Combined Mechanism Of Action Research Articles

Evaluation of Cross-Talk and Alleviate Potential of Cytotoxic Factors Induced by Deoxynivalenol in IPEC-J2 Cells Interference with Curcumin.

Deoxynivalenol (DON) is a mycotoxin produced by Fusarium graminearum, and curcumin (CUR) is a natural polyphenolic compound found in turmeric. However, the combined treatment of CUR and DON to explore the mitigating effect of CUR on DON and their combined mechanism of action is not clear. Therefore, in this study, we established four treatment groups (CON, CUR, DON and CUR + DON) to investigate their mechanism in the porcine intestinal epithelial cells (IPEC-J2). In addition, the cross-talk and alleviating potential of CUR interfering with DON-induced cytotoxic factors were evaluated by in vitro experiments; the results showed that CUR could effectively inhibit DON-exposed activated TNF-α/NF-κB pathway, attenuate DON-induced apoptosis, and alleviate DON-induced endoplasmic reticulum stress and oxidative stress through PERK/CHOP pathways, which were verified at both mRNA and protein levels. In conclusion, these promising findings may contribute to the future use of CUR as a novel feed additive to protect livestock from the harmful effects of DON.

Readily available drugs and other interventions to potentially improve the efficacy of immune checkpoint blockade in cancer.

To improve the efficacy of immune checkpoint inhibitors (ICIs) for cancer treatment, various strategies, including combination therapies with repurposed drugs, are being explored. Several readily available interventions with potential to enhance programmed death 1 (PD-1) blockade have been identified. However, these interventions often remain overlooked due to the lack of financial incentives for their development, making them financial orphans. This review summarizes current knowledge regarding off-label drugs, supplements, and other readily available interventions that could improve the efficacy of PD-1 blockade. The summary of each intervention includes the proposed mechanism of action for combination with checkpoint inhibitors and data from animal and human studies. Additionally, we include summaries of common interventions to be avoided by patients on PD-1 blockade. Finally, we present approaches for conducting further studies in patients, with the aim of expediting the clinical development of these interventions. We strive to increase awareness of readily available combination therapies that may advance cancer immunotherapy and help patients today.

Surface Grafted N‐Oxides have Low‐Fouling and Antibacterial Properties

AbstractLow‐fouling materials are often generated by surface zwitterionization with polymers. In this context, poly‐N‐oxides have recently attracted considerable attention as biomimetic stealth coatings with low protein adsorption. Herein, this study reports that poly‐N‐oxides can be grafted from plasma‐activated plastic base materials. The resulting hydrophilic surfaces have low‐fouling properties in bacterial suspensions and suppress the formation of biofilms. Moreover, efficient antibacterial activity against Gram‐negative and Gram‐positive bacteria caused by release of reactive oxygen species is observed. The latter effect is specific for polymeric N‐oxides and is most likely triggered by a reductive activation of the N‐oxide functionality in the presence of bacteria. In contrast to other zwitterionic polymers, N‐oxides combine thus low‐fouling (stealth) properties with antibacterial activity. The bioactive N‐oxide groups can be regenerated after use by common oxidative disinfectants. Poly‐N‐oxides are thus attractive antibacterial coatings for many base materials with a unique combined mechanism of action.

Rational Use of Drugs in the Complex Treatment of Bronchobstructive Syndrome in Children

Treatment of biofeedback in children and the complex use of drugs, that is, each drug must be pathogenetically justified, taking into account the individual characteristics of the child, and also based on knowledge of the mechanism of their action and pharmacokinetics. It is necessary to have a complex effect on individual links in the pathogenesis of broncho-obstructive syndrome in many cases, which justifies the use of complex drugs with a combined mechanism of action. Thus, the treatment of biofeedback in children is a responsible task for the pediatrician, which consists in the rational selection of drugs.

Dietary patterns and fertility status in men: Mediterranean diet does make a difference in ameliorating the rise in male infertility problems due to changing lifestyle

Dietary patterns and fertility status in men: Mediterranean diet does make a difference in ameliorating the rise in male infertility problems due to changing lifestyle

Предпочтения практикующих российских врачей-офтальмологов при определении стратегии лечения пациентов с первичной открытоугольной глаукомой (результаты многоцентрового научно-аналитического исследования)

The aim of the study was to establish the preferences of domestic ophthalmologists in the selection of prescribing schemes and approaches in the treatment of patients with different stages of primary open-angle glaucoma (POAG). The results of a questionnaire survey of 472 ophthalmologists conducted during the period from August to November 2022 were analyzed. The main part of the questionnaire contained questions concerning the preferences of specialists in selecting the tactics of treatment of patients with glaucoma, for example, treatment schemes for patients with different stages of POAG, including priorities of particular prescriptions (groups of drugs and other approaches), details of current clinical practice — patients' compliance with the prescribed treatment and its cost, expediency of using combined antiglaucoma drugs in the form of their fixed combinations (FC), as well as preservative-free drugs. It was established that 328 (69.5%) ophthalmologists prefer to use the possibility of combined mechanism of action of antiglaucoma hypotensive drugs, 92 (19.5%) - the possibility of targeted influence on uveoscleral outflow. In patients with the initial stage of glaucoma the prescription of monotherapy with the use of prostaglandin analogs (PGAs) is used, in persons with the advanced stage of glaucoma the priority in the prescription of combined forms of drugs is determined, and at the highly advanced stage of the disease surgical treatment is performed. Polypragmasy in prescriptions of antiglaucoma topical drugs impedes effective treatment, and in this regard, ¾ of respondents were in favor of a more active use of FC drugs, considering their use more justified to achieve the goal of treatment than the use of separate prescription schemes. The use of preservative-free forms of drugs allows to keep the ocular surface of glaucoma patients intact for a long time, to predict the results of the expected (and imminent) surgical treatment and to increase the compliance to treatment. The results of the study indicate a confident adherence of ophthalmologists to the guidelines of current clinical recommendations when choosing drug regimens and treatment regimens in patients with different stages of glaucoma.

Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma.

Simple SummaryMantle cell lymphoma (MCL) is associated with poor response to anthracycline-based chemotherapy, and high-dose cytarabine offers a durable response. Recently, multiple targeted therapies have been approved for the treatment of MCL, highlighting the role of the tumor microenvironment (TME) in the expansion and resistance of the disease. We review herein the TME in MCL and the different therapeutic strategies of treatment.Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease.

Beneficial Effects of Antioxidants in Male Infertility Management: A Narrative Review

Background: Infertility, defined as the failure to conceive after one year of regular, unprotected intercourse, affects 50–80 million people worldwide. A male factor is involved in approximately 20–30% of cases. In the etiology of male infertility, the association between poor semen quality and oxidative stress (OS) is well known. High levels of reactive oxygen species (ROS) allow the oxidation of DNA, proteins, and lipids of sperm cells, modifying their vitality, motility, and morphology. Methods: To evaluate the effects of antioxidants on sperm in infertile men, we queried the MEDLINE database (via the PubMed interface) for published studies in the last 10 years (2011–2021). The following keywords were used: “infertility” and -“inositol”, -“alpha-lipoic acid”, -“zinc”, -“folate”, -“coenzyme Q10”, -“selenium”, and -“vitamin”. Results: Inositol regulates OS levels in sperm cells thanks to its role in mitochondrial reactions and is involved in several processes favoring sperm–oocyte interactions. Alpha-lipoic acid (ALA) reduces ROS damage and improves semen parameters in terms of spermatozoa’s motility, morphology, and count. Poor zinc nutrition may be related to low quality of sperm. Supplementation of folate plus zinc has a positive effect on the sperm concentration and morphology. Supplementation with CoQ10 increases sperm concentration, total and progressive motility. Selenium (Se) supplementation improves the overall semen quality and is related to a higher ejaculated volume. Among vitamins, only vitamin B12 shows a positive effect on semen quality; it increases sperm count and motility and reduces sperm DNA damage. Conclusions: In men showing low-quality semen, diet supplementation with antioxidants may improve the sperm quality by alleviating OS-induced sperm damage and enhancing hormone synthesis and spermatozoa concentration, motility, and morphology. Future clinical trials should be focused on the possible association of several antioxidants to take advantage of combined mechanisms of action.

Synthesis of Antibacterially ActiveSilver Nanoparticles by Galvanic Replacement on Magnesium in Solutions of Sodium Polyacrylate in an Ultrasound

“Green” synthesis of silver nanoparticles (AgNPs) by a galvanic replacement (GR) on magnesium in solutions of sodium polyacrylate (NaPA) under ultrasound (42 kHz) is reported. The mechanism of combined action of GR and ultrasound on the formation of nanoparticles is proposed. Synthesized solutions of AgNPs are characterized by an absorption maximum at 410 nm, the value of which does not depend on the concentrations of precursors (AgNO3 and NaPA) and the duration of the process. The dimensions of nanoparticles that have a spherical shape do not exceed 30 nm. With increasing concentration of surfactant, there is a tendency to decrease in size. The rate of synthesis of AgNPs increases almost in proportion to the concentration of AgNO3 in the solution, while the effect of NaPA concentration is negligible. The synthesized nanoparticles efficiently demonstrated a bactericide effect on Escherichia coli and Staphylococcus aureus.

In Situ Vaccination with Combination of Class B and Class C Toll-like Receptor 9 Agonist CpG Immune Adjuvant Nanoparticles to Induce a Systemic Anti-Lymphoma Response

Introduction: Treatment of relapsed and refractory aggressive B cell lymphomas is challenging, especially after autologous stem cell transplant or chimeric antigen receptor T cell therapy. CpG oligodeoxynucleotides (CpGs) mimic bacterial DNA and bind to toll-like receptor 9 (TLR9). TLR9 is expressed in the endosomes of innate immune cells and B lymphocytes as well as B cell lymphomas. CpG binding to TLR9 in these cells leads to a pro-inflammatory response and induces apoptosis of lymphoma cells by altering NF-kB activation. However, clinical utility of CpGs is limited due to difficulties delivering the DNA directly to the innate immune cells and lymphoma cells, and these DNA strands are easily degraded in biological fluids. Therefore, we designed a nano-carrier to deliver two classes of CpGs to improve clinical efficacy of CpGs in treating lymphoma. Class B CpGs (B-CpGs) mainly stimulate B cells while class C CpGs (C-CpGs) act on both B cells and plasmacytoid dendritic cells. Though C-CpGs are the focus of current clinical trials, B-CpGs may have a special a role in the treatment of lymphoma due to their more potent, direct cytotoxic effect on the malignant lymphoma cells. Here, we evaluated the anti-lymphoma effect of the combination of B-CpG nanoparticles (BNP) and C-CpG nanoparticles (CNP) by optimizing lymphoma cell death and immune stimulation.Methods: BNP and CNP were synthesized by surface-functionalizing gold nanoparticles with modified B-CpGs and C-CpGs, followed by purification via centrifugation. We used a dual flank tumor murine lymphoma model to evaluate the local and systemic anti-lymphoma efficacy of the CpG NPs and screen for the most effective formulation. A20 lymphoma tumors were implanted on both flanks of Balb/c mice. When the tumors were 5-7mm in diameter, various treatments were injected intratumorally on days 1, 4, and 8 on the side with the larger tumor. Treatment groups include PBS, B-CpG, C-CpG, B+C-CpG, BNP, CNP, BNP+CNP. Free CpGs were injected at 50ug/ml in 50ul (2.5ug CpG per injection) and nanoparticles at 100nM (equivalent to 50ug/ml CpGs) in 50ul. Tumor growth were measured every other day. Event is defined as tumor volume > 3cm 3. Second, we used an advanced disease lymphoma model to evaluate intravenous delivery of combination NPs. We implanted A20 lymphoma cells on a flank tumor (on day -14), then we injected A20 cells intravenously to mimic advanced disease (on day -7). We treated the mice with intravenous (tail vein) injections of PBS, B+C-CpG, or BNP+CNP on days 1, 4, and 8.Results: We found that the combination of BNP and CNPs had the most significant reduction in total tumor volume (TTV) (treated + untreated tumor size) (393mm 3 on day 22). The PBS group demonstrated rapid tumor growth (TTV 3516mm 3). The experimental treatment groups, B-CpG (TTV 949mm 3), C-CpG (TTV 2230mm 3), B+C-CpGs (TTV 1680mm 3), BNP (TTV 1224mm 3), and CNP (1894mm 3) had similar TTV growth curves. Separating the treated tumor and untreated tumor growth curves, we found that B-CpG and BNP along with combination of BNP+CNP had the best tumor suppression on the treated side. This is not surprising as B-CpG sequences are more directly cytotoxic to lymphoma cells versus C-CpGs. Interestingly, combination nanoparticle treatment (BNP+CNP) was the only group that had significantly reduced tumor growth of the untreated tumor compared with all other conditions (p<0.03) where no statistical difference was measured when the PBS treatment group with the other groups. The BNP+CNP treatment group also had significantly prolonged event free survival compared with all other treatment groups. Furthermore, in the advanced disease model, when BNP and CNP were both injected intravenously, the flank tumor was notably smaller (149mm 3) compared with the other two groups (B+C-CpG 1310mm 3 or PBS 1555mm 3). Importantly, there were no visible lymphoma nodules on liver in the nanoparticle treatment group while there are obvious nodules for both the PBS and the free CpG groups.Conclusions: Overall, the combination of class B and class C CpG nanoparticles can generate a strong in situ anti-lymphoma vaccination response, presumably through the combination of by combining the superior cytotoxicity of BNPs with the enhanced immune stimulation effect of the CNPs. Further evaluation of the combined mechanism of action of this dual CpG nanoparticle approach and toxicity studies are in progress. DisclosuresThaxton: Zylem biosciences: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding.

The Effect of Ceiling Heating and Mechanical Ventilation on Thermal Comfort

In the case of public buildings with ceiling heating and mechanical ventilation, radiant temperature asymmetry caused by the warm ceiling and draught occur simultaneously. The currently available literature does not offer an exhaustive description of the comfort conditions resulting from such a thermal environment. This research focuses on complementing the available knowledge, using instrumental measurements, as well as subject measurements carried out on 20 individuals. Relying on these measurements, the purpose of the research is to support the understanding of the combined mechanisms of action of the two local discomfort parameters. The main result of this research is that, if the predicted percentage dissatified is less than 6%, the radiant temperature asymmetry is in an interval of 5–15 °C, and the draught rate is 15% or 25%, the actual mean vote and the predicted mean vote values differ significantly, and the actual mean vote is always lower, with a few exceptions. In addition, the research highlights the changes of the actual mean vote caused by raising the draught rate from 15% to 25%, in the presence of radiant temperature asymmetry caused by warm ceilings.

Rational Use Of Drugs In The Comprehensive Treatment Of Bronchoobstructive Syndrome In Children

Treatment of bronchoobstructive syndrome in children and integrated use of drugs, that is, each drug should be pathogenetically justified, taking into account the individual characteristics of the child, and based on knowledge of the mechanism of their action and pharmacokinetics. It is necessary to have a complex effect on individual links of the pathogenesis of bronchoobstructive syndrome in many cases makes the use of complex drugs with combined mechanism of action justified. Thus, treatment of bronchoobstructive syndrome in children before a pediatrician is a responsible task, which consists in rational selection of medicines.

Ginsenoside Rh1 Improves Type 2 Diabetic Nephropathy through AMPK/PI3K/Akt-Mediated Inflammation and Apoptosis Signaling Pathway.

Although ginseng (Panax ginseng C.A. Meyer) has received extensive attention in the treatment and prevention of type 2 diabetes mellitus (T2DM) in the past few decades, there are few studies on the complications of T2DM. At present, obesity-linked diabetic nephropathy (DN) has become the most prevailing element of the end-stage renal failure in the world. The aim of this work is to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on DN induced by high fat diet plus streptozotocin (HFD/STZ) through some potential and combined mechanisms of action. The results showed that G-Rh1 treatment at 5 and 10 mg/kg for 8 weeks exerted excellent effects in controlling fasting blood glucose (FBG), improving glucose tolerance, and increasing insulin level. In addition, G-Rh1 effectively prevents the excessive production of advanced glycation end products (AGEs), a diabetic nephropathy marker, in HFD/STZ induced DN mice. Meanwhile, oxidation indicators including SOD, GSH, and MDA were improved by G-Rh1 treatment to varying degrees. It is worth noting that G-Rh1 not only inhibits the secretion of Nox1 and Nox4 in kidney tissues, but also has an inhibitory effect on inflammatory factors and NF-[Formula: see text]B signaling pathway. Importantly, further in-depth research on molecular mechanisms provides vital evidence that the ameliorative effect of G-Rh1 on DN is related to the inhibition of apoptosis and the AMPK/PI3K/Akt signaling pathway. In summary, G-Rh1 may be of great value in improving the treatment of DN although more experimental data is needed.

A Comprehensive Review of Biological Agents for Lupus: Beyond Single Target.

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cells. Due to its complex pathogenesis, the effectiveness of traditional treatment methods is limited. Many patients have developed resistance to conventional treatment or are not sensitive to steroid and immunosuppressant therapy, and so emerging therapeutic antibodies have become an alternative and have been shown to work well in many patients with moderate and severe SLE. This review summarizes the biological agents that are in the preclinical and clinical trial study of SLE. In addition to the various monoclonal antibodies that have been studied for a long time, such as belimumab and rituximab, we focused on another treatment for SLE, bispecific antibodies (BsAbs) such as tibulizumab, which simultaneously targets multiple pathogenic cytokines or pathways. Although the application of BsAbs in cancer has been intensively studied, their application in autoimmune diseases is still in the infant stage. This unique combined mechanism of action may provide a novel therapeutic strategy for SLE.

Therapeutic Potential of Phosphodiesterase Inhibitors against Neurodegeneration: The Perspective of the Medicinal Chemist.

Increasing human life expectancy prompts the development of novel remedies for cognitive decline: 44 million people worldwide are affected by dementia, and this number is predicted to triple by 2050. Acetylcholinesterase and N-methyl-d-aspartate receptors represent the targets of currently available drugs for Alzheimer’s disease, which are characterized by limited efficacy. Thus, the search for therapeutic agents with alternative or combined mechanisms of action is wide open. Since variations in 3′,5′-cyclic adenosine monophosphate, 3′,5′-cyclic guanosine monophosphate, and/or nitric oxide levels interfere with downstream pathways involved in memory processes, evidence supporting the potential of phosphodiesterase (PDE) inhibitors in contrasting neurodegeneration should be critically considered. For the preparation of this Review, more than 140 scientific papers were retrieved by searching PubMed and Scopus databases. A systematic approach was adopted when overviewing the different PDE isoforms, taking into account details on brain localization, downstream molecular mechanisms, and inhibitors currently under study, according to available in vitro and in vivo data. In the context of drug repurposing, a section focusing on PDE5 was introduced. Original computational studies were performed to rationalize the emerging evidence that suggests the role of PDE5 inhibitors as multi-target agents against neurodegeneration. Moreover, since such compounds must cross the blood–brain barrier and reach inhibitory concentrations in the central nervous system to exert their therapeutic activity, physicochemical parameters were analyzed and discussed. Taken together, literature and computational data suggest that some PDE5 inhibitors, such as tadalafil, represent promising candidates.

The state of antioxidant protection system in cows under the influence of heavy metals

A highly relevant problem of modern veterinary science is the study of features and mechanisms of combined action of the most common heavy metals – cadmium and plumbum and their influence on the body of humans and animals in the regions of Ukraine under technogenic pollution. The purpose of the work was to study the influence of heavy metals on the state of the antioxidant protection system of cows, in particular on the content of lipid peroxidation products (malonic dialdehyde, lipid hydroperoxides and diene conjugates), and activity of antioxidant enzymes (glutathione peroxidase and superoxide dismutase), depending on the distance to the heaps of mines in the coal basin. The study objects were cows of black-and-white breed at the age of 3–7 years. It was established that this parameter in the place with the highest concentration of diene conjugates in the blood of cows was by 25.8 % higher compared to the place of low concentration and 12.1 % higher compared to the place with medium concentration. In the place with the highest content of lipid hydroperoxides in the blood of cows the parameter was 23.7 % higher compared to the cows from the place with the low content. The concentration of lipid hydroperoxides in the blood of cows from the place with the medium content was 16.7% higher compared to the cows from the place with the low content. The parameter from the place with the lowest content of lipid hydroperoxides in the blood of cows was 12.1% lower compared to the place with the highest content. The level of malonic dialdehyde in the blood of cows from the technogenic pollution zone in the place with the largest amount was higher by 36.2; 34.0 and 18.8 % – compared to places with medium and low levels, respectively. The activity of superoxide dismutase in the blood of cows in the place with its highest activity was 0.284 ± 0.0099 % block. reac/g Hb, and in the place with the lowest activity – 0.23 ± 0.0051 % block. reac/g Hb. The activity of glutathione peroxidase in the blood of cows in farms of the technogenic pollution zone depended on the distance to the mine. These researches will further develop effective methods of treating cows under the influence of heavy metals, in particular regarding the antioxidant system.

EXPERIENCE OF COMBINING PLATELET-RICH AUTOPLASM THERAPY AND LOW-INTENSITY SHOCK-WAVE THERAPY IN TREATMENT OF PEYRONIE’S DISEASE

Relevance. The spectrum of combined mechanisms of action of PRP-therapy, LISWT and LNP therapy suggests the clinical eff ect for patients with fi broplastic penile induration, which currently does not have conservative therapies that have suffi cient effi cacy.The aim of the study was to determine the effi cacy of combined PRP-therapy with intracavernous activation of growth factors by LISWT method + LNP and ICA pharmacotherapy in treatment of fi broplastic penile induction.Design. The study group comprised 23 patients of the Men’s Health Clinic in Kyiv, suff ering from fi broplastic penile inducing (Peyronie’s disease, ICD-10: N48.6) with erectile dysfunction.Results of the study. A 6-month follow-up observation showed a reduction of pain during erection, a signifi cant improvement in erectile function, a total regression of the areas less than 25 mm2 and a signifi cant decrease in the density and area of the induration areas that over 25 mm2. Conclusions. It has been established that the therapeutic model of the combined use of PRP-therapy with intracavernous activation of growth factors by LISWT method + LOD + ICA in the treatment of fi broplastic penile induration, shows a pronounced clinical eff ect, which makes this therapeutic model a promising option for conservative correction of pain and erectile dysfunction in fi broplastic penile induration.

EXPERIENCE OF PREMATURE EJACULATION CORRECTION BY COMBINED THERAPY OF PLATELET-RICH PLASMA AND LOW-INTENSITY SHOCK-WAVE THERAPY

Relevance. The spectrum of combined mechanisms of action of PRP-therapy, LISWT and LNP therapy suggests the clinical eff ect for patients with fi broplastic penile induration, which currently does not have conservative therapies that have suffi cient effi cacy.The aim of the study was to determine the effi cacy of combined PRP-therapy with intracavernous activation of growth factors by LISWT method + LNP and ICA pharmacotherapy in treatment of fi broplastic penile induction.Design. The study group comprised 23 patients of the Men’s Health Clinic in Kyiv, suff ering from fi broplastic penile inducing (Peyronie’s disease, ICD-10: N48.6) with erectile dysfunction.Results of the study. A 6-month follow-up observation showed a reduction of pain during erection, a signifi cant improvement in erectile function, a total regression of the areas less than 25 mm2 and a signifi cant decrease in the density and area of the induration areas that over 25 mm2.Conclusions. It has been established that the therapeutic model of the combined use of PRP-therapy with intracavernous activation of growth factors by LISWT method + LOD + ICA in the treatment of fi broplastic penile induration, shows a pronounced clinical eff ect, which makes this therapeutic model a promising option for conservative correction of pain and erectile dysfunction in fi broplastic penile induration.

Functional relaxant effect of 6,7-dipropoxy-2H-chromen-2-one is mainly by calcium channel blockade in ex vivo assay of tracheal rings

Asthma is a prevalent disease characterized by airway chronic inflammation, airway hyperresponsiveness, edema and excess of mucus production. Molecules with coumarin scaffold have shown multiple biological effects, including anti-asthmatic. This study describes relaxant effect and mechanism of action of novel semisynthetic 6,7-dipropoxy-2H-chromen-2-one (6,7-DPC) on smooth muscle airways and in silico approaches. 6,7-DPC induced significant relaxant effect on tracheal rings pre-contracted with carbachol (Emax = 100%; EC50 = 89 µM). Concentration-response curve of 6,7-DPC showed a significant shift to the left with respect to theophylline (positive control). Moreover, pre-treatment with 6,7-DPC inhibited the carbachol-induced contraction in a concentration-dependent manner with suppression of the maximum response. Also, KCl [80 mM]-induced contraction was partially abolished by 6,7-DPC compared with nifedipine; however, CaCl2 contraction curve only reached 30% of maximal response in the tissues pre-incubated with the test sample. 6,7-DPC was docked on an outer cavity located on the intracellular side of the human L-type calcium channel model and interacts in the following chains and residues: IIIS5.M26, IIIP.T45, IIIP.F49, IIIP.G51, IIIP.P53, IVP.C46, IVP.G49, IVP.E50, IVP.A51, IVP.W52, IVP.Q53, IVP.D54, IVS6.I4, IVS6.F7, IVS6.I8, IVS6.F10, and IVS6.F11. Also, nifedipine made unique interactions with IIIP.E50, IIIP.W52, IIIP.L55. Meanwhile, 6,7-DPC interacted with IIIS5.A22, IIIS2.Q27, and IVS6.C14, exclusively. In conclusion, 6,7-DPC showed a relaxant effect due to combined mechanism of action on rat tracheal rings, through non-competitive muscarinic receptor functional antagonism and preventing the calcium influx. This provides pharmacological basis for the use of 6,7-DPC in airways disorders, such as asthma or chronic obstructive pulmonary disease (COPD).

M19 - ESTIMATE SPATIOTEMPORAL IMPACT OF BRAIN VARIANTS

Background Functional characterization for genetic variants is a major challenge in whole-genome sequencing-based studies. Recent approaches, such as TiSAn (Vervier et al., 2017) or GenoSkyline (Lu et al., 2016), estimate tissue-specific impact of variations, in particular in human brain tissues. However, such annotations do not provide insights on which brain regions or development time points might be especially vulnerable to a given variant. Methods In this work, we propose to integrate spatiotemporal gene expression from BrainSpan (BrainSpan, 2014) to estimate what the 'context matrix' of a variant is. Variants found in non-coding regions are represented as a combination of gene expression matrices, where weights are based on associations demonstrated in SLINGER models (Vervier et al., 2016). Results We validate our approach on psychiatric disorder datasets, and use temporal patterns to discriminate early- and late-onset damaging variants. Brain region-specific variants also help to identify combined mechanisms of action, in complex traits. Discussion Spatio-temporal profiles could also be combined with polygenic risk score approaches, and provide new dimensions to study psychiatric disorders.