Nicotinic acid attenuates amyloid ß1-42-induced mitochondrial dysfunction and inhibits the mitochondrial pathway of apoptosis in differentiated SH-SY5Y cells.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive memory loss and behavioral disorders. The excessive accumulation of amyloid ß (Aß) and the formation of neurofibrillary tangles (NFTs) damage synaptic connections and the death of neurons. However, the underlying mechanisms of pathogenesis of AD remain unclear. Growing evidence indicates that impaired mitochondrial function may play a crucial role in the development of AD. In the current study, we investigated whether nicotinic acid (NA) could protect against amyloid ß1-42-induced cytotoxicity in differentiated SH-SY5Y cells. Our results revealed the neuroprotective effects of NA on the differentiated SH-SY5Y cells treated with Aß1-42. In detail, the 1-h pre-incubation with NA increased cell viability and lowered LDH levels. NA pre-incubation abolished Aß1-42 treatment-associated alterations of mRNA levels of synaptic genes and enhanced the relative ß3 Tubulin fluorescence intensity. NA eliminated the Aß1-42-induced mitochondrial dysfunction by increasing the potential of mitochondrial membranes and maintaining a balance between the fusion and fission of mitochondria. Moreover, Aß1-42 decreased mRNA levels of anti-apoptotic bcl2 and increased mRNA levels of pro-apoptotic: bim, bak, cytochrome c, and caspase 9. At the same time, the NA pre-treatment reduced Aß1-42-dependent apoptotic death of differentiated SH-SY5Y cells. The above data suggest that NA presents a protective activity against Aß1-42-induced cytotoxicity in differentiated SH-SY5Y cells by inhibiting the mitochondrial pathway of apoptosis and restoring the proper function of mitochondria.

Epicardial fat and ventricular arrhythmias.

The arrhythmogenic role of epicardial adipose tissue (EAT) in atrial arrhythmias is well established, but its effect on ventricular arrhythmias has been significantly less investigated. Since ventricular arrhythmias are thought to cause 75%-80% of cases of sudden cardiac death, this is not a trivial issue. We provide an overview of clinical data as well as experimental and molecular data linking EAT to ventricular arrhythmias, attempting to dissect possible mechanisms and indicate future directions of research and possible clinical implications. However, despite a wealth of data indicating the role of epicardial and intramyocardial fat in the induction and propagation of ventricular arrhythmias, unfortunately there is currently no direct evidence that indeed EAT triggers arrhythmia or can be a target for antiarrhythmic strategies.

The role of glial autophagy in Alzheimer's disease.

Although Alzheimer's disease is the most pervasive neurodegenerative disorder, the mechanism underlying its development is still not precisely understood. Available data indicate that pathophysiology of this disease may involve impaired autophagy in glial cells. The dysfunction is manifested as reduced ability of astrocytes and microglia to clear abnormal protein aggregates. Consequently, excessive accumulation of amyloid beta plaques and neurofibrillary tangles activates microglia and astrocytes leading to decreased number of mature myelinated oligodendrocytes and death of neurons. These pathologic effects of autophagy dysfunction can be rescued by pharmacological activation of autophagy. Therefore, a deeper understanding of the molecular mechanisms involved in autophagy dysfunction in glial cells in Alzheimer's disease may lead to the development of new therapeutic strategies. However, such strategies need to take into consideration differences in regulation of autophagy in different types of neuroglia.

In the Pursuit of Metabolic Markers of Systemic Sclerosis-Plasma Adiponectin and Omentin-1 in Monitoring the Course of the Disease.

Systemic sclerosis (SSc) is a connective tissue disease leading to cutaneous and visceral fibrosis. Pathological features of SSc include immune dysregulation, vasculopathy, and impaired angiogenesis. Adipokines act as cytokines and hormones and are involved in various pathological processes, including metabolic disorders, inflammation, vasculopathy, and fibrosis. This study aimed to determine the level of omentin-1 and adiponectin to evaluate their potential role in the pathogenesis of SSc. We assessed serum omentin-1 and adiponectin as well as metabolic parameters in 58 patients with SSc and 30 healthy controls. The follow-up was performed in SSc individuals. Omentin-1 levels were significantly higher in SSc individuals as compared to the controls. In post-hoc analysis, omentin-1 was higher in the group with disease duration ≥7 years than in the control group. A positive correlation was noted between disease duration and both adipokines and increased with longer disease duration. However, there were no correlations between selected adipokines and metabolic parameters. Enhanced omentin-1 levels and higher levels of omentin-1 in patients with longer disease duration may suggest that omentin-1 is involved in the pathomechanisms of SSc as its concentrations are not directly related to BMI, age, and insulin resistance.

Obesity as a Risk Factor for Breast Cancer-The Role of miRNA.

Breast cancer (BC) is the most common cancer diagnosed among women in the world, with an ever-increasing incidence rate. Due to the dynamic increase in the occurrence of risk factors, including obesity and related metabolic disorders, the search for new regulatory mechanisms is necessary. This will help a complete understanding of the pathogenesis of breast cancer. The review presents the mechanisms of obesity as a factor that increases the risk of developing breast cancer and that even initiates the cancer process in the female population. The mechanisms presented in the paper relate to the inflammatory process resulting from current or progressive obesity leading to cell metabolism disorders and disturbed hormonal metabolism. All these processes are widely regulated by the action of microRNAs (miRNAs), which may constitute potential biomarkers influencing the pathogenesis of breast cancer and may be a promising target of anti-cancer therapies.

Contribution of Mitochondrial Dysfunction Combined with NLRP3 Inflammasome Activation in Selected Neurodegenerative Diseases.

Alzheimer's disease and Parkinson's disease are the most common forms of neurodegenerative illnesses. It has been widely accepted that neuroinflammation is the key pathogenic mechanism in neurodegeneration. Both mitochondrial dysfunction and enhanced NLRP3 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 3) inflammasome complex activity have a crucial role in inducing and sustaining neuroinflammation. In addition, mitochondrial-related inflammatory factors could drive the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). The present review includes a broadened approach to the role of mitochondrial dysfunction resulting in abnormal NLRP3 activation in selected neurodegenerative diseases. Moreover, we also discuss the potential mitochondria-focused treatments that could influence the NLRP3 complex.

The Beneficial Role of Natural Endocrine Disruptors: Phytoestrogens in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia with a growing incidence rate primarily among the elderly. It is a neurodegenerative, progressive disorder leading to significant cognitive loss. Despite numerous pieces of research, no cure for halting the disease has been discovered yet. Phytoestrogens are nonestradiol compounds classified as one of the endocrine-disrupting chemicals (EDCs), meaning that they can potentially disrupt hormonal balance and result in developmental and reproductive abnormalities. Importantly, phytoestrogens are structurally, chemically, and functionally akin to estrogens, which undoubtedly has the potential to be detrimental to the organism. What is intriguing, although classified as EDCs, phytoestrogens seem to have a beneficial influence on Alzheimer's disease symptoms and neuropathologies. They have been observed to act as antioxidants, improve visual-spatial memory, lower amyloid-beta production, and increase the growth, survival, and plasticity of brain cells. This review article is aimed at contributing to the collective understanding of the role of phytoestrogens in the prevention and treatment of Alzheimer's disease. Importantly, it underlines the fact that despite being EDCs, phytoestrogens and their use can be beneficial in the prevention of Alzheimer's disease.

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid ß (Aß) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1ß signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD.

Exogenous orexin-A downregulates luteinizing hormone secretory activity in prepubertal female rats.

INTRODUCTION: Orexin-A is a neuropeptide synthesized in the lateral hypothalamus. Orexin-A immunoreactive fibres overlap distribution with GnRH neurons. In adult rats, orexin A is known to affect LH secretion via GnRH release modulation. Because data concerning the impact of orexin-A on the hypothalamo-pituitary axis activity are limited, we focused on the involvement of orexin-A and receptors of NPY in the modulation of LH release and LH subunit b (Lhb) mRNA expression in prepubertal female rats. MATERIAL AND METHODS: Forty immature female Wistar rats were divided into 4 groups and received 2 intracerebroventricular (icv) microinjections of: 1 - artificial cerebrospinal fluid (CSF) (controls); 2 - CSF followed by orexin A; 3 - selective NPY receptor antagonist (BIBP) followed by CSF; 4 - BIBP followed by orexin A. One hour after the last microinjection, all rats were decapitated. Trunk blood was collected, and serum was stored at -20°C for the LH RIA examination. The adenohypophysis was immediately excised, flash-frozen, and kept at -80°C for RNA extraction. Real-time PCR amplification was carried out, and relative Lhb gene expression was calculated. RESULTS: In comparison to the CSF-treated controls with a mean LH serum concentration of 0.40 ± 0.02 ng/mL, the mean LH serum level was diminished both after orexin-A (0.27 ± 0.01 ng/mL) and after BIBP (0.30 ± 0.02 ng/mL) icv microinjections. In the presence of BIBP, orexin-A more effectively inhibited LH release (0.20 ± 0.01 ng/mL) when compared to the BIBP-treated group. Orexin-A and BIBP exerted a consistent inhibitory effect on Lhb mRNA expression levels in the anterior pituitary gland. In comparison to the CSF-treated controls, orexin-A, and BIBP-treated females responded with, respectively, 35% and 40% reduction of Lhb mRNA expression. Orexin-A and BIBP co-administration evoked a further reduction of Lhb gene transcriptional activity. CONCLUSIONS: Orexin-A exerts a down-regulatory effect on LH synthesis and release in immature female rats. Considering that Y1R-oriented down-regulation of endogenous NPY activity did not reverse the suppressive effect of exogenous orexin-A, it might be suggested that NPY and orexin A systems can operate independently to affect gonadotropin activity in the anterior pituitary of the immature female rats.

Role of chymase in blood pressure control, plasma and tissue angiotensin II, renal Haemodynamics, and excretion in spontaneously hypertensive rats.

Background: Chymase generates angiotensin II (ANG II) independently of angiotensin-converting enzyme in tissues and it contributes to vascular remodeling and development of hypertension, however the exact mechanism of its action is unclear. Methods: Hence, the effects of chymase inhibition were examined in anesthetized spontaneously hypertensive rats (SHR) in two stages of the disease development, ie. pre-hypertensive (SHR7) and with established hypertension (SHR16). Chymostatin, a commercial chymase inhibitor, was infused intravenously alone or in subsequent groups co-infused with captopril. Results: Mean blood pressure (MBP), total renal blood flow (RBF) and ANG II content (plasma and tissues) were measured. In SHR16 chymase blockade significantly decreased MBP (-6%) and plasma (-38%), kidney (-71%) and heart (-52%) ANG II levels. In SHR7 chymostatin did not influence MBP or RBF, but significantly decreased heart ANG II level. Conclusion: Jointly, functional studies and ANG II determinations support the evidence that in SHR chymase can raise plasma ANG II and contribute to blood pressure elevation. We propose that addition of chymase blockade to ACE inhibition could be a promising approach in the treatment of hypertensive patients resistant to therapy with ACE-inhibitors alone.

All-trans-retinoic acid ameliorates atherosclerosis, promotes perivascular adipose tissue browning, and increases adiponectin production in Apo-E mice.

All-trans-retinoic acid (atRA), an active metabolite of vitamin A, exerts a potential role in the prevention of cardiovascular diseases. It has been shown that atRA ameliorates atherosclerosis while the exact mechanism underlying this protection remains unknown. This study investigated the influence of atRA on insulin resistance (IR), atherosclerosis, and the process of perivascular adipose tissue (PVAT) browning. Moreover, syntheses of adiponectin, adipokine with anti-atherogenic effects, and tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, were determined in PVAT. Apolipoprotein E-deficient mice (Apo-E) and control C57BL/6J wild-type mice were treated with atRA (5 mg/kg/day) or vehicle (corn oil) by plastic feeding tubes for 8 weeks. Long-term atRA treatment in Apo-E mice did not affect insulin resistance. AtRa administration ameliorated atherosclerosis, induced PVAT browning, and increased adiponectin production in PVAT in Apo-E mice. Furthermore, atRA increased nitric oxide (NO) level but did not affect adiponectin concentration in the aorta of Apo-E mice. These results indicate that atRA ameliorates atherosclerosis in Apo-E mice. We also observed the browning of PVAT. Besides, atRA increased the synthesis of adiponectin in PVAT and augmented NO level in the aorta in ApoE mice.

The Effects of Alpha-Linolenic Acid on the Secretory Activity of Astrocytes and ß Amyloid-Associated Neurodegeneration in Differentiated SH-SY5Y Cells: Alpha-Linolenic Acid Protects the SH-SY5Y cells against ß Amyloid Toxicity.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Amyloid ß- (Aß-) induced mitochondrial dysfunction may be a primary process triggering all the cascades of events that lead to AD. Therefore, identification of natural factors and endogenous mechanisms that protect neurons against Aß toxicity is needed. In the current study, we investigated whether alpha-linolenic acid (ALA), as a natural product, would increase insulin and IGF-I (insulin-like growth factor I) release from astrocytes. Moreover, we explored the protective effect of astrocytes-derived insulin/IGF-I on Aß-induced neurotoxicity, with special attention paid to their impact on mitochondrial function of differentiated SH-SY5Y cells. The results showed that ALA induced insulin and IGF-I secretion from astrocytes. Our findings demonstrated that astrocyte-derived insulin/insulin-like growth factor I protects differentiated SH-SY5Y cells against Aß 1-42-induced cell death. Moreover, pretreatment with conditioned medium (CM) and ALA-preactivated CM (ALA-CM) protected the SH-SY5Y cells against Aß 1-42-induced mitochondrial dysfunction by reducing the depolarization of the mitochondrial membrane, increasing mitochondrial biogenesis, restoring the balance between fusion and fission processes, and regulation of mitophagy and autophagy processes. Our study suggested that astrocyte-derived insulin/insulin-like growth factor I suppresses Aß 1-42-induced cytotoxicity in the SH-SY5Y cells by protecting against mitochondrial dysfunction. Moreover, the neuroprotective effects of CM were intensified by preactivation with ALA.

Peripheral levels of selected adipokines in patients with newly diagnosed multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The exact aetiology is unknown. However, genetic and environmental factors are suggested to be involved in the pathogenesis of MS. Improper diet, resulting in obesity and metabolic syndrome, can contribute to this disease. Adipokines, secreted by adipose tissue, link the metabolism and immune system. MATERIAL AND METHODS: We aimed to assess plasma levels of selected adipokines in newly diagnosed, treatment-naïve individuals with multiple sclerosis. Our group comprised 58 individuals (31 MS patients and 27 controls, matched for age and BMI) without diabetes, hypertension, or dyslipidaemia. Circulating adiponectin and all adiponectin fractions, visfatin, and omentin concentrations were measured. Metabolic parameters were also assessed. RESULTS: In MS individuals we observed the following results: higher concentrations of visfatin, lower levels of omentin, and no differences in adiponectin array. There were also correlations between some adipokines and metabolic parameters. After adjustment to BMI, a significant decrease in total adiponectin, high-molecular weight (HMW) adiponectin and omentin, and an increase in medium-molecular-weight (MMW) adiponectin were observed in the group of MS patients when compared to those of the controls. CONCLUSIONS: Our results indicate that adiponectin with its fractions, visfatin, and omentin cannot be considered as causative factors in the early phase of multiple sclerosis. However, the potential role of adipokines in MS is possible because they might be involved in the pathogenesis of MS, regarded as an autoimmune disorder.

Geranylgeraniol Prevents Statin-Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy.

The present study investigated the cytotoxic effects of statins (atorvastatin (ATR) and simvastatin (SIM), resp.) and methyl-beta-cyclodextrin (MßCD), at their respective IC50 concentrations, on muscle regeneration in the in vitro model of murine C2C12 myoblasts. Cotreatment with mevalonate (MEV), farnesol (FOH), geranylgeraniol (GGOH), or water-soluble cholesterol (Chol-PEG) was employed to determine whether the statin-dependent myotoxicity resulted from the lower cholesterol levels or the attenuated synthesis of intermediates of mevalonate pathway. Our findings demonstrated that while GGOH fully reverted the statin-mediated cell viability in proliferating myoblasts, Chol-PEG exclusively rescued MßCD-induced toxicity in myocytes. Statins caused loss of prenylated RAP1, whereas the GGOH-dependent positive effect was accompanied by loss of nonprenylated RAP1. Geranylgeranyltransferases are essential for muscle cell survival as inhibition with GGTI-286 could not be reversed by GGOH cotreatment. The increase in cell viability correlated with elevated AKT 1(S463) and GSK-3ß(S9) phosphorylations. Slight increase in the levels of autophagy markers (Beclin 1, MAP LC-3IIb) was found in response to GGOH cotreatment. Autophagy rose time-dependently during myogenesis and was inhibited by statins and MßCD. Statins and MßCD also suppressed myogenesis and neither nonsterol isoprenoids nor Chol-PEG could reverse this effect. These results point to GGOH as the principal target of statin-dependent myotoxicity, whereas plasma membrane cholesterol deposit is ultimately essential to restore viability of MßCD-treated myocytes. Overall, this study unveils for the first time a link found between the GGOH- and Chol-PEG-dependent reversal of statin- or MßCD-mediated myotoxicity and cytoprotective autophagy, respectively.

Adipokine profile in patients with anorexia nervosa.

INTRODUCTION: Anorexia nervosa (AN) is an eating disorder characterised with extremely low weight. Adipokines are adipose tissue-derived substances that show a wide spectrum of biological activities. We aimed to assess selected adipokine levels in women with AN before and after nutritional intervention. We also sought to examine whether BMI is the only confounding factor influencing adipokine assessment in AN. MATERIAL AND METHODS: Sixty-five women participated in the study: 20 individuals with AN before any treatment, 18 AN patients after nutritional intervention lasting for at least six months, and 27 women as controls. In all participants blood collection and anthropometric measurements were performed. ELISA was used for evaluation of leptin receptor, adiponectin and its isoforms, and resistin. Leptin was assessed with RIA, and visfatin was measured with EIA assay. RESULTS: Leptin and free leptin index (FLI) were lowest in treatment-naïve AN women. HMW-adiponectin and visfatin were enhanced in AN. Other adipokine levels showed no significant differences. When two subsets of anorexia nervosa were compared, only leptin, leptin receptor, and FLI were markedly different. When data were adjusted to BMI, leptin and FLI remained significantly different in the pre-treated AN subgroup when compared with the control group. CONCLUSIONS: Our results suggest that leptin is the most important adipokine in AN. It is also important that in our AN population leptin and FLI are the only factors that are influenced not only by the fat content.

Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism.

Verapamil, an L-type calcium channel blocker, has been used successfully to treat cardiovascular diseases. Interestingly, we have recently shown that treatment of cancer cells with verapamil causes an effect on autophagy. As autophagy is known to modulate chemotherapy responses, this prompted us to explore the impact of verapamil on autophagy and cell viability in greater detail. We report here that verapamil causes an induction of autophagic flux in a number or tumor cells and immortalized normal cells. Moreover, we found that inhibition of autophagy in COLO 205 cells, via treatment with the chloroquine (CQ) or by CRISPR/Cas9-mediated disruption of the autophagy genes Atg7 and Atg5, causes an upregulation of apoptotic markers in response to verapamil. In search of a mechanism for this effect and because autophagy can often mitigate metabolic stress, we examined the impact of verapamil on cellular metabolism. This revealed that in normal prostate cells, verapamil diminishes glucose and glycolytic intermediate levels leading to adenosine 5'-triphosphate (ATP) depletion. In contrast, in COLO 205 cells it enhances aerobic glycolysis and maintains ATP. Importantly, we found that the autophagic response in these cells is related to the activity of l-lactate dehydrogenase A (LDHA, EC 1.1.1.27), as inhibition of LDHA reduces both basal and verapamil-induced autophagy and consequently decreases cell viability. In summary, these findings not only identify a novel mechanism of cytoprotective autophagy induction but they also highlight the potential of using verapamil together with inhibitors of autophagy for the treatment of malignant disease. ENZYMES: l-lactate dehydrogenase (LDHA, EC 1.1.1.27).

FOXO1 and GSK-3ß Are Main Targets of Insulin-Mediated Myogenesis in C2C12 Muscle Cells.

Myogenesis and muscle hypertrophy account for muscle growth and adaptation to work overload, respectively. In adults, insulin and insulin-like growth factor 1 stimulate muscle growth, although their links with cellular energy homeostasis are not fully explained. Insulin plays critical role in the control of mitochondrial activity in skeletal muscle cells, and mitochondria are essential for insulin action. The aim of this study was to elucidate molecular mechanism(s) involved in mitochondrial control of insulin-dependent myogenesis. The effects of several metabolic inhibitors (LY294002, PD98059, SB216763, LiCl, rotenone, oligomycin) on the differentiation of C2C12 myoblasts in culture were examined in the short-term (hours) and long-term (days) experiments. Muscle cell viability and mitogenicity were monitored and confronted with the activities of selected genes and proteins expression. These indices focus on the roles of insulin, glycogen synthase kinase 3 beta (GSK-3ß) and forkhead box protein O1 (FOXO1) on myogenesis using a combination of treatments and inhibitors. Long-term insulin (10 nM) treatment in "normoglycemic" conditions led to increased myogenin expression and accelerated myogenesis in C2C12 cells. Insulin-dependent myogenesis was accompanied by the rise of mtTFA, MtSSB, Mfn2, and mitochondrially encoded Cox-1 gene expressions and elevated levels of proteins which control functions of mitochondria (kinase--PKB/AKT, mitofusin 2 protein--Mfn-2). Insulin, via the phosphatidylinositol 3-kinase (PI3-K)/AKT-dependent pathway reduced transcription factor FOXO1 activity and altered GSK-3ß phosphorylation status. Once FOXO1 and GSK-3ß activities were inhibited the rise in Cox-1 gene action and nuclear encoded cytochrome c oxidase subunit IV (COX IV) expressions were observed, even though some mRNA and protein results varied. In contrast to SB216763, LiCl markedly elevated Mfn2 and COX IV protein expression levels when given together with insulin. Thus, inhibition of GSK-3ß activity by insulin alone or together with LiCl raised the expression of genes and some proteins central to the metabolic activity of mitochondria resulting in higher ATP synthesis and accelerated myogenesis. The results of this study indicate that there are at least two main targets in insulin-mediated myogenesis: notably FOXO1 and GSK-3ß both playing apparent negative role in muscle fiber formation.

Assessment of plasma brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophin protein (ADNP) and vasoactive intestinal peptide (VIP) concentrations in treatment-naïve humans with multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by coexisting processes of inflammation, demyelination, axonal neurodegeneration and gliosis. Autoimmune processes play a pivotal role in the disease. The immune system may be modulated by neurotrophins and neurotrophin factors. Aim of the study was to assess plasma levels of brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophin protein (ADNP) and vasoactive intestinal peptide (VIP) in treatment-naïve humans with newly diagnosed multiple sclerosis. We also elucidated the potential influence of selected inflammatory agents on peripheral concentration of BDNF and ADNP. MATERIAL AND METHODS: The study population comprised of 31 untreated patients with MS and 36 controls from a single hospital centre. Assessment of BDNF and ADNP was performed with use of ELISA methods. VIP was measured with RIA. Selected cytokine levels (IL 6, IL 10, and TNF α) were evaluated with ELISA tests. Statistical analyses were performed. RESULTS: We failed to find any significant differences between ADNP, BDNF, VIP, CRP levels and concentration of cytokines between individuals with MS and the controls. No correlation was observed between ADNP, BDNF and VIP as the first parameter and CRP, IL 6, IL 10, TNFα levels and the Expanded Disability Status Scale score in MS. CONCLUSIONS: Newly diagnosed, treatment-naïve patients with MS have comparable levels of plasma BDNF, ADNP and VIP to those of healthy controls.

Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat.

NEW FINDINGS: What is the central question of this study? We examined, in hypertensive rats, whether the angiotensin-converting enzyme-independent enzymes generating angiotensin II in the tissues modulate blood pressure, peripheral circulation and renal function. What is the main finding and its importance? The results suggest that chymostatin-sensitive enzymes diminish vascular tone in renal and extrarenal vascular beds. Chymase or similar chymostatin-sensitive enzymes have a significant role in the synthesis of angiotensin II in different tissues but do not control blood pressure in the short term, similarly in salt-dependent or Goldblatt-type rat hypertension. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing the angiotensin II content in the kidney. Chymase is presumed to be a crucial enzyme of the non-angiotensin-converting enzyme pathway of angiotensin II (Ang II) generation in tissues, a process involved in vascular remodelling and development of hypertension. We examined the role of chymase in hypertension induced by exposure of uninephrectomized rats to high dietary salt intake (UNX HS) and in the Goldblatt renal artery stenosis (two-kidney, one-clip) model. In acute experiments with anaesthetized rats of either model, chymostatin at 2 mg kg(-1) h(-1) or 0.05% DMSO solvent was infused i.v. Mean arterial blood pressure, heart rate, iliac blood flow (a measure of hindlimb perfusion), total renal blood flow and intrarenal regional perfusion (laser-Doppler technique) were measured continuously, along with the glomerular filtration rate and renal excretion. In both models, chymase blockade distinctly decreased plasma and tissue Ang II without lowering mean blood pressure or consistently altering the other functional parameters measured. Unexpectedly, in Goldblatt hypertensive rats the blockade increased the renal and hindlimb vascular resistances by 51 and 33%, respectively (P < 0.05). In UNX HS hypertensive rats, chymase blockade abolished the solvent-induced decrease in outer medullary blood flow. We conclude that chymase or similar chymostatin-sensitive enzyme(s) has a significant role in the synthesis of Ang II in different tissues but does not participate in short-term control of blood pressure in salt-dependent or Goldblatt-type rat hypertension. In the Goldblatt model, chymase appeared to reduce the renal and hindlimb vascular resistances by an unknown mechanism. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing Ang II content in the kidney.

Association of copeptin and cortisol in newly diagnosed multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Obesity may increase the risk of developing MS. The aim of this study was to evaluate copeptin and cortisol plasma levels in newly diagnosed untreated MS patients and to determine whether copeptin and cortisol are related to the patients' clinical statuses. We report that copeptin and cortisol were higher in overweight/obese MS patients. Positive correlations were observed between the two parameters. We conclude that alterations of copeptin and cortisol levels in multiple sclerosis patients may be related to adiposity. An increase in cortisol may also be associated with copeptin secretion.