Synthesis of Cyclopentenone Isoprostanes and Highly Functionalized Cyclopentanes

Cyclopentane ring itself or as an element of bicyclic or polycyclic systems is not only ubiquitous in nature but also an increasingly recognized structural motif for biomedical research and drug discovery. In this context, the first part of the thesis describes our efforts towards synthetic analogs of a natural epoxy cyclopentenone isoprostane known to possess anti-inflammatory bioactivity. Employing reported strategies seven novel cyclopentenone isoprostanes were provided to our collaborators to examine their bioactivity. Additionally, preliminary studies demonstrated that the analog bearing an azide functionality could be labeled with an alkyne-containing cyanine (Cy5) and thus could serve as a valuable tool to further study the signaling pathway of related isoprostanes. While numerous methodologies have been developed for the synthesis of this structural entity, the employment of known strategies to access relevant structural analogs can still be tedious and challenging. Acknowledging that, the second part of the thesis covers our investigations towards the use of vinylboron derivatives in radical-mediated [3 + 2] annulation reactions. The development of an efficient route giving access to 1,1-diborylethene in gram scale allowed us to extend the scope of this reaction allowing the synthesis of substituted cyclopentanes flanked with two boronic ester moieties. The established processes are operationally simple, convergent, atom economical, and mild. Thus, the synthesis of cyclopentanes presenting sensitive functional groups is enabled. Additionally, the utility of the synthesized cyclopentane platforms was demonstrated by taking advantage of the presence of either the iodine atom, the boron atom(s), or both functionalities. These functionalization products include intriguing and applicable bicyclo[3.1.0]hexanes decorated with a boronic ester moiety, allylic gem-diboronates, and homoallyiodides among others, and are all easily accessible in one or two steps

Samat dilemmat - eri ratkaisut : Suomen ja Baltian maiden kansalliskulttuurien ilmeneminen johtamisessa

Siirretty Doriast

Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats

1. The potential for the N-hydroxyguanidine compound PR5 (N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited repel fusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P < 0.05); mortality 47 vs 0% (P < 0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0% P < 0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10-20 min) increased malondialdehyde (MDA) of rat hearts (0.88 ± 0.13 for sham vs 1.45 ± 0.12 nmol mg-1 protein for ischaemic; P < 0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04 ± 0.12; P < 0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326 ± 32 mg for controls vs 137 ± 21 mg for animals treated with 3 x 3 mg kg-1 of PR5 (P < 0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7. We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron accepters at the xanthine oxidase enzyme.publishersversionPeer reviewe

Inhibition of Fatty Acid Metabolism Increases EPA and DHA Levels and Protects against Myocardial Ischaemia-Reperfusion Injury in Zucker Rats

Publisher Copyright: © 2021 Janis Kuka et al.Long-chain ω-3 polyunsaturated fatty acids (PUFAs) are known to induce cardiometabolic benefits, but the metabolic pathways of their biosynthesis ensuring sufficient bioavailability require further investigation. Here, we show that a pharmacological decrease in overall fatty acid utilization promotes an increase in the levels of PUFAs and attenuates cardiometabolic disturbances in a Zucker rat metabolic syndrome model. Metabolome analysis showed that inhibition of fatty acid utilization by methyl-GBB increased the concentration of PUFAs but not the total fatty acid levels in plasma. Insulin sensitivity was improved, and the plasma insulin concentration was decreased. Overall, pharmacological modulation of fatty acid handling preserved cardiac glucose and pyruvate oxidation, protected mitochondrial functionality by decreasing long-chain acylcarnitine levels, and decreased myocardial infarct size twofold. Our work shows that partial pharmacological inhibition of fatty acid oxidation is a novel approach to selectively increase the levels of PUFAs and modulate lipid handling to prevent cardiometabolic disturbances.publishersversionPeer reviewe

Protective effects of meldonium in experimental models of cardiovascular complications with a potential application in COVID‐19

Funding Information: This study was supported by the Latvian State Research Program project VPP?COVID? 2020/1?0014 ?Towards new therapeutic and prophylactic treatments against Covid?19 and corona-viruses?. Dana Kigitovica received Doctoral study grant from Riga Stradins University. Funding Information: Funding: This study was supported by the Latvian State Research Program project VPP‐COVID‐ 2020/1‐0014 ʺTowards new therapeutic and prophylactic treatments against Covid‐19 and corona‐ virusesʺ. Dana Kigitovica received Doctoral study grant from Riga Stradins University. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID‐19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID‐19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension‐induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hyper-trophy and increased RVFAC by 50%. Mice with inflammation‐induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID‐19 patients.publishersversionPeer reviewe

LC-MS/MS method for simultaneous quantification of the first-line anti-tuberculosis drugs and six primary metabolites in patient plasma : Implications for therapeutic drug monitoring

Funding Information: This study was funded by the Latvian Council of Science. Project No: lzp-2020/1-0050. Publisher Copyright: © 2021 The AuthorsThe pharmacokinetic profiling of drug substances and corresponding metabolites in the biological matrix is one of the most informative tools for the treatment efficacy assessment. Therefore, to satisfy the need for comprehensive monitoring of anti-tuberculosis drugs in human plasma, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of first-line anti-tuberculosis drugs (ethambutol, isoniazid, pyrazinamide, and rifampicin) along with their six primary metabolites. Simple single-step protein precipitation with methanol was chosen as the most convenient sample pre-treatment method. Chromatographic separation of the ten analyte mixture was achieved within 10 minutes on a reverse-phase C8 column using mobile phase gradient mode. The multiple reaction monitoring mode (MRM) was used for analyte detection and quantification in patient samples. The chosen quantification ranges fully covered expected plasma concentrations. The method exhibited acceptable selectivity; the within- and between-run accuracy ranged from 87.2 to 113.6%, but within- and between-run precision was between 1.6 and 14.9% (at the LLOQ level CV < 20%). Although the response of the isonicotinic acid varied depending on the matrix source (CV 21.8%), validation results proved that such inconsistency does not affect the accuracy and precision of results. If stored at room temperature plasma samples should be processed within 4 h after collection, temporary storage at −20 °C up to 24 h is acceptable due to stability issues of analytes. The developed method was applied for the patient sample analysis (n = 34) receiving anti-tuberculosis treatment with the first-line drugs.publishersversionPeer reviewe

Work conditions and occupational morbidity in Latvia

Copyright: Copyright 2012 Elsevier B.V., All rights reserved.The aim of study was to analyse work conditions and occupational morbidity in Latvia during a 15-year period for recommendations to employment policy programmes. The study included the analysis of the database of occupational risk factor measurements in more than 7000 enterprises and companies performed in period 1995-2010 by the Laboratory of Hygiene and Occupational Diseases of the Institute of Occupational Safety and Environmental Health of Riga Stradins University. The analysis of registered occupational diseases according to the data from the Latvian State Registry of Occupational diseases run by the Centre of Occupational and Radiation Medicine of Pauls Stradins Clinical University Hospital for the same period was performed. Occupational diseases in Latvia are diagnosed and coded in accordance with the International Classification of Diseases. Results of measurements showed that for one third of measured occupational risk factors values exceeded recommended limits. The traditional work risk factors (chemical, physical, biological etc.) have been partly replaced by new risks (ergonomic and psychosocial factors). The results of the study indicated that the following enterprises form a major risk group of non-compliance with legislation regarding occupational health and safety: small enterprises; enterprises of private and non-governmental sectors; enterprises of different industries (construction, metal processing and wood processing). The number of firstly diagnosed occupational diseases and patients has gradually increased. The total number of firstly diagnosed and registered occupational patients per 100,000 employees was 11.2 in 1995 and 140.5 in 2009. The structure of occupational diseases shows musculoskeletal diseases (46.1%) as the leading group of diseases followed by diseases of the nervous system and organs of sense (29.3%), traumatic disorders and intoxications (11.7%).publishersversionPeer reviewe

Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships

Publisher Copyright: Copyright © 2024 Ulanova, Kivrane, Viksna, Pahirko, Freimane, Sadovska, Ozere, Cirule, Sevostjanovs, Grinberga, Bandere and Ranka.Objectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes.  Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia ( N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0 h), 2 h and 6 h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student's t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC.  Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotype-dependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity. Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies.Peer reviewe

Penetration of Wood Preservatives into Thermally Modified Birch and Pine Wood

The objective of the present study was to investigate the interaction between Cu-containing preservatives and birch (Betula spp.) and pine (Pinus sylvestris L.) wood, modified at a relatively mild temperatures (150 – 180ºC). The disposition of wood to absorb water was evaluated by capillary absorption (CA) tests through the specimens’ tangential and radial surface. Changes in wood drying characteristics due to thermal modification (TM) were evaluated by monitoring wood moisture dynamics after impregnation. In order to assess the capacity of wood to absorb preservatives, a vacuum/pressure process was used to impregnate small specimens for which uniform saturation into the entire volume can easily be reached. Quantitative determination of copper Cu content in the specimens was performed by using atomic absorption spectroscopy (AAS). The fixation of the absorbed Cu was evaluated by subjecting the specimens to leaching procedures according to EN 84 and assessing the ratio of retained Cu in the specimens. The CA test showed deceleration of capillary absorption in TM birch wood through both surfaces, with similar absorption rates regardless of treatment temperatures. A significant increase in the absorption rate through the tangential surface was recorded for TM pine wood and the increase was greater for specimens treated at higher temperatures. The results of moisture content monitoring showed a similar reduction in the drying rate due to thermal modification regardless of species. Comparing wood of one species with similar densities, less preservative was absorbed by TM wood. However, the results of AAS showed that, in comparison with unmodified wood, 10% (birch) and 25% (pine) more Cu per one gram of wood was introduced during impregnation. Nevertheless, TM also resulted in higher Cu leaching rates for both species