAIDs) and opioids. However, these medications are usually accompanied with many side effects upon prolonged use. Physical exercise is an example of non‐pharmacological interventions for pain control. In this study, we examined the effect of one of the most commonly prescribed NSAIDs, ibuprofen, on nociception threshold, with or without swimming exercise in rats. Two swimming protocols were used; Prophylactic group and treatment group. Nociception was induced by the intraplantar injection of Complete Freund's Adjuvant (CFA). Nociception threshold was measured using von Frey filaments in an up‐down protocol. The goal of this study was to determine the effect of swimming exercise on nociception threshold and ibuprofen‐induced antinociception in inflammatory pain rat model. We hypothesized that swimming exercise will enhance the ibuprofen‐induced antinociception in rats. Ibuprofen produced an antinociception effect only at the highest dose (32 mg/kg), with a duration that lasted for 17 days. A dose of 32 mg/kg ibuprofen produced significant increase in pain threshold in swimming treatment and prophylactic swimming groups when compared to ibuprofen alone group. Moreover, Ibuprofen produced significant antinociception after 10 mg/kg drug dose compared to vehicle in the prophylactic swimming group only. The duration of mechanical allodynia after CA injection was decreased in both swimming groups to 7 days only. In conclusion, the combination of ibuprofen and swimming exercise was shown to be effective in controlling nociception in a rat inflammatory pain model. The combination of exercise and ibuprofen could be suggested as an effective intervention to help control chronic pain. In addition, prophylactic swimming can increase the potency of analgesic medications, by lowering the administered drug dose, and thus, lowering the risk for ibuprofen‐induced side effects.Support or Funding InformationJUST 130/2016This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Conformational Dynamics Contribute to Phospholipase Cβ Activity
Authors: Van Camp Michelle Marie , Garland‐Kuntz Elisabeth , Lyon Angeline 
Published: June 2021

Phospholipase Cβ (PLCβ) enzymes hydrolyze the lipid phosphatidylinositol‐4,5‐bisphosphate (PIP2) to produce the second messengers inositol‐1,4,5‐triphosphate (IP3) and diacylglycerol (DAG). Production of these second messengers leads to many diverse physiological responses, including vascular smooth muscle contraction and inflammation. Previous structural and functional studies of PLCβ have revealed a highly conserved catalytic core that adopts a compact, globular structure and forms the minimal fragment that retains lipase activity. However, a growing body of evidence suggests that the PLCβ PH domain, which interacts with EF hands and TIM barrel of the catalytic core in crystal structures, may be flexible in solution. Using a combination of small angle x‐ray scattering (SAXS), cross‐linking studies, and biochemical assays, we provide the first structural data demonstrating that the PH is in fact conformationally flexible in solution. The PH domain adopts two major states: an open state wherein the PH domain is extended away from the core, and a closed state consistent with the crystal structures. We also provide evidence that these conformational states are functionally significant. These findings provide new evidence of conformational heterogeneity of PLC enzymes in solution and reveal new insights into their roles in cell signaling and cardiovascular disease.Support or Funding InformationAmerican Heart Association Scientist Development Grant 16SDG29920017; Purdue Center for Cancer Research; Showalter Foundation; all to A.M.LThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Amino‐terminal region plays an important role in transport function of human organic anion transporting polypeptide 1B1
Authors: Hong Mei , Chen Jie , Xiang Zhaojian , Fang Zihui , Ni Chunxu 
Published: June 2021

ObjectiveThe family of organic anion transporting polypeptides (OATPs, gene symbol SLCO) mediates sodium‐independent transport of a wide variety of endogenous and exogenous compounds. OATPs are considered as key players in drug absorption, distribution and excretion due to their broad substrate specificity, wide tissue distribution and involvement in drug‐drug interactions. OATP1B1 is specifically located at the basolateral membrane of human hepatocytes and serves a crucial role in drug clearance from the body. Previous studies have shown that transmembrane domains (TMs) of OATP1B1 are essential structural features for proper function of the transporter.MethodsAlanine‐scanning of the putative transmembrane domain 1 and truncation of the N‐terminus of OATP1B1 were carried out, and the uptake function and protein expression of mutants were analyzed.ResultsTwo positively charged amino acid residues, K41 and K49, were identified to be important for uptake function of the transporter protein. Alanine substitution of K41 altered substrate binding at the high affinity component; while K49A exhibited increased Km value at the low affinity site. In addition, our study of the N‐terminal residues of OATP1B1 found out that residues ranging from 19–27 are essential for protein stability and uptake function of the transporter protein.ConclusionsThe N‐terminus region of OATP1B1 is important for maintaining proper function and protein expression level of the transporter.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China Grants [81373473] to Mei Hong.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Rgs8 and Rgs16 protect against pancreatitis and PDA cancer progression
Authors: Wilkie Tom , Choudhuri Shreoshi Pal , Zolghadri Yalda 
Published: June 2021

Pancreatic ductal adenocarcinoma (PDA) has the highest death rate among major cancers, and new treatments are desperately needed. KCR8‐16 mice are an excellent model for identification, characterization, and in vivo validation of novel PDA therapeutics. Kras oncogenic mutations (e.g. KrasG12D) are found in over 90% of human PDA. Kras can be activated by protein kinase and G‐Protein Coupled Receptor (GPCR) signaling. Regulator of G protein signaling (Rgs) proteins regulate GPCR signaling by accelerating the GTPase activity of Gq/11‐ and Gi‐class alpha subunits. Activating alleles of Gq/11 that are resistant to Rgs inhibition are found in benign precursors of PDA in humans. We previously reported that Rgs8 and Rgs16 are in vivo reporters of Kras activity in pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and PDA progression in KIC;Rgs16::GFP mice (p48::Cre/+; KrasG12D/+; Cdkn2af/f; Rgs16GFP ) (DMM 8, 2015). To identify the role Rgs8 and Rgs16 in PDA, we crossed the Rgs8‐16 double knockout into pancreas specific KrasG12D (KC) mutant mice (termed KCR8‐16). We found that deletion of Rgs8 and Rgs16 dramatically accelerated PDA progression in the KC backgrond. Additional pancreatic stress evoked by caerulein treatment caused immediate and pancreas‐wide progression to PDA in KCR8‐16 mice. Our study suggest Rgs8 and Rgs16 act as tumor suppressor genes in PDA initiation and progression. Moreover, KCR8‐16 and KIC;Rgs16::GFP mice can be used as excellent models for identification and rapid in vivo validation of PDA therapeutics.Support or Funding InformationNCI R01 CA192381This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.