Potentiation of NMDA Receptors by AT1 Angiotensin Receptor Activation in Layer V Pyramidal Neurons of the Rat Prefrontal Cortex.

NMDA receptors in the prefrontal cortex (PFC) play a crucial role in cognitive functions. Previous research has indicated that angiotensin II (Ang II) affects learning and memory. This study aimed to examine how Ang II impacts NMDA receptor activity in layer V pyramidal cells of the rat PFC.

CardiLect: A combined cross-species lectin histochemistry protocol for the automated analysis of cardiac remodelling.

Background: Cardiac remodelling, a crucial aspect of heart failure, is commonly investigated in preclinical models by quantifying cardiomyocyte cross-sectional area (CSA) and microvascular density (MVD) via histological methods, such as immunohistochemistry. To achieve this, optimized protocols are needed, and the species specificity is dependent on the antibody used. Lectin histochemistry offers several advantages compared to antibody-based immunohistochemistry, including as cost-effectiveness and cross-species applicability.

Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice.

Despite accumulating data on underlying mechanisms, the influence of sex and prevalent cardio-metabolic co-morbidities on the manifestation and severity of immune checkpoint inhibitor (ICI)-induced cardiotoxicity has not been well defined. To elucidate whether sex and prevalent cardio-metabolic co-morbidities affect ICI-induced cardiotoxicity, we randomized 17-month-old male and female mice to receive control diet (CON) or high-fat diet (HFD) + L-NAME-a well-established mouse model of cardio-metabolic co-morbidities-for 17 weeks (n = 5-7), and evaluated markers of T-cell function in the spleen. As expected, HFD + L-NAME significantly increased body- and heart weight, and serum cholesterol levels, and caused no systolic dysfunction, however, led to diastolic dysfunction, cardiomyocyte hypertrophy, and increased fibrosis only in males compared to corresponding CON.

Pharmacokinetics and cardioprotective efficacy of intravenous miR-125b* microRNA mimic in a mouse model of acute myocardial infarction.

Background And Purpose: MicroRNA (miRNA) therapy is a promising approach to induce cardioprotection. We have previously identified cardiac microRNA-125b* (microRNA-125b-2-3p; miR-125b*) as a potential cardioprotective miRNA, termed ProtectomiR. We aimed to characterize the pharmacokinetics and pharmacodynamics, and the effect of miR-125b* mimic on infarct size using an in vivo mouse model.

Reduced circulating CD63 extracellular vesicle levels associate with atherosclerosis in hypercholesterolaemic mice and humans.

Aims: The association and co-isolation of low-density lipoproteins (LDL) and extracellular vesicles (EVs) have been shown in blood plasma. Here we explore this relationship to better understand the role of EVs in atherogenesis.

Methods And Results: Wild type (WT), PCSK9, and LDLR C57BL/6 mice were used in this study.

Treatment options for immune-related adverse events associated with immune checkpoint inhibitors.

The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs).

NASH triggers cardiometabolic HFpEF in aging mice.

Both heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) develop due to metabolic dysregulation, has similar risk factors (e.g., insulin resistance, systemic inflammation) and are unresolved clinical challenges.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies.

Depletion of muscularis macrophages ameliorates inflammation-driven dysmotility in murine colitis model.

Previously, the presence of a blood-myenteric plexus barrier and its disruption was reported in experimentally induced colitis via a macrophage-dependent process. The aim of this study is to reveal how myenteric barrier disruption and subsequent neuronal injury affects gut motility in vivo in a murine colitis model. We induced colitis with dextran sulfate sodium (DSS), with the co-administration of liposome-encapsulated clodronate (L-clodronate) to simultaneously deplete blood monocytes contributing to macrophage infiltration in the inflamed muscularis of experimental mice.

A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy.

Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2) mice were treated with a single, large dose (20 or 30 mg/kg, i.

Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction.

The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF.

Antineoplastic drugs inducing cardiac and vascular toxicity - An update.

With the improvement in cancer prognosis due to advances in antitumor therapeutic protocols and new targeted and immunotherapies, we are witnessing a growing increase in survival, however, at the same timeincrease in morbidity among cancer survivors as a consequences of the increased cardiovascular adverse effects of antineoplastic drugs. Common cardiovascular complications of antineoplastic therapies may include cardiac complications such as arrhythmias, myocardial ischemia, left ventricular dysfunction culminating in heart failure as well as vascular complications including arterial hypertension, thromboembolic events, and accelerated atherosclerosis. The toxicity results from the fact that these drugs not only target cancer cells but also affect normal cells within the cardiovascular system.

Inflammasome Activity in the Skeletal Muscle and Heart of Rodent Models for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by wasting of muscles that leads to difficulty moving and premature death, mainly from heart failure. Glucocorticoids are applied in the management of the disease, supporting the hypothesis that inflammation may be driver as well as target. However, the inflammatory mechanisms during progression of cardiac and skeletal muscle dysfunction are still not well characterized.

Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats.

Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration.

BRAF RNA is prognostic and widely expressed in lung adenocarcinoma.

Background: BRAF is a critical member of proliferation pathways in cancer, and a mutation is present in only 2-4% of lung adenocarcinomas (LADC). There is no data available on the expression pattern of BRAF RNA that might result in enhanced signalling and drug resistance.

Methods: LADC tissue samples (n=64) were fixed and processed into paraffin blocks.

Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling.

Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (β-cat) as well as with compensatory and failing hypertrophic remodeling. We show that functional enrichment analysis points to an involvement of extracellular vesicles (EVs) related processes in hearts of β-cat mice.

IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH.

Interleukin-1β (IL-1β) is a key mediator of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of systemic inflammation-driven aging. IL-1β contributes to cardio-metabolic decline, and may promote hepatic oncogenic transformation. Therefore, IL-1β is a potential therapeutic target in these pathologies.

Drug repurposing for cardiovascular diseases: New targets and indications for probenecid.

The available pharmacological options in the management of cardiovascular diseases such as ischaemic heart disease and subsequent heart failure are effective in slowing the progression of this condition. However, the long-term prognosis is still poor, raising the demand for new therapeutic strategies. Drug repurposing is a time- and cost-effective drug development strategy that offers approved and abandoned drugs a new chance for new indications.