Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular ...disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF ...patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The regulator of G protein signaling (RGS) proteins are crucial for the termination of G protein signals elicited by G protein-coupled receptors (GPCRs). This superfamily of cell membrane receptors, ...by far the largest and most versatile in mammals, including humans, play pivotal roles in the regulation of cardiac function and homeostasis. Perturbations in both the activation and termination of their G protein-mediated signaling underlie numerous heart pathologies, including heart failure (HF) and atrial fibrillation (AFib). Therefore, RGS proteins play important roles in the pathophysiology of these two devasting cardiac diseases, and several of them could be targeted therapeutically. Although close to 40 human RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type. Numerous in vitro and in vivo studies in animal models, and also in diseased human heart tissue obtained from transplantations or tissue banks, have provided substantial evidence of the roles various cardiomyocyte RGS proteins play in cardiac normal homeostasis as well as pathophysiology. One RGS protein in particular, RGS4, has been reported in what are now decades-old studies to be selectively upregulated in human HF. It has also been implicated in protection against AFib via knockout mice studies. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of HF and AFib, with a specific focus on RGS4 for the aforementioned reasons but also because it can be targeted successfully with small organic molecule inhibitors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•We used tri-axial accelerometers to discriminate sheep behaviours at pasture.•Three time epochs were tested: 3, 5 and 10s.•The 5s time epoch had the highest precision to predict grazing ...behaviour.•Natural log transformed X-axis mean can identify grazing and non-grazing behaviour.
Identifying and classifying feeding behaviour in free-ranging ruminants will help improve efficiency of animal production. Another potential benefit would be in understanding the role behaviour has in determining heritability of methane measurement. The aim of this study was to determine the accuracy, sensitivity, specificity and precision with which tri-axial accelerometers can identify sheep behaviour at pasture. Two studies, the first over six days and the other over two days were conducted using South African Meat Merino×Merino ewes averaging 55 (±5)kg and 22 months of age, respectively. The animals were located in either a semi-improved pasture (0.3ha) or in a small (30m2) area with access to water to observe five mutually exclusive behaviours, grazing, lying, running, standing and walking. A tri-axial accelerometer was attached to a halter on the under-jaw of each animal. Three epochs (3s, 5s and 10s) with forty-four features calculated from acceleration signals were used to classify behaviours. The five most important features for each epoch were determined using random forest and the five behaviours were classified using a decision-tree algorithm to determine model accuracy, sensitivity, specificity and precision. The decision-tree algorithm correctly classified 90.5, 92.5 and 91.3% of the evaluation data set for grazing behaviour for the 3, 5 and 10s epochs, respectively. There was no difference in the accuracy between the evaluation and validation data sets for grazing behaviour at each epoch. The model predicted grazing and running behaviour highly accurately and with the highest precision, sensitivity and specificity for the validation data set for the 10s epoch. The 5s epoch for both the evaluation and validation data sets was selected as the most suitable epoch based on the Kappa values. We successfully identified from the distribution of component populations that the natural log-transformation of the mean of X-axis accelerations for each epoch could identify grazing and non-grazing states. Therefore, this methodology will be useful in identifying sheep activity for research applications such as before methane measurement using portable accumulation chambers or other applications addressing temporal grazing patterns.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Single-sheet nanoclusters of MoS
2
, NiMoS or CoMoS are widely used in hydrodesulfurization (HDS) catalysis in the petroleum industry. In HDS reactions under microwave irradiation, experiments ...indirectly pointed out that for pristine MoS
2
reaction rates are accelerated because hot spots are generated on the catalyst bed. In this work, we investigated NiMoS and CoMoS isolated single-sheet substituted catalysts before and after thiophene adsorption focusing on quantifying the effect of microwave irradiation. For that purpose, density functional theory (DFT) molecular charge densities of each system were decomposed according to the distributed multipole analysis (DMA) of Stone. Site dipole values of each system were directly associated with a larger or smaller interaction with the microwave field according to a proposed general approach. We showed that microwave enhancement of HDS reaction rates can occur more efficiently in the CoMoS and NiMoS promoted clusters compared to pristine MoS
2
in the following order: CoMoS > NiMoS > MoS
2
. The atomic origin of the catalyst hot spots induced by microwaves was clearly established in the promoted clusters.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral ...sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Glucagon-like peptide-1 (GLP-1) is a multifunctional incretin hormone with various physiological effects beyond its well-characterized effect of stimulating glucose-dependent insulin secretion in the ...pancreas. An emerging role for GLP-1 and its receptor, GLP-1R, in brain neuroprotection and in the suppression of inflammation, has been documented in recent years. GLP-1R is a G protein-coupled receptor (GPCR) that couples to Gs proteins that stimulate the production of the second messenger cyclic 3’,5’-adenosine monophosphate (cAMP). cAMP, acting through its two main effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), exerts several anti-inflammatory (and some pro-inflammatory) effects in cells, depending on the cell type. The present review discusses the cAMP-dependent molecular signaling pathways elicited by the GLP-1R in cardiomyocytes, cardiac fibroblasts, central neurons, and even in adrenal chromaffin cells, with a particular focus on those that lead to anti-inflammatory effects by the GLP-1R. Fully elucidating the role cAMP plays in GLP-1R’s anti-inflammatory properties can lead to new and more precise targets for drug development and/or provide the foundation for novel therapeutic combinations of the GLP-1R agonist medications currently on the market with other classes of drugs for additive anti-inflammatory effect.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of ...the propionate's actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by β-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1β and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-β synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional βAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background Sex chromosome abnormalities associated with disorders of sexual development (DSD) are rarely described in cats, mainly due to the lack of chromossome studies that precisely ...reveal the condition. Genetic approaches are therefore required in order to detect sex chromossomes abnormalities as variations in the number and structure of chromosomes, or the presence of a second cell line as mosaicim or chimerism. Case presentation A male Shorthair cryptorchid cat was presented with clinical signs of anorexia, tenesmus and hyperthermia. Ultrasonography revealed a fluid-filled structure, with approximately 1 cm in diameter, adjacent to the descending colon. Computed tomography evidenced a tubular structure, ventral to the descending colon and caudal to the bladder, which extended cranially, through two branches. Histopathological evaluation confirmed the presence of two atrophic uterine horns and one hypoplastic testicle with epididymis at the end of one of the uterine horns. The end of the other uterine horn was attached to a structure composed by a mass of adipocytes. Cytogenetic analysis revealed a mosaic 37,X/38,XY karyotype. The two cell lines were found in 15% and 85% of the lymphocytes, respectively. Genetic analysis confirmed the presence of SRY and ZFY genes in blood and hair bulbs, and revealed a marked reduction in SRY expression in the testicle. Additionally, this case presented exceptionally rare features, such as a Leydig’ cell tumour and a chronic endometritis in both uterine horns. Conclusions Complete imaging workup, cytogenetic analysis and SRY gene expression should be systematically realized, in order to properly classify disorders of sexual development (DSD) in cats.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Discrimination of biting and chewing behaviours from sheep while grazing.•Three time intervals were tested: 1, 3 and 5 s.•The 5 s window was the best to identify and classify Bite and Chewing ...behaviours.•Tri-axial accelerometer can discriminate Bite and Chewing behaviours in sheep.
The aim of the current studies was to evaluate the capability of a tri-axial accelerometer, attached to the under-side of a halter and positioned on the under-jaw of a sheep, to discriminate biting and chewing activities of sheep during grazing. Two studies were conducted, the first study evaluated the effect of two diverse pasture species on feeding behaviour using micro-sward boxes: forage oats (Avena sativa cv Eulabah) and perennial ryegrass (Lolium perenne cv Wimmera). Two, 4-year old Merino ewes grazed each species for approximately four, two minute sessions over two separate days, one week apart. In the second study, the effect of sward height was investigated using nine plots of ryegrass with three different sward heights (mean ± se 4.0 ± 0.15, 6.2 ± 0.17 and 10.3 ± 1.05 cm; P = 0.005) grazed by three 3-year old Merino ewes for 10 min each. Video recordings of behaviours from both studies were visually assessed and annotated into Bite, Chewing and Other. They were then manually synchronised in time with accelerometer output to create annotated data files which were partitioned into three time intervals (1 s, 3 s and 5 s). Forty-four features were calculated from the acceleration signals and used to classify behaviours using a decision tree to determine model accuracy, sensitivity, specificity and precision. For the micro-sward study, Bite activity was classified with a precision of 90.5% for the evaluation data set, whereas for the validation data set it was classified with a precision of 98.1% for the 5 s time interval. Accuracy of the decision-tree model increased as time interval increased for both data sets. For the sward height study, as time interval increased model sensitivity for Bite and Chewing activity improved from 91.2% to 95.5% and from 75.0% to 93.0%, respectively, while model specificity improved from 88.1% to 98.2% and from 92.1% to 95.9%, respectively in the evaluation data set. The same pattern occurred when the model was applied to the validation data set. The accuracy of the decision-tree algorithm to classify Bite, Chewing and Other activities increased as time interval length increased for both data sets. These two studies have shown that tri-axial accelerometers can successfully discriminate feeding behaviours in sheep when placed under the jaw.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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