Trimethylamine-oxide (TMAO) is present in seafood which is considered to be beneficial for health. Deep-water animals accumulate TMAO to protect proteins, such as lactate dehydrogenase (LDH), against hydrostatic pressure stress (HPS). We hypothesized that TMAO exerts beneficial effects on the circulatory system and protects cardiac LDH exposed to HPS produced by the contracting heart. Male, Sprague-Dawley and Spontaneously-Hypertensive-Heart-Failure (SHHF) rats were treated orally with either water (control) or TMAO. In vitro, LDH with or without TMAO was exposed to HPS and was evaluated using fluorescence correlation spectroscopy. TMAO-treated rats showed higher diuresis and natriuresis, lower arterial pressure and plasma NT-proBNP. Survival in SHHF-control was 66% vs 100% in SHHF-TMAO. In vitro, exposure of LDH to HPS with or without TMAO did not affect protein structure. In conclusion, TMAO reduced mortality in SHHF, which was associated with diuretic, natriuretic and hypotensive effects. HPS and TMAO did not affect LDH protein structure.

Acute pancreatitis (AP) is a disease defined as acute or chronic inflammatory process of the pancreas characterized by premature activation of digestive enzymes within the pancreatic acinar cells and causing pancreatic auto-digestion. In mammalian tissues, H2S is synthesized endogenously from L-cysteine in regulated enzymatic pathways catalyzed by pyridoxal phosphate-dependent enzymes: cystathionine beta - synthase (CBS), gamma - cystathionase (CTH) and cysteine aminotransferase (CAT) coupled with 3-mercaptopyruvate sulfurtransferase (MPST). In the mitochondria, hydrogen sulfide is oxidized to sulfite, which is then converted to thiosulfate (sulfane sulfur-containing compound) by thiosulfate sulfurtransferase (rhodanese; TST). The activity and the expression of CBS, CTH, MPST, and TST have been determined in vivo in pancreas of control rats, rats with acute pancreatitis and sham group. Levels of low-molecular sulfur compounds such as reduced and oxidized glutathione, cysteine, cystine and cystathionine were also determined. The study showed the significant role of MPST in H2S metabolism in pancreas. Stress caused by the surgery (sham group) and AP cause a decrease in H2S production associated with a decrease of MPST activity and expression. Markedly higher level of cysteine in the AP pancreas may be caused by a reduced rate of cysteine consumption in reaction catalyzed by MPST but it can also be a sign of the processes of proteolysis occurring in the changed tissue.

Background Trimethylamine oxide (TMAO) is a biomarker in cardiovascular and renal diseases. TMAO originates from the oxidation of trimethylamine (TMA), a product of gut microbiota and manufacturing industries-derived pollutant, by flavin monooxygenases (FMOs). The effect of chronic exposure to TMA on cardiovascular and renal systems is undetermined. Methods Metabolic, hemodynamic, echocardiographic, biochemical and histopathological evaluations were performed in 12-week-old male SPRD rats receiving water (controls) or TMA (200 or 500 µM/day) in water for 18 weeks. TMA and TMAO levels, the expression of FMOs and renin-angiotensin system (RAS) genes were evaluated in various tissues. Results In comparison to controls, rats receiving high dose of TMA had significantly increased arterial systolic blood pressure (126.3 ± 11.4 vs 151.2 ± 19.9 mmHg; P = 0.01), urine protein to creatinine ratio (1.6 (1.5; 2.8) vs 3.4 (3.3; 4.2); P = 0.01), urine KIM-1 levels (2338.3 ± 732.0 vs. 3519.0 ± 953.0 pg/mL; P = 0.01), and hypertrophy of the tunica media of arteries and arterioles (36.61 ± 0.15 vs 45.05 ± 2.90 µm, P = 0.001 and 18.44 ± 0.62 vs 23.79 ± 2.60 µm, P = 0.006; respectively). Mild degeneration of renal bodies with glomerulosclerosis was also observed. There was no significant difference between the three groups in body weight, water-electrolyte balance, echocardiographic parameters and RAS expression. TMA groups had marginally increased 24 h TMA urine excretion, whereas serum levels and 24 h TMAO urine excretion were increased up to 24-fold, and significantly increased TMAO levels in the liver, kidneys and heart. TMA groups had lower FMOs expression in the kidneys. Conclusions Chronic exposure to TMA increases blood pressure and increases markers of kidney damage, including proteinuria and KIM-1. TMA is rapidly oxidized to TMAO in rats, which may limit the toxic effects of TMA on other organs.

Background. There is an ongoing debate whether trimethylamine-oxide (TMAO), a molecule present in seafood and a derivate of microbiota metabolism, is beneficial or harmful for the circulatory system. Interestingly, deep-water animals accumulate TMAO that protects proteins such as lactate dehydrogenase (LDH) against high hydrostatic pressure. We hypothesized that TMAO may benefit the circulatory system by protecting cardiac LDH exposed to hydrostatic stress (HS) produced by contracting heart.Methods and Results. Male, 6-week-old, Sprague-Dawley (SD, n=40) and Spontaneously-Hypertensive-Heart-Failure (SHHF n=18) rats were divided into either Water or TMAO oral treatment. After 56 weeks, half of Water and TMAO SD rats were given isoprenaline (ISO) to produce catecholamine stress. In vitro, LDH with or without TMAO was exposed to HS (changes in pressure 0-250mmHg x 280min -1 ) and was evaluated using fluorescence correlation spectroscopy. After 58 weeks of the treatment survival was 100% in SD-Water, SD-TMAO, ISO-TMAO and 90% in ISO-Water. In SHHF-Water survival was 66% vs 100% in SHHF-TMAO. In general, TMAO-treated rats showed higher diuresis and natriuresis. In comparison to SHHF-Water, SHHF-TMAO showed significantly lower diastolic arterial blood pressure, plasma NT-proBNP and expression of angiotensinogen and AT1 receptors in the heart. In separate experiments, intravenous TMAO but not vehicle or urea significantly increased diuresis in SD. In vitro, exposure of LDH to HS with or without TMAO did not affect the protein structure.Conclusions. TMAO reduces mortality in SHHF rats that is associated with diuretic, natriuretic and hypotensive effects. HS produced by the contracting heart is neutral for cardiac LDH structure. Study protocolSix-week-old SHHF (n=18) and SD (n=40) were randomly assigned to either Water group (rats drinking tap water) or TMAO group (rats drinking TMAO solution in tap water, TMAO -abcr GmbH -Karlsruhe, Germany, 333 mg/l). The dose of TMAO have been selected in order to increase plasma TMAO concentration by 3-5 times (to mimic possible physiological concentrations) and to avoid suprapharmacological effects of TMAO, based on our previous study [7]. Rats were housed in groups of 2-3 animals, in polypropylene cages with environmental enrichment, 12hrs light/12hrs dark cycle, temperature 22-23 o C, humidity 45-55%, fed standard laboratory diet (0.19 % Na, Labofeed B standard, Kcynia, Poland) and water ad libitum. SHHF-TMAO (n=9), SHFF-Water (n=9), SD-TMAO (n=10), SD-Water (n=10) were not subjected to any interventions except of standard animal care until the age of 58 weeks. At the age of 56 weeks ISO-Water (n=10) and ISO-TMAO (n=10) series were given (s.c.) isoprenaline at a dose of 100 mg/kg b.w. (isoprenaline hydrochloride, Sigma-Aldrich, SaintLouis, MO, USA) to produce catecholamine stress as previously described by others [19]. The experimental protocol is depicted in Fig. 1. Experimental protocol in SD and SHHF58-week-old rats were maintained in metabolism cages for 2 days to evaluate 24hr...

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