PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury.

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure.

Possible retinotoxicity of long-term vardenafil treatment.

Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform.

Data-driven transcriptomics analysis identifies PCSK9 as a novel key regulator in liver aging.

The liver, as a crucial metabolic organ, undergoes significant pathological changes during the aging process, which can have a profound impact on overall health. To gain a comprehensive understanding of these alterations, we employed data-driven approaches, along with biochemical methods, histology, and immunohistochemistry techniques, to systematically investigate the effects of aging on the liver. Our study utilized a well-established rat aging model provided by the National Institute of Aging.

Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis.

Diabetes mellitus promotes accelerated cardiovascular aging and inflammation, which in turn facilitate the development of cardiomyopathy/heart failure. High glucose-induced oxidative/nitrative stress, activation of various pro-inflammatory, and cell death pathways are critical in the initiation and progression of the changes culminating in diabetic cardiomyopathy. Cannabinoid 2 receptor (CBR) activation in inflammatory cells and activated endothelium attenuates the pathological changes associated with atherosclerosis, myocardial infarction, stroke, and hepatic cardiomyopathy.

Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts.

Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks.

The Predictive Role of Thyroid Hormone Levels for Early Diabetic Retinal Changes in Experimental Rat and Human Diabetes.

Purpose: In diabetic subjects, early visual functional alterations such as color vision deficiencies (CVDs) are known to precede clinically apparent diabetic retinopathy. Prominent photoreceptor outer segment degeneration and an increase in the number of retinal dual cones (co-expressing S- and M-opsins simultaneously) have been described in diabetic rat models, suggesting a connection with the development of CVDs. As cone opsin expression is controlled by thyroid hormones, we investigated the diabetic retina in association with thyroid hormone alterations.

Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis.

Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223-enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent.

Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications.

The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression.

Chronic swimming training resulted in more relaxed coronary arterioles in male and enhanced vasoconstrictor ability in female rats.

Background: Exercise training is associated with hypertrophy of left ventricle (LV). The aim of the present study is to evaluate sex differences in the adaptation of the coronary contractile function in physiological left ventricular hypertrophy induced by long-term swim training.

Methods: Thirty-two Wistar rats were randomly divided into 4 groups: exercised male (ExM), exercised female (ExF), untrained control male (CoM), and untrained control female (CoF).

Long-term exercise results in morphological and biomechanical changes in coronary resistance arterioles in male and female rats.

Background: Biomechanical remodeling of coronary resistance arteries in physiological left ventricular hypertrophy has not yet been analyzed, and the possible sex differences are unknown.

Methods: Wistar rats were divided into four groups: male and female sedentary controls (MSe and FSe) and male and female animals undergoing a 12-week intensive swim training program (MEx and FEx). On the last day, the in vitro contractility, endothelium-dependent dilatation, and biomechanical properties of the intramural coronary resistance arteries were investigated by pressure microarteriography.

Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice.

Background & Aims: Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on pre-existing chronic liver disease. It is often associated with bacterial infection and high short-term mortality. Experimental models that fully reproduce ACLF are lacking, so too are effective pharmacological therapies for this condition.

Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome.

Study Rationale: Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease characterized by the rapid decline of kidney function. Herein, we explored the therapeutic potential of targeting the cannabinoid-2 receptor (CB-R) utilizing a commonly used mouse model of liver fibrosis and hepatorenal syndrome (HRS), induced by bile duct ligation (BDL).

Methods: Gene expression analysis, histological evaluation, determination of serum levels of renal injury-biomarkers were used to characterize the BDL-induced organ injury; laser speckle analysis to measure microcirculation in the kidneys.

Alcohol Binge-Induced Cardiovascular Dysfunction Involves Endocannabinoid-CB1-R Signaling.

Excessive binge alcohol drinking may adversely affect cardiovascular function. In this study we characterize the detailed hemodynamic effects of an acute alcohol binge in mice using multiple approaches and investigate the role of the endocannabinoid-cannabinoid 1 receptor (CB1-R) signaling in these effects. Acute alcohol binge was associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction lasting for several hours and redistribution of circulation.

PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease.

Alcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet.

Interplay of Liver-Heart Inflammatory Axis and Cannabinoid 2 Receptor Signaling in an Experimental Model of Hepatic Cardiomyopathy.

Background And Aims: Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)-induced liver fibrosis, by monitoring echocardiography and intracardiac pressure-volume relationships and myocardial structural alterations.

Sex Differences in Morphological and Functional Aspects of Exercise-Induced Cardiac Hypertrophy in a Rat Model.

Recent evidences suggest that sex hormones may be involved in the regulation of exercise-induced left ventricular (LV) hypertrophy. However, the sex-specific functional consequences of exercise-induced myocardial hypertrophy is still not investigated in detail. We aimed at understanding the sex-specific functional and morphological alterations in the LV and the underlying molecular changes in a rat model of athlete's heart.

Detailed Evaluation of Possible Ganglion Cell Loss in the Retina of Zucker Diabetic Fatty (ZDF) Rats.

A thinning of the inner retina is one of the earliest potential markers of neuroretinal damage in diabetic subjects. The histological background is uncertain; retinal ganglion cell (RGC) loss and changes in the structure or thickness of the inner plexiform layer (IPL) have been suspected. Studies conducted on animal models on RGC pathology gave contradictory results.

Common garden comparisons confirm inherited differences in sensitivity to climate change between forest tree species.

The natural distribution, habitat, growth and evolutionary history of tree species are strongly dependent on ecological and genetic processes in ecosystems subject to fluctuating climatic conditions, but there have been few experimental comparisons of sensitivity between species. We compared the responses of two broadleaved tree species ( and ) and two conifer tree species ( and ) to climatic transfers by fitting models containing the same climatic variables. We used published data from European provenance test networks to model the responses of individual populations nested within species.

Characterization of the dynamic changes in left ventricular morphology and function induced by exercise training and detraining.

Background: Although exercise-induced cardiac hypertrophy has been intensively investigated, its development and regression dynamics have not been comprehensively described. In the current study, we aimed to characterize the effects of regular exercise training and detraining on left ventricular (LV) morphology and function.

Methods: Rats were divided into exercised (n = 12) and control (n = 12) groups.

Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice.

Unlabelled: Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)-induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy.

Comparison of speckle-tracking echocardiography with invasive hemodynamics for the detection of characteristic cardiac dysfunction in type-1 and type-2 diabetic rat models.

Background: Measurement of systolic and diastolic function in animal models is challenging by conventional non-invasive methods. Therefore, we aimed at comparing speckle-tracking echocardiography (STE)-derived parameters to the indices of left ventricular (LV) pressure-volume (PV) analysis to detect cardiac dysfunction in rat models of type-1 (T1DM) and type-2 (T2DM) diabetes mellitus.

Methods: Rat models of T1DM (induced by 60 mg/kg streptozotocin, n = 8) and T2DM (32-week-old Zucker Diabetic Fatty rats, n = 7) and corresponding control animals (n = 5 and n = 8, respectively) were compared.

Pharmacological preconditioning with gemfibrozil preserves cardiac function after heart transplantation.

While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging. Pharmacological activation of soluble guanylate cyclase (sGC) and increased cGMP-signalling have been reported to have cardioprotective properties. Gemfibrozil has recently been shown to exert sGC activating effects in vitro.