bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locomotor Effects of Substituted Amphetamines and Cathinones in Mice: Structure‐Activity Relationships
Authors: Russell Lauren , Fukuda Saki , Hyatt William , Berquist Michael , Landavazo Antonio , Blough Bruce , Fantegrossi William 
Published: June 2021

Substituted amphetamines represent one of the largest and most pharmacologically‐diverse classes of abused drugs. Modifications to the amphetamine base structure are seemingly limitless, and novel psychoactive substituted amphetamines continuously emerge on the illicit market. Amphetamine analogues containing a ketone at the beta carbon are referred to as cathinones, which are typically the active constituents in abused “bath salts” products. Each “generation” of cathinone analogues introduces new structural motifs, most likely in response to regulatory control of previous compounds. One recently identified “bath salts” constituent is 4‐chloroethcathinone (4‐CEC), consisting of the base amphetamine structure with the addition of an ethyl side chain, a chlorine at the 4‐position, and a ketone group at the beta carbon. In these studies, we compared 12 structurally‐analogous substituted amphetamines and cathinones increasing in structural complexity from amphetamine to 4‐CEC in order to assess structure‐activity relationships for locomotor stimulant and toxic effects in mice. Automated photobeam chambers were used to record various aspects of mouse locomotor activity including jump count, time in stereotypy, vertical time, speed, and distance. Full dose‐effect curves were determined for each compound, starting with a dose that produced saline‐like distance traveled, and increasing in half‐log units until distance decreased from that drug's peak, or until lethal effects were observed. For the substituted amphetamines, increasing the length of the side chain increased maximal effectiveness on locomotor endpoints. As compared to analogous unsubstituted compounds, addition of a chlorine at the 4‐position did not substantially impact distance traveled, but increased time spent in stereotypy. These same trends were also observed with the substituted cathinones. Interestingly, 4‐CEC produced lethality in all subjects at doses on the ascending limb of the dose‐effect curve for distance traveled. Further development of structure‐activity relationships for these drugs may determine which moieties of their chemical structures are involved in producing specific pharmacological effects, and may allow predictions about abuse liability or toxic effects of new pharmacological entities with similar structural motifs.Support or Funding InformationThese studies supported by DA022981, R01‐DA039195, and DEA/FDA HHSF223201610079C.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Serotonin 2A and Sigma 1 Receptor Antagonists Synergize to Block the Acute Toxicity of Methamphetamine
Authors: Ray Azizi 
Published: June 2021

Currently there are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public‐health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH.Determine whether antagonism of serotonin 2A (5‐HT2A) and sigma 1 (σ1) alone or in combination attenuates METH‐induced lethality, hyperthermia, convulsions, and seizures.Male, Swiss Webster mice received intraperitoneal injections of the selective 5‐HT2A receptor antagonist M100907 (1–10 mg/kg), the selective σ1 receptor antagonist BD 1047 (10–30 mg/kg), and a combination of M100907/BD 1047 (1:10 mg/kg) prior to treatment with METH (78 mg/kg ‐ LD67). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography.M100907 and BD 1047 administered alone had no significant effect on METH‐induced lethality. However, combined antagonism of 5‐HT2A and σ1 receptors eliminated lethality in all mice tested (a reduction from LD67 to LD0). Similarly, only the combination of 5‐HT2A and σ1 receptor antagonism eliminated seizure activity. All three treatments decreased tonic‐clonic convulsions as measured on a modified Racine scale. None of the treatments decreased METH‐induced hyperthermia.This research suggests that reducing METH‐induced seizures may be critical for reducing METH‐induced lethality. These data support the continued investigation of the role of 5‐HT2A and σ1 receptors in METH overdose, including their potential to yield emergency reversal agents.Support or Funding InformationThese studies were supported by the National Institutes on Drug Abuse [NS100512] and by funding from the Mercer University College of Pharmacy (Murnane KS‐ Principal Investigator; Canal CE– Principal Investigator)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
To Study the Correlation of Vitamin D and Metabolic Syndrome in Schizophrenia
Authors: Ambwani Sneha R , Nebhinani Naresh , Sharma Praveen , Misra Arup Kumar , Saini Vijay Kumar , Sharma Pramod Kumar , Dwivedi Pradeep 
Published: June 2021

ObjectivesSchizophrenia, a highly heterogeneous & biological disorder of the brain, is associated with biochemical, metabolic & cardiovascular derangements. Vitamin D is known to have the role as a neuro‐modulator/neuroprotection in the brain. Prevalence of metabolic syndrome in schizophrenia is very high & it further increases with the use of atypical antipsychotic drugs. The present study is conducted to correlates the association between serum levels of vitamin D and parameters of metabolic syndrome in the patient of schizophrenia.MethodsVenous blood sample was collected from 50 adult schizophrenic patients. Serum vitamin D and parameters of metabolic syndrome like waist circumference, blood pressure (systolic as well as diastolic), fasting blood glucose (FBS), triglycerides (TG) and high‐density lipoprotein (HDL) was measured. An analysis was done using the SPSS version 20.0 for Windows (Chicago, Illinois, USA). Mean and the standard deviation is calculated for the continuous variables. Pearson's correlation was used to assess the relationship between vitamin D level and parameters of metabolic syndrome.ResultsSystolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBS) and triglycerides (TG) were found to have an inverse relation with serum vitamin D level. Vitamin D level was found in the deficient category (<20 ng/dl) in most of the patients. Waist Circumference and high‐density lipoprotein (HDL) was found to have a direct correlation with vitamin D in the patient of schizophrenia of the population.ConclusionsThe study showed the possible clinical role of vitamin D level in initiating changes in the biochemical and physical parameters of metabolic syndrome in patients of schizophrenia even though the sample size is small. It might signify the role of Vitamin D in the pathogenesis of metabolic syndrome in schizophrenia.Support or Funding InformationThe present study is a part of my intramural project funded by All India Institute of Medical Sciences, Jodhpur, Rajasthan, IndiaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Allostatic plasticity of cAMP system drives opioid induced adaptations in striatal dopamine signaling
Authors: Muntean Brian S , Dao Maria T , Martemyanov Kirill A 
Published: June 2021

Opioids generate euphoria by activating the reward system in the brain, however chronic exposure generates plastic changes in signal processing to program aversive reactions. A core element of the reward circuit involves the integration of dopamine in subpopulations of medium spiny striatal neurons, D1‐MSN and D2‐MSN, whereby these two parallel channels encode the opponent processes through cAMP‐dependent signaling. However, the precise mechanisms that bias circuit activity to encode a range of hedonic states during various stages of opioid exposure are not well understood. Uncovering the fundamental properties and molecular machinery for parsing GPCR signal integration in striatal neurons is a critical step in advancing our understanding of neurobiology necessary to comprehend the adaptations induced by opioids. By recording cAMP dynamics with nanomolar resolution from genetically defined striatal neurons in an intact neuronal circuit, we revealed elemental properties that promote D1‐MSN signaling during acute opioid exposure while favoring D2‐MSN signaling following chronic drug administration. Additionally, we identified two key molecular components that shape plasticity of cAMP signaling. We found that opioids enable phosphodiesterases to regulate D1‐MSN signaling capacity while reducing the role of presynaptic dopamine transporters to influence D2‐MSN response strength. Our results demonstrate the importance of balancing signal integration between concurrently activated subpopulations of striatal neurons while exploring pre‐ and postsynaptic mechanisms that impact accompanying computations performed by the circuit. We propose a quantitative model whereby differential exposure to opioids provides cell‐specific adjustments in cAMP signal strength that imbalances circuit activity to promote transitions between states of reward and aversion.Support or Funding InformationThis work was supported by NIH grants: DA041207 (to B.S.M.), DA036596 (to K.A.M.), and DA026405 (to K.A.M.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
HISTOPATHOLOGICAL EFFECTS OF A GLUTAMINE‐FREE DIET IN A MOUSE MODEL OF ASTROCYTOPATHY (ALEXANDER DISEASE)
Authors: PALOMEQUE JESUS CARLOS GARCIA , CHAMIZO ANDRES MOLERO , BAÑARES ROSA LEON 
Published: June 2021

The aim of this study was to explore the histopathological effects of a glutamic acid and glutamine‐free diet (the Glutamic deficient Diet U8958V243) in mice with a selective mutation (R76H, R236H) for the glial fibrillary acidic protein gene (GFAP). This diet was administered for 5 months after weaning. Four groups were included in the study: (i) mice with GFAP active and standard diet (n = 6); mice with GFAP active and glutamic deficient diet (n = 6); mice without GFAP active and standard diet (n =6); mice without GFAP active and glutamic free diet (n =6). Hematoxylin‐eosin and Klüver‐Barrier procedures were used for histological analysis. The histopathological differences between groups were analyzed by unifactorial ANOVA and t‐test post‐hoc comparisons. Different degrees of histopathological changes, including demyelination, Rosenthal fibers formation, modification in oligodendrocytes, and accumulation of astrocytes, were found in the groups of transgenic mice, in areas typically affected in astrocytopathy models. These results show for the first time the effect of the control of aminoacids in the diet on the histopathology of mouse models of Alexander’ disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Druggability evaluation of a protamine‐like peptide
Authors: Li Tong , Dou Guifang 
Published: June 2021

BackgroundProtamine (Protamine sulfate, PS) is a highly cationic arginine‐rich peptide isolated from sperm of the salmonidae or clupeidae family. PS which is widely used as an UFH antidote. PS, which possessed good efficacy, however, has many adverse effects including systematic hypotension, anaphylactic reaction, anaphylactoid reactions and catastrophic pulmonary hypertension by the virtue of its heterogeneous and highly alkaline nature.PurposeTo prepare and evaluate an effective and low toxic heparin antagonistic drug.MethodsStability of R15S samples in room temperature during 30 days was measured using High performance liquid chromatograph (HPLC). Comparisons on UFH neutralization ability, between PS and R15S, were made aided by active partial thromboplastin time (APTT), anti‐Xa and anti‐IIa assays in vitro and in vivo. For the drug toxicity, MTT tests and acute toxicity assays.ResultsThe R15 sulfate, R15S, was prepared in our lab and its stability for 30 days in room temperaturewas good. The results of APTT, anti‐Xa assays and anti‐IIa assays in vitro and in vivo showed that R15S has equal heparin neutralizing ability to PS. There was no cytotoxicity for R15S and PS at the concentration of 60μg·mg‐1 or below, but R15S showed lower cytotoxicity than PS at 250 μg·mg‐1 to1000 μg·mg‐1.ConclusionWe prepared and evaluated a new UFH antagonist, R15S. R15S showed compatable UFH reversal ability, similar drug toxicity and superior safety in immunology, which made it a potential candidate deserving further studies.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identification of Potent Pyrazole‐Based Biased Small Molecule APJ Receptor Agonists
Authors: Narayanan Sanju , Vasukuttan Vineetha , Rajagopal Sudarshan , Maitra Rangan , Runyon Scott P 
Published: June 2021

The apelinergic system comprises the APJ receptor and its cognate apelin and ELABELA peptides of various lengths. This system has become an increasingly attractive target for cardiometabolic diseases. However, in vivo studies of this receptor are difficult because endogenous peptides are labile with short half‐lives and small molecule ligands are under reported. Recently, we discovered a novel pyrazole based small molecule agonist of APJ (EC50 = 21.5 μM, Ki = 5.2 μM) through focused screening of a compound library, which was further optimized to our initial lead (EC50 = 800 nM, Ki = 1.3 μM). In our efforts to synthesize more potent agonists and to explore the structural features important for APJ agonism, we carried out structural modifications at the pyrazole core as well as the amino acid side‐chain of our initial lead. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC50 values of ~100 nM using separate calcium mobilization and cAMP generation functional assays. Recruitment of β‐arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β‐arrestin recruitment. These compounds may be suitable for chronic in vivo studies of APJ and await additional characterization.Support or Funding InformationNIH Grants: 1R01HD079547‐01A1 and 1R01DK103625‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Structure‐based design and in vivo anti‐arthritic activity evaluation of a potent cyclopropyl peptidyl nitrile inhibitor of cathepsin C
Authors: Korkmaz Brice , Lesner Adam , Gieldon Artur , Lauritzen Conni , Pedersen John 
Published: June 2021

Cathepsin C (CatC) is a dipeptidyl‐exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N‐terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active neutrophil serine proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive neutrophil serine protease activities in various neutrophil mediated diseases. We designed and synthesized a series of peptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One of these compounds, IcatC ((S)‐2‐amino‐N‐((1R,2R)‐1‐cyano‐2‐(4′‐(4‐methylpiperazin‐1‐ylsulfonyl)biphenyl‐4‐yl)cyclopro‐pyl)butanamide)) was identified as a cell‐permeable and potent inhibitor of both human and rodent CatC. Pharmacokinetic analysis in mice showed that IcatC was retained in the bone marrow and reached sufficient tissue levels for CatC inhibition. Subcutaneous administration of IcatC in a mouse model of rheumatoid arthritis induced by monoclonal anti‐collagen antibodies exhibited statistically significant anti‐arthritic activity, with sustained reductions in mean total arthritis scores, mean rear paw arthritis scores and mean rear paw thickness.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of antioxidants and biotransformation inhibitors on 1,2,3‐trichlorobenzene nephrotoxicity in vitro
Authors: Rankin Gary O'Neal , Harvey Brandon , Nguyen Vy , Hicks Mason , Anestis Dianne , Leader Tori , Dial Mason , Brown Kathleen , Valentovic Monica 
Published: June 2021

Chlorinated benzenes are used as chemical intermediates in the manufacture of a wide range of commercial products and are environmental contaminants in soil and waste water. Toxicity induced by chlorobenzenes includes nephrotoxicity with in vivo nephrotoxicity associated with rat α2u‐globulin. A recent study in our laboratory demonstrated that trichlorobenzenes (TCBs) are directly toxic to the kidney, with 1,2,3‐TCB being the most potent nephrotoxicant in isolated renal cortical cells (IRCC) from male Fischer 344 rats. The purpose of this study was to evaluate several antioxidants and inhibitors of biotransformation pathways to determine their impact on 1,2,3‐TCB nephrotoxicity. IRCC (~4 million cells/ml; 3 ml) were incubated with shaking at 37°C under a 95% oxygen/5% carbon dioxide atmosphere with 1,2,3‐TCB (1.0 mM) or vehicle (dimethyl sulfoxide) for 60 min with or without a pretreatment. General cytotoxicity was determined by assessing trypan blue exclusion of IRCC, measuring changes in lactate dehydrogenase (LDH) release, and quantitating ATP levels. 1,2,3‐TCB cytotoxicity was reduced by all antioxidants (ascorbate, glutathione, alpha‐tocopherol) and general cytochrome P450 (CYP) inhibitors (metyrapone and piperonyl butoxide), but not by peroxidase inhibitors (mercaptosuccinate, indomethacin). Several selective CYP inhibitors (isoniazid, omeprazole, sulfaphenazole, oleandomycin, thiotepa) were tested, and all provided some protection against 1,2,3‐TCB cytotoxicity. Protective pretreatments also generally attenuated 1,2,3‐TCB‐induced reductions in ATP levels. These results suggest that free radicals/oxidative stress and CYP‐mediated biotransformation play a role in 1,2,3‐TCB nephrotoxicity in vitro.Support or Funding InformationSupported in part by NIH grant P20GM103434.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Nephrotoxicity of Three Brominated Flame Retardants in Rat and Human Renal Cells
Authors: Cummings Brian S , Barnett Lillie M , Siddiquee Naomi M 
Published: June 2021

Brominated flame retardants (BFRs) are a class of organohalogens commonly added to commercial products such as computers, electronics, textiles, and furniture to reduce their flammability. BFRs have significant environmental persistence and are reported to be detected in human blood and breastmilk. In particular, tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD), and polybrominated diphenyl ethers (PBDEs) occupy nearly 20 percent of the global flame retardant market and have been reported to have adverse effects on humans and wildlife. As such, the mechanisms of BFR‐induced toxicity are actively being explored under the U.S. EPA Toxic Substance Control Act. Previous research shows that these compounds cause nephrotoxicity in rats and mice; however, the mechanisms mediating this nephrotoxicity are unknown. In the present study, we determined the effects of TBBPA, HBCD, and BDE 47 on cell viability in rat (NRK), human embryonic (HEK‐293), and adult human (HK‐2) kidney cells after 48 hours. We observed a concentration‐ and species‐dependent effect on MTT staining, with IC50 values of 58, 38, and 3 μM for TBBPA; 20, 16, and 7 μM for HBCD; and 46, 40, and 14 μM for BDE 47 in NRK, HEK‐293, and HK‐2 cells, respectively. We assessed the mechanisms of cell death by measuring annexin V staining and propidium iodide (PI) staining as markers of apoptosis and necrosis, and by studying changes in nuclear morphology via DAPI staining. Significant increases in both the percentage of annexin V‐positive cells and the percentage of annexin V and PI double‐positive cells suggested that all compounds were inducing apoptosis. These data suggest that BFRs induce species‐dependent toxicity in renal cells, with higher levels of toxicity being induced in human cells. The mechanisms mediating this differential toxicity is the subject of future studies.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hepatoprotective Properties of Aqueous and Ethanolic Stem Bark Extracts of Hura crepitans Linn. Against CCl4− Induced Acute Liver Damage in Rats
Authors: Owojuyigbe Oluwole Sunday , Larbie Christopher 
Published: June 2021

Medicinal plants are gaining wide acceptance even amongst the literate population of the world. Secondary metabolites obtained from herbal sources contain bioactive phytochemicals, many of which have little or no side effects. The hepatoprotective properties of Hura crepitans against CCl4‐induced acute hepatoxicity were investigated, using 48 male Sprague‐Dawley rats. Liver damage was induced with administration of a 1:1 (v/v) CCl4 and olive oil after pre‐treating for 7 days with ethanolic stem bark extract (EES) and aqueous stem bark extract (AES). Hepatoprotective effects of Hura crepitans were investigated by estimating the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin levels (TBIL). Effects of Hura crepitanson biomarkers of lipid peroxidation (oxidative damage) and antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S‐transferase (GST) and the non‐enzymic antioxidant, reduced glutathione (GSH) were determined in liver post mitochondrial fraction (PMF). EES, AES and Silymarin displayed significant hepatoprotective activities by reducing the activities of ALT, AST and ALP on one hand, and also decreased the level of TBIL on the other hand. Pre‐treatment with Hura crepitans extracts and the standard drug Silymarin led to reduction in the activities of antioxidant enzymes, reduction in levels of malondialdehyde (MDA) and reduction in serum levels of GSH in a significant manner. The histopathological studies also demonstrate the protective effect of pre‐treatment with Hura crepitans and Silymarin against oxidative damage by CCl4. Our investigations show that Hura crepitans extracts possess significant hepatoprotective effect against CCl4‐induced hepatoxicity, an endowment arising from the constituent phytochemicals. The present study has demonstrated that EES and AES protected the liver from the detrimental effects of CCl4 through their effects on the antioxidant defence system and their abilities to mitigate against lipid peroxidation.Support or Funding InformationTertiary Education Trust Fund (TETFund), Nigeria/ASPET.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.