Effect of liposomal formulation of ascorbic acid on corneal permeability.

Ascorbic acid (AA) has a pivotal role in corneal wound healing via stimulating the biosynthesis of highly organized extracellular matrix components, but its rapid degradation and low corneal permeability limits its therapeutic effects. In this paper, we present the pharmacokinetic properties of a liposomal-based formulation of AA in terms of corneal permeation. Chemical stability, shelf-life, and drug release rate of lyophilized liposome (AA-LLipo) formulation was determined in comparison to free-form of AA solution using high-performance liquid chromatography (HPLC) and rapid equilibrium dialysis. In vitro transcorneal permeability was studied using a parallel artificial membrane permeability assay (PAMPA). Ex vivo permeation was examined on AA-LLipo-treated porcine cornea by determining the AA content on the ocular surface, in the cornea as well as in the aqueous humor using HPLC, and by Raman-mapping visualizing the AA-distribution. Our results showed that the liposomal formulation improved the chemical stability of AA, while drug release was observed with the same kinetic efficiency as from the free-form of AA solution. Both corneal-PAMPA and porcine corneal permeability studies showed that AA-LLipo markedly improved the corneal absorption kinetics of AA, thus, increasing the AA content in the cornea and aqueous humor. AA-LLipo formulation could potentially increase the bioavailability of AA in corneal tissues.

Effects of Chemical Structures Interacting with Amine Oxidases on Glucose, Lipid and Hydrogen Peroxide Handling by Human Adipocytes.

Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.

Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing.

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a "computer-aided drug repurposing" approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators.

Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions.

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.

Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain.

SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.

Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs.

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion and reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged the frequency-corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations, blocked I Kr in isolated cardiomyocytes (Class III effects), and reduced the maximum rate of depolarization (V max) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent reentry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats.

Diabetes mellitus is a common metabolic disease leading to hyperglycemia due to insufficient pancreatic insulin production or effect. Amine oxidase copper containing 3 (AOC3) is an enzyme that belongs to the semicarbazide-sensitive amine oxidase family, which may be a novel therapeutic target to treat diabetic complications. We aimed to explore the effects of AOC3 inhibition and to test the actions of our novel AOC3 inhibitor multi-target drug candidate, SZV 1287, compared to a selective reference compound, LJP 1207, in an 8-week long insulin-controlled streptozotocin (STZ)-induced (60 mg/kg i.p.) rat diabetes model. Both AOC3 inhibitors (20 mg/kg, daily s.c. injections) were protective against STZ-induced pancreatic beta cell damage determined by insulin immunohistochemistry and radioimmunoassay, neuropathic cold hypersensitivity measured by paw withdrawal latency decrease from 0 °C water, and retinal dysfunction detected by electroretinography. SZV 1287 showed greater inhibitory effects on beta cell damage, and reduced retinal apoptosis shown by histochemistry. Mechanical hypersensitivity measured by aesthesiometry, cardiac dysfunction and nitrosative stress determined by echocardiography and immunohistochemistry/Western blot, respectively, serum Na+, K+, fructosamine, and urine microalbumin, creatinine, total protein/creatinine ratio alterations did not develop in response to diabetes. None of these parameters were influenced by the treatments except for SZV 1287 reducing serum fructosamine and LJP 1207 increasing urine creatinine. We provide the first evidence for protective effects of AOC3 inhibition on STZ-induced pancreatic beta cell damage, neuropathic cold hypersensitivity and diabetic retinal dysfunction. Long-term treatment with our novel multi-target analgesic candidate, SZV 1287, is safe and effective also under diabetic conditions.

Radiosynthesis and Preclinical Investigation of 11 C-Labelled 3-(4,5-Diphenyl-1,3-oxazol-2-yl)propanal Oxime ([11 C]SZV 1287).

The radiosynthesis, as well as the in vivo and ex vivo biodistribution of the 11 C radiolabelled 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime (6, [11 C]SZV 1287) are reported. SZV 1287 is a novel semicarbazide-sensitive amine oxidase (SSAO) inhibitor and a promising candidate to be a novel analgesic for the treatment of neuropathic pain. Its radiolabelling was developed via a four-step radiosynthesis which started from the reaction of a Grignard reagent with [11 C]CO2 to produce [11 C]oxaprozin (3). In the next step this carboxylic acid 3 was directly reduced to yield the corresponding aldehyde, which was then converted into the oxime. [11 C]SZV 1287 was administered to male NMRI mice. The animals were examined with dynamic PET/MR imaging for 90 minutes. Biodistribution studies were performed at 10, 30, 60 and 120 minutes post injection. The accumulation of the labelled compound was observed in the brain of the animals. The main excretion pathway was found to be through the liver and intestines. These studies provide preliminary information for pharmacokinetic characterization of the SZV 1287.

[Multi-targeting drugs: past, present and future]. / Több támadáspontú gyógyszerek: múlt, jelen és jövo.

The one disease - one target - one drug paradigm was an almost dominant principle in drug discovery from the 1960s to the 2000s. The stagnation and even decline in the productivity of drug innovation around the turn of the millennium and beyond, the realization of limitations of the one-target approach, especially in the treatment of multifactorial diseases, have drawn attention considerably to the one disease - multiple target - one drug multi-targeting drug concept. In this review, we outline old and new molecular design strategies and their practical implementation with own and other examples that also demonstrate unique therapeutic and diagnostic values and benefits of the multi-targeting approach. Finally, we point out that the full potential of the multi-targeting concept can emerge through data analytics and association methods (such as artificial intelligence) and system-based approach, preferably by linking it to quantitative systems pharmacology. This new systems pharmacology drug approach may also lead to novel breakthrough drugs, drug combinations and drug repositioning. Orv Hetil. 2020; 161(14): 523-531.

[1,5]-Hydride Shift-Cyclization versus C(sp2)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines.

Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp2)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp3)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp2)-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative had a 6.98 µM IC50 value.

Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel.

Cloxyquin has been reported as a specific activator of TRESK [TWIK-related spinal cord K+ channel (also known as K2P18.1)] background potassium channel. In this study, we have synthetized chemically modified analogs of cloxyquin and tested their effects on TRESK and other K2P channels. The currents of murine K2P channels, expressed heterologously in Xenopus oocytes, were measured by two-electrode voltage clamp, whereas the native background K+ conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell patch-clamp method. Some of the analogs retained the activator character of the parent compound, but, more interestingly, other derivatives inhibited mouse TRESK current. The inhibitor analogs (A2764 and A2793) exerted state-dependent effects. The degree of inhibition by 100 µM A2764 (77.8% ± 3.5%, n = 6) was larger in the activated state of TRESK (i.e., after calcineurin-dependent stimulation) than in the resting state of the channel (42.8% ± 11.5% inhibition, n = 7). The selectivity of the inhibitor compounds was tested on several K2P channels. A2793 inhibited TWIK-related acid-sensitive K+ channel (TASK)-1 (100 µM, 53.4% ± 13, 5%, n = 5), while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and TWIK-related alkaline pH-activated K+ channel. The effect of A2764 was also examined on the background K+ currents of DRG neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed background K+ currents sensitive to A2764, whereas the inhibitor did not affect the currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove to be useful for the identification of TRESK current in native cells, and for the investigation of the role of the channel in nociception and migraine. SIGNIFICANCE STATEMENT: TRESK background potassium channel is a potential pharmacological target in migraine and neuropathic pain. In this study, we have identified a selective inhibitor of TRESK, A2764. This compound can inhibit TRESK in native cells, leading to cell depolarization and increased excitability. This new inhibitor may be of use to probe the role of TRESK channel in migraine and nociception.

[Databases in neurological diseases: overview of international examples in multiple sclerosis]. / Nagy adatbázisok neurológiai kórképekben: nemzetközi áttekintés a sclerosis multiplex példáján.

Vast amounts of data are created during routine patient care which are stored in unstructured digital and hardcopy formats in healthcare institutions. Analysis of large databases help to define the healthcare needs of the population and to organize healthcare services for specific diseases. As a model, we selected multiple sclerosis (MS), a disease with well-defined diagnostic criteria, a usually inpatient initial diagnosis, and a need for regular outpatient check-up. Using multiple sclerosis as an example, we set forth to screen and analyze international and Hungarian databases. In the framework of the initiation of the data lake system of Semmelweis University, we aim to define features of the data system needed for disease-specific databases for future applications. To determine essential data-entry criteria for such a database, we review the most important multiple sclerosis registries. We evaluate the type of registered data, structure of database, privacy issues, the availability and ways of application of the databases. Initially, the MS databases were created locally, aiming for better care of patients. As a further step, data were collected for scientific research by national and international co-operations. Disease-specific databases have become of high priority for national healthcare providers, and long-term information on a population ("real-world" data) is extremely important to assess the effectivity and safety of a treatment at the population level. Our analysis contributes to a project which focuses on the aspects of developing a data lake at a service provider level including clinical, diagnostic and digital healthcare departments of Semmelweis University, Budapest, Hungary. Orv Hetil. 2019; 160(4): 123-130.

[Multiple sclerosis in central Hungary: experiences and future possibilities of developing a local database]. / Sclerosis multiplex a közép-magyarországi régióban: a helyi adatbázisfejlesztés tapasztalatai és jövobeli lehetoségei.

INTRODUCTION: Data during routine patient care are created in multiple digital and paper-based hardcopy systems, therefore their retrieval is cumbersome in the follow-up of patients. Multiple sclerosis is the most prevalent neurological disorder in the young age, with major consequences on health and socio-economic status. AIM: We set forth to create a user-friendly, detailed local database where it is easy to access, register and analyze data. Based on our experiences during building this registry, we develop the model of a modern type of database. METHOD: First we established a local registry in Excel, then data were transferred to the worldwide used iMed system. Separate pages were used to register basic data, follow-up visits, relapses, accompanying diseases, results of neuroimaging, cerebrospinal fluid, evoked response and other tests, pharmacological and non-pharmacological treatments. RESULTS: The database currently contains data of 316 patients. MRI was performed in 96%, cerebrospinal fluid examination in 45% of the patients. The rate of primary progressive disease at disease onset is 9%. Disease modifying treatments were applied in 82% of the patients. CONCLUSION: The traditional manual data entry and data export in PDF format is obsolete and time-consuming. The development of local disease-specific databases appropriate for clinical and research purposes requires continuous and mostly automatic data entry. In future local registries the establishment of uniform documentational language and structure, and automatic transfer of information among different digital systems are required. We present the model of such a registry, which is based on a healthcare data lake. Orv Hetil. 2019; 160(4): 131-137.

HPLC-ECD and TDDFT-ECD study of hexahydropyrrolo[1,2-a]quinoline derivatives.

Synthesis of racemic hexahydropyrrolo[1,2-a]quinoline derivatives (1-8) was performed by utilizing the Knoevenagel-[1,5]-hydride shift-cyclization domino reaction. Separation of the enantiomers of the chiral products (1-8) was carried out by chiral high-performance liquid chromatography, and online high-performance liquid chromatography-electronic circular dichroism (ECD) spectra were recorded to elucidate the absolute configuration by comparing the experimental and time-dependent density functional theory-ECD spectra obtained at various theoretical levels. For 1 of the products, the time-dependent density functional theory-ECD calculations allowed determining both the relative and the absolute configuration by distinguishing the 4 stereoisomers. One of the compounds with spiro 1,3-cyclohexanedione moiety (7) possessed moderate acetylcholinesterase inhibitory activity, while 3 showed neuroprotective activity in oxygen-glucose deprivation-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.

Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors.

Semicarbazide-sensitive amine oxidase (SSAO) produces tissue irritants by deamination of primary amines, which activate transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly on nociceptors. Since there are no data about its functions in pain, we studied the effects and mechanisms of action of our novel SSAO inhibitor and dual TRPA1/TRPV1 antagonist multi-target drug SZV 1287 in different pain models. Acute chemonociception was induced by TRPV1 and TRPA1 activation (resiniferatoxin and formalin, respectively), chronic arthritis by K/BxN serum transfer, traumatic mononeuropathy by sciatic nerve ligation. SZV 1287 (20 mg/kg i.p.) was investigated in C57BL/6J wildtype (WT), TRPA1- (TRPA1-/-) and TRPV1-deficient (TRPV1-/-) mice. Paw mechanonociception was measured by aesthesiometry, thermonociception by hot plate, nocifensive behavior by licking duration, volume by plethysmometry, myeloperoxidase activity by luminescence and plasma extravasation by fluorescence imaging, glia activation in pain-related brain regions by immunohistochemistry. SZV 1287 significantly inhibited both TRPA1 and TRPV1 activation-induced acute chemonociception and hyperalgesia. In K/BxN arthritis, daily SZV 1287 injections significantly decreased hyperalgesia, L4-L6 spinal dorsal horn microgliosis, edema and myeloperoxidase activity. SZV 1287-evoked antihyperalgesic and anti-edema effects were absent in TRPV1-/-, and remarkably reduced in TRPA1-/- mice. In contrast, myeloperoxidase-inhibitory effect was absent in TRPA1-/-, but not in TRPV1-/- animals. Acute SZV 1287 administration resulted in approximately 50% significant reduction of neuropathic hyperalgesia 7 days after nerve ligation, which was not observed in either TRPA1-/- or TRPV1-/- mice. SZV 1287 inhibits chronic inflammatory and neuropathic pain via TRPV1 and TRPA1/TRPV1 activation, respectively, highlighting its drug developmental potential.

Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle.

Racemic mexiletine is a widely used antiarrhythmic agent that blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization ([Formula: see text]), conduction time, and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µmol/L of therapeutically and experimentally relevant concentration, significantly depressed the [Formula: see text] at fast heart rates (BCLs 300-700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the [Formula: see text] of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD90 ratio. The time constant (τ) of recovery of [Formula: see text] was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine, which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be a more potent antiarrhythmic agent than S-(+) mexiletine.

Through scaffold modification to 3,5-diaryl-4,5-dihydroisoxazoles: new potent and selective inhibitors of monoamine oxidase B.

3,5-Diaryl-4,5-dihydroisoxazoles were synthesized and evaluated as monoamine oxidase (MAO) enzyme inhibitors and iron chelators. All compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was preliminarily evaluated for its ability to bind iron II and III cations, indicating that neither iron II nor iron III is coordinated. The best compounds racemic mixtures were separated and single enantiomers inhibitory activity evaluated. Furthermore, none of the synthesised compounds exhibited activity towards MAO A. Overall, these data support our hypothesis that 3,5-diaryl-4,5-dihydroisoxazoles are promising scaffolds for the design of neuroprotective agents.

Analgesic and Anti-Inflammatory Effects of the Novel Semicarbazide-Sensitive Amine-Oxidase Inhibitor SzV-1287 in Chronic Arthritis Models of the Mouse.

Semicarbazide-sensitive amine oxidase (SSAO) catalyses oxidative deamination of primary amines. Since there is no data about its function in pain and arthritis mechanisms, we investigated the effects of our novel SSAO inhibitor SzV-1287 in chronic mouse models of joint inflammation. Effects of SzV-1287 (20 mg/kg i.p./day) were investigated in the K/BxN serum-transfer and complete Freund's adjuvant (CFA)-evoked active immunization models compared to the reference SSAO inhibitor LJP-1207. Mechanonociception was assessed by aesthesiometry, oedema by plethysmometry, clinical severity by scoring, joint function by grid test, myeloperoxidase activity by luminescence, vascular leakage by fluorescence in vivo imaging, histopathological changes by semiquantitative evaluation, and cytokines by Luminex assay. SzV-1287 significantly inhibited hyperalgesia and oedema in both models. Plasma leakage and keratinocyte chemoattractant production in the tibiotarsal joint, but not myeloperoxidase activity was significantly reduced by SzV-1287 in K/BxN-arthritis. SzV-1287 did not influence vascular and cellular mechanisms in CFA-arthritis, but significantly decreased histopathological alterations. There was no difference in the anti-hyperalgesic and anti-inflammatory actions of SzV-1287 and LJP-1207, but only SzV-1287 decreased CFA-induced tissue damage. Unlike SzV-1287, LJP-1207 induced cartilage destruction, which was confirmed in vitro. SzV-1287 exerts potent analgesic and anti-inflammatory actions in chronic arthritis models of distinct mechanisms, without inducing cartilage damage.

The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases.

Oxidative stress is a much-appreciated phenomenon associated with the progression of neurodegenerative diseases (NDDs) due to imbalances in redox homeostasis. The poor correlations between the in vitro benefits and clinical trials of direct radical scavengers have prompted research into indirect antioxidant enzymes such as Nrf2. Activation of Nrf2 leads to the upregulation of a myriad of cytoprotective and antioxidant enzymes/proteins. Traditionally, early Nrf2-activators were studied as chemoprotective agents. There is a consequential lack of clinical trials testing Nrf2 activation in NDDs. However, there is abundant evidence of their utility in pre-clinical studies. Herein, we review the endogenous Nrf2 regulatory pathway and avenues for targeting this pathway. Furthermore, we provide updated information on pre-clinical studies for natural and synthetic Nrf2 activators. On the basis of our findings, we posit that successful therapeutics for NDDs rely on the design of potent synthetic Nrf2 activators with a careful combination of other neuroprotective activities.

Dietary Phenolic Compounds Interfere with the Fate of Hydrogen Peroxide in Human Adipose Tissue but Do Not Directly Inhibit Primary Amine Oxidase Activity.

Resveratrol has been reported to inhibit monoamine oxidases (MAO). Many substrates or inhibitors of neuronal MAO interact also with other amine oxidases (AO) in peripheral organs, such as semicarbazide-sensitive AO (SSAO), known as primary amine oxidase, absent in neurones, but abundant in adipocytes. We asked whether phenolic compounds (resveratrol, pterostilbene, quercetin, and caffeic acid) behave as MAO and SSAO inhibitors. AO activity was determined in human adipose tissue. Computational docking and glucose uptake assays were performed in 3D models of human AO proteins and in adipocytes, respectively. Phenolic compounds fully inhibited the fluorescent detection of H2O2 generated during MAO and SSAO activation by tyramine and benzylamine. They also quenched H2O2-induced fluorescence in absence of biological material and were unable to abolish the oxidation of radiolabelled tyramine and benzylamine. Thus, phenolic compounds hampered H2O2 detection but did not block AO activity. Only resveratrol and quercetin partially impaired MAO-dependent [(14)C]-tyramine oxidation and behaved as MAO inhibitors. Phenolic compounds counteracted the H2O2-dependent benzylamine-stimulated glucose transport. This indicates that various phenolic compounds block downstream effects of H2O2 produced by biogenic or exogenous amine oxidation without directly inhibiting AO. Phenolic compounds remain of interest regarding their capacity to limit oxidative stress rather than inhibiting AO.