Search Results (137)

Metabolic syndrome (MetS) increases the risk of cardiovascular disease development, with sex differences playing a significant role. AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, becomes dysregulated in MetS, making it a potential therapeutic target. Therefore, we aimed to investigate the role of AMPK in the development of cardiovascular comorbidities in male and female rats with MetS. MetS was induced in young Wistar–Kyoto (WKY) rats through a high-fat diet (HFD; 10 weeks), and the function of AMPK was studied using Compound C (Cmpd C; 1.5 mg/kg, twice per week, during the last 4 weeks). An HFD induced MetS in males, but, in females, it did not affect body weight, blood pressure, or glycemia until AMPK inhibition occurred. Endothelial dysfunction, oxidative stress, and inflammation developed in both HFD male groups, while, in females, these arose only with AMPK inhibition. In both sexes, α1-AMPK activation decreased with eNOS and Nrf2 protein levels after HFD + Cmpd C treatment. Estradiol levels significantly dropped in HFD and Cmpd C females, whereas testosterone levels remained unchanged. Our results suggest that MetS and related cardiovascular comorbidities in males are driven by oxidative stress, inflammation, and endothelial dysfunction, with minimal additive effect of AMPK. In females, MetS arose only when inhibition of AMPK impaired estrogen signalling, emphasising their protective roles. Targeting AMPK-estrogen pathways may provide a therapeutic strategy, particularly for high-risk cardiovascular females and menopausal women. Full article

Background/Objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, impulsivity, and hyperactivity. However, inattention remains unexplored. Methods: We assessed automatic attention in Lphn3 KO (n = 19) and their control line (wildtype/WT, n = 20) through use of the following auditory event-related potentials (ERPs): P1, N1, P2, and N2. We also extended this exploratory study by comparing these same ERPs in spontaneously hypertensive rats (SHRs, n = 16), the most commonly studied animal model of ADHD, to their control line (Wistar–Kyoto/WKY, n = 20). Electroencephalograms (EEG) were recorded using subdermal needle electrodes at frontocentral sites while freely moving rats were presented with five-tone trains (50 ms tones, 400 ms tone onset asynchronies) with varying short (1 s) and long (5 s) inter-train intervals. Peak amplitudes and latencies were analyzed using GLM-mixed ANOVAs to assess differences across genotypes (KO vs. WTs) and strains (SHRs vs. WKYs). Results: The KOs did not demonstrate any significant differences in peak amplitudes relative to the WT controls, suggesting that the null expression of Lphn3 does not result in the development of inefficiencies in automatic attention. However, the SHRs exhibited significantly reduced peak P1 (and peak-to-peak P1–N1) values relative to the WKYs. These attenuations likely reflect inefficiencies in bottom-up arousal networks that are necessary for efficient automatic processing. Conclusions: Distinct findings between these animal models likely reflect differing alterations in dopamine and noradrenaline neurotransmission that may underlie ADHD-relevant phenotypes. Full article

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder that significantly impacts learning, daily functioning, and personal development. Astaxanthin (ASTA), a naturally occurring antioxidant, has garnered interest as a potential therapeutic agent for various diseases, particularly in mitigating oxidative stress. This study explores a novel application of ASTA in the context of ADHD, aiming to investigate its therapeutic effects and underlying mechanisms. Spontaneously hypertensive rats (SHRs), widely used ADHD model animals, were treated with ASTA (50/100 mg/kg/day) for three weeks, 5 mg/kg/day atomoxetine (ATO) as the positive, and Wistar Kyoto (WKY) rats as control. Behavioral improvements were assessed using the open field test (OFT) and the Morris water maze (MWM). Biochemical analyses were conducted to evaluate changes in the levels of various neurotrophic factors, while histological examinations were performed to assess neuroprotective effects. Additionally, the role of ASTA in the brain–gut axis was investigated. The behavioral symptoms of hyperactivity, anxiety, and impaired spatial memory in ADHD animals were mitigated by ASTA. This improvement is primarily attributed to the restoration of neurotransmitter levels, particularly dopamine (DA), achieved through the modulation of several critical components within the dopamine system, including dopamine receptor 1 (DR1), dopamine transporter (DAT), tyrosine hydroxylase (TH), and synaptic-associated protein 25 (SNAP-25). Additionally, regulating the serotonin transporter (SERT) and glial cell-derived neurotrophic factor (GDNF) supports the recovery of serotonin levels and facilitates optimal brain development. Furthermore, cerebellar cells were protected, and the structure of the intestinal microbiota was regulated. ASTA can mitigate ADHD symptoms in SHR through the modulation of the dopaminergic system, multiple neurotransmitters, neurotrophic factors, and the neuro-intestinal environment, which establishes ASTA as a promising nutraceutical candidate for adjunctive therapy in pediatric ADHD. Full article

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats (SHR) and controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) and biochemical (Western blot) studies were conducted on the third-order of the superior mesenteric arteries (sMAs) and/or aortas. EMPA induced concentration-dependent relaxation of preconstricted sMAs in both groups. In SHR, EMPA enhanced acetylcholine (Ach)-induced relaxation in sMAs and aortas and reduced constriction induced by phenylephrine (Phe) and U46619 in sMAs. The SIRT1 inhibitor (EX527) abolished EMPA’s effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. SHR showed increased SGLT2 and SIRT1 expression and decreased pAMPK/AMPK levels in sMAs. In conclusion, EMPA might exert vasoprotective effects in hypertension by enhancing endothelium-dependent relaxation and reducing constriction via AMPK/SIRT1 pathways. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors. Full article

Using an atrial fibrillation (AF) model in spontaneously hypertensive rats (SHRs), we aimed to identify circulating miRNAs for AF diagnosis and prediction and to confirm the cardiac origin of these miRNAs. A total of 31 SHRs and 39 Wistar Kyoto (WKY) normotensive controls were randomized into six groups: young, adult, and aging SHR and WKY. Spontaneous AF burden and atrial and circulating levels of 11 miRNAs were quantified. Spontaneous AF was absent in all WKY rats. In the SHRs, AF episodes were observed in two adult animals and in all aging animals (13.6 ± 2.3 episodes/24 h). The atrial levels of five miRNAs were significantly higher in adult and aging SHRs compared to their WKY controls (all p < 0.05). Of these, only the circulating levels of miR-328 were significantly higher in the aging SHRs vs. WKYs (p < 0.0001). Atrial miR-328 levels in the SHRs increased progressively with age (p < 0.001) and correlated with circulating miR-328 levels (r = 0.58; p < 0.01). Among aging SHRs, atrial levels of miR-328 strongly correlated with AF burden (r = 0.79; p < 0.01). These data suggest that the circulating level of miR-328 could emerge as a promising marker for both AF diagnosis and, if assessed dynamically, for AF prediction. Full article

This study investigates the effects of alcoholic (AB) and non-alcoholic beer (NAB) consumption on blood pressure and the activity of enzymes regulating the renin–angiotensin system (RAS) in Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHRs), with WKY rats used as normotensive controls for SHRs. The RAS is crucial for long-term blood pressure regulation, with angiotensin II (AngII) being a potent vasoconstrictor. The aim was to explore the biochemical mechanisms by which beer might influence cardiovascular health. WKY and SHRs were divided into groups receiving tap water (TW), non-alcoholic beer (NAB), alcoholic beer (AB), TW or NAB and TW or AB for 12 weeks. Systolic blood pressure (SBP), body weight, and biochemical parameters (electrolytes, glucose, renal and liver function, lipid profile) were monitored, and the RAS enzyme activity in serum and various tissues was analyzed. Beer consumption, regardless of alcohol content, did not significantly affect SBP or body weight. However, NAB and AB altered the serum electrolyte levels in both strains. AB consumption increased liver enzyme activity. Significant changes were observed in the RAS enzyme activity across tissues, varying by strain, beer type, and tissue. Moderate beer consumption did not elevate blood pressure in WKY or SHRs. Nevertheless, beer modulated RAS-regulating enzyme activities, indicating potential impacts on cardiovascular homeostasis. Full article

Attention deficit/hyperactivity disorder (ADHD) is defined as a neurodevelopmental condition. The precise underlying mechanisms remain incompletely elucidated. A body of research suggests disruptions in both the cellular architecture and neuronal function within the brain regions of individuals with ADHD, coupled with disturbances in the biochemical parameters. This study seeks to evaluate the morphological characteristics with a volume measurement of the striatal regions and a neuron density assessment within the studied areas across different developmental stages in Spontaneously Hypertensive Rats (SHRs) and Wistar Kyoto Rats (WKYs). Furthermore, the investigation aims to scrutinize the levels and activities of specific markers related to immune function, oxidative stress, and metabolism within the striatum of juvenile and maturing SHRs compared to WKYs. The findings reveal that the most pronounced reductions in striatal volume occur during the juvenile stage in SHRs, alongside alterations in neuronal density within these brain regions compared to WKYs. Additionally, SHRs exhibit heightened levels and activities of various markers, including RAC-alpha serine/threonine-protein kinase (AKT-1), glucocorticoid receptor (GCsRβ), malondialdehyde (MDA), sulfhydryl groups (-SH), glucose (G), iron (Fe), lactate dehydrogenase (LDH). alanine transaminase (ALT), and aspartate transaminase (AST). In summary, notable changes in striatal morphology and elevated levels of inflammatory, oxidative, and metabolic markers within the striatum may be linked to the disrupted brain development and maturation observed in ADHD. Full article

Background/Objectives: Hypertension and its associated complications, such as cardiac remodeling and dysfunction, continue to impose a significant burden on global healthcare. Nutritional interventions have been recognized as playing a crucial role in addressing this devastating condition termed a ‘silent killer’. Plant-based proteins could potentially be utilized as a non-pharmacological strategy to combat hypertension and its related risk factors. In this study, we investigated the efficacy of an oat protein diet in managing hypertension and cardiac abnormalities. Methods: Four-week-old male spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats were fed a regular diet with casein as a protein source or an oat-protein-based diet for 16 weeks. Twenty-week-old male SHRs showed high blood pressure (BP), cardiac remodeling, cardiac dysfunction, higher levels of markers of oxidative stress [malondialdehyde (MDA)] and inflammation [tumor necrosis factor-α (TNF-α)], as well as lower levels of a marker of vascular function (nitric oxide). Results: The oat protein diet was able to significantly lower high BP, prevent cardiac remodeling and dysfunction, improve the levels of nitric oxide, and reduce the levels of TNF-α. Oat protein, after in vitro gastrointestinal digestion, also exhibited angiotensin-converting enzyme inhibition and significantly higher antioxidant activity than casein when assessed with the 2,2-diphenyl-1-picrylhydrazyl and the iron-chelating assays in vitro. Conclusions: oat protein lowers BP and prevents cardiac remodeling and dysfunction partly via improving the levels of nitric oxide and TNF-αin SHRs. Its high antioxidant potential could contribute to the observed cardiovascular effects. Full article

Background: Hypertension is a major cause of mortality worldwide. The kidneys play a crucial role in regulating blood pressure and fluid volume. The relationship between the kidneys and hypertension is complex, involving factors such as the renin–angiotensin system, oxidative stress, and inflammation. This study aims to assess the levels of inflammatory markers, oxidative stress, and metabolic factors in the kidneys, focusing on their potential role in early renal damage and their association with the development of hypertension. Methods: This study was designed to compare the levels of selected inflammatory markers, e.g., interleukins, tumor necrosis factor-α (TNF-α), transforming growth factor, and serine/threonine-protein (mTOR); oxidative stress markers such as malondialdehyde, sulfhydryl group, and glucose (GLC); and metabolic markers among other enzymes, such as alanine transaminase (ALT), aspartate transaminase (AST), hexokinase II (HK-II), and hypoxia-inducible factor-1α (HIF-1α), as well as creatinine in the kidneys of spontaneously hypertensive rats (SHR/NCrl, n = 12) and Wistar Kyoto rats (WKY/NCrl, n = 12). Both juvenile (5 weeks old) and maturing (10 weeks old) specimens were examined using spectrophotometric methods, e.g., ELISA. Results: Juvenile SHRs exhibited reduced renal levels of all studied cytokines and chemokines, with lower oxidative stress and deficits in the mTOR and HK-II levels compared to the age-matched WKYs. Maturing SHRs showed increased renal levels of interleukin-1β (IL-1β), IL-6, IL-18, and TNF-α, alongside elevated carbonyl stress and increased HIF-1α as opposed to their control peers. The levels of all other studied markers were normalized in these animals, except for ALT (increased), ALP, and GLC (both reduced). Conclusions: This study underscores the significant impact of inflammatory, oxidative stress, and metabolic marker changes on renal function. Juvenile SHRs display lower marker levels, indicating an immature immune response and potential subclinical kidney damage that may contribute to hypertension development. In contrast, mature SHRs exhibit chronic inflammation, oxidative dysregulation, and metabolic disturbances, suggesting cellular damage. These changes create a feedback loop that worsens kidney function and accelerates hypertension progression, highlighting the kidneys’ crucial role in both initiating and exacerbating this condition. Full article

Coronary microvascular dysfunction (CMD) represents a principal etiological factor in ischemic heart disease. Nonetheless, a considerable subset of CMD patients experiences diagnostic delays attributable to the inadequacy of current diagnostic methodologies; which in turn results in deferred therapeutic interventions and elevated mortality rates. This study seeks to elucidate the distinct metabolic profile associated with CMD in rat models and to identify specific diagnostic markers that could enhance the diagnostic accuracy for CMD. In this study, 18 Wistar rats were randomly allocated into two groups: the sham group and the CMD group. The CMD group received injections of embolic microspheres into the left ventricle to establish a CMD model. Subsequently, non-targeted metabolomics and acetylated proteomics analyses were conducted. Machine-learning techniques were employed to identify the co-diagnostic markers of the disease. This study identified 53 key proteins through differential expression proteins (DEPs) and modular proteins analysis. Subsequently, four core proteins (Emc1; Ank1; Fbln2; and Hp) were determined as diagnostic markers for CMD using lasso regression, support vector machine, and random forest methodologies. Receiver operating characteristic curve analysis further demonstrated robust diagnostic performance. Gene ontology and kyoto encyclopedia of genes and genome enrichment analyses indicated that the DEPs were predominantly associated with metabolic pathways. Ultimately, the integrative analysis of proteomics and metabolomics suggested that the central metabolic mechanism underlying CMD pathogenesis may be linked to the tricarboxylic acid cycle. This study revealed specific changes in the proteomic and metabolic profiles of CMD rats and identified four diagnostic markers, which are proteins and metabolites that could be potential diagnostic biomarkers for CMD. Full article

In recent years, various drug delivery systems circumventing the blood–brain barrier have emerged for treating brain tumors. This study aimed to improve the efficacy of brain tumor treatment in boron neutron capture therapy (BNCT) using cerebrospinal fluid (CSF) circulation to deliver boronophenylalanine (BPA) to targeted tumors. Previous experiments have demonstrated that boron accumulation in the brain cells of normal rats remains comparable to that after intravenous (IV) administration, despite BPA being administered via CSF at significantly lower doses (approximately 1/90 of IV doses). Based on these findings, BNCT was conducted on glioma model rats at the Kyoto University Research Reactor Institute (KUR), with BPA administered via CSF. This method involved implanting C6 cells into the brains of 8-week-old Wistar rats, followed by administering BPA and neutron irradiation after a 10-day period. In this study, the rats were divided into four groups: one receiving CSF administration, another receiving IV administration, and two control groups without BPA administration, with one subjected to neutron irradiation and the other not. In the CSF administration group, BPA was infused from the cisterna magna at 8 mg/kg/h for 2 h, while in the IV administration group, BPA was intravenously administered at 350 mg/kg via the tail vein over 1.5 h. Thermal neutron irradiation (5 MW) for 20 min, with an average fluence of 3.8 × 10¹²/cm², was conducted at KUR’s heavy water neutron irradiation facility. Subsequently, all of the rats were monitored under identical conditions for 7 days, with pre- and post-irradiation tumor size assessed through MRI and pathological examination. The results indicate a remarkable therapeutic efficacy in both BPA-administered groups (CSF and IV). Notably, the rats treated with CSF administration exhibited diminished BPA accumulation in normal tissue compared to those treated with IV administration, alongside maintaining excellent overall health. Thus, CSF-based BPA administration holds promise as a novel drug delivery mechanism in BNCT. Full article

This study aimed to analyze the effects of systemic arterial hypertension (SAH) in a model of permanent ischemic stroke (focal ischemia due to thermocoagulation of pial vessels) on sensorimotor function (cylinder test and patch removal test), behavioral tasks (novelty habituation memory open field task) and cerebral infarct size in adult male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) for 42 days after the occurrence of a stroke. We observed that the stroke caused asymmetry in the front paws and delayed adhesive removal. These effects were spontaneously reduced in WKY rats, but not in SHR. Short- and long-term novelty habituation memories were abolished by stroke in WYK and SHR. On the 3rd day after stroke, the size of the focal cerebral infarct was the same in WKY and SHR. However, on the 7th day, the infarct size decreased in WKY rats, but not SHR. These results suggested that SAH impairment of sensorimotor recovery in rats subjected to cerebral ischemia could be related to augmented focal cerebral infarct size. Moreover, the behavioral tasks used in this study were unaffected by Systemic Arterial Hypertension. Our results highlight the need for animal models of comorbidities in stroke research. Full article

This study aimed to prepare, characterize and assess the antioxidant activity of yellow bedstraw extracts (YBEs), focusing on identifying extracts with high antioxidant capacity. The selected extract was loaded into an oral liquid formulation and further investigated for its therapeutic potential in reducing blood pressure and associated complications in spontaneously hypertensive Wistar kyoto rats (SHR). Rats were divided into untreated SHR and SHR treated with a YBE-based oral formulation over four weeks. After treatment, blood pressure was measured, and cardiac function was assessed using the Langendorff technique to simulate ex vivo ischemic conditions. Prooxidant levels were assessed in plasma while antioxidant activity was evaluated in red blood cells. Histological analyses of heart, kidney, and liver samples were conducted to assess pathological changes induced by hypertension. Our results showed that the oral formulation loaded with ethanol YBE effectively reduced blood pressure, preserved myocardial function under ischemic stress, and decreased oxidative stress markers in blood. Importantly, our formulation with YBE demonstrated potential in attenuating structural kidney damage associated with hypertension. Overall, these findings suggest a cardioprotective effect of orally administered YBE formulation, highlighting its potential as an herbal supplement. However, clinical studies are warranted to validate these findings and explore the extract’s suitability for clinical use. Full article

Supplementation of betaine is associated with improved cardiac health, potentially due to its function in re-methylation of homocysteine, an independent risk factor for cardiovascular diseases. We investigated the effects of oral betaine supplementation on blood pressure homeostasis in spontaneously hypertensive (SHR) rats and Wistar Kyoto (WKY) rats in an 8 week-feeding trial with control (SHR-con and WKY-con) and 1% betaine supplemented (SHR-b and WKY-b) diets. Systolic, diastolic, and mean blood pressure in the SHR-b group were significantly lower at week 8 (p = 0.013, p = 0.011, p = 0.010, respectively). Furthermore, serum nitric oxide (NO) levels were significantly (p < 0.05) improved in the WKY-b and SHR-b groups, suggesting a healthy endothelial function. Additionally, the serum angiotensin I converting enzyme level in SHR-b rats was also significantly lowered, which may have been another reason for lower blood pressure. A significantly higher non-HDL level in the SHR-b group might reflect enhanced lipid secretion into the circulation in the form of very-low-density lipoprotein (VLDL). Betaine is known for its effect on the synthesis of phosphatidylcholine, a key component of VLDL. However, the long-term net outcomes of both blood pressure lowering and serum lipid increment should be further studied. Full article

Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD. Full article