Canadian journal of physiology and pharmacology最新文献

Hypotensive influences of benzodiazepines and other GABA_A receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABA_A receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABA_A receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABA_A γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABA_A receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ2 over other αxβ3γ2 GABA_A receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABA_A receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.

Prenatal glucocorticoid exposure has been shown to alter hypothalamic-pituitary-adrenal axis function resulting in altered fetal development that can persist through adulthood. Fetal exposure to excess dexamethasone, a synthetic glucocorticoid, has been shown to alter adult behaviour and metabolism. This study investigated the effects prenatal dexamethasone exposure had on adult offspring cardiac and liver metabolism and oxidative stress. Pregnant C57BL/6 mice received a dose of 0.4 mg/kg dexamethasone on gestational days 15-17. Once pups were approximately 7 months old, glucose uptake was determined using positron emission tomography and insulin resistance (IR) was determined by homeostatic model assessment (HOMA) IR calculation. Oxidative stress was assessed by measuring 4-hydroxynonenal protein adduct formation and total reactive oxygen species. Female dexamethasone group had significantly increased glucose uptake when insulin stimulated compared to vehicle-treated mice. HOMA IR revealed no evidence of IR in either male or female offspring. There was also no change in oxidative stress markers in either cardiac or liver tissues of male or female offspring. These data suggest that prenatal dexamethasone exposure in male mice does not alter oxidative stress or metabolism. However, prenatal dexamethasone exposure increased glucocorticoids, cardiac glucose uptake, and pAkt signaling in female heart tissues in adult mice, suggesting there are sex differences in prenatal dexamethasone exposure.

Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 µg/paw); AM251 (80 µg/paw) and AM630 (100 µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.

Cardiac disorders remain the leading cause of mortality worldwide. Current clinical strategies, including drug therapy, surgical interventions, and organ transplantation offer limited benefits to patients without regenerating the damaged myocardium. Over the past decade, stem cell therapy has generated a keen interest owing to its unique self-renewal and immune privileged characteristics. Furthermore, the ability of stem cells to differentiate into specialized cell types, has made them a popular therapeutic tool against various diseases. This comprehensive review provides an overview of therapeutic potential of different types of stem cells in reference to cardiovascular diseases. Furthermore, it sheds light on the advantages and limitations associated with each cell type. An in-depth analysis of the challenges associated with stem cell research and the hurdles for its clinical translation and their possible solutions have also been elaborated upon. It examines the controversies surrounding embryonic stem cells and the emergence of alternative approaches, such as the use of induced pluripotent stem cells for cardiac therapeutic applications. Overall, this review serves as a valuable resource for researchers, clinicians, and policymakers involved in the field of regenerative medicine, guiding the development of safe and effective stem cell-based therapies to revolutionize patient care.

The Toll-like receptor (TLR)/mammalian target of rapamycin (mTOR) signaling pathway is involved in the intracellular regulation of protein synthesis, specifically the ones that mediate neuronal morphology and facilitate synaptic plasticity. The activity of TLR/mTOR signaling has been disrupted, leading to neurodevelopment and deficient synaptic plasticity, which are the main symptoms of schizophrenia. The TLR receptor activates the mTOR signaling pathway and increases the elevation of inflammatory cytokines. Interleukin (IL)-6 is the most commonly altered cytokine, while IL-1, tumor necrosis factor, and interferon (IFN) also lead to SCZ. Anti-inflammatory and anti-oxidative agents such as celecoxib, aspirin, minocycline, and omega-3 fatty acids have shown efficiency against SCZ. As a result, inhibition of the inflammatory process could be suggested for the treatment of SCZ. So mTOR/TLR blockers represent the treatment of SCZ due to their inflammatory consequences. The objective of the present work was to find a novel anti-inflammatory agent that may block the mTOR/TLR inflammatory signaling pathways and might pave the way for the treatment of neuroinflammatory SCZ. Data were collected from experimental and clinical studies published in English between 1998 and October 2022 from Google Scholar, PubMed, Scopus, and the Cochrane library.

Although the collagenase enzyme activity of matrix metalloproteinase-9 (MMP9) is well-documented, its non-enzymatic functions remain less understood. The interaction between intracellular superoxide dismutase-1 (SOD1) and MMP9 is known, with SOD1 suppressing MMP9. However, the mechanism by which MMP9, a secretory protein, influences the extracellular antioxidant superoxide dismutase-3 (SOD3) is not yet clear. To explore MMP9's regulatory impact on SOD3, we employed human embryonic kidney-293 cells, transfecting them with MMP9 overexpresssion and catalytic-site mutant plasmids. Additionally, MMP9 overexpressing cells were treated with an MMP9 activator and inhibitor. Analyses of both cell lysates and culture medium provided insights into MMP9's intracellular and extracellular regulatory roles. In-silico analysis and experimental approaches like proximal ligation assay and co-immunoprecipitation were utilized to delineate the protein-protein interactions between MMP9 and SOD3. Our findings indicate that activated MMP9 enhances SOD3 levels, a regulation not hindered by MMP9 inhibitors. Intriguingly, catalytically inactive MMP9 appeared to reduce SOD3 levels, likely due to MMP9's binding with SOD3, leading to their proteolytic degradation. This MMP9 influence on SOD3 was consistent in both intracellular and extracellular environments, suggesting a parallel in MMP9-SOD3 interactions across these domains. Ultimately, this study unveils a novel interaction between MMP9 and SOD3, highlighting the unique regulatory role of catalytically inactive MMP9 in diminishing SOD3 levels, contrasting its usual upregulation by active MMP9.

The decision to use the optimal animal model to mimic the various types of cardiovascular disease is a critical one for a basic scientist. Clinical cardiovascular disease can be complex and presents itself as atherosclerosis, hypertension, ischemia/reperfusion injury, myocardial infarcts, and cardiomyopathies, amongst others. This may be further complicated by the simultaneous presence of two or more cardiovascular lesions (for example, atherosclerosis and hypertension) and co-morbidities (i.e., diabetes, infectious disease, obesity, etc). This variety and merging of disease states creates an unusually difficult situation for the researcher who needs to identify the optimal animal model that is available to best represent all of the characteristics of the clinical cardiovascular disease. The present manuscript reviews the characteristics of the various animal models of cardiovascular disease available today, their advantages and disadvantages, with the goal to allow the reader access to the most recent data available for optimal choices prior to the initiation of the study. The animal species that can be chosen, the methods of generating these models of cardiovascular disease, as well as the specific cardiovascular lesions involved in each of these models are reviewed. A particular focus on the JCR:LA-cp rat as a model of cardiovascular disease is discussed.

Introduction: Chronic suppurative otitis media (CSOM) is a long standing infection of the middle ear cleft. Mastoidectomy, with or without tympanoplasty, is the preferred treatment for CSOM. However, the drill used during ear surgery generates noise that may potentially cause hearing damage in both the operated and opposite inner ear, leading to temporary or permanent hearing loss.

Materials and methods: The study included patients diagnosed with CSOM who underwent surgeries in the Otorhinolaryngology department. Postoperatively, all patients were followed up on the 7th day and 1 month after the surgery. Pure Tone Audiometry (PTA) was performed to evaluate the hearing outcomes.

Results: A total of 61 patients were included in the study. The mean preoperative PTA of contralateral ear bone conduction among the study participants was 6.48. At the 7th day post-operation, the mean post-operative PTA of contralateral ear bone conduction for the same participants was 7.77. This difference was statistically significant according to the Paired T-test (P = 0.001).However, when evaluating the mean preoperative PTA of contralateral ear bone conduction (6.48) and the mean post-operative PTA at 1st month (6.02), the difference was not statistically significant (P = 0.208).Additionally, there was no statistical difference in air conduction and air-bone gap before and after surgery.

Conclusion: The study suggests that mastoid drilling is associated with a significant temporary hearing loss in the contralateral ear immediately after surgery, which eventually recovers within a month. However, the hearing loss is considered negligible and not statistically significant in the long term. It is worth considering additional audiological investigations, such as otoacoustic emissions, to detect this type of hearing loss more accurately.

Previous studies from our laboratory revealed that the gaseous molecule hydrogen sulfide (H₂S), a metabolic product of epigenetics, involves trans-sulfuration pathway for ensuring metabolism and clearance of homocysteine (Hcy) from body, thereby mitigating the skeletal muscle's pathological remodeling. Although the master circadian clock regulator that is known as brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (i.e., BMAL 1) is associated with S-adenosylhomocysteine hydrolase (SAHH) and Hcy metabolism but how trans-sulfuration pathway is influenced by the circadian clock remains unexplored. We hypothesize that alterations in the functioning of circadian clock during sleep and wake cycle affect skeletal muscle's biology. To test this hypothesis, we measured serum matrix metalloproteinase (MMP) activities using gelatin gels for analyzing the MMP-2 and MMP-9. Further, employing casein gels, we also studied MMP-13 that is known to be influenced by the growth arrest and DNA damage-45 (GADD45) protein during sleep and wake cycle. The wild type and cystathionine β synthase-deficient (CBS^-/+) mice strains were treated with H₂S and subjected to measurement of trans-sulfuration factors from skeletal muscle tissues. The results suggested highly robust activation of MMPs in the wake mice versus sleep mice, which appears somewhat akin to the "1-carbon metabolic dysregulation", which takes place during remodeling of extracellular matrix during muscular dystrophy. Interestingly, the levels of trans-sulfuration factors such as CBS, cystathionine γ lyase (CSE), methyl tetrahydrofolate reductase (MTHFR), phosphatidylethanolamine N-methyltransferase (PEMT), and Hcy-protein bound paraoxonase 1 (PON1) were attenuated in CBS^-/+ mice. However, treatment with H₂S mitigated the attenuation of the trans-sulfuration pathway. In addition, levels of mitochondrial peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC 1-α) and mitofusin-2 (MFN-2) were significantly improved by H₂S intervention. Our findings suggest participation of the circadian clock in trans-sulfuration pathway that affects skeletal muscle remodeling and mitochondrial regeneration.

RAD54B belongs to the SNF2/SWI2 superfamily, participating in homologous recombination repair. DNA damage is the central driver of aging, but there is no direct evidence of an association between RAD54B and vascular aging. The present study sought to investigate the role and mechanisms of RAD54B in endothelial senescence. In senescent animal models, including spontaneously hypertensive rats, normal aging mice, and D-gal-induced senescent mice, and senescent cell models induced by H₂O₂, D-gal, and culture, RAD54B was remarkably downregulated. Knockdown of RAD54B increased the expression of p53 and p21, increased the ratio of SA-β-gal-positive cells, and decreased the proportion of EdU-positive cells. Conversely, overexpression of RAD54B reversed the senescent phenotypes stimulated by H₂O₂ and delayed replicative endothelial senescence. Mechanistically, silencing RAD54B compensatorily increased the expression of RAD51/XRCC4, which remained unchanged in H₂O₂-induced senescence. RAD54B lacking the SNF2 domain could still reverse the increasing expression of p53/p21 induced by H₂O₂. RAD54B reduced γH2A.X expression and inhibited the expression and phosphorylation of CHK1. In conclusion, RAD54B exerts a direct protective effect against DNA damage through enhancing homologous recombination repair in endothelial senescence, resulting in inhibition of the downstream CHK1/p53/p21 pathway, suggesting that RAD54B may be a potential therapeutic target for vascular aging-associated diseases.