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G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic.

Background: Sevoflurane is metabolised into Compound A and fluoride that carry a hypothetical risk of nephrotoxicity. However, a clinically significant association between sevoflurane use and acute kidney injury (AKI) in humans has not been established.Methods: We retrospectively reviewed 15 552 patients who underwent noncardiac surgery under general anaesthesia using a volatile agent lasting >3 h between July 2016 and May 2019 at a single centre. Patients were divided into a sevoflurane group or no sevoflurane group (desflurane or isoflurane). The primary outcome was incidence of postoperative AKI, which was defined based on the Kidney Disease: Improving Global Outcomes criteria using creatinine concentration within 48 h postoperatively. Propensity score analysis using inverse probability of treatment weighting and propensity score matching was designed to compare outcomes between groups.Results: Amongst 13 701 included patients, 11 070 (80.8%) received sevoflurane during anaesthesia. The incidence of AKI was 2.3% (257/11 070) and 2.5% (66/2631) in the sevoflurane and no sevoflurane groups, respectvely (P=0.57). After inverse probability of treatment weighting adjustment, sevoflurane anaesthesia was not significantly associated with postoperative AKI (odds ratio [OR] 1.32; 95% confidence interval [CI]: 0.99-1.76; P=0.059). In the matched cohort, the incidence of AKI was 3.1% (81/2626) and 2.4% (62/2626) in the sevoflurane and no sevoflurane groups, respectively, and sevoflurane anaesthesia was not associated with postoperative AKI (OR 1.32; 95% CI: 0.94-1.86; P=0.11).Conclusions: Sevoflurane anaesthesia for >3 h was not associated with postoperative renal injury compared with anaesthesia using other volatile agents. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) regulate astrocyte function, while glutamine synthetase (GS), an enzyme highly expressed in astrocytes, is one of the most remarkable GCs-induced genes. GCs mediate their effects through their cognate glucocorticoid receptor (GRα and GRβ isoforms); however, the mechanism via which these isoforms regulate GS activity in astrocytes remains unknown. We used dexamethasone (DEX), a classical GRα/GRβ agonist, RU486, which is a specific GRβ ligand, and Compound A, a known "dissociated" ligand, to delineate the mechanism via which GR modulates GS activity. Aged Mouse Cerebral Hemisphere astrocytes were treated with DEX (1 μM), RU486 (1 nM–1 μM) or compound A (10 μM), alone or in combination with DEX. GS activity and expression, GR isoforms (mRNA and protein levels), and GRα subcellular trafficking were measured. DEX increased GS activity in parallel with GRα nuclear translocation. RU486 increased GS activity in absence of GRα nuclear translocation implicating thus a role of GRβ-mediated mechanism compound A had no effect on GS activity implicating a GRα–GRE-mediated mechanism. None of the compounds affected whole-cell GRα protein content. DEX reduced GRα and GRβ mRNA levels, while RU486 increased GRβ gene expression. We provide evidence that GS activity, in astrocytes, is regulated via GRα- and GRβ-mediated pathways with important implications in pathological conditions in which astrocytes are involved. [ABSTRACT FROM AUTHOR]

Context: Allergic asthma is a multifactorial airway disease characterised by chronic lung inflammation and airway remodelling. The histamine H4 receptor involved in the chemotaxis of leukocytes and mast cells to the site of inflammation is suggested to be a potential drug target for allergy and asthma. In this study we examined the effect of Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide a H4 receptor antagonist in allergic asthma mice model. Objective: To investigate the anti-asthmatic effect of compound A in in vivo, airway inflammation in ovalbumin (OVA) induced allergic asthma mouse model was used. Methodology: Allergic asthma was induced in Balb/c mice using ovalbumin. BAL fluid was examined for the level of IgE, IL-4, IL-5, IL-13 and IL-17 using ELISA. Furthermore, infiltration of leucocytes by histopathology and effect of compound A on signalling molecules were examined in lung tissue. Results: In mice pre-treatment with compound A (10 mg/kg, 20 mg/kg, 30 mg/kg) at different concentrations markedly reduced the levels of IgE, Th2 cytokine IL-4, IL-5, IL-13 and Th17 cytokine IL-17 in BAL fluid. Histopathological examination of lung tissue showed that compound A was able to reduce the level of inflammatory infiltrates. Furthermore, lung tissue from Compound A treated group shown to down-regulate the levels of signalling molecules such as ERK1/2, Akt, SAPK/JNK and NF-κB compared to OVA treated group. Discussion and conclusion: Taken together our data demonstrates that compound A has shown to block the H4R-mediated allergic inflammation in this allergic asthma mice model and may be used as a molecule to study the function of H4R. Abbreviations: Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide; JNJ7777120, 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine; H4R: Histamine 4 Receptor; AHR: Airway hyper responsiveness [ABSTRACT FROM AUTHOR]

Volatile anesthetic agents act as greenhouse gases. Low-flow anesthesia techniques (< 1 L/min) are associated with lower costs. Decreasing volatile anesthetic delivery provides safe and effective strategies for anesthesia providers to decrease costs and reduce environmental pollution. This evidence-based project aimed to estimate cost savings and reduction in the environmental release of anesthetic gases, under simulated lower fresh gas flow (FGF) practices. For each surgical case, the exhaled anesthetic gas percent and FGF data were used to calculate the volume of fluid volatile anesthetic. The fluid volatile anesthetic for each case was then estimated using simulated FGFs. Changes in volatile agent cost and environmental release of anesthetic gases were predicted. Sevoflurane was the most commonly used volatile agent. The mean FGF for cases using sevoflurane was 2.5 L/min. The simulated FGF of 1 L/min FGF across all agents predicted a 48% ($50,892) reduction in costs of volatile anesthetics and a 42% (33 metric tons of carbon dioxide equivalent) decrease in carbon emissions. Simulated low-flow anesthesia demonstrated cost savings and environmental conservation. Project findings align with current literature showing that lowering FGFs represents an area of cost containment and an opportunity to lessen the environmental impact of anesthesia. [ABSTRACT FROM AUTHOR]

Abstract Background Paclitaxel (PTX) is a potent anti-cancer drug commonly used for the treatment of advanced breast cancer (BCA) and melanoma. Toll-like receptor 4 (TLR4) promotes the production of pro-inflammatory cytokines associated with cancer chemoresistance. This study aims to explore the effect of TLR4 in PTX resistance in triple-negative BCA and advanced melanoma and the effect of compound A (CpdA) to attenuate this resistance. Methods BCA and melanoma cell lines were checked for the response to PTX by cytotoxic assay. The response to PTX of TLR4-transient knockdown cells by siRNA transfection was evaluated compared to the control cells. Levels of pro-inflammatory cytokines, IL-6 and IL-8, and anti-apoptotic protein, XIAP were measured by real-time PCR whereas the secreted IL-8 was quantitated by ELISA in TLR4-transient knockdown cancer cells with or without CpdA treatment. The apoptotic cells after adding PTX alone or in combination with CpdA were detected by caspase-3/7 assay. Results PTX could markedly induce TLR4 expression in both MDA-MB-231 BCA and MDA-MB-435 melanoma cell lines having a basal level of TLR4 whereas no significant induction in TLR4-transient knockdown cells occurred. The siTLR4-treated BCA cells revealed more dead cells after PTX treatment than that of mock control cells. IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. Conclusions The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner. In conclusion, the possible impact of TLR4-dependent signaling pathway in PTX resistance in BCA and melanoma is proposed and using PTX in combination with CpdA may attenuate TLR4-mediated PTX resistance in the treatment of the patients.

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Glucocorticoids (GCs) are often used as an adjuvant therapy to reduce the adverse effects of chemotherapy in breast cancer patients. Moreover, GCs can display pro-proliferative or anti-proliferative effects on BC cells depending on their molecular subtype. In addition, long-term use of GCs can induce drug resistance and tumor progression. The biological activity of GCs is mediated by glucocorticoid receptor (GR) via either transrepression or transactivation. The anti-inflammatory effects of GCs are thought to be due to transrepression, while side effects, drug resistance and tumor progression/metastasis are associated with transactivation. We have previously demonstrated that Compound A, a selective GR agonist (SEGRA), has a GR-dependent antitumor effect on blood cancer cells in vitro, not triggering the GR transactivation. This study was focused on the analysis of the CpdA activity in BC models in vitro. We demonstrated the antiproliferative effect of CpdA on BC cells and its ability to induce transrepression of GR-depended genes such as CCND1-3, COX-2, iNOS without the induction of transactivation. A comparative analysis showed that CpdA was an effective and safe alternative to dexamethasone in adjuvant chemotherapy for breast cancer.

Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy. Dimerization of the GR is an integral step in glucocorticoid signaling and has been identified as a possible molecular site to target for drug development of anti-inflammatory drugs with an improved therapeutic index. Most of the current understanding regarding the role of GR dimerization in GC signaling derives for dimerization deficient mutants, although the role of ligands biased toward monomerization has also been described. Even though designing for loss of dimerization has mostly been applied for reduction of side-effect profile, designing for loss of dimerization may also be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. GC-induced resistance affects up to 30% of users and is due to a reduction in the GR functional pool. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR dimerization prevents autologous down-regulation of the receptor through modulation of interactions with components of the UPS and post-translational modifications (PTMs), such as phosphorylation, which prime the GR for degradation. Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore. However, potential drawbacks to this approach should be considered as well as the advantages and disadvantages in chronic vs. acute treatment regimes.

Systemic steroids are used to treat acute graft-versus-host disease (aGVHD) caused by allogenic bone marrow transplantation (allo-BMT); however, their prolonged use results in complications. Hence, new agents for treating aGVHD are required. Recently, a new compound A (CpdA), with anti-inflammatory activity and reduced side effects compared to steroids, has been identified. Here, we aimed to determine whether CpdA can improve the outcome of aGVHD when administered after transplantation in a mouse model (C57BL/6 in B6D2F1). After conditioning with 9Gy total body irradiation, mice were infused with bone marrow (BM) cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors. The animals were subsequently treated (3 days/week) with 7.5 mg/kg CpdA from day +15 to day +28; the controls received 0.9% NaCl. Thereafter, the incidence and severity of aGVHD in aGVHD target organs were analyzed. Survival and clinical scores did not differ significantly; however, CpdA-treated animals showed high cell infiltration in the target organs. In bulk mixed lymphocyte reactions, CpdA treatment reduced the cell proliferation and expression of inflammatory cytokines and chemokines compared to controls, whereas levels of TNF, IL-23, chemokines, and chemokine receptors increased. CpdA significantly reduced proliferation in vitro but increased T cell infiltration in target organs.

Glucokinase (GK), a monomeric glucose-phosphorylating enzyme characterised by high structural flexibility, acts as a glucose sensor in pancreatic beta cells and liver. Pharmaceutical efforts to control the enzyme are hampered by an incomplete understanding of GK regulation. We investigated GK characteristics of wild-type and activating S64Y and G68V mutant proteins in the presence of various combinations of the synthetic activators RO-28-1675 and compound A, the endogenous activator fructose-2,6-bisphosphatase (FBPase-2), and the inhibitor mannoheptulose. S64Y impedes formation of a turn structure that is characteristic for the inactive enzyme conformation, and complex formation with compound A induces collision with the large domain. G68V evokes close contact of connecting region I and helix α13 with RO-28-1675 and compound A. Both mutants showed higher activity than the wild-type at low glucose and were susceptible to further activation by FBPase-2 and RO-28-1675, alone and additively. G68V was less active than S64Y, but was activatable by compound A. In contrast, compound A inhibited S64Y, and this effect was even more pronounced in combination with mannoheptulose. Mutant and wild-type GK showed comparable thermal stability and intracellular lifetimes. A GK-6-phosphofructo-2-kinase (PFK-2)/FBPase-2 complex predicted by in silico protein-protein docking demonstrated possible binding of the FBPase-2 domain near the active site of GK. In summary, activating mutations within the allosteric site of GK do not preclude binding of chemical activators (GKAs), but can alter their action into inhibition. Our postulated GK-PFK-2/FBPase-2 complex represents the endogenous principle of activation by substrate channelling which permits binding of other small molecules and proteins. [ABSTRACT FROM AUTHOR]

Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy. Dimerization of the GR is an integral step in glucocorticoid signaling and has been identified as a possible molecular site to target for drug development of anti-inflammatory drugs with an improved therapeutic index. Most of the current understanding regarding the role of GR dimerization in GC signaling derives for dimerization deficient mutants, although the role of ligands biased toward monomerization has also been described. Even though designing for loss of dimerization has mostly been applied for reduction of side-effect profile, designing for loss of dimerization may also be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. GC-induced resistance affects up to 30% of users and is due to a reduction in the GR functional pool. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR dimerization prevents autologous down-regulation of the receptor through modulation of interactions with components of the UPS and post-translational modifications (PTMs), such as phosphorylation, which prime the GR for degradation. Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore. However, potential drawbacks to this approach should be considered as well as the advantages and disadvantages in chronic vs. acute treatment regimes. [ABSTRACT FROM AUTHOR]

ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™-induced psoriasis-like dermatitis, K/ BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid diseaselike dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3-PUFAs, this also suggests that GPR120/FFA4 activation by ω3-PUFAs does not significantly contribute to the health-promoting effects of ω3-PUFAs in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Compound A (CpdA), or 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethyl-ammonium chloride, is a stable analog of the hydroxyl phenyl aziridine precursor found in the Namibian shrub Salsola tuberculatiformis Botschantzev. It belongs to the group of so-called “dissociated” GC receptor ligands that downmodulate pro-inflammatory gene expression via the transrepression mechanism, but without physically binding to DNA. We have recently reported that the in vivo administration of CpdA exerts a strong protective effect in a pharmacological model of type 1 diabetes in mice. The goal of this study was to investigate in more detail the effects of CpdA on multiple immune system components, as well as on target pancreatic beta cells in direct in vitro exposure. The utility of CpdA in diabetes prevention was evaluated through its addition to mitogen-activated spleen, lymph node and peritoneal cells of C57BL/6 mice, and to murine pancreatic islets and INS-1 and RINm5F beta cell lines. CpdA modulated immune cell-derived cytokine production in vitro by restraining the pro-inflammatory M1/Th1/Th17 response and switching it towards an anti-inflammatory Th2 profile. However, it did not preserve beta cells from the cytotoxic action of inflammatory cytokines. Thus, the anti-diabetic properties of CpdA are mediated through the modulation of immune cell differentiation pathways rather than through rescue of target cells from autoimmune attack. [Projekat Ministarstva nauke Republike Srbije, br. 173013]

Objective: This study aims to describe the overall cumulative effect of sevoflurane on kidney function in healthy patients in terms of mean plasma creatinine, blood urea nitrogen (BUN), creatinine clearance, urinary protein, and glucose excretion at 24 and 72 hours post-anesthesia. Data retrieval: A systematic literature search using MEDLINE and EMBASE as primary search engines was conducted. Articles, relevant abstracts, and citations dated January 1, 1995 to June 30, 2016 were retrieved. Data selection: Search terms included the pharmacological generic name sevoflurane. Search was expanded using the terms "renal function" OR "kidney" function AND "creatinine" OR "blood urea nitrogen" OR "creatinine clearance" OR "proteinuria" OR "glucosuria" OR "nephrotoxicity." Limitations included randomized controlled trial, humans, and ages 19 and above, to include English and non-English text formats. All bibliographic indices for the relevant journals identified were also searched and collated according to relevance. Main outcome measures: Changes in serum/plasma creatinine, BUN, urinary protein, and glucose excretion of sevoflurane at 24 and 72-hours were determined. Results: Six relevant studies were qualified by both the inclusion criteria and inclusion dates. This review consists of 873 patients, 65% are males and 35% are females, with mean age of 56 ± 3 years. Sevoflurane was compared to isoflurane with regard to its nephrotoxic potential. Analyses on the effects of sevoflurane were performed on serum/plasma creatinine, BUN, urinary protein, and glucose excretion at 24 and 72 hours which showed no statistical difference between sevoflurane and isoflurane. Conclusion: In an apparently healthy adult without coexisting renal disorder, sevoflurane does not produce elevations in creatinine and BUN above the established upper limit of the reference range. [ABSTRACT FROM AUTHOR]

Context:The histamine plays a decisive role in acute and chronic inflammatory responses and is regulated through its four types of distinct receptors designated from H1 to H4. Recently histamine 4 receptor (H4R) antagonists have been reported to possess various pharmacological effects against various allergic diseases. Objective:To investigate the inhibitory effect ofN-(2-aminoethyl)-5-chloro-1H-indol-2-carboxamide (Compound A) and 5-chloro-2-(piperazin-1-ylmethyl)-1H-benzimidazole (Compound L) on H4R-mediated calcium mobilization, cytokine IL-13 production, ERK1/2, Akt and NF-κB activation in human mastocytoma cells-1 (HMC-1). Materials and methods:Compounds A and L were synthesized chemically and their inhibitory effect on intracellular calcium release was analyzed by Fluo-4 calcium assay, cytokine measurement through ELISA and activation of signaling molecules by western blot. Results:Pre-treatment with compounds A and L significantly reduced the H4R-mediated intracellular calcium release. Histamine and 4-methylhistamine (4-MH) induced Th2 cytokine IL-13 production in HMC-1 cells, was inhibited by compound A (77.61%, 74.25% at 1 μM concentration) and compound L (79.63%, 81.70% at 1 μM concentration). Furthermore, histamine induced the phosphorylation of ERK1/2, Akt and NF-κB was suppressed by compounds A and L at varying levels, ERK1/2 (88%, 86%), Akt (88%, 89%) and NF-κB (89%, 87%) in HMC-1 cells. Discussion and conclusions:Taken together these data demonstrate that compound A and compound L may block H4R-mediated downstream signaling events. [ABSTRACT FROM PUBLISHER]

Background: Selective glucocorticoid receptor modulators (SEGRMs) comprise a novel class of drugs promising both reduced side effects and similar pharmacological potency relative to glucocorticoids, which presently serve as the only clinical treatment for many otologic disorders. In the first otologic SEGRM experiment in an animal model of noise trauma, we compare the effects of Compound A (a SEGRM) and dexamethasone (potent glucocorticoid). Methods: Forty adult guinea pigs received experimental treatment once daily for ten days. The animals were divided into four cohorts based on the treatment received: Compound A (1 mg/kg or 3 mg/kg), dexamethasone (1 mg/kg) as gold standard, or water as negative control. After five applications, animals were exposed to broadband noise (8-16 kHz) at 115 dB for three hours. Hearing thresholds were determined by recording auditory brainstem responses to clicks and noise bursts (1-32 kHz) and were assessed a week prior to and immediately after exposure, as well as on days 1, 3, 7, 14, 21, and 28. Cochleae were prepared as whole-mounts or embedded and sectioned for histological analysis. Results: Relative to the control treatments, Compound A failed to preserve auditory thresholds post-noise exposure with statistical significance. Histological analyses confirm the physiological result. Conclusion: The present findings suggest that Compound A does not have substantial otoprotective capacities in a noise trauma model. [ABSTRACT FROM AUTHOR]

The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK profile in rats (lower clearance [1.54 L/h/kg] and higher bioavailability [123%]). Ko143 on the other hand suffers from poor bioavailability. Compared to Ko143, compound A would be a useful probe for delineating the role of BCRP during in vivo studies in animals. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) infection is a worldwide public health problem with an increasing magnitude. The severity of disease in the patients with DENV infection correlates with high viral load and massive cytokine production – the condition referred to as “cytokine storm”. Thus, concurrent inhibition of DENV and cytokine production should be more effective for treatment of DENV infection. In this study, we investigated the effects of the antiviral agent – ribavirin (RV), and the anti-inflammatory compound – compound A (CpdA), individually or in combination, on DENV production and cytokine/chemokine transcription in human lung epithelial carcinoma (A549) cells infected with DENV. Initially, the cells infected with DENV serotype 2 (DENV2) was studied. The results showed that treatment of DENV-infected cells with RV could significantly reduce both DENV production and cytokine (IL-6 and TNF-α) and chemokine (IP-10 and RANTES) transcription while treatment of DENV-infected cells with CpdA could significantly reduce cytokine (IL-6 and TNF-α) and chemokine (RANTES) transcription. Combined RV and CpdA treatment of the infected cells showed greater reduction of DENV production and cytokine/chemokine transcription. Similar results of this combined treatment were observed for infection with any one of the four DENV (DENV1, 2, 3, and 4) serotypes. These results indicate that combination of the antiviral agent and the anti-inflammatory compound offers a greater efficiency in reduction of DENV and cytokine/chemokine production, providing a new therapeutic approach for DENV infection. [ABSTRACT FROM AUTHOR]

Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the performance of carbon dioxide absorbent Yabashi lime as compared to conventional carbon dioxide absorbent during sevoflurane anesthesia in dogs. The four dogs used in the study were anesthetized with sevoflurane, with four preparations. Compound A and carbon monoxide concentrations in the blood were measured. Findings of the study indicated that Yabashi lime with sevoflurane anesthesia in dogs is safer than conventional carbon dioxide absorbent.

Objective. Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-bsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone. Methods. Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-b1, TNF-a and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, a-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting. Results. CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisoloneinduced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-a-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion. Conclusion. CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio. [ABSTRACT FROM AUTHOR]

The glucocorticoid receptor functions as a ligand-dependent transcription factor that positively or negatively regulates the transcription of various specific target genes. Not only steroidal glucocorticoids can bind and activate the glucocorticoid receptor, but also the intensively examined non-steroidal selective glucocorticoid receptor modulators can do so, albeit with a select effector profile skewed to glucocorticoid receptor transrepression. Glucocorticoids are widely used to treat inflammatory afflictions, but also as anti-cancer therapies or adjuvants thereof. As the impact of glucocorticoids and selective glucocorticoid receptor modulators has scarcely been researched in this setting, we focused on colon cancer and its stromal environment, in particular the stromal myofibroblasts, which are known to influence cancer cells via paracrine signaling. In these myofibroblasts, the glucocorticoid dexamethasone is able to drive the glucocorticoid receptor into the nucleus and thus negatively regulates the expression of particular pro-inflammatory genes in TNFα-stimulated cells. The selective glucocorticoid receptor modulator compound A has an impaired ability to translocate GR, presumably underpinning its modest anti-inflammatory properties in these cells. Only dexamethasone, and not compound A, can upregulate the glucocorticoid receptor transactivation-dependent GILZ expression. Neither dexamethasone, nor compound A affects myofibroblast cell viability. However, compound A retards the growth of this myofibroblast cell line. Additionally, dexamethasone can inhibit the expression of Tenascin C, hepatocyte growth factor, and TGFβ, which are all factors known for their impact on colon cancer cell invasion, in a glucocorticoid receptor-dependent manner. In contrast, compound A can only slightly diminish the expression of just hepatocyte growth factor, and not tenascin C or TGFβ. Combined, our results expose new tumor microenvironment-modulating effects of glucocorticoids and the selective GR modulator compound A. [ABSTRACT FROM AUTHOR]

Purpose: To compare the stability, effectiveness, and safety profiles of a new generic sevoflurane with those of the original sevoflurane formulation in patients undergoing elective surgery. Methods: An accelerated 3-month storage test was performed to evaluate the compositional changes in generic sevoflurane stored in glass bottles. In addition, 182 patients were randomly allocated to receive generic (n = 89 [54 men and 35 women]; mean [SD] age, 49.9 [11.6] years) or original (n = 93 [61 men and 32 women]; mean [SD] age, 49.6 [11.1] years) sevoflurane at a gas flow of 3 L/min for approximately 3 hours. The mean minimum alveolar concentration (MAC) during sevoflurane anesthesia was evaluated, and gas samples for measuring compound A were collected from the inspiratory limb of the circuit at preset intervals. Blood samples for measuring serum inorganic fluoride were obtained at preset intervals (pharmacokinetic group: generic/original sevoflurane = 45/46). Renal biomarkers, such as N-acetyl-β-glucosaminidase, α- and π-glutathione-Stransferase, albumin, urine protein and osmolality, serum creatinine and osmolality, creatinine clearance, and blood urea nitrogen, were measured at preset intervals (renal biomarker group: generic/original sevoflurane = 44/47). Adverse reactions were monitored for 72 hours after discontinuation of sevoflurane use. Findings: Generic sevoflurane contained in glass bottles was stable for 3 months. The mean MAC was similar for generic and original sevoflurane (median [range], 0.93 [0.67-1.29] vs 0.94 [0.63-1.5] vol%). Adverse event rates were similar (90.3% vs 84.3%), as were the AUClast of inorganic fluoride (333.7 [112.7-1264.7] vs 311.9 [81.5-1266.5] hours - μmol/L) and compound A (51.8 [6.3-204.5] vs 55.3 [10.8-270.6] hours - ppm). Biomarkers associated with renal injury were not significantly different between the 2 formulations. Implications: No significant difference was found in the mean MAC between generic and original sevoflurane. ClinicalTrials.gov identifier: NCT01096212. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis To evaluate the selective glucocorticoid receptor agonist (SEGRA) compound A, a potential novel therapeutic for inner ear disorders, for ototoxic effects. Study Design Laboratory animal study. Methods Experimental guinea pigs were grouped as follows: Systemic application of compound A (1.5 mg/kg and 4.5 mg/kg; n = 6/group) and intratympanic application of compound A (1 mM and 10 mM; n = 6/group). Contralateral ears in topically treated animals served as controls. Hearing thresholds were determined by auditory brainstem response before and directly after the application of compound A, as well as on days 3, 7, 14, 21, and 28. At the end of the experiments, temporal bones were harvested for histological evaluation. Results Systemic administration of compound A (1.5 mg/kg and 4.5 mg/kg) did not cause hearing threshold shifts, whereas the intratympanic injection (1 mM and 10 mM) resulted in a hearing loss. Histological analysis of the middle and inner ears after topical compound A application showed alterations in the tympanic membranes, the auditory ossicles, and the round window membranes, whereas spiral ganglion cells and hair cells were not affected. Conclusion SEGRAs such as compound A could provide novel therapeutic options for the treatment of inner ear disorders and reduce metabolic side effects. Whereas the intratympanic application of compound A resulted in a hearing loss, the systemic application of compound A merits evaluation for otoprotective effects in trauma models. Level of Evidence N/A. Laryngoscope, 125:E149-E155, 2015 [ABSTRACT FROM AUTHOR]