Cannabis has attracted growing interest for its therapeutic potential, especially in pain management. This study explores the antinociceptive effects of two promising non-psychoactive cannabinoids, cannabivarin (CBV) and tetrahydrocannabivarin (THCV), using , a nematode model that expresses homologs of mammalian cannabinoid and vanilloid receptors. Thermotaxis assays were employed to quantify the antinociceptive effects of CBV and THCV in . Wild-type animals were exposed to increasing concentrations of each compound to establish dose-response relationships. To investigate potential molecular targets, additional experiments were performed using mutant strains deficient in vanilloid receptor homologs (OCR-2 and OSM-9) and cannabinoid receptor homologs (NPR-19 and NPR-32). Mass spectrometry-based proteomics combined with network biology analyses were used to identify the biological pathways associated with drug response. Results confirmed that both compounds elicit dose-dependent antinociceptive effects. Mutant analyses support the involvement of vanilloid and cannabinoid signaling pathways in mediating these responses. These findings highlight the potential of CBV and THCV as non-psychoactive analgesic agents and support further research into their mechanisms of action and translational relevance for mammalian pain management.

Ischemic stroke is characterized by brain tissue iron accumulation. Alpha-synuclein (α-Syn) is a neuronal protein, its overexpression in ischemic stroke triggers apoptosis. Lymphocyte activation gene-3 (LAG-3), a receptor for α-Syn, enhances its neurotoxic effects. It is split from the cell membrane forming soluble LAG-3 (sLAG-3) in the bloodstream. The expression of LAG-3 in the brain, its relation to iron and α-Syn, as well as the association between serum sLAG-3 levels, iron, α-Syn, and stroke severity remains poorly understood. A case-control study was generated involving 24 patients with acute ischemic stroke and 24 healthy controls. In addition, an experimental study was designed involving 24 Wistar-albino rats. We randomly assigned rats to three groups: sham-operated, brain ischemia, and deferoxamine treated ischemic rats. Ischemia decreased serum levels of iron, while increased serum levels of α-Syn and sLAG-3. Significant diagnostic performance of serum α-Syn and sLAG-3 was determined using the ROC curve (AUC = 0.962, 83.33% sensitivity, and 95.83 % specificity for α-Syn; AUC = 0.755 with 62.50% sensitivity and 87.50% specificity for LAG-3). In rats, ischemia elevated brain tissue iron, α-Syn, and LAG-3 which were reduced following deferoxamine treatment. In conclusion, brain ischemia is associated with iron accumulation that promotes α-Syn expression and aggregation potentially through increasing LAG-3 expression which improved after deferoxamine injection. In addition this study illuminates the future beneficial targeting of LAG-3 in brain ischemia.

High-sensitivity cardiac troponin I (hs-TnI) is a promising biomarker for cardiovascular disease (CVD) risk stratification. This study assessed clinical outcomes and cost-effectiveness of an hs-TnI-guided CVD screening strategy in a general asymptomatic adult population. In a modeled observational program, 4000 adults aged 40-70 years without known CVD underwent hs-TnI testing. Participants were stratified into low (<4 ng/L), moderate (4-10 ng/L), and high (>10 ng/L) risk categories, and underwent further cardiac evaluation, and intervention, if indicated. A discrete-event microsimulation estimated CVD events, mortality, quality-adjusted life years (QALYs), and costs over 10 years. Among 4000 participants (mean age 57.1 ± 8.6 years; 52% women), 3548 (88.7%) were low-risk, 390 (9.8%) moderate-risk, and 62 (1.5%) high-risk. Noninvasive cardiac workup was performed in 452 (11.3%), and coronary angiography in 112 (2.8%). Significant coronary artery disease (CAD) was diagnosed in 49 (1.2%), with revascularization in 45. Compared to standard care, hs-TnI screening reduced CVD events by 37% and cardiovascular deaths by 34%, gaining 16.3 QALYs per 1000 participants. Incremental cost per person was €528, with an incremental cost-effectiveness ratio of €32 100/QALY, remaining cost effective in 93% of simulations. hs-TnI-guided cardiovascular risk assessment effectively stratifies asymptomatic adults, identifies subclinical CAD, and facilitates preventive intervention, appearing cost effective in reducing CVD burden.

Oxidative stress plays a critical role in the pathogenesis of various diseases. Oxygen-containing reactive molecules commonly called as reactive oxygen species (ROS), generated during the utilization of oxygen molecule by aerobic metabolism, often form the primary cause of oxidative stress. It leads to oxidative damage to lipids, proteins, and DNA, thus contributing to mitochondrial dysfunction, inflammation, and cell death. In systemic conditions such as neurodegenerative, cardiovascular, metabolic, and oncological disorders, ROS function both as signaling molecules and mediators of pathological processes. Central to the cellular defense against oxidative stress is the transcription factor called nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of antioxidant and cytoprotective genes. Activation of the Nrf2 pathway enhances redox homeostasis, detoxification, and cell survival, thereby offering significant therapeutic potential across diverse disease states. Particularly in the field of reproductive biology, ROS-induced damage to sperm DNA, membranes, and mitochondria impairs sperm function and viability, especially under pathological conditions and during sperm cryopreservation. Similarly, in female reproductive disorders, oxidative stress disrupts hormonal balance, follicular development, and implantation. Activation of Nrf2 through natural or synthetic compounds has shown promise in preserving sperm integrity, improving post-thaw outcomes, enhancing oocyte quality, and overall reproductive outcomes by augmenting antioxidant defense. The Nrf2 activators, such as flavonoid-based modulators, offer a protective mechanism by reducing oxidative injury and restoring reproductive homeostasis. Emerging evidence from both human and animal studies highlights the utility of flavonoids and Nrf2 activators in enhancing reproductive health, providing a foundation for novel antioxidant-based therapeutic interventions.

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), exert a wide range of beneficial effects beyond glycemic control, largely mediated by their anti-inflammatory properties. Chronic low-grade inflammation is a common pathological mechanism underlying metabolic, cardiovascular, hepatic, and neurodegenerative diseases. GLP-1RAs reduce systemic and tissue-specific inflammation through both direct and indirect mechanisms, including inhibition of nuclear factor kappa B signaling, reduction of proinflammatory cytokines, and modulation of immune cell activity, such as that of macrophages and microglia. In type 2 diabetes and obesity, GLP-1RAs improve insulin sensitivity and endothelial function by attenuating inflammation. In metabolic dysfunction-associated steatotic liver disease, GLP-1RAs reduce hepatic steatosis and fibrosis by modulating inflammation in hepatocytes and Kupffer cells. In cardiovascular disease, they mitigate atherosclerosis progression and improve vascular health. GLP-1RAs also exert direct nephroprotective effects by reducing renal inflammation, oxidative stress, and glomerular hyperfiltration in both diabetic and nondiabetic models. GLP-RAs have been also associated with the preservation of cognitive and motor function. Preclinical studies suggest that these neuroprotective effects may involve the attenuation of neuroinflammation and reduced aggregation of pathological proteins. Overall, these pleiotropic actions position incretin-based therapies as promising tools for the management of complex chronic diseases with an inflammatory component.

Aging is a process characterized by the progressive decline in physiological function and increased susceptibility to disease. Many cellular functions, including unfolded protein responses (UPR, an endoplasmic reticulum stress coping mechanism), Ca signaling, cellular signaling, and inflammatory responses are affected by aging. These significantly impact Ca handling by cardiac cells and the architecture of cardiomyocytes, leading to impaired contractility, and increased risk of arrhythmias. Cellular Ca homeostasis and the UPR are interdependent, therefore, understanding and influencing these key cellular pathways should provide new therapeutic strategies for managing age-related cardiac diseases. Modulating Ca handling and cellular stress pathways presents distinctive approaches to preventing molecular alterations linked to aging, while providing opportunities to reduce molecular damage and promote the effectiveness of cellular repair processes.

Fructose is a simple sugar or monosaccharide, which is abundant in nature and commonly used in food industry as a strong natural sweetener. The growing epidemic of high fructose consumption has been linked to increased prevalence of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Increasing evidence indicates that high dietary fructose can exert direct effects on the heart as well as the vasculature. Several underlying mechanisms involving metabolic disturbances, oxidative stress, and inflammation have been demonstrated to induce cardiac dysfunction and vascular abnormalities. Accordingly, the intent of this review is to discuss the metabolic consequences of increased fructose consumption and to provide an overview of the mechanisms associated with fructose-enriched diet-induced cardiovascular abnormalities. A description of some novel interventions that attenuate both cardiac and vascular dysfunction subsequent to fructose over consumption is also provided. The high intakes of fructose present a public health hazard, and thus, there is a pressing need to increase public awareness on the harmful health effects, including cardiovascular health, of high intake of foods and beverages enriched with fructose. Furthermore, the supplementation of processed foods and beverages with fructose additives needs regulation.

Despite the known association between hypertension and nonalcoholic fatty liver disease (NAFLD), the cut-off values of blood pressure for identifying risk of NAFLD have not yet been determined. The aim of this study was to determine the diagnostic performance and optimal cut-off values of blood pressure for detecting NAFLD defined by fatty liver index (FLI). This cross-sectional study included 1227 participants aged 35-55 years. NAFLD was determined by FLI with a cut-off value of ≥60. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic ability of blood pressure parameters for screening FLI-defined NAFLD and to determine their cut-off values. The results of this study showed that systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly correlated with FLI values. The prevalence of NAFLD defined by FLI was 23.5% in men and 18.2% in women. The ROC curve analysis showed a good ability of blood pressure for the prediction of FLI-defined NAFLD. The optimal cut-off values of SBP and DBP were 136 and 88 mmHg in men and 137 and 85 mmHg in women, respectively. Thus, high-normal blood pressure is associated with the risk of NAFLD defined by FLI in both men and women.

In this study, we evaluate the exposure and pharmacokinetic/pharmacodynamic target attainment of meropenem in critically ill patients. We conducted a prospective observational study in two Canadian intensive care units (ICUs) from January 2021 to December 2023. We included adult patients admitted in the ICU who received meropenem. On study days 1, 4, and 7 of antimicrobial therapy, three blood samples were collected: 1 h after end of infusion, at the middle, and at the end of the dosing interval. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector. The pharmacokinetic profile of meropenem was evaluated, as well as the attainment of serum concentrations above minimum inhibitory concentrations of 2, 4, and 8 mg/L at midpoint and at trough. We enrolled 28 patients and analyzed 167 meropenem concentrations. We observed large interindividual variability, but intraindividual variability was low. At midpoint, 52% of concentrations were below the target concentration of 8 mg/L, while this proportion increased to 73% for trough concentrations. Patients who failed to reach therapeutic concentrations all had normal to increased renal function. The majority of ICU patients who received meropenem were underexposed for a target concentration of 8 mg/L, with notable interindividual variability but low intraindividual variability. More aggressive dosing administration protocols are warranted to facilitate target attainment of meropenem.

Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS), offering unparalleled efficacy but accompanied by significant interindividual variability in response and risk of severe adverse effects. Pharmacogenomics (PGx), the study of how genetic variations influence drug response, has transformed treatment for other medications like warfarin but remains underutilized in clozapine prescribing. This review synthesizes current evidence on the potential of PGx to enhance clozapine treatment by improving the prediction of therapeutic response, metabolism, and adverse drug reactions. Key genetic markers, such as variants in serotonin receptor genes (e.g., HTR2A and HTR3A), metabolism-related enzymes (CYP1A2), and immune-related genes (HLA-DQB1 and HLA-B59:01), show promise in guiding personalized clozapine prescribing. However, economic, educational, and systemic challenges, particularly in Canada, hinder broader implementation. PGx testing in psychiatry is available but lacks standardization in cost, accessibility, and test panels. Additionally, PGx research remains Eurocentric, with limited data on Indigenous and diverse populations. In Canada, initiatives like Go-PGx reflect growing national interest, but mental health applications remain minimal. Bridging research with practice through inclusive research, clinician education, artificial intelligence and machine learning, and cost-effectiveness analyses may help unlock PGx's full potential for over 200 000 Canadians living with schizophrenia.

Breast cancer affects 1 in 8 Canadian women over their lifetime. Triple-negative breast cancer (TNBC) represents 10-20% of all advanced stage breast cancers, often developing multi-drug resistance (MDR), commonly resulting in treatment failure. Jadomycin B (JB), a natural product of Streptomyces venezuelae, maintains cytotoxicity against MDR TNBCs, and its activity is enhanced when combined with selective COX-2 inhibitor, celecoxib (CXB) in vitro. Our objectives were to evaluate the toxicity and anticancer effects of JB combined with CXB using zebrafish larval xenografts as a model system. Fluorescent human TNBC MDA-MB-231 cells (231-EGFP) were generated and characterized for zebrafish larval xenografts. A maximum tolerated dose (MTD) in zebrafish larvae were determined for JB (20 mM) and CXB (5 mM). Zebrafish embryos were xenotransplanted with 50 to 100 231-EGFP cells and treated with the MTDs of JB and CXB alone or in combination. The combination of JB and CXB resulted in a 75% reduction in 231-EGFP fluorescence intensity, significantly higher than reductions caused by either drug alone (39% for JB, 15 % for CXB) (p <0.05). This study demonstrates that combining JB with CXB enhances anticancer activity in a zebrafish larval xenograft model of human TNBC, validating effects previously determined in vitro.

The treatment of metabolic syndrome (MS), characterized by type 2 diabetes (T2D), obesity, dyslipidemias, and cardiovascular problems, requires integral treatment. In addition to its central activity, serotonin also has peripheral effects, implying regulation of blood glucose and insulin levels. Indorenate is a serotonin analog with antihypertensive properties and possible activity on the metabolism of carbohydrates. However, its effect on glucose levels has not been explored, which is relevant in searching for the indorenate's potential as an alternative to treatment of MS. This investigation aimed to study the effects of indorenate on glycemia through in vivo and in silico assays. In normal rats, indorenate was co-administrated with two serotoninergic antagonists: pelanserin (5-HT2a antagonist) and WAY-100635 (5-HT1a antagonist). Indorenate caused a hypoglycemic effect in normal rats. Pelanserin and WAY-100635 inhibited this effect. In diabetic rats, indorenate increased insulin levels. In addition, indorenate decreased glycemia in an euglycemic clamp test, while pelanserin inhibited this effect. In silico, indorenate exhibited a higher affinity and interactions than serotonin for 5-HT2a and 5HT1a receptors. The data suggests that the hypoglycemic effect of indorenate requires the participation of the 5-HT2a receptor and partially of the 5-HT1a receptor. Finding drugs with beneficial multimodal effects for blood pressure and glycemic control, such as indorenate, might be relevant for treating MS and its associated pathologies.

We previously showed that male rats develop more severe cardiac hypertrophy than female rats following abdominal aortic constriction (AAC), and highlighted corresponding changes in cardiac cytochrome P450 (CYP) enzymes and their arachidonic acid (AA) metabolites. In this study, we report sex-specific changes in renal CYP enzymes and AA metabolites after AAC. Kidneys were isolated from adult male and female Sprague-Dawley rats five weeks after sham or AAC surgeries. Renal CYP, lipoxygenase, and epoxide hydrolase enzyme levels were measured by PCR and Western blot, and renal microsomal formation of hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) was measured by liquid chromatography-tandem mass spectrometry. Protein levels of CYP2E1 and CYP4F were significantly elevated post-AAC only in female rats, paralleled by a significant increase in their respective metabolites, 19(R)-HETE and 20-HETE. On the other hand, CYP2C23 mRNA levels were significantly decreased only in male rats, with no significant decrease in EETs. Our findings indicate that renal CYP-mediated AA metabolism undergoes sex-specific reprogramming in response to cardiac pressure overload, which may contribute to the observed divergent cardiac remodeling. This research highlights the importance of the kidney-heart axis and supports the potential for sex-specific metabolic targets in the treatment of cardiovascular diseases.

Hypertrophic cardiomyopathy (HCM) is a relatively common heritable cardiac condition (~1 in 500) that can significantly reduce quality and quantity of life. Severe symptoms are often from dynamic left ventricular outflow tract (LVOT) obstruction which may result in dyspnea, chest pain, fatigue, and (pre)syncope. This obstructive phenotype is present in more than half of cases. Traditional pharmacological therapies used to treat symptomatic LVOT obstruction are ineffective in many patients thereby necessitating septal reduction therapy in the form of alcohol septal ablation or surgical myectomy. In recent years, the demand for improved HCM treatment without surgical intervention has led to the development of a new class of drugs called cardiac myosin inhibitors. Mavacamten represents the first-in-class cardiac myosin inhibitor, which is now approved in Canada, available for special authorization cost coverage in most provinces, and is increasingly being prescribed in both specialized HCM programs and general cardiology clinics. As such, many general cardiologists, internists, and family physicians will need to be familiar with these agents. This review on the myosin inhibitors, particularly mavacamten, provides a perspective for more general cardiovascular providers by summarizing the key mechanisms, clinical trials, expected outcomes, and potential impacts on the Canadian healthcare system.

The Guest Editors provide highlights and overview of the eCollection which was based on the International Academy of Cardiovascular Sciences-North American Section (IACS-NAS) 2023 annual meeting. The overall impact generated by the papers published in eCollection with emphasis on cutting edge topics including FDA-Adverse Event Reporting System (FAERS), ChatGPT and physician recommendation, small molecule research, sarcopenia and aging, metabolism, and orphan receptors and weight loss. The editorial overview provides insights into the continued success of the eCollection.

Cardiovascular autonomic dysfunction (CVAD) is a prevalent yet underrecognized non-motor manifestation of Parkinson's disease (PD) that adversely affects morbidity, prognosis, and quality of life. Framed by the heart-brain axis, this review examines bidirectional interactions between neurodegeneration and cardiovascular control, synthesizing clinical and preclinical evidence from 2015-2025. We searched PubMed for English-language studies addressing autonomic involvement in PD and cardiovascular outcomes; of 1,035 records identified, 240 met inclusion criteria following removal of duplicates, commentaries, and off-topic articles. Consistent clinical observations include orthostatic hypotension, diminished heart rate variability, impaired baroreflex sensitivity, and blood pressure lability, though heterogeneity in acquisition protocols and analytics limits comparability. Experimental models reveal mechanistic leads but often lack integration of central and peripheral endpoints, sex-inclusive cohorts, aging variables, and longitudinal designs. We highlight methodological constraints, particularly the interpretive limits of HRV, anesthesia effects in preclinical work, and inconsistent preprocessing, and outline priorities for standardized, multimodal approaches that couple neural markers with cardiovascular readouts. Advancing an integrative, translational framework may enable earlier diagnosis, robust autonomic biomarkers, risk stratification across "body-first" and "brain-first" trajectories, and targeted interventions, including neuromodulation and metabolic strategies, aimed at mitigating CVAD and potentially modifying PD progression.

Ischemia-reperfusion (IR) injury of vascular grafts used in coronary artery bypass surgery can compromise outcomes. This study examined whether GYY4137, a slow-release hydrogen sulfide donor, protects against IR-induced vascular damage in rat thoracic aorta. Twenty male Sprague-Dawley rats (21-22 months old) were randomly assigned to Control, IR, IR+GYY4137 (100 µM), and IR+GYY4137 (300 µM) groups. To induce IR injury, aortic rings were incubated in nitrogen-gassed saline at 4°C for 24 hours, then exposed to sodium hypochlorite (200 μM) at 37°C for 30 minutes. Vascular function was evaluated in organ baths; malondialdehyde, glutathione, and caspase-3 were quantified. IR injury markedly impaired contraction and endothelium-dependent relaxation, which GYY4137 did not restore. In contrast, IR increased malondialdehyde (p=0.02), which fell to near-control with both 100 µM (p=0.008) and 300 µM GYY4137 (p=0.012). IR lowered glutathione (p=0.012) was restored by 300 µM GYY4137 (p=0.004). Likewise, caspase-3 rose (p=0.02) but returned to near-control with both 100 µM (p=0.004) and 300 µM GYY4137 (p=0.02). In conclusion, GYY4137 reduces oxidative stress and apoptosis markers without improving vascular dysfunction in an IR model of rat thoracic aorta. This disparity underscores the complex pathophysiology of vascular IR injury, where cellular-level protection does not readily translate to functional recovery.

Cardiogenic shock is a clinical syndrome characterized by cardiac pump failure, resulting in low cardiac output and subsequent tissue hypoperfusion. Current guidelines define cardiogenic shock based on the presence of hypotension and signs of hypoperfusion. However, recent randomized clinical trials have demonstrated that these criteria are imperfect and may not reliably distinguish cardiogenic shock from other forms of shock, such as hypovolemic, distributive, or mixed types. Therefore, new clinical diagnostic criteria are urgently needed. A revised definition, grounded in the underlying pathophysiology, should diagnose cardiogenic shock based on low cardiac output, objective evidence of tissue hypoperfusion from reliable biomarkers, and the exclusion of hypovolemia. Enhancing the accuracy of cardiogenic shock diagnosis could significantly improve patient selection for therapies specifically targeted at this condition.

Generation of reactive oxygen species (ROS) is a physiological product of cell activity that is mainly generated by the mitochondria as well as by transmembrane NADPH oxidases (NOX1-5) present at the plasma and nuclear envelope membranes. The level of basal intracellular ROS is regulated by endogenous antioxidants such as glutathione (GSH) and the endogenous and exogenous antioxidant taurine. These two antioxidants are present in all types of cells and more particularly in the heart and the vascular system. They regulate and control intracellular ROS levels in order to prevent this latter from inducing dysfunction of the cardiovascular system. There are also exogenous antioxidants that are present in many types of food, such as vitamin C, vitamin E, and resveratrol. These exogenous antioxidants are necessary to complement the effect of endogenous antioxidants. However, according to the literature, it is difficult to generalize about the beneficial effect of exogenous antioxidants in preventing cardiovascular disease. This does not necessarily seem to be the case for endogenous antioxidants. In this review, we will discuss the advantages and disadvantages of using exogenous and endogenous antioxidants, and suggest the potential application of one of them.