Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System

The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.

Anti-Inflammatory Mesenchymal Stromal Cell-Derived Extracellular Vesicles Improve Pathology in Niemann–Pick Type C Disease

Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1−/− mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features.

575 Heart failure as the cancer for the heart: the prognostic role of the new TNM-like classification

Aims Heart failure (HF) is the pandemic of the third millennium accounting for the highest mortality rate among general population, second only to lung cancer. Beside heart, HF can affect lungs and peripheral organs, such as kidney, liver, brain, erythropoiesis, leading to multiorgan dysfunction. This is similar to spread of cancer. We proposed a new staging system of HF, named HLM, analogous to TNM classification used in oncology, which refers to heart damage (H), instead of T for tumour, lung involvement (L), instead of N for lymphnodes, and malfunction (M) of peripheral organs, instead of M for metastasis. The aim of this study was a comparison of HLM score with NYHA classes, ACC/AHA stages and HF classification by left ventricular ejection fraction (LVEF), to assess the most accurate prognosis tool for HF patients, in terms of a composite endpoint of all-cause death and hospitalization. Methods and results We performed a multicentre observational, prospective study of consecutive patients admitted for HF, or at risk for HF. All parameters for heart, lungs, and peripheral organ function were collected and examined. Each patient was classified according to HLM, NYHA, ACC/AHA scores and LVEF, at hospital admission and at discharge. The composite endpoint was all-cause death and rehospitalization; the secondary endpoints were all-cause death, cardiac death, and rehospitalization. Patients were followed up at 12 months. We enrolled 2152 patients. Among those, 1720 patients completed the 12-months follow-up. Comparing HLM with other nosologies, the area under the ROC curve (AUC) was greater for HLM score than NYHA, ACC/AHA and LVEF scores regarding the composite endpoint (HLM = 0.644; NYHA = 0.580; ACC/AHA = 0.572; EF = 0.572) and all-cause death (HLM = 0.713; NYHA = 0.596; ACC/AHA = 0.594; EF = 0.565). HLM score related AUC showed statistically significant differences compared to LVEF (P < 0.001), ACC-AHA (P < 0.001), and NYHA (P < 0.001) scores’ AUC, in terms of all-cause death and the composite of all-cause death and rehospitalization, at 12 months follow-up. Moreover, the AIC and BIC values to predict the composite of all-cause death and rehospitalization, all-cause death, cardiac death and rehospitalization rate at 12 months follow-up were always lower for HLM model compared with the others. Conclusions According to our results, HLM score has greater prognostic power compared to other nosologies, in terms of composite outcome, rehospitalization, and all-cause death, as well as all-cause death, cardiac death, and rehospitalization, at 12 months follow-up in HF patients. HLM score overcomes the cardiocentric view of HF and it addresses the pathophysiological mechanisms underlining heart abnormalities. Such a multivariable, holistic staging system may be used in HF patients, in order to improve clinical management and to reduce healthcare costs.

Complementary Role of Oxytocin and Vasopressin in Cardiovascular Regulation

The neurons secreting oxytocin (OXY) and vasopressin (AVP) are located mainly in the supraoptic, paraventricular, and suprachiasmatic nucleus of the brain. Oxytocinergic and vasopressinergic projections reach several regions of the brain and the spinal cord. Both peptides are released from axons, soma, and dendrites and modulate the excitability of other neuroregulatory pathways. The synthesis and action of OXY and AVP in the peripheral organs (eye, heart, gastrointestinal system) is being investigated. The secretion of OXY and AVP is influenced by changes in body fluid osmolality, blood volume, blood pressure, hypoxia, and stress. Vasopressin interacts with three subtypes of receptors: V1aR, V1bR, and V2R whereas oxytocin activates its own OXTR and V1aR receptors. AVP and OXY receptors are present in several regions of the brain (cortex, hypothalamus, pons, medulla, and cerebellum) and in the peripheral organs (heart, lungs, carotid bodies, kidneys, adrenal glands, pancreas, gastrointestinal tract, ovaries, uterus, thymus). Hypertension, myocardial infarction, and coexisting factors, such as pain and stress, have a significant impact on the secretion of oxytocin and vasopressin and on the expression of their receptors. The inappropriate regulation of oxytocin and vasopressin secretion during ischemia, hypoxia/hypercapnia, inflammation, pain, and stress may play a significant role in the pathogenesis of cardiovascular diseases.

Transorgan Short-Chain Fatty Acid Fluxes in the Fasted and Postprandial State in the Pig

The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, isovalerate, and valerate are end products of intestinal bacterial fermentation and important mediators in the interplay between the intestine and peripheral organs. To unravel the transorgan fluxes and mass balance comparisons of SCFAs, we measured their net fluxes across several organs in a translational pig model. In multi-catheterized conscious pigs (n=12, 25.6 (95% CI [24.2, 26.9]) kg, 8-12 weeks old), SCFA fluxes across portal drained viscera (PDV), liver, kidneys, and hindquarter (muscle compartment) were measured after an overnight fast and in the postprandial state, 4 h after administration of a fiber-free, mixed meal. PDV was the main releasing compartment of acetate, propionate, butyrate, isovalerate, and valerate during fasting and in the postprandial state (all P=0.001). Splanchnic acetate release was high due to the absence of hepatic clearance. All other SCFAs were extensively taken up by the liver (all P<0.05). Even though only 7% [4, 10] (propionate), 42% [23, 60] (butyrate), 26% [12, 39] (isovalerate), and 3% [0.4, 5] (valerate) of PDV release were excreted from the splanchnic area in the fasted state, splanchnic release of all SCFAs was significant (all P≤0.01). Splanchnic propionate, butyrate, isovalerate and valerate release remained low but significant in the postprandial state (all P<0.01). We identified muscle and kidneys as main peripheral SCFA metabolizing organs, taking up the majority of all splanchnically released SCFAs in the fasted state and in the postprandial state. We conclude that the PDV is the main SCFA releasing and the liver the main SCFA metabolizing organ. Splanchnically released SCFAs appear to be important energy substrates to peripheral organs not only in the fasted but also in the postprandial state.

New Peptides as Potential Players in the Crosstalk Between the Brain and Obesity, Metabolic and Cardiovascular Diseases

According to the World Health Organization report published in 2016, 650 million people worldwide suffer from obesity, almost three times more than in 1975. Obesity is defined as excessive fat accumulation which may impair health with non-communicable diseases such as diabetes, cardiovascular diseases (hypertension, coronary artery disease, stroke), and some cancers. Despite medical advances, cardiovascular complications are still the leading causes of death arising from obesity. Excessive fat accumulation is caused by the imbalance between energy intake and expenditure. The pathogenesis of this process is complex and not fully understood, but current research is focused on the role of the complex crosstalk between the central nervous system (CNS), neuroendocrine and immune system including the autonomic nervous system, adipose tissue, digestive and cardiovascular systems. Additionally, special attention has been paid to newly discovered substances: neuropeptide 26RFa, preptin, and adropin. It was shown that the above peptides are synthesized both in numerous structures of the CNS and in many peripheral organs and tissues, such as the heart, adipose tissue, and the gastrointestinal tract. Recently, particular attention has been paid to the role of the presented peptides in the pathogenesis of obesity, metabolic and cardiovascular system diseases. This review summarizes the role of newly investigated peptides in the crosstalk between brain and peripheral organs in the pathogenesis of obesity, metabolic, and cardiovascular diseases.

The redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required for Listeria monocytogenes pathogenesis

The Gram-positive bacterium Listeria monocytogenes is the causative agent of the foodborne disease listeriosis, one of the deadliest bacterial infections known. In order to cause disease, L. monocytogenes must properly coordinate its metabolic and virulence programs in response to rapidly changing environments within the host. However, the mechanisms by which L. monocytogenes senses and adapts to the many stressors encountered as it transits through the gastrointestinal (GI) tract and disseminates to peripheral organs are not well understood. In this study, we investigated the role of the redox-responsive transcriptional regulator Rex in L. monocytogenes growth and pathogenesis. Rex is a conserved canonical transcriptional repressor that monitors the intracellular redox state of the cell by sensing the ratio of reduced and oxidized nicotinamide adenine dinucleotides (NADH and NAD+, respectively). Here, we demonstrated that L. monocytogenes Rex represses fermentative metabolism and is therefore required for optimal growth in the presence of oxygen. We also show that in vitro, Rex represses the production of virulence factors required for survival and invasion of the GI tract, as a strain lacking rex was more resistant to acidified bile and invaded host cells better than wt. Consistent with these results, Rex was dispensable for colonizing the GI tract and disseminating to peripheral organs in an oral listeriosis model of infection. However, Rex-dependent regulation was required for colonizing the spleen and liver, and L. monocytogenes lacking the Rex repressor were nearly sterilized from the gallbladder. Taken together, these results demonstrated that Rex functions as a repressor of fermentative metabolism and suggests a role for Rex-dependent regulation in L. monocytogenes pathogenesis. Importantly, the gallbladder is the bacterial reservoir during listeriosis, and our data suggest redox sensing and Rex-dependent regulation are necessary for bacterial survival and replication in this organ.

Histological and histochemical changes in the peripheral organs of the immune system of dogs in cases of isoniazid poisoning

Most publications on isoniazid poisoning in dogs are devoted to clinical diagnostics, treatment, and prevention of the disease. Histological and histochemical changes are not fully described, though they are important in assessing the toxic effects of isoniazid. Isoniazid is used to treat tuberculosis in humans. Dogs are hypersensitive to this drug. The article highlights the results of macroscopic, histological, and histochemical studies of the dogs’ lymph nodes and spleen in cases of isoniazid poisoning. A pathological examination of 19 corpses of dogs of different ages was performed, during which isoniazid poisoning was posthumously diagnosed, based on anamnesis, clinical signs, pathological autopsy, histological, and histochemical examination. Samples of lymph nodes and spleen were fixed in a 10% aqueous neutral formalin solution, Carnoy’s solution, and Bouin’s fixative. Histoсuts were prepared using a sled microtome and stained with hematoxylin and eosin. Staining was also performed according to the techniques suggested by McManus, Brachet, and Perls. The pathomorphological changes in lymph nodes and spleen were characterized by disorganization of vascular walls and connective tissue fibers of the stroma, dilatation of veins, their overflow with hemolyzed blood, and, in cases of the long clinical course, thrombosis of small vessels. Intravascular hemolysis of erythrocytes resulted in an excessive formation of hemosiderin. Histochemically, the spleen and lymph nodes showed a significant increase in the number of hemosiderophages in the spleen’s red and white pulp and the lymph nodes’ central sinuses and pulp cords. In the spleen, mucoid swelling and necrobiotic changes in the wall structures of the arterioles and arteries progressed with a narrowing of their lumen in dogs suffering from the long clinical course. Increased permeability of the microcirculatory tract vessels of the spleen and lymph nodes, transudate formation, and the destructive changes in the reticular skeleton accompanied hemodynamic violations. A sharp change in blood rheology caused the violation of trophism and metabolism in the immune system. Lymphoid elements of the lymph nodes and white pulp of the spleen were in a state of karyorrhexis and karyolysis. The morphological study of the immune system’s peripheral organs suggests that dogs poisoned by isoniazid demonstrate hemodynamic disorders, changes in the physicochemical properties of blood (hemolysis of erythrocytes and thrombosis). This is the basis of trophic disorders, metabolic malfunctions, and the development of dystrophic processes in all structural elements of the spleen and lymph nodes.