Partial Attenuation Research Articles

Biochanin-A elicits relaxation in coronary artery of goat through different mechanisms

Flavonoids have shown beneficial effects in various disease conditions as reported by various previous studies. Biochanin-A is a flavonoid present in various plants in nature. Present investigation was done to assess the vasorelaxant potential of biochanin-A on isolated coronary artery of goat and its possible mechanism of action. Vascular reactivity experiments were done on circumflex coronary artery of goats using the tension experiments. Goat coronary arterial rings were relaxed with biochanin-A in concentration (0.1–100 μM)-dependent manner. Endothelium had no effect on biochanin-A-induced relaxation. Maximum relaxation induced by biochanin-A was 116.54 ± 12.21% in endothelium-intact artery and it was not significantly different with maximal relaxation (108.22 ± 1.88%) of endothelium-denuded vessel. L-NAME (100 μM) did not show any effect on biochanin-A-induced relaxation. TEA (BKCa channel blocker), and BaCl2 (KIR blocker) had no effect on biochanin-A-induced relaxation. However, biochanin-A-induced maximal relaxation (71.72 ± 4.50%) was reduced significantly (P < .001) in the presence of 4-aminopyridine (KV channel blocker, 3 mM) in comparison with control (114.07 ± 4.33%). Glibenclaminde (KATP channel blocker), H89 (PKA inhibitor), ICI182780 (estrogen receptor antagonist) showed partial attenuation in the biochanin-A-induced relaxation. ODQ (sGC blocker) and HC067047 (TRPV4 channel blocker) had no effect on biochanin-A-induced relaxation. In K+-depolarized endothelium-denuded arterial rings, biochanin-A (30 μM) significantly (P < .05; P < .001) decreased CaCl2-induced contractions (0.02 ± 0.01 g vs. control 0.73 ± 0.30 g). Biochanin-A did not influence the fasudil (rho kinase inhibitor) and SNP (NO-donor)-induced relaxation in this vessel. Biochanin-A showed relaxation in goat coronary artery in endothelium-independent pathways and showed the partial involvement of KATP, protein kinase A and estrogen receptors and full involvement of Cav1.2 channels.

Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic Endocrine Progenitor Cells After Implantation in Mice.

The host environment is a crucial factor for considering the transplant of stem cell-derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell-derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A+ NK6 homeobox 1+ cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell-derived pancreatic cells.

Field Observations of Wind Waves in Upper Delaware Bay with Living Shorelines

Constructed oyster reefs (CORs) provide shore protections and habitats for fish and shellfish communities via wave energy attenuation. However, the processes and mechanism of CORs on wave attenuation remain unclear, thus limiting the effective assessment of CORs for shoreline protection. This paper presents results of a field investigation on wave characteristics and wave spectral variations along a shoreline with CORs in an estuary with a large tidal range as well as large wind waves and swell energy. Six pressure transducers were deployed from January 31 to April 2, 2018, in Gandy’s Beach, New Jersey, in upper Delaware Bay. CORs were constructed at the study site in 2016 as living shoreline structures after Hurricane Sandy. The data collected from the study site exhibits the wave variations and spectral characteristics over the span of 2 months, including four winter storms (i.e., nor’easters). The spatial variations of wave heights measured on both sides of CORs show a strong dependence on the ratio between the freeboard of CORs and the offshore wave heights. Due to the large tidal range (> 2 m), the crests of CORs remain submerged over 85% of the time. The submerged CORs only provide partial attenuation of wave energy. The wave environment in the estuary is complex, especially during nor’easters. For instance, winds with rapid changing fetches could lead to bi-modal wind seas. Due to the complex wave spectra, the bulk wave heights such as the significant wave heights cannot be adopted to adequately reveal the capacity of CORs to attenuate wave energy. Spectral analysis is conducted to investigate the spatial and temporal variations of wave energy in targeted frequency bins. The spectral analysis results reveal the energy transfer from the primary waves to the high harmonics after waves propagate over the submerged CORs. Moreover, it is found that swell energy originated from the Atlantic Ocean can penetrate CORs without any dampening even when CORs are emergent. This study could help resource managers for in-depth evaluation of living shoreline effectiveness and improvement of living shoreline structures such as CORs.

Investigation of the Role of the Spike Protein in Reversing the Virulence of the Highly Virulent Taiwan Porcine Epidemic Diarrhea Virus Pintung 52 Strains and Its Attenuated Counterpart.

Porcine epidemic diarrhea virus (PEDV) has continuously caused severe economic losses to the global swine industries; however, no successful vaccine against PEDV has been developed. In this study, we generated four autologous recombinant viruses, including the highly virulent iPEDVPT-P5, attenuated iPEDVPT-P96, and two chimeric viruses (iPEDVPT-P5-96S and iPEDVPT-P96-5S) with the reciprocally exchanged spike (S) gene, to study the role of the S gene in PEDV pathogenesis. A deeper understanding of PEDV attenuation will aid in the rational design of a live attenuated vaccine (LAV) using reverse genetics system. Our results showed that replacing the S gene from the highly virulent iPEDVPT-P5 led to complete restoration of virulence of the attenuated iPEDVPT-P96, with nearly identical viral shedding, diarrhea pattern, and mortality rate as the parental iPEDVPT-P5. In contrast, substitution of the S gene with that from the attenuated iPEDVPT-P96 resulted in partial attenuation of iPEDVPT-P5, exhibiting similar viral shedding and diarrhea patterns as the parental iPEDVPT-P96 with slightly severe histological lesions and higher mortality rate. Collectively, our data confirmed that the attenuation of the PEDVPT-P96 virus is primarily attributed to mutations in the S gene. However, mutation in S gene alone could not fully attenuate the virulence of iPEDVPT-P5. Gene (s) other than S gene might also play a role in determining virulence.

The origin of R CrA variability

Context. R CrA is the brightest member of the Coronet star-forming region and is the closest Herbig AeBe star with a spectrum dominated by emission lines. Its luminosity has been monitored since the end of the nineteenth century, but the origin of its variability, which shows a stable period of 65.767 ± 0.007 days, is still unknown. Aims. We studied photometric and spectroscopic data for this star to investigate the nature of the variability of R CrA. Methods. We exploited the fact that the near-infrared luminosity of the Herbig AeBe stars is roughly proportional to the total luminosity of the stars to derive the absorption, and then mass and age of R CrA. In addition, we modeled the periodic modulation of the light curve as due to partial attenuation of a central binary by a circumbinary disk. This model reproduces the observations very well. Results. We found that the central object in R CrA is a very young (1.5 ± 1.5 Myr) highly absorbed (AV = 5.47 ± 0.4 mag) binary; we obtain masses of MA = 3.02 ± 0.43 M⊙ and MB = 2.32 ± 0.35 M⊙ for the two components. We propose that the secular decrease of the apparent luminosity of R CrA is due to a progressive increase of the disk absorption. This might be related to precession of a slightly inclined disk caused by the recently discovered M-dwarf companion. This means that R CrA might be a triple system hosting a disk.

Early infantile epileptic encephalopathy type 4: clinical, neurophysiological and therapeutic aspects

Objective . Study the clinical and neurophysiological evolution of early infantile epileptic encephalopathy type 4 (EIEE4) caused by a STXBP1 gene mutation. Material and methods. During 2016-2019, we conducted dynamic observation and treatment of a girl with EIEE4 combined with a mutation in the STXBP1 gene. DNA sequencing was performed using the Hereditary epilepsies panel (Next Generation Sequencing on the platform of Illumina HiSeq 2500, USA). Dynamic video-EEG monitoring was performed with an “Encephalan-Video RM-19/26 (Medicom MTD“, Russia). Results. In this 3.5 y.o. patient with infantile epileptic encephalopathy, a heterozygous autosomal dominant de novo mutation in the STXBP1 gene was found. This mutation (not described previously) is located in chromosome 9, specifically, in the 20th exon with genome coordinates Chr9:130453 (C.*96T>A). This child suffered from severe neonatal hypoxic-ischemic encephalopathy, which led to spastic cerebral palsy. In addition, she developed seizures as early as at the age of 6 month; the seizures (flexor tonic spasms) were paralleled with EEG changes similar to the Mar-kand-Blume-Ohtahara syndrome, namely, multiple independent spike-wave foci in combination with the partial attenuation pattern (kind of the burst-suppression pattern). Valproate monotherapy had little effect, and hormonal treatment caused a temporary improvement. Permanent clinical remission with no seizures was achieved by including leveti-racetam in the therapeutic combination. A number of studies demonstrated a high efficacy of levetiracetam in cases of STXBP1 gene mutations. At the age of 2,5years, the girl demonstrated changes in her EEG records toward the continuous spike-wave during sleep (CSWS) pattern with the morphology of benign epileptiform discharges of childhood (BEDC). Conclusions. In spite of the aggravated perinatal anamnesis, children with epileptic encephalopathy need genetic examination using the Next Generation Sequencing (NGS) methods (such as Hereditary epilepsies panel), combined with full exome sequencing. Such genetic examinations are helpful for establishing the exact etiology of epilepsy and developing a personalized approach to antiepileptic therapy.

1833-P: PERK Inhibitors Enhanced Glucose-Stimulated Insulin Secretion in a Mouse Model of Type 2 Diabetes

Background: PERK (pancreatic endoplasmic reticulum (ER) kinase) has been reported to have important implications in the generation, function, and viability of β cells. We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets, through induction of ER chaperone BiP and regulation of ER calcium, but not through the EIF2A-ATF4 pathway. In the current study, we investigated if PI have the same effects under metabolic stress condition. Methods: GSK2606414, a specific PERK inhibitor, was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. Male C57BL/6J mice were fed with high-fat diet combined with streptozotocin injections to mimic type 2 diabetes (DM). Several doses (6 ∼ 16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. Results: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain, insulin insufficiency, and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. Conclusion: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress, and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM. Disclosure Y. Yang: None. M. Kim: None. M. Kim: None. J. Kim: None. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. K. Park: None. H. Jung: None. Funding Korean Ministry of Health and Welfare (A062260)

A general approach to precise tracking of nonlinear systems subject to non-vanishing uncertainties

In this work we introduce a new and systematic methodology for precise tracking control of normal-form nonlinear systems subject to non-vanishing/non-parametric uncertainties. We propose a general solution to achieving robust tracking with a rate of convergence that can be pre-assigned as fast as desired (e.g. super exponential or even closer to a pre-specified finite time). The key design tool is the utilization of a time-varying feedback gain through a time-varying scaling function that satisfies certain conditions. Our method also features with complete rejection (rather than partial attenuation) of uncertainties/disturbances and regulation of the tracking error to zero. A generic and analytical procedure to construct the time-varying rate function is provided, extending and generalizing the existing results in the literature.

Effect of dexmedetomidine on ischemia-reperfusion injury of liver and kidney tissues in experimental diabetes and hepatic ischemia-reperfusion injury induced rats

Background: Reperfusion following ischemia can lead to more injuries than ischemia itself especially in diabetic patients. The aim of this study was to evaluate the effect of dexmedetomidine on ischemia-reperfusion injury (IRI) in rats with have hepatic IRI and diabetes mellitus.

Photon attenuation coefficients of oxide dispersion strengthened steels by Geant4, XCOM and experimental data

The total mass attenuation coefficients (μ/ρ) of oxide dispersion strengthened (ODS) steels have been investigated by using Geant4 simulation toolkit at energies ranging from 0.01 MeV to 100 GeV. Moreover, Geant4 is applied to further study on the partial mass attenuation coefficient of three main interactions including photoelectric effect, compton scattering, gamma conversion between incident photon and ODS steels. Then molecular cross-section (σm) and mean free path (λ) are obtained by the total mass attenuation coefficients. The results obtained by Geant4 are compared with those obtained by experiments and XCOM program and these results agree with each other very well. It is concluded that Geant4 Monte Carlo toolkit is a powerful tool in studying interaction of photons in material and energies. The shielding parameters of ODS steels presented in this paper can be very useful for the potential nuclear application and other industries in future.

Radiation attenuation properties based on the quantification of soil components using the Rietveld Method

Abstract We propose the use of X-ray diffraction associated with Rietveld Method (RM-XRD) for soil components quantification aiming at evaluating photon attenuation parameters (total and partial attenuation coefficients (µ), effective atomic number (Zeff), effective electron density (Nel) and cross-sections per atom (σa) and per electron (σe)). The XCOM computer code was utilized to calculate these parameters. The X-ray fluorescence spectroscopy (XRF) technique was used as reference for the quantification of soil components. Good agreement was found between XRF and RM-XRD for photons ranging from medium to high energies. Photons of low energy (

Problematic eating behaviors and attitudes predict long-term incident metabolic syndrome and diabetes: The Coronary Artery Risk Development in Young Adults Study.

Problematic relationship to eating and food (PREF) captures a broad range of unhealthy eating behaviors. We previously reported that higher BMI is associated with PREF and graded by the number of PREF endorsed. In this study, we prospectively examined the association between PREF and metabolic syndrome and diabetes. Eight PREF behaviors were assessed and summed to form the PREF score in 3800 black and white adults (age 27-41 years) in the Coronary Artery Risk Development in Young Adults Study. Diagnoses of incident metabolic syndrome and diabetes were made through 15 years of follow-up. Logistic regression estimated the association with metabolic syndrome. Proportional hazards regression estimated the association with diabetes. The odds ratio of metabolic syndrome was 1.25 per PREF point through 5 years of follow-up (95% CI: 1.17-1.34) and 1.17 per point from 5 to 10 years of follow-up (95% CI: 1.08-1.27). Hazard of diabetes was 1.20 per PREF point through 15 years of follow-up (95% CI: 1.12-1.28). Both associations attenuated after adjustment for BMI. Among participants with PREF, higher scores associate with metabolic syndrome and diabetes, with partial attenuation after adjustment for BMI. Early identification of PREF in middle-aged adults may reduce the burden of metabolic health outcomes.

Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes

BackgroundWe have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. MethodsGSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6–16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. ResultsHigh-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. ConclusionPI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.

Generation of a potential koi herpesvirus live vaccine by simultaneous deletion of the viral thymidine kinase and dUTPase genes.

Koi herpesvirus (KHV, Cyprinidherpesvirus 3) causes a fatal disease of koi and common carp. To obtain safe and efficacious live vaccines, we generated deletion mutants of KHV lacking the nonessential genes encoding two enzymes of nucleotide metabolism, thymidine kinase (TK, ORF55) and deoxyuridine-triphosphatase (DUT, ORF123). Since single-deletion mutants based on a KHV isolate from Israel (KHV-I) only exhibited partial attenuation (Fuchs W, Fichtner D, Bergmann SM, Mettenleiter TC. Arch Virol 2011;156 : 1059-1063), a corresponding double mutant was generated and tested in vivo, and shown to be almost avirulent but still protective. To overcome the low in vitro virus titres of KHV-I (≤105 p.f.u. ml-1), single and double TK and DUT deletions were also introduced into a cell culture-adapted KHV strain from Taiwan (KHV-T). The deletions did not affect in vitro virus replication, and all KHV-T mutants exhibited wild-type-like plaque sizes and titres exceeding 107 p.f.u. ml-1, as a prerequisite for economic vaccine production. Compared to wild-type and revertant viruses, the single-deletion mutants of KHV-T were significantly attenuated in vivo, and immersion of juvenile carp in water containing high doses of the double mutant caused almost no fatalities. Nevertheless, the deletion mutants induced similar levels of KHV-specific serum antibodies to the parental wild-type virus, and conferred solid protection against disease after challenge with wild-type KHV. For the convenient differentiation of DNA samples prepared from gill swabs of carp infected with wild-type and TK-deleted KHV we developed a triplex real-time PCR. Thus, KHV-TΔDUT/TK might be suitable as a genetic DIVA vaccine in the field.

Anti-inflammatory Effects of Gossypol on Human Lymphocytic Jurkat Cells via Regulation of MAPK Signaling and Cell Cycle.

Gossypol, a natural polyphenolic compound extracted from cottonseed oil, has been reported to possess pharmacological properties via modulation cell cycle and immune signaling pathway. However, whether gossypol has anti-inflammatory effects against phytohemagglutinin (PHA)-induced cytokine secretion in T lymphocytes through similar mechanism remains unclear. Using the T lymphocytes Jurkat cell line, we found that PHA exposure caused dramatic increase in interleukin-2 (IL-2) mRNA expression as well as IL-2 secretion. All of these PHA-stimulated reactions were attenuated in a dose-dependent manner by being pretreated with gossypol. However, gossypol did not show any in vitro cytotoxic effect at doses of 5-20μM. As a possible mechanism underlying gossypol action, such as pronounced suppression IL-2 release, robust decreased PHA-induced phosphorylation of p38 and c-Jun N-terminal kinase expressions was found with gossypol pretreatment, but not significant phosphorylation of extracellular signal-regulated kinase expression. Furthermore, gossypol could suppress the Jurkat cells' growth, which was associated with increased percentage of G1/S phase and decreased fraction of G2 phase in flow cytometry test. We conclude that gossypol exerts anti-inflammatory effects probably through partial attenuation of mitogen-activated protein kinase (phosphorylated JNK and p38) signaling and cell cycle arrest in Jurkat cells.

Impaired chronic pain-like behaviour and altered opioidergic system in the TASTPM mouse model of Alzheimer's disease.

BackgroundChronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under‐diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD.MethodsUnilateral OA pain was induced chemically, via an intra‐articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD‐mice (TASTPM) and age‐ and gender‐matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue.Results MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re‐established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD‐mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of β‐endorphin post‐MIA which correlated with impaired allodynia.ConclusionsThese results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re‐evaluation of opioid analgesic use for management of pain in AD.SignificanceThis study shows attenuated pain‐like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain.

PO-320 Anti-inflammatory effects of gossypol on human lymphocytic jurkat cells via regulation of MAPK signalling and cell cycle

IntroductionGossypol, a natural polyphenolic compound extracted from the cotton seed oil, have been reported to possess pharmacological properties via modulation of cell cycle and immune signalling pathway. However, whether gossypol has anti-inflammatory effects against phytohemagglutinin (PHA)-induced cytokine secretion in T lymphocytes through similar mechanism remains unclear.Material and methodsHuman T-cell leukaemia Jurkat cells were employed and cultured in the presence or absence of gossypol with or without PHA stimulation. The cell cycle was analysed by flow cytometry. The cytotoxicity was measured by evaluating lactate dehydrogenase (LDH) activity using LDH detecting kit. The protein expressions in Jurkat cell were analysed by Western blot assay. Total RNA from Jurkat cells were extracted and the gene-expressions were measured by real-time polymerase chain reaction technique. IL-2 levels were determined by an ELISA kit.Results and discussionsUsing the T lymphocytes Jurkat cell line, PHA exposure caused dramatically interleukin-2 (IL-2) mRNA expression as well as IL-2 secretion. All of these PHA-stimulated events were attenuated in a dose-dependent manner by pretreating with gossypol. However, gossypol did not show any in vitro cytotoxic effects at doses of 5–20 mM. As a possible mechanism underlying of gossypol action such as pronounced suppression of IL-2 release, we found robust decrease of PHA-induced phosphorylation of p38 and c-Jun N-terminal kinases (JNK) expressions after gossypol pretreatment, but not phosphorylation of extracellular signal-regulated kinase (ERK) expression. Furthermore, gossypol suppressed the Jurkat cells growth, which was associated with increased percentage of G1 phase and decreased fraction of G2 phase in flow cytometry test.ConclusionGossypol exerts anti-inflammatory effects probably through partial attenuation of mitogen-activated protein kinase signalling and cell-cycle arrest in Jurkat cell.

AMPA receptor modulators selective for the accessory protein TARP‐g8

BackgroundThe α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediates the majority of fast synaptic transmission within the mammalian brain. The ubiquitous expression of the primary subunits of AMPA receptors (AMPARs), and the lack of pharmacological selectivity amongst them, preclude regional or neuronal subtype specificity. In vivo, AMPARs comprise a variety of accessory proteins. Of particular interest, TARP‐γ8 is highly expressed in the hippocampus, a region of the brain implicated in several psychiatric and neurological disorders.MethodsWe used high‐throughput screening to discover compounds that selectively modulate AMPARs containing TARP‐γ8. Subsequent medicinal chemistry efforts were used to improve potency and pharmacokinetics of the hits. Assays were developed to measure target occupancy and functional effects of the compounds in vivo.ResultsThese compounds possess a novel mechanism‐of‐action consistent with a partial attenuation of the interaction between the TARP and the pore‐forming subunits of the channel. Lead molecules with oral bioavailability and high brain penetration allowed demonstration of a strong relationship between pharmacokinetics and pharmacodynamics. The compounds show anticonvulsant and anxiolytic profiles in rodent. Molecules in this class provide large safety margins in preclinical species relative to non‐specific AMPAR antagonists due to the improved regional specificity of TARP‐γ8 modulators.ConclusionsAMPAR modulators selective for TARP‐γ8 have the potential to be novel treatments for anxiety/depression, bipolar disorder, temporal lobe epilepsy, and/or prodromal schizophrenia. This project also represents proof‐of‐concept for pharmacological targeting of accessory proteins and small‐molecule modulation of protein‐protein interactions.Support or Funding InformationAuthors are employees of Janssen R &amp; D, LLCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Combination therapy of lovastatin and AMP-activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model.

Recent studies report that loss and dysfunction of mitochondria and peroxisomes contribute to the myelin and axonal damage in multiple sclerosis (MS). In this study, we investigated the efficacy of a combination of lovastatin and AMP-activated protein kinase (AMPK) activator (AICAR) on the loss and dysfunction of mitochondria and peroxisomes and myelin and axonal damage in spinal cords, relative to the clinical disease symptoms, using a mouse model of experimental autoimmune encephalomyelitis (EAE, a model for MS). We observed that lovastatin and AICAR treatments individually provided partial protection of mitochondria/peroxisomes and myelin/axons, and therefore partial attenuation of clinical disease in EAE mice. However, treatment of EAE mice with the lovastatin and AICAR combination provided greater protection of mitochondria/peroxisomes and myelin/axons, and greater improvement in clinical disease compared with individual drug treatments. In spinal cords of EAE mice, lovastatin-mediated inhibition of RhoA and AICAR-mediated activation of AMPK cooperatively enhanced the expression of the transcription factors and regulators (e.g. PPARα/β, SIRT-1, NRF-1, and TFAM) required for biogenesis and the functions of mitochondria (e.g. OXPHOS, MnSOD) and peroxisomes (e.g. PMP70 and catalase). In summary, these studies document that oral medication with a combination of lovastatin and AICAR, which are individually known to have immunomodulatory effects, provides potent protection and repair of inflammation-induced loss and dysfunction of mitochondria and peroxisomes as well as myelin and axonal abnormalities in EAE. As statins are known to provide protection in progressive MS (Phase II study), these studies support that supplementation statin treatment with an AMPK activator may provide greater efficacy against MS.

Valsartan Attenuates Cardiotoxicity in Breast Cancer Patients A fter Chemotherapy

Objective: To determine whether valsartan would be useful in attenuating Adriamycin/Cyclophosphamide/ Herceptin (ACH)-induced cardiotoxicity and to assess the role of biomarkers as indicators of cardiotoxicity in patients with breast cancer undergoing cancer therapy.Background: Valsartan is indicated to reduce the risk of cardiovascular death and hospitalization in patients with chronic heart disease. The administration of cancer drugs, in particular (ACH) is associated with increased risk of cardiotoxicity. The use of herceptin improves survival of women with early-stage positive human epidermal growth factor receptor 2 (HER2) breast cancer but also adds substantially to cost, toxicity, and inconvenience. Little is known about the potential role of valsartan in the prevention of ACH-mediated cardiotoxicity and the predictive role of biomarkers.Method: A total of 60 untreated HER-2 positive breast cancer patients (ages 24 –70 yr, mean 56 yr) were enrolled in this study and were divided to two groups. Group 1 and 2 had 30 patients each, and group 1 received ACH plus valsartan, group 2 received ACH alone. HER2- positive patients were recruited at the Cancer Therapy Center in Najaf, Iraq. Ejection fraction % (EF%), cardiac Troponin I (cTnI) and high sensitivity C-reactive protein (hsCRP) were measured at baseline and at six months after ACH administration.Results: Chemotherapy induced significant transient increase in EF%, cTnI, and hsCRP compared to baseline values (P < 0.001). Within one week after valsartan treatment, all these increases returned back to nearly normal levels. Notably, valsartan administration caused a significant decrease in cTnI and hsCRP values compared to baseline (P < 0.001) and it improved EF% value.Conclusion: This study demonstrated that prophylactic administration of valsartan resulted in the partial attenuation of cardiotoxicity caused by chemotherapy which was characterized by the improvement of EF% and in lowering serum level of cTnI and hsCRP.