Kura B, Pavelkova P, Kalocayova B
… +7 more, Sykora M, Vlkovicova J, Kluknavsky M, LeBaron T, Pobijakova M, Sagatova A, Slezak J
Can J Physiol Pharmacol
· 2026 Jan · PMID 41806364
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Ionizing radiation is a known risk factor for the occurrence and development of cardiovascular diseases, particularly in patients receiving thoracic radiotherapy. This exposure leads to oxidative stress and inflammation,...Ionizing radiation is a known risk factor for the occurrence and development of cardiovascular diseases, particularly in patients receiving thoracic radiotherapy. This exposure leads to oxidative stress and inflammation, which can damage cardiac tissue and vascular endothelium. Molecular hydrogen (H) has been recognized for its therapeutic potential, including antioxidant effects. In this study, male Wistar rats were irradiated with a dose of 10 Gy (X-rays) in the chest area. Two and 9 days post-irradiation, significant increases in lactate dehydrogenase (LDH), catalase, glutathione peroxidase activity, malondialdehyde, superoxide, and tumor necrosis factor alpha levels were observed in the rat blood plasma or heart tissue. Administration of H either via drinking H-rich water (min. 4 mg/L) or inhaling H in air (4%), effectively decreased oxidative stress, LDH, and inflammatory proteins to normal levels. H also normalized the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associating protein 1 (Nrf2/Keap1) pathway, an important antioxidative response regulator activated by irradiation. Based on these results, we can conclude that H administration through both routes mitigated heart damage caused by irradiation after 2 and 9 days. The mitigating effect exerted more pronounced trend with H gas inhalation, but further research is needed for statistically relevant data and mechanistic insights.
Li W, Karakaya E, Edwards J
… +7 more, Li A, McCrorey M, Butler H, Van Beusecum J, Jamil S, Abdul Y, Ergul A
Can J Physiol Pharmacol
· 2026 Jan · PMID 41780034
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Diabetes increases the risk of vascular contributions to cognitive impairment and dementia (VCID). Using a microemboli (ME) model, we found that diabetic rats experience more severe white matter damage and progressive co...Diabetes increases the risk of vascular contributions to cognitive impairment and dementia (VCID). Using a microemboli (ME) model, we found that diabetic rats experience more severe white matter damage and progressive cognitive decline than controls. Moreover, the restoration of endothelial function before ME injection prevents VCID in diabetes. Given that diabetes mediates early endothelial dysfunction, activates the endothelin (ET) system, and the post-mortem brain (b) ET-1 levels correlate with tissue hypoxia in dementia patients, this study investigated the relationship between ET system, hypoxia, and neuroinflammation in this clinically relevant VCID model. While there were no ME-mediated changes or differences between control and diabetic groups in plasma and bET-1 levels, bET-1 levels correlated with hypoxia markers. ETR expression was reduced by the ISMN (75 mg/kg/day) and cilostazol (60 mg/kg/day) treatment. On the other hand, ETR expression was lower in the sham diabetic group compared to the sham controls, and ME injection did not have further effect. The treatment restored ETR expression to comparable levels in the control sham group. These findings suggest a link between the ET system, hypoxia, and neuroinflammation in diabetic VCID. Modulating the ET system may be a viable therapeutic strategy to improve vascular function and prevent VCID.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41762750
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Propionyl L-carnitine (PPLC), a short-chain fatty acid derivative of carnitine, has been reported to produce beneficial effects in various cardiovascular diseases such as maladaptive cardiac hypertrophy, heart failure, i...Propionyl L-carnitine (PPLC), a short-chain fatty acid derivative of carnitine, has been reported to produce beneficial effects in various cardiovascular diseases such as maladaptive cardiac hypertrophy, heart failure, ischemic heart disease, different types of cardiomyopathies and peripheral artery disease. Although all these cardiovascular diseases have diverse epidemiology and pathophysiology, both clinical and preclinical studies have indicated the role of oxidative stress, Ca-handling defects and metabolic abnormalities in their development and progression. In heart failure due to myocardial infarction, treatment with PPLC attenuated the inhibition of Na-K ATPase and Na-Ca exchange activities. PPLC therapy of animals with diabetic cardiomyopathy improved Ca-handling abnormalities in cardiomyocytes by affecting the entry of Ca through sarcolemma and regulating the sarcoplasmic reticular Ca-pump activities. The improvement of cardiac function recovery by PPLC treatment in ischemia-reperfused hearts was associated with its ability to antagonize the deleterious effects of palmitoyl L-carnitine on Ca-handling proteins. Treatment of peripheral artery disease with PPLC increased blood flow by affecting the vascular endothelium and smooth muscle functions in lower limbs. These observations support the view that PPLC improves cardiovascular function in diseased conditions by promoting mitochondrial metabolism, reducing oxidative stress and preventing Ca-handling abnormalities.
Marinković S, Šobot T, Maksimović Ž
… +11 more, Ðukanović Ð, Uletilović S, Mandić-Kovačević N, Jovičić S, Matičić M, Gajić Bojić M, Stojmenovski A, Bojanić A, Lončar-Stojiljković D, Škrbić R, Stojiljković M
Can J Physiol Pharmacol
· 2026 Jan · PMID 41747235
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Acetylcholinesterase (AChE) inhibitors constitute a large and chemically diverse group of compounds that inhibit the enzyme AChE. Some of these compounds that are used to treat Alzheimer's disease have been reported to h...Acetylcholinesterase (AChE) inhibitors constitute a large and chemically diverse group of compounds that inhibit the enzyme AChE. Some of these compounds that are used to treat Alzheimer's disease have been reported to have favourable cardiovascular effects, i.e., a 35% reduction of the risk for cardiovascular disease. There has been a growing interest in AchE inhibitors as a potential therapeutic approach for cardiovascular diseases, especially heart failure (HF), since they correct the autonomic imbalance, a key component in the development of heart failure. In the present study, HF was induced in male Wistar albino rats using an isoprenaline model (85 mg/kg/day s.c. for 2 days, followed by 3 weeks of HF development) of heart failure with preserved ejection fraction. Afterwards, rats were treated with pyridostigmine (20 mg/kg/day in tap water for 14 days), while the controls received no treatment. Electrocardiographic and echosonographic measurements were obtained, and samples were taken for antioxidative status measurement and histopathological analysis. Administration of pyridostigmine resulted in preservation of cardiac contractile function (↑ EF), coupled with a decrease in chamber wall thinning (↑ PWDd, ↑ PWDs) and dilatation progression (↓ LVIDd, ↓ LVIDs). Additionally, histopathological findings showed significantly reduced tissue damage score and attenuation of cardiac fibrosis development, indicating the cardioprotective potential of pyridostigmine when used as treatment for the early stages of heart failure; however, further investigations are needed to fully investigate the interplay between the several proposed mechanisms through which AChE inhibitors express their protective effects.
Garg R, Hamzat B, Cheung G
… +10 more, Eurich D, Kaboré J, de Léséleuc L, Liu Z, Missaoui H, Randall J, Shearer D, Stock D, Yang J, Gomes T
Can J Physiol Pharmacol
· 2026 Jan · PMID 41701964
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Opioid agonist treatment (OAT) is the recommended first-line therapy for individuals with opioid use disorder. The availability of different products and prescribing guidance for OAT has rapidly evolved in recent years....Opioid agonist treatment (OAT) is the recommended first-line therapy for individuals with opioid use disorder. The availability of different products and prescribing guidance for OAT has rapidly evolved in recent years. Therefore, we conducted a repeated cross-sectional study using pharmacy dispensing data from six Canadian provinces to examine trends in methadone and buprenorphine use between January 2018 and December 2022. Monthly population-adjusted rates of OAT recipients were calculated by province, and annual cohorts were stratified by demographic characteristics and OAT type. Prevalence of OAT use varied across provinces, ranging from 1.03 per 1000 in Quebec to 3.59 per 1000 in British Columbia. Increases in OAT use between 2018 and 2022 were observed in Alberta (3.00-3.75 per 1000) and Manitoba (1.68-2.39 per 1000), while rates remained relatively stable elsewhere. OAT use was highest among adults aged 25-44 years, males, and residents of lower-income neighbourhoods. A notable shift toward buprenorphine prescribing was observed across all provinces, with 45%-74% of OAT recipients dispensed a buprenorphine product in 2022. These cross-provincial differences in OAT rates likely reflect variations in opioid use disorder prevalence, prescribing practices, and access to care.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41687086
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Pain is commonly experienced among Canadians but can be difficult to treat due to complex mechanisms. Several medications used for analgesia (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, a...Pain is commonly experienced among Canadians but can be difficult to treat due to complex mechanisms. Several medications used for analgesia (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, anticonvulsants), can have variable responses, limiting their safety and effectiveness. Pharmacogenomics studies have uncovered genetic variation found within drug processing (i.e., pharmacokinetic) and response (i.e., pharmacodynamic) pathways that are linked to the development of ineffectiveness and/or adverse effects to analgesics. As a result, several gene-drug associations with strong evidence have been incorporated into clinical practice guidelines. For example, individuals are currently recommended to undergo genetic testing for variation within (adverse effects to some NSAIDs and anticonvulsants), (ineffectiveness/adverse effects to some opioids, antidepressants, and anticonvulsants), (ineffectiveness/adverse effects to some antidepressants), (adverse effects to some antidepressants), and and (adverse effects to some anticonvulsants) so that modifications can be made to reduce the likelihood of treatment ineffectiveness/adverse effects. As there is limited evidence for treatment recommendations for all analgesics, and in children and minority ancestral groups, further pharmacogenomics studies are needed to identify additional genetic variation that contributes to undesirable outcomes. Ultimately, pharmacogenomics is helping to develop personalized pain management strategies to improve pain treatment outcomes for all patients.
Olaniyi K, Moodley J, Moodley R
… +1 more, Mackraj I
Can J Physiol Pharmacol
· 2026 Jan · PMID 41687083
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This study evaluated the presence of bacterial species in the placenta of women with pre-eclampsia and compared with that of normotensive women. One hundred and twenty participants, comprising 60 pre-eclamptic (30 early-...This study evaluated the presence of bacterial species in the placenta of women with pre-eclampsia and compared with that of normotensive women. One hundred and twenty participants, comprising 60 pre-eclamptic (30 early- and late-onset, respectively) and 60 age-matched normotensive women (30 early and late-gestation normotensive, respectively) were recruited. After informed consent was obtained, the placenta were obtained through caesarean section with sterile and standardized clinical procedures. DNA was extracted from each tissue, and the samples were pooled into six libraries and sequenced on Illumina NextSeq500 using a shotgun metagenomic approach. Bioinformatics was used to analyse the reads with the implementation of Kraken2/MetaPhlAn classification methods and complemented by multi-layered contamination assessment strategy that included frequency-based decontam filtering. Most reads were classified as belonging to the phyla , and various species. PE samples showed notable and species, while dominated normotensive samples. Further analysis showed no significant difference between bacterial species of pre-eclamptic and normotensive placental samples. The results show very low levels of bacteria in the placental samples. In addition, a little difference was observed between the bacterial compositions of pre-eclamptic and age-matched normotensive placental tissues, but not statistically significant.
Melo W, Dos Santos Silva R, Santos Soares I
… +4 more, de Sousa Barbosa B, Cardoso de Brito F, Argôlo Neto N, Bezerra D
Can J Physiol Pharmacol
· 2026 Jan · PMID 41593860
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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 ident...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 GO 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 noncanonical 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.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41565628
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Maximal oxygen consumption (VO 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-intensi...Maximal oxygen consumption (VO 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 with BFR straps improves VO, tidal volume, and respiratory frequency in older adults. Twenty-five participants (mean age: 70 ± 5.6 years) completed bi-weekly trainings. VO and respiratory measures were assessed during a 30 s sit-to-stand test. The BFR group showed significant VO gains, while respiratory measures remained unchanged. BFR may offer an effective strategy to enhance aerobic capacity in aging adults. ClinicalTrials.gov: NCT06724393.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41565627
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has many traits that 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...has many traits that 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 ) and opioid (e.g., opioid receptor ) 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 (orthologous to human ), involved in opioid sensitivity, and (orthologous to human ), involved in opioid tolerance. 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 as a model for uncovering the genetic underpinnings of pain and its management.
Salem H, Eldesouky A, Amer M
… +2 more, Shebl D, El-Roghy E
Can J Physiol Pharmacol
· 2026 Jan · PMID 41565621
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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 th...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.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41549365
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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 differ...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, and CD106), and lacked hematopoietic marker CD45. Multipotency was confirmed by adipogenic, chondrogenic, and osteogenic differentiation assays. Cells were then exposed to acitretin (10, 100, and 1000 µg/L) or vehicle (dimethyl sulfoxide, DMSO), and osteogenic differentiation was assessed at day 14 by Alizarin Red-S staining and semiquantitative 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 the frequency of skeletal system-related side effects in patients using retinoids, and determining the conditions of use of acitretin in high-risk patients.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41549356
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Obesity, type 2 diabetes (T2D), and cardiovascular disease are closely related conditions contributing to the global rise in cardiometabolic disease. Incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-depende...Obesity, type 2 diabetes (T2D), and cardiovascular disease 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 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 has been shown to aid in managing metabolic dysfunction and, more recently, in preventing cardiovascular complications.
Kennedy K, Wallace J, Koller K
… +7 more, Patten C, Thomas T, Murphy N, Flanagan C, Hughes C, Holloway A, Sloboda D
Can J Physiol Pharmacol
· 2026 Jan · PMID 41499767
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Cigarette smoking is associated with numerous adverse pregnancy outcomes, due in part to polycyclic aromatic hydrocarbons and free radicals produced by combustion. Less is known about the impact of smokeless tobacco (ST)...Cigarette smoking is associated with numerous adverse pregnancy outcomes, due in part to polycyclic aromatic hydrocarbons and free radicals produced by combustion. Less is known about the impact of smokeless tobacco (ST) use during pregnancy. Alaska Native women report higher rates of cigarette and ST use during pregnancy than non-Native women. We investigated oxidative stress and hypoxia pathways in term placentae from Alaska Native women who did (commercial or ; = 10) or did not ( = 18) use ST during pregnancy. Despite substantial maternal exposure to nicotine, placentae of women who used ST had similar mRNA levels of antioxidant enzymes and markers of hypoxia compared to those who did not use tobacco. Although mRNA levels of angiogenesis markers and were similar between groups, mRNA levels are increased in placentae of women using ST compared to women who did not use tobacco. Together these results suggest that, while ST use may not have as significant an effect on oxidative stress pathways in the placenta as cigarette smoking, an effect is present. It is not clear what this limited effect may have on the developing fetus.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41499766
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Obesity is a global epidemic, posing significant challenges to individual health and healthcare systems. This article explores the pharmacology of incretin-based therapies beyond single receptor agonists and focuses on t...Obesity is a global epidemic, posing significant challenges to individual health and healthcare systems. This article explores the pharmacology of incretin-based therapies beyond single receptor agonists and focuses on their emerging role in obesity management. The complex interplay between metabolic, environmental, and psychosocial factors contributes to obesity and its wide-ranging clinical sequelae. Emphasis is placed on the physiological functions of key hormones, such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), amylin, and glucagon, in regulating energy balance, appetite, and insulin secretion. The commentary discusses novel therapeutic approaches, including dual and triple receptor agonists. Future directions in personalized medicine are included to highlight innovative drug-delivery systems and potential new targets. Collectively, incretin-targeted therapies have the potential to be the next generation of obesity treatments, effective in achieving outcomes and tailored for individual patient needs.
Araujo F, Moraes R, Dos Passos R
… +6 more, Fontes M, Wenceslau C, Webb R, Priviero F, McCarthy C, Silva D
Can J Physiol Pharmacol
· 2026 Jan · PMID 41499765
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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 vascu...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.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41499764
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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...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.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41420876
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Incretin therapy, utilizing glucagon-like peptide-1 (GLP-1) receptor agonists and dual receptor agonists, is a cornerstone of obesity management due to effects on appetite suppression, weight loss, and metabolic improvem...Incretin therapy, utilizing glucagon-like peptide-1 (GLP-1) receptor agonists and dual receptor agonists, is a cornerstone of obesity management due to effects on appetite suppression, weight loss, and metabolic improvement. Liraglutide, semaglutide, and tirzepatide promote weight reduction by modulating incretin hormone pathways, leading to decreased caloric intake. Recent studies with semaglutide and tirzepatide have demonstrated substantial weight loss outcomes beyond glucose-lowering benefits, shifting the paradigm of obesity treatment toward pharmacological interventions. While effective in weight loss, challenges remain regarding long-term efficacy, tolerability, and accessibility. Future directions include optimizing combination therapies and exploring novel incretin-based molecules with dual or triple receptor activity. This review focuses on the clinical application of incretin therapy in obesity, emphasizing practical considerations and highlighting therapeutic benefits for obesity to improve outcomes and public health.