showing 27 related works from this author
The anti-inflammatory and antinociceptive effects of NF-κB inhibitory guanidine derivative ME10092
2010
The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine) is known to possess anti-radical and anti-ischemic activity but its molecular targets have not been identified. This study investigated whether ME10092 regulates the nuclear factor kappa B (NF-kappaB)-mediated signal transduction in vivo. The effect of ME10092 treatment (1-100 pmol/mouse) on nuclear translocation of NF-kappaB, activation of expression of inflammatory mediators and production of nitric oxide were measured in the lipopolysaccharide (LPS)-induced brain inflammation model in mice in vivo. The antinociceptive activity of ME10092 was tested in the formalin-induced paw licking test. ME10092 dose-…
Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients
2013
Abstract Aims The present study was undertaken to investigate the relationship between glyoxalase 1 (Glo1) enzyme activity and painful diabetic neuropathy (DN) in patients with diabetes mellitus. Methods Glo1 activity and biochemical markers were determined in blood samples from 108 patients with type 1 diabetes, 109 patients with type 2 diabetes, and 132 individuals without diabetes as a control. Painful and painless peripheral DN was assessed and multivariate regression analysis was used to determine independent association of Glo1 activity with occurrence of painful DN. Results In patients with type 1 and type 2 diabetes mellitus and painful DN compared to patients with painless DN, Glo1…
Functional Evaluation of THIQ, a Melanocortin 4 Receptor Agonist, in Models of Food Intake and Inflammation
2007
The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 …
Decreases in Circulating Concentrations of Long-Chain Acylcarnitines and Free Fatty Acids During the Glucose Tolerance Test Represent Tissue-Specific…
2019
Background: Insulin plays a pivotal role in the regulation of both carbohydrate and lipid intermediate turnover and metabolism. In the transition from a fasted to fed state, insulin action inhibits lipolysis in adipocytes, and acylcarnitine synthesis in the muscles and heart. The aim of this study was to measure free fatty acid (FFA) and acylcarnitine levels during the glucose tolerance test as indicators of tissue-specific insulin resistance. Results: Insulin release in response to glucose administration decreased both FFA and long-chain acylcarnitine levels in plasma in healthy control animals by 30% (120 min). The glucose tolerance test and [3H]-deoxy-D-glucose uptake in tissues revealed…
Mitochondrial Function in the Kidney and Heart, but Not the Brain, is Mainly Altered in an Experimental Model of Endotoxaemia
2019
Significant impairments in mitochondrial function are associated with the development of multi-organ failure in sepsis/endotoxaemia, but the data on the dynamics of simultaneous mitochondrial impairment in multiple organs are limited. The aim of this study was to evaluate the changes in heart, brain and kidney mitochondrial function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia.Samples were collected 4 and 24 h after single injection of LPS (10 mg/kg) in mice. Marked increases in inflammation-related gene expression were observed in all studied tissues 4 h after LPS administration. At 24 h post LPS administration, this expression of inflammation-related genes rem…
Iodine Deficiency in Latvia: Current Status and Need for National Recommendations
2017
Abstract In the absence of a mandatory salt iodisation programme, two nationwide cross-sectional cluster surveys revealed persisting iodine deficiency among Latvian schoolchildren during the spring season and a noteworthy iodine deficiency in pregnant women in Latvia; these deficiencies warrant intervention. The consequences of mild-to-moderate iodine deficiency during pregnancy and lactation can adversely affect foetal brain development. Data from a Latvian population survey revealed the consumption of approximately 100 μg of iodine per day through foods and iodised salt. Therefore, strategies to increase the consumption of iodine-containing products should be implemented, particularly for…
Flow cytometric analysis of glyoxalase-1 expression in human leukocytes.
2011
Altered glyoxalase-1 (GLO-1) activity and expression is associated with the development of late diabetic complications, malignancy and oxidative stress- and aging-related diseases. In the present study, we developed a flow cytometry method for GLO-1 detection in human leukocytes isolated from peripheral blood samples to investigate GLO-1 expression in leukocyte subsets from type 1 and 2 diabetes mellitus patients (n = 11) and healthy subjects (n = 8). The flow cytometry analysis of GLO-1 in leukocytes showed that expression index of GLO-1-positive cells was slightly increased in mononuclear leukocytes from diabetic patients. This result correlated with the increase in GLO-1 activity in the …
Administration of L-carnitine and mildronate improves endothelial function and decreases mortality in hypertensive Dahl rats.
2010
Hypertension is a well established risk factor for the development of cardiovascular diseases and increased mortality. This study was performed to investigate the effects of the administration of L-carnitine or mildronate, an inhibitor of L-carnitine biosynthesis, or their combination on the development of hypertension-related complications in Dahl salt-sensitive (DS) rats fed with a high salt diet. Male DS rats were fed laboratory chow containing 8% NaCl from 7 weeks of age. Experimental animals were divided into five groups and treated for 8 weeks with vehicle (water; n = 10), L-carnitine (100 mg/kg, n = 10), mildronate (100 mg/kg, n = 10) or a combination of L-carnitine and mildronate at…
Mildronate, a Regulator of Energy Metabolism, Reduces Atherosclerosis in apoE/LDLR<sup>–/–</sup> Mice
2009
<i>Background/Aims:</i> Mildronate, an inhibitor of <i>L</i>-carnitine biosynthesis and transport, is used in clinics as a modulator of cellular energy metabolism and is a cardioprotective drug. <i>L</i>-Carnitine is a pivotal molecule in fatty acid oxidation pathways and its regulation in vasculature might be a promising approach for antiatherosclerotic treatment. This study was performed to evaluate the effects of mildronate treatment on the progression of atherosclerosis and the content of <i>L</i>-carnitine in the vascular wall. <i>Methods:</i> ApoE/LDLR<sup>–/–</sup> mice received mildronate at doses of 30 and 100 …
The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model
2006
Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides. beta-MSH, gamma1-MSH, gamma2-MSH…
Comparative pharmacological activity of optical isomers of phenibut
2007
Phenibut (3-phenyl-4-aminobutyric acid) is a GABA (gamma-aminobutyric acid)-mimetic psychotropic drug which is clinically used in its racemic form. The aim of the present study was to compare the effects of racemic phenibut and its optical isomers in pharmacological tests and GABAB receptor binding studies. In pharmacological tests of locomotor activity, antidepressant and pain effects, S-phenibut was inactive in doses up to 500 mg/kg. In contrast, R-phenibut turned out to be two times more potent than racemic phenibut in most of the tests. In the forced swimming test, at a dose of 100 mg/kg only R-phenibut significantly decreased immobility time. Both R-phenibut and racemic phenibut showed…
Mildronate, the inhibitor of l-carnitine transport, induces brain mitochondrial uncoupling and protects against anoxia-reoxygenation
2013
Abstract The preservation of mitochondrial function is essential for normal brain function after ischaemia-reperfusion injury. l -carnitine is a cofactor involved in the regulation of cellular energy metabolism. Recently, it has been shown that mildronate, an inhibitor of l -carnitine transport, improves neurological outcome after ischaemic damage of brain tissues. The aim of the present study was to elucidate the mitochondria targeted neuroprotective action of mildronate in the model of anoxia-reoxygenation-induced injury. Wistar rats were treated daily with mildronate ( per os ; 100 mg/kg) for 14 days. The acyl-carnitine profile was determined in the brain tissues. Mitochondrial respirati…
Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels
2016
Recent studies have revealed strong associations between systemic trimethylamine N-oxide (TMAO) levels, atherosclerosis and cardiovascular risk. In addition, plasma L-carnitine levels in patients with high TMAO concentrations predicted an increased risk for cardiovascular disease and incident major adverse cardiac events. The aim of the present study was to investigate the relation between TMAO and L-carnitine plasma levels and diabetes. Blood plasma samples were collected from 12 and 20 weeks old db/db mice and patients undergoing percutaneous coronary intervention. Diabetic compared to non-diabetic db/L mice presented 10-fold higher TMAO, but lower L-carnitine plasma concentrations at 12 …
Effect of inhibiting carnitine biosynthesis on male rat sexual performance.
2008
l-carnitine has a documented role as a cofactor in cellular energy metabolism and fatty acid beta-oxidation pathways and it has also been considered to function in reproductive biology. We investigated whether decreasing concentrations of L-carnitine using an inhibitor of its biosynthesis, mildronate (3-(2,2,2-trimethylhydrazinium)-propionate), would influence the sexual behavior or sperm quality in male rats. Mildronate treatment induced a significant decrease in carnitine concentration and an increase in gamma-butyrobetaine (GBB) concentration in both plasma and testes extracts. However, the expression of carnitine palmitoyltransferase I in testes and testosterone concentration in plasma …
A cross-sectional survey of urinary iodine status in Latvia
2014
Background and objective: A nationwide survey of schoolchildren was conducted to detect regional differences in urinary iodine excretion in Latvia and to compare the results with data from the newborn thyroid-stimulating hormone (TSH) screening database as well with the results of a similar study performed in Latvia 10 years ago. Materials and methods: We conducted a cross-sectional school-based cluster survey of 915 children aged 9–12 years in 46 randomly selected schools in all regions of Latvia. Urine samples, questionnaires on the consumption of iodized salt and information on socioeconomic status were collected. TSH levels in newborns were also measured. Results: The median creatinine-…
Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats
2010
Abstract Mildronate is a cardioprotective drug, the mechanism of action of which is based on the regulation of l -carnitine concentration. We studied the metabolic effects of treatment with mildronate, metformin and a combination of the two in the Zucker rat model of obesity and impaired glucose tolerance. Zucker rats were p.o. treated daily with mildronate (200 mg/kg), metformin (300 mg/kg), and a combination of both drugs for 4 weeks. Weight gain and plasma metabolites reflecting glucose metabolism were measured. The expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ and target genes was measured in rat heart and liver tissues. Each treatment decreased the blood …
Structure and Function of CutC Choline Lyase from Human Microbiota Bacterium Klebsiella pneumoniae.
2015
CutC choline trimethylamine-lyase is an anaerobic bacterial glycyl radical enzyme (GRE) that cleaves choline to produce trimethylamine (TMA) and acetaldehyde. In humans, TMA is produced exclusively by the intestinal microbiota, and its metabolite, trimethylamine oxide, has been associated with a higher risk of cardiovascular diseases. Therefore, information about the three-dimensional structures of TMA-producing enzymes is important for microbiota-targeted drug discovery. We have cloned, expressed, and purified the CutC GRE and the activating enzyme CutD from Klebsiella pneumoniae, a representative of the human microbiota. We have determined the first crystal structures of both the choline-…
Beta-MSH inhibits brain inflammation via MC(3)/(4) receptors and impaired NF-kappaB signaling.
2005
The anti-inflammatory effects of melanocortin peptides have been demonstrated in different inflammation models. This is the first report describing the molecular mechanisms for the beta-MSH-induced suppression of bacterial lipopolisaccharide (LPS)-caused brain inflammation. We found that beta-MSH suppresses LPS-induced nuclear translocation of the transcription factor NF-kappaB, and inhibits the expression of inducible nitric oxide synthase, and the following nitric oxide overproduction in the brain, in vivo. Moreover, administering the preferentially MC(4) receptor selective antagonist HS014 blocked completely these effects, suggesting a tentative MC(4) receptor mediated mechanism of actio…
Low-intensity exercise stimulates bioenergetics and increases fat oxidation in mitochondria of blood mononuclear cells from sedentary adults.
2020
Aim Exercise training induces adaptations in muscle and other tissue mitochondrial metabolism, dynamics, and oxidative phosphorylation capacity. Mitochondrial fatty acid oxidation was shown to be pivotal for the anti‐inflammatory status of immune cells. We hypothesize that exercise training can exert effects influence mitochondrial fatty acid metabolism in peripheral blood mononuclear cells (PBMCs). The aim was to investigate the effect of exercise on the fatty acid oxidation‐dependent respiration in PBMCs. Design Twelve fasted or fed volunteers first performed incremental‐load exercise tests to exhaustion on a cycle ergometer to determine the optimal workload ensuring maximal health benefi…
Seasonal Iodine Deficiency in Latvian School Children
2012
Rats with congenital hydronephrosis show increased susceptibility to renal ischemia‐reperfusion injury
2020
Abstract Many drug candidates have shown significant renoprotective effects in preclinical models; however, there is no clinically used effective pharmacotherapy for acute kidney injury. The failure to translate from bench to bedside could be due to misleading results from experimental animals with undetected congenital kidney defects. This study was performed to assess the effects of congenital hydronephrosis on the functional capacity of tubular renal transporters as well as kidney sensitivity to ischemia‐reperfusion (I‐R)‐induced injury in male Wistar rats. Ultrasonography was used to distinguish healthy control rats from rats with hydronephrosis. L‐carnitine or furosemide was administer…
Determination of trimethylamine-N-oxide in combination withl-carnitine andγ-butyrobetaine in human plasma by UPLC/MS/MS
2015
An ultra-high-performance liquid chromatography-mass spectrometry (UPLC/MS/MS) method was developed and validated for the quantification of trimethylamine-N-oxide (TMAO) simultaneously with TMAO-related molecules L-carnitine and γ-butyrobetaine (GBB) in human blood plasma. The separation of analytes was achieved using a Hydrophilic interaction liquid chromatography (HILIC)-type column with ammonium acetate-acetonitrile as the mobile phase. TMAO determination was validated according to valid US Food and Drug Administration guidelines. The developed method was successfully applied to plasma samples from healthy volunteers.
Beta- and gamma-melanocortins inhibit lipopolysaccharide induced nitric oxide production in mice brain.
2003
The pro-opiomelanocortin-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH) mediates many diverse physiological actions, including anti-inflammatory and immunomodulatory effects. However, little is known about the physiological roles of the other melanocortins, beta- and gamma-MSH. Here, we investigated the effects of melanocortin peptides in an in vivo neuroinflammation model. Six hours following intracisternal (i.c.) administration of 10 microg lipopolysaccharide (LPS) to mice a five-fold increase in the nitric oxide (NO) level was seen in the animals' brains, when detected by electron paramagnetic resonance (EPR). All tested melanocortins, alpha-, beta-, gamma1- and gamma2-…
Crystal structure of human gamma-butyrobetaine hydroxylase.
2010
Gamma-butyrobetaine hydroxylase (GBBH) is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthesis of l-carnitine by hydroxylation of gamma-butyrobetaine (GBB). l-carnitine is required for the transport of long-chain fatty acids into mitochondria for generating metabolic energy. The only known synthetic inhibitor of GBBH is mildronate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), which is a non-hydroxylatable analog of GBB. To aid in the discovery of novel GBBH inhibitors by rational drug design, we have solved the three-dimensional structure of recombinant human GBBH at 2.0A resolution. The GBBH monomer consists of a catalytic double-stranded beta-helix (DBSH) domai…
The sensorimotor and cognitive deficits in rats following 90- and 120-min transient occlusion of the middle cerebral artery
2012
Middle cerebral artery occlusion (MCAO) is the most commonly used method to study the neurological and histological outcomes and the pathological mechanisms of ischaemic stroke. The current work compares sensorimotor and cognitive deficits and the infarct volume in rats following a transient 90- or 120-min MCAO, which allows the appropriate behavioural tests to be chosen based on the goal and design of the experiment. In the beam-walking test, we found significant differences between the 90- and 120-min MCAO groups in the number of foot faults made with the impaired hindlimb on post-stroke days 3, 7 and 14. In the cylinder test, a difference between the 90- and 120-min groups was observed o…
Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats
2011
Mildronate (3-(2,2,2-trimethylhydrazinium) propionate) is an inhibitor of l-carnitine biosynthesis and an anti-ischemic drug. In the present study, we investigated the effects of mildronate in rats following focal cerebral ischemia. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) for 90min, followed by the intraperitoneal administration of mildronate at doses of 100 and 200mg/kg 2h after reperfusion and then daily for an additional 14days. The beam-walking, rota-rod and cylinder tests were used to assess sensorimotor function, and vibrissae-evoked forelimb-placing and limb-placing tests examined responses to tactile and proprioceptive stimulation.…
Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation.
2014
Abstract Aims Trimethylamine-N-oxide (TMAO) is produced in host liver from trimethylamine (TMA). TMAO and TMA share common dietary quaternary amine precursors, carnitine and choline, which are metabolized by the intestinal microbiota. TMAO recently has been linked to the pathogenesis of atherosclerosis and severity of cardiovascular diseases. We examined the effects of anti-atherosclerotic compound meldonium, an aza-analogue of carnitine bioprecursor gamma-butyrobetaine (GBB), on the availability of TMA and TMAO. Main methods Wistar rats received L-carnitine, GBB or choline alone or in combination with meldonium. Plasma, urine and rat small intestine perfusate samples were assayed for L-car…