bluuebunny/crossref_metadata_2025_split huggingface dataset:
G protein‐coupled receptor kinase selective small molecule inhibitors (843.9)
Authors: Homan Kristoff , Larimore Kelly , Wu Emily , Waldschmidt Helen , Wilson Michael , Larsen Scott , Tesmer John 
Published: June 2021

Inhibition of G protein‐coupled receptor kinase 2 (GRK2) and GRK5 has emerged as potential therapeutic routes for the treatment of heart failure and cardiac hypertrophy. However, there are no commercially available small molecule therapeutics selective for either of these kinases. High‐throughput screening campaigns with representative GRKs from each subfamily (GRK1, GRK2, and GRK5) have identified first generation small molecule inhibitors with low‐micromolar potency and orders of magnitude selectivity between GRKs. The most potent of these scaffolds have additionally been shown to mediate increased contractility in isolated cardiomyocytes as well as whole animals, thus demonstrating their potential to be developed into viable therapeutics. Crystallographic analysis of several GRK‐scaffold complexes reveal molecular mechanisms of selectivity among GRKs and AGC kinases. Based on these structures, iterative rounds of rational design have resulted in compounds with nanomolar potency, high subfamily selectivity, which has provided new insights into structure activity relationships. These compounds form the basis of a novel ‘GRK inhibitor toolkit’ that can be used to elucidate GRK roles in cellular signaling and spur development of novel therapeutics.Grant Funding Source: NIH grants [HL071818 & HL086865] to J.J.G.T. and the American Heart Association [N014938] K.T.H.
Pentadecapeptide BPC 157 counteracts heterotopic ossification in rats (844.10)
Authors: Sikiric Predrag , Starcevic Neven , Sever Marko , Rasic Zarko , Zenko Sever Anita , Krstonijevic Zoran , Baric Marko , Radulovic Bojana , Seiwerth Sven 
Published: June 2021

Heterotopic ossification (HO) is a condition that can occur as a result of tissue trauma, characterized by mature bone formation outside of anatomic bone. In this study we investigated the effect of stable gastric pentadecapeptide BPC 157 on heterotopic ossification in rats. A mature bone and bone marrow cylinder was implanted in the quadriceps muscle of the hind leg. BPC 157 treated rats received BPC 157 (10 μg/kg) dissolved in drinking water (0.16 μg/ml/12ml/day) till sacrifice (1‐4 weeks). Rats in control group received only drinking water. Throughout the duration of the experiment we conducted functional measurements (MFI‐ modified motor function index, shortening of the leg). After sacrifice X ray examination was performed on the donor site and on the locus of the induced HO. Formation of heterotopic bone was reduced on radiographs, the experimental fractures healed better and the function of the leg was improved in BPC 157 treated group. The control group deteriorated in all of the before mentioned parameters. We can conclude that the pentadecapeptide BPC 157 induces both bone formation in fracture and heterotopic bone ossification absorption in rats.Grant Funding Source: Supported by Grant 108‐1083570‐3635, Ministry of Science, Education and Sports, Croatia
Pentadecapeptide BPC 157 given intraarticulary counteracts knee osteoarthritis in rats (844.11)
Authors: Sikiric Predrag , Krstonijevic Zoran , Sever Marko , Lojo Nermin , Drmic Domagoj , Zenko Sever Anita , Baric Marko , Starcevic Neven , Buljan Matko , Zoricic Ivan , Rasic Zarko , Seiwerth Sven 
Published: June 2021

Rat osteoarthritis (transected anterior cruciate and medial collateral ligament, medial meniscectomy) exhibited large cartilage destruction, still preserved bone (4 weeks), proximal tibia (cartilage and bone) totally destructed (8 weeks), and severely impaired knee function (4, 8 weeks), in controls (saline, intraarticulary, volume 0.2 mL, bi‐weekly till 2 weeks prior to sacrifice (at weeks 4, 8). This was counteracted with pentadecapeptide BPC 157 (10 µg/kg), respectively. In BPC 157 rats knee articular (tibial and femoral) surface similar to nonoperative animals at 4 weeks, only few cartilage lesions at 8 weeks, thus, cartilage and bone preservation confirmed by X ray examination. Functionally, all parameters analysed (walking, leg pressure force, knee mobility (o)) were improved and rat's leg length maintained. Unlike general failure in controls, BPC 157 rats walked as non‐operated rats, exhibiting better leg pressure force: i.e., BPC 157 rats after 4 weeks 23+/‐0.2N (operated) and 24+/‐0.5N (non‐operated leg) vs. controls 14+/‐1.1 N (operated) and 22+/‐ 0.3 N (non‐operated leg). BPC 157 rats exhibited constantly improved knee mobility (82 +/‐ 2.4o (BPC 157) vs. 15 +/‐2.5o (controls, 8 weeks).Grant Funding Source: Supported by Grant 108‐1083570‐3635, Ministry of Science, Education and Sports, Croatia
Evaluation of safety and efficacy antifungal of an amide derivative of amphotericin B as scaling product on in vitro models (844.12)
Authors: Rodriguez ‐Lopez Anahí , Ortega Ivan , Fernandez‐Zertuche Mario , Regla Ignacio , Reyes‐Esparza Jorge , Rodríguez‐Fragoso Lourdes 
Published: June 2021

To evaluate the efficacy and safety of amide derivative of amphotericin B, as scaling product at in vitro experimental assays. Amphotericin B (AmB) has been considered the gold standard drug for treating mycosis, however, it produce nephrotoxicity, hepatotoxicity and hemolytic anemia. For evaluating the antifungal activity of the AmB and DA, we used six strains of Candida. Yeasts were seeded in 96‐well plates in SD broth media. Cells were treated with AmB and DA at concentrations of 1, 10, 50, 100, 250 and 500 mM and 0.1 to 1 µM in order to determine the IC50. Safety was evaluate in kidney and liver cells. These cells were treated with AmB and DA at different concentrations 1, 10, 50, 100, 250 and 500 μM and the citotoxicity was evaluated by MTT technique and also identified the type of cell death by immunofluorescence microscopy. The DA was effective on 6 yeast Candida species treated with AmB and DA. IC50 founds were: C. albicans (SC5314) AmB= 0.13 µM vs DA= 0.26 µM; C. albicans (10231) AmB= 0.13 µMvs DA= 0.26 µM; C. albicans (131334) AmB= 0.21 µMvs DA: 0.26 µM; C. parapsolosis AmB= 0.26 µMvs DA= 0.25 µM; C. glabrata (122246) AmB= 0.34 µMvs DA= 0.26 µM; C. tropicalis (41997) AmB= 0.29 vs DA= 0.26 µM. DA produced cell death by apoptosis at concentrations 50 μM in kidney cells, but in liver cells produced cell deth by necrosis and apoptosis at concentrations 10μM. The DA as a scaling product was more safe and effective as compared to AmB.Grant Funding Source: CONACYT
CSF1 over‐expression has pleiotropic effects on microglia in vivo (844.13)
Authors: De Ishani , Nikodemova Maria , Steffen Megan , Sokn Emily , Watters Jyoti , Collier Lara 
Published: June 2021

Increased microglial numbers and activated microglial phenotypes are associated with many central nervous system (CNS) disorders including gliomas, neurodegeneration and brain injury. Thus, microglia are being tested as potential drug targets. Macrophage Colony Stimulating Factor (CSF1), an important cytokine for microglia and macrophages, is upregulated in these CNS disorders, but the effects of CSF1 on microglial phenotypes have not been well‐characterized in vivo. To study the effects of CSF1 over‐expression on microglia in the unperturbed CNS in vivo, we generated a transgenic mouse model in which CSF1 is inducibly over‐expressed in the GFAP compartment. We found that CSF1 over‐expression results in increased microglial proliferation, increased microglial numbers and an altered microglial phenotype compared to control mice. Microglia in CSF1 over‐expressing mice do not exhibit gene expression profiles typical of either M1 or M2 polarization, however they are defective in their response to the inflammatory stimulus LPS. Treatment with a small molecule inhibitor of the CSF1 receptor (CSF1R) and related kinases, decreased microglial numbers through apoptosis in both CSF1 over‐expressing and control mice. These results indicate that CSF1 signaling has multiple effects on microglia in vivo, and pharmacological inhibition of this signaling pathway may have efficacy in reversing the pathological levels of microglial accumulation in various CNS diseases by promoting microglial apoptosis. Moreover, our CSF1 over‐expressing genetic model should have utility for studying the impact of CSF1 over‐expression in mouse models of human disease.Grant Funding Source: Goldhirsh Foundation, the University of Wisconsin Graduate School and the NIH
Effect of pentadecapeptide BPC 157 on rotator cuff tear injury in rat (844.9)
Authors: Sikiric Predrag , Buljan Matko , Vnuk Drazen , Krstonijevic Zoran , Sever Marko , Lojo Nermin , Drmic Domagoj , Zenko Sever Anita , Baric Marko , Starcevic Neven , Zoricic Ivan , Brcic Luka , Seiwerth Sven 
Published: June 2021

The rotator cuff musculature imparts dynamic stability to the glenohumeral joint. In particular, the balance between the subscapularis anteriorly and the infraspinatus posteriorly, often referred to as the rotator cuff “force couple,” is critical for concavity compression and concentric rotation of the humeral head. Our goal was to determine the effect of pentadecapeptide BPC 157 on rotator cuff tear injury in rat model. 48 rats underwent detachment of the supraspinatus and infraspinatus and were randomly assigned to control and pentadecapeptide BPC 157 group. BPC 157 animals were regularly treated with pentadecapeptide BPC 157 (10µg/kg) intraperitoneally, control animals got equivalent volume of saline. Animals were observed during experiment and were sacrificed 2, 4, 8 and 12 weeks after the surgery. Macroscopic observation (muscle atrophy (m(non‐operated m triceps)/m‐operated(m triceps)), movement range, front leg length) and functional analysis (walk pattern (SFI), front limb muscle strength (weightlifting time) were performed. In animals treated with pentadecapeptide BPC 157 was observed total functional recovery similar to healthy animals, along with supraspinate and infraspinate tendon healing. In controls, mobility rage, muscle strength, and leg length were reduced compared to pentadecapeptide BPC 157 treated animals. In conclusion, pentadecapeptide BPC 157 could be successfully used in healing and functional recovery of rotator cuff tear injury.Grant Funding Source: Supported by Grant 108‐1083570‐3635, Ministry of Science, Education and Sports, Croatia
Rescuing aberrant phenotypes and cognitive deficits in FMRP‐deficient female mice (845.6)
Authors: Ray Sucharit , Tejada‐Simon Maria 
Published: June 2021

Identifying the causes and pathogenic mechanisms of neurodevelopmental diseases such as Fragile X syndrome (FXS) is complex. It has been reported that, in FXS, there is an unusually high density of long, thin, immature dendritic spines accompanied by aberrant long‐term plasticity and cognitive abnormalities. Our lab has recently demonstrated that, in the brain of FXS mice, there is an over‐activation of Rac1, a protein of the Rho GTPase subfamily implicated in neuronal and dendritic spine development. This mouse model also exhibits alteration of synaptic plasticity and deficits in learning and memory. Since this particular disease is linked to the X chromosome, most of the existing studies, including ours, make use of male knockouts. Thus, this study was undertaken to provide analogous studies in FXS female mice. Expression of Rac1 levels was determined in Fmr1‐KO female mice. Furthermore, Fmr1‐KO female mice were treated with a Rac1 inhibitor and subjected to behavioral, biochemical and morphological studies to determine whether modification of the levels of Rac1 could rescue these deficiencies. We observed that pharmacological inhibition of Rac1 indeed ameliorates cognitive deficits observed in untreated Fmr1‐KO females, as measured in a fear conditioning paradigm and other associative learning and memory function tests. Our biochemical data suggested decreased levels of activated Rac1 in FXS mice and WT mice after treating with inhibitor which correlated with morphological studies showing normalization of aberrant dendritic spines which are characteristic in FXS mice. Additionally, treatment with the inhibitor protected against audiogenic seizures, a strong phenotype in this animal model of FXS. This suggests that Rac1 activity may contribute to FXS etiology, and that Rac1 could be involved in the mechanism responsible for the deficient neuronal morphology, perturbed synaptic plasticity and cognition impairment associated with this disorder.Grant Funding Source: Jérôme LeJeune Foundation (France), FRAXA Research Foundation (USA) and UH GEAR
Effects of the M4 muscarinic receptor positive allosteric modulator VU0467154 on cognition and pyramidal cell firing properties in layer V of the mPFC (845.9)
Authors: Grannan Michael , Bubser Michael , Bridges Thomas , Gould Robert , Dencker Thorbek Ditte , Daniels J , Noetzel Meredith , Niswender Colleen , Duggan Mark , Brandon Nicholas , Dunlop John , Wood Michael , Wess Jurgen , Wood Michael , Lindsley Craig , Conn P , Jones Carrie 
Published: June 2021

Many symptoms in schizophrenia are attributed to alternations in normal glutamatergic signaling in the prefrontal cortex (PFC). In preclinical studies, psychotomimetic agents like the N‐methyl‐D‐aspartate receptor antagonist MK‐801 induce enhanced spontaneous firing at glutamatergic synapses within the medial PFC and cognitive impairments. Recently, we reported the discovery of VU0467154, an optimized positive allosteric modulator (PAMs) of the M4 muscarinic acetylcholine receptor with low nanomolar potency in vitro and suitable pharmacokinetic properties for in vivo studies. Here we evaluated the ability of VU0467154 to reverse alterations in mPFC signaling and behavioral deficits induced by MK‐801. In vivo electrophysiology studies in anesthetized rats revealed that pretreatment with VU0467154 reversed MK‐801‐induced changes in firing rates in layer V pyramidal cells of the mPFC, while having no effect on firing rates when administered alone. Moreover, VU0467154 produced dose‐related reversals of MK‐801‐induced hyperlocomotion and deficits in contextual‐ and cue‐mediated conditioned fear responding in rodents. These findings suggest that M4 PAMs may have important therapeutic potential for addressing the negative symptoms and cognitive deficits associated abnormal PFC glutamatergic neurotransmission in schizophrenia.Grant Funding Source: Supported by 2R01 MH73676‐06, 1R01 MH086601‐04, AstraZeneca
Pomegranate ameliorates Alzheimer’s disease‐type neurodegeneration in tg 2576 mouse model (846.1)
Authors: Subash Selvaraju , Braidy Nady , Essa Musthafa , Al‐Adawi Samir , Al‐Asmi Abdullah , Vaishnav Ragini , Guillemin Gilles 
Published: June 2021

Alzheimer disease (AD) is a neurodegenerative disease which is characterized by the presence of extracellular senile plaques mainly composed of amyloid‐β peptide (Aβ), intracellular neurofibrillary tangles, and selective synaptic and neuronal loss. AD brains revealed elevated levels of oxidative stress markers which have been implicated in Aβ‐induced toxicity. Multiple components present in pomegranate and various pomegranate preparations are known to exert pleiotropic protective effects as demonstrated in various in vitro and in vivo model systems. The present study was designed to investigate the dietary supplementation of 4% pomegranate fruit grown in Oman on oxidative stress in the hippocampus, and hippocampal neuron injury in Tg2576 mice. The Tg 2576 mice were treated with 4% pomegranate by dietary supplementation for 15 months. After 15 months, the mice were sacrificed for measuring non‐enzymatic [4‐hydroxynonenal, TBARS, hydrogen peroxide, reduced glutathione (GSH), vitamin A, E, C and enzymatic antioxidants activity in the hippocampus, and expression of choline acetyltransferase (ChAT) positive neuron. The non‐enzymatic and enzymatic antioxidants were significantly reduced along with elevated oxidative stress markers. Loss of ChAT positive neuron and severe damage to hippocampal neurons in Tg 2576 were also found. These abnormalities were significantly improved by 4% pomegranate treatment. In contrast, administration of 4% pomegranate diet to mice strongly suggested a putative delay in the formation of plaques, as indicated by a decreasing tendency of soluble and fibrillar Aβ levels in hippocampus which correlated with a decrease in Aβ (1‐40, 1‐42) plasma content. The study suggests that pomegranate could offer protection against neuronal injury and oxidative stress, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD. This project was supported by a research grant from The Research Council, Oman (RC/AGR/FOOD/11/01).Grant Funding Source: Supported by The Research Council, Oman (RC/AGR/FOOD/11/01).
The therapeutic efficacy of cannabinoid receptor type 1 ligands in Huntington's disease may depend on their functional selectivity (846.6)
Authors: Laprairie Robert , Bagher Amina , Kelly Melanie , Dupre Denis , Denovan‐Wright Eileen 
Published: June 2021

Levels of the type 1 cannabinoid receptor (CB1) decline prior to Huntington’s disease (HD) symptom onset in the striatum and this decline is correlated with disease progression. Consequently, strategies that increase type CB1 expression and activity are being explored as a potential means of treating HD. However, CB1 agonists are biased ligands that differ in their functional selectivity and efficacy. Certain agonists, such as Δ9‐tetrahydrocannabinol (THC), are arrestin‐biased ligands, while other agonists, such as anandamide (AEA), are Gαi/o‐biased ligands.The objective of this study was to determine which CB1 agonists effectively enhanced Gαi/o‐ and Gαq‐dependent neuroprotective signalling and determine whether these agonists promoted survival in a cell culture model of HD striatal neurons. We hypothesized that endocannabinoids, such as AEA and 2‐arachidonylglycerol (2‐AG) would promote neuronal survival in HD cells whereas THC and THC‐like cannabinoids would exacerbate cell death.We used bioluminescence resonance energy transfer (BRET), ELISA, qRT‐PCR, and cytotoxicity assays to examine the efficacy of 6 cannabinoids: AEA, 2‐AG, WIN 55,212‐2, CP 55,940, cannabidiol (CBD), and THC on restoring neuronal function in the mouse STHdh cell culture model of HD striatal neurons that endogenously express CB1.We observed that 2‐AG, AEA, and WIN 55,212‐2 were Gαi/o‐ and αq‐biased ligands that increased CB1 levels and reduced GABA release. CBD was a Gαs‐biased ligand that increased neurotrophic factor levels. THC and CP 55,940 were arrestin2‐biased ligands that enhanced receptor internalization and downregulation.Therapies for HD that aim to enhance or maintain CB1 signaling should exploit the functional selectivity of AEA and 2‐AG. CBD‐derived therapies may also be useful in HD because CBD‐biased CB1 signaling increased the levels of neurotrophic factors and improved neuronal viability. In contrast to AEA, 2‐AG, and CBD, THC‐like compounds may exacerbate CB1 loss in HD.Grant Funding Source: Supported by Canadian Institutes of Health Research (CIHR) and Nova Scotia Health Research (NSHRF)
MJ33, an inhibitor of peroxiredoxin 6 phospholipase A2 activity, reduces lung damage resulting from oxygen exposure through inhibition of NADPH oxidase (NOX2) activation (847.5)
Authors: Benipal Bavneet , Dodia Chandra , Fisher Aron , Feinstein Sheldon 
Published: June 2021

Hyperoxia‐induced lung injury results in pulmonary inflammation, increased alveolar permeability and respiratory failure. Peroxiredoxin 6 (Prdx6) plays a major role in protecting lung cells against oxidative stress through both its peroxidase and phospholipase A2 (PLA2) activities. andPrdx6 PLA2 activity also activates Nox2, leading to generation of reactive O2 species. Thus, in vivo, Prdx6 PLA2 could trigger lung damage due to activation of Nox2 in pulmonary endothelium and lung neutrophils or macrophages. To evaluate the role of Nox2, we compared the effect of 100% O2 on Nox2 null versus wild type (WT) mice. Mice were sacrificed when lsigns of severe respiratory distress were observed. The time until sacrifice for Nox2 null mice was significantly longer than for WT, suggesting that absence of Nox2 was protective against lung injury. The role of Nox2 was evaluated further by treating WT mice with MJ33, considereda potent inhibitor of Prdx6 PLA2 activity. Intraperitoneal (IP) injection of 50 nmol MJ33 inhibited lung PLA2 levels for at least 48 h. Mice exposed continuously to 100% O2 were injected IP at 0 and 48 hours with PBS +/‐ 50 nmol MJ33 and the effect on the lung was evaluated after 80 h. Treatment with MJ33 reduced the number of neutrophils obtained by bronchoalveolar lavage and inhibited the increase in lung permeability and lung lipid peroxidation induced by hyperoxia. Thus, blocking Prdx6 PLA2 activity by MJ33 significantly protects lungs against damage from oxygen exposure, presumably by preventing activation of Nox2. Supported by NIH/RO1‐HL105509 and NIH‐T32‐HL07748.Grant Funding Source: NIH/R01‐HL105509
The effects of a humanized anti‐cocaine monoclonal antibody on the cardiovascular effects of cocaine in mice (848.2)
Authors: Lorenz John , Lasko Valerie , Nieman Michelle , Ball William , Norman Andrew 
Published: June 2021

A humanized anti‐cocaine monoclonal antibody, h2E2, in mice increased plasma cocaine concentrations 10‐20‐fold with a concomitant decrease in brain concentrations. This antagonized cocaine‐induced reinstatement of self‐administration behavior but the cocaine buildup in the peripheral circulation may cause adverse effects on cardiovascular function. To examine this, mice were pre‐treated 24 hours prior to cocaine administration with h2E2 (120 ug/g iv) or vehicle control. h2E2 alone had only mild effects on cardiac and vascular function. Left ventricular (LV) performance and carotid blood flow were measured during cumulative dosing with cocaine (1, 3, 10 and 30 ug/g; 5 min intervals). In vehicle‐treated mice (Veh), cocaine increased LV dP/dt and this effect was not altered by the presence h2E2 (34% vs. 36% increase Veh vs. h2E2, at the highest dose). Measurements of blood pressure revealed similar changes. h2E2 modestly increased cerebral vascular resistance at baseline (60 ± 7 vs. 82 ± 12 ml/min/mmHg in Veh vs. h2E2, respectively), but had no effect on the constrictor effects of cocaine (21% vs 26% increase in Veh vs. h2E2). These data show that there were no adverse cardiovascular effects of h2E2 in mice, and its sequestering cocaine in the vascular space did not increase the cardiotonic or vasoactive effects of cocaine. We conclude that cocaine bound to the antibody within the circulation is not bioactive.Grant Funding Source: Supported by NIH grant DP1DA031386