Canadian journal of physiology and pharmacology最新文献

Glucagon-like peptide-1 (GLP-1) receptor agonists provide renoprotective benefits in diabetes, yet the molecular mechanisms linking GLP-1 signaling to diabetic nephropathy remain poorly defined. This study aimed to identify shared molecular targets between GLP-1 activity and diabetic kidney disease by integrating protein targets of GLP-1 from UniProt with disease-associated genes from GeneCards. The overlapping gene set was analyzed using STRING and Cytoscape with MCODE clustering, followed by Gene Ontology and KEGG enrichment through the clusterProfiler package. Molecular docking with HADDOCK was employed to validate structural interactions between GLP-1 and central network proteins. We identified 17 shared genes, including STAT3, EP300, MAPK1, and INSR, which formed a densely connected cluster enriched in pathways related to insulin response, hypoxia adaptation, apoptosis, and glucose metabolism. Docking analysis demonstrated direct and favorable binding of GLP-1 to STAT3, PIK3R1, and EP300, suggesting non-canonical intracellular mechanisms involving transcriptional regulation and epigenetic modulation. These findings reveal a novel convergence between GLP-1 signaling and diabetic nephropathy pathways, providing mechanistic insights that guide the experimental determination of the underlying molecular interactions. This framework may ultimately contribute to the refinement of renal therapies based on GLP-1 modulation.

Management of metabolic dysfunction-associated steatotic liver disease (MASLD) remains a significant clinical challenge. This study evaluated the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapy to metformin in the treatment of MASLD using an experimentally induced type 2 diabetes (T2D) rat model. T2D was induced in 18 rats through a high-fat diet combined with a low dose of streptozotocin. The diabetic rats were then randomly allocated into three equal groups: untreated, metformin-treated, and metformin/CoQ10-treated. An additional six rats maintained on a normal chow diet served as the control group. Development of MASLD was confirmed through biochemical assays and histopathological analyses. Liver histology and electron microscopy were performed, along with immunohistochemistry for BAX and CD68 markers. Our results demonstrated that T2D rats exhibited impaired glucose and lipid profiles, elevated liver enzymes, and reduced adiponectin levels. These alterations were accompanied by hepatic oxidative stress, histopathological features of MASLD, fibrosis, and increased expression of BAX and CD68. Treatment with either metformin monotherapy or metformin/CoQ10 combination therapy significantly ameliorated the biochemical and histopathological manifestations of MASLD, as well as reduced the expression of BAX and CD68 in the liver. Importantly, combined metformin/CoQ10 therapy exerted a stronger hepatoprotective effect than metformin alone.

Maximal oxygen consumption (VO₂ max) reflects the greatest amount of oxygen utilized upon exertion. Blood flow restriction (BFR) limits venous return, enabling low-intensity exercise to yield adaptations like high-intensity training. This study examined whether 5 weeks of online resistance training (RT) with BFR straps improves VO₂, tidal volume, and respiratory frequency in older adults. Twenty-five participants (mean age: 70 ± 5.6) completed bi-weekly trainings. VO₂ and respiratory measures were assessed during a 30-second sit-to-stand test. The BFR group showed significant VO₂ gains, while respiratory measures remained unchanged. BFR may offer an effective strategy to enhance aerobic capacity in aging adults. ClinicalTrials.gov: NCT06724393.

Caenorhabditis elegans has many traits which make it a valuable model for human neurobiology, including the study of pain-related processes. In particular, its genetic tractability can help uncover novel genetic factors involved in pain-related signal transduction. This can be beneficial for studying pain medications, such as cannabinoids and opioids. Here, we review how the pain-related impacts of cannabinoids/opioids have been assessed using behavioural assays (e.g., measuring feeding, locomotion, and nociception). Reviewed studies identified genetic factors responsible for both cannabinoid (e.g., endocannabinoid receptor npr-19) and opioid (e.g., opioid receptor npr-17) signalling, which were in turn used to characterize neurotransmission (e.g., monoaminergic, neuropeptidergic, and Hedgehog signalling) and complex modulators (e.g., TRP channels involved in cannabinoid signalling) contributing to cannabinoid/opioid signalling. Additionally, studies using these models were able to discover novel genetic components, including frpr-13 (orthologous to human GRP139), involved in opioid sensitivity, and ptr-25 (orthologous to human PTCHD1), involved in opioid tolerance. Additionally, the pathways highlighted in this review represent clear paths for further investigation of the genetic mechanisms underlying individual differences in pain sensitivity, pain relief and drug tolerance. Overall, this review demonstrates the value of C. elegans as a model for uncovering the genetic underpinnings of pain and its management.

Obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD) are closely related conditions contributing to the global rise in cardiometabolic disease. Incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have emerged as critical regulators of glucose metabolism, pancreatic function, and cardiovascular physiology. However, despite increasing clinical use of GLP-1 receptor agonists and dual GLP-1/GIP agonists, the precise mechanisms by which endogenous incretins influence cardiovascular tissues remain incompletely understood, particularly in the context of obesity and T2D. This review explores the history, signalling mechanisms, and physiological actions of natural endogenous GLP-1 and GIP, with a focus on cardiovascular physiology. Endogenous GLP-1 promotes insulin secretion, β-cell survival, and appetite suppression, and exerts protective effects on the endothelium. GLP-1 also reduces inflammation, enhances nitric oxide production, and improves myocardial glucose utilization during ischemia. Endogenous GIP is involved in insulin secretion, β-cell survival, and adipogenesis. In obesity and T2D, incretin secretion and insulinotropic effects are altered. The therapeutic potential of GLP-1 receptor agonists and emerging dual GLP-1/GIP agonists have been shown to aid in managing metabolic dysfunction and more recently in preventing cardiovascular complications.

Acitretin, a widely used second-generation retinoid, has diverse systemic effects, yet its influence on osteogenic processes remains unclear. This study investigated the effects of acitretin on in vitro osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMD-MSCs). BMD-MSCs were isolated from femur and tibia of six male Wistar rats (200-250 g, 4-6 weeks). At passage 3, cells exhibited spindle-shaped morphology, expressed mesenchymal markers (CD90, CD44, CD29, CD54, CD106), and lacked hematopoietic marker CD45. Multipotency was confirmed by adipogenic, chondrogenic, and osteogenic differentiation assays. Cells were then exposed to acitretin (10, 100, 1000 µg/L) or vehicle (dimethyl sulphoxide, DMSO), and osteogenic differentiation was assessed at day 14 by Alizarin Red-S staining and semi-quantitative RT-PCR analysis of collagen I alpha 2, osteonectin, and osteopontin expression. High-dose acitretin (1000 µg/L) significantly inhibited osteogenic differentiation, independent of DMSO, while lower concentrations showed no marked effect. These findings demonstrate that acitretin suppresses osteogenic differentiation of BMD-MSCs under in vitro conditions, suggesting potential implications for bone metabolism in patients receiving retinoid therapy. Further studies should focus on elucidating the mechanism of this effect, determining frequency of skeletal system-related side effects in patients using retinoids, and determining the conditions of use of acitretin in high-risk patients.

Sexual dysfunction affects the quality of life for both men and women. Menthol, a TRPM8 agonist, is widely used in products to enhance sexual performance due to its cooling effect. Beyond this, menthol also induces vascular effects in male arteries. To explore its effects on female vasculature, we studied male and female C57BL/6 mice, along with female TRPM8 knockout (KO) mice. We isolated the internal pudendal artery and aorta to assess isometric contractile force. Menthol-induced relaxation of the pudendal artery was reduced in both female TRPM8 KO and male mice compared to female controls. Acetylcholine-induced relaxation was not affected in females, but in males, it was attenuated by menthol and enhanced by M8-B, a TRPM8 inhibitor. Menthol did not alter responses to norepinephrine, serotonin, or histamine in either sex. Notably, menthol-induced relaxation was also reduced in the aortas of female TRPM8 KO mice. In both the aorta and pudendal arteries of female mice, the TRPA1 inhibitor HC030031 significantly diminished menthol-induced relaxation. These findings suggest that TRPM8 modulation plays a role in acetylcholine-induced relaxation in male, but not female, pudendal arteries. Moreover, the menthol vascular effect in female arteries relies on TRPM8 and TRPA1 activation.

Endothelial cells play a key role in maintaining vascular homeostasis, and disruption of their function contributes to endothelial dysfunction. The underlying mechanisms have been studied using primary endothelial cells (HUVEC) and hybrid endothelial cell line EA.hy926, and their responses to disrupting agents should be similar. In this study, we investigated the effects of elevated homocysteine (HCY) concentrations, a risk factor for endothelial dysfunction development, in both cell types. Using multiple approaches, the inhibitory effect of HCY was consistently observed in HUVEC. In contrast, EA.hy926 cells exhibited increased proliferation and viability at lower doses, whereas the highest dose (10 mM) was inhibitory to both cell types. The bimodal and stimulatory effect of HCY in EA.hy926 cells was abolished by aminooxyacetic acid, a dominant inhibitor of cystathionine beta-synthase suggesting that decreased HCY levels and the formation of glutathione and hydrogen sulfide protected these cells. No such effect was found in HUVEC. The PI3K/Akt and MAPK/ERK signaling pathways were differentially activated in both models, suggesting their differing contributions to the HCY response. These findings reveal the cell-specific mechanisms of HCY-induced endothelial disruption, contributing to a better understanding of the mechanisms underlying endothelial dysfunction.

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), Ca²⁺ signaling, cellular signaling, and inflammatory responses are affected by aging. These significantly impact Ca²⁺ handling by cardiac cells and the architecture of cardiomyocytes, leading to impaired contractility, and increased risk of arrhythmias. Cellular Ca²⁺ 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 Ca²⁺ 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.

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.