Canadian journal of physiology and pharmacology最新文献

Perivascular adipose tissue (PVAT) plays an important role in many physiological and pathological processes, such as regulation of vascular tone. The aim of this study is to evaluate the effects of pioglitazone on functional, structural, and biochemical properties of PVAT in an experimental model of type-2 diabetes (T2DM). T2DM was induced by high-fat-diet/low-dose-streptozotocin in rats, and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters, PVAT-mass, vascular-reactivity in thoracic-aorta, as well as PVAT adipocytokine and PPARG-expression levels, and histopathology were evaluated. Pioglitazone administration improved blood glucose and lipid profiles in T2DM. Pioglitazone did not change the anticontractile effect of PVAT on aortic contractile reactivity and besides, had no influence on endothelium-dependent and -independent relaxation responses. Pioglitazone administration increased PVAT-mass and tumor necrotizing factor-α levels, while adiponectin, leptin, and interleukin-6 levels were unchanged. Also, a prominent increase was observed in PPARG-expression in T2DM-Pio group. Moreover, pioglitazone decreased liver steatosis, aortic wall thickening, and myocardial damage, whereas increased adipocyte size and adiposity in PVAT. Overall, pioglitazone treatment changed the mass and in part the inflammatory profile of PVAT but did not modify vasoreactivity in T2DM. This study provides novel findings in relationship with the adipogenic effect of pioglitazone and PVAT function.

Norepinephrine-dopamine reputake inhibitors (NDRIs), including bupropion, methylphenidate, atomoxetine, and reboxetine, are commonly prescribed for psychiatric disorders such as narcolepsy, attention-deficit/hyperactivity disorder, and depression. Cardiovascular adverse events have been reported to the FDA despite their effectiveness. This pharmacovigilance study analyzed cardiovascular adverse events associated with NDRIs using the FDA Adverse Event Reporting System data from January 2004 to December 2021. A retrospective analysis of adverse event reports was conducted, employing time-trend analysis and disproportionality evaluation to assess cardiovascular risks. Bupropion had the greatest reported odds ratios (RORs) for tachycardia (ROR = 4.2, 95% CI: 4.0-4.4) and hypertension (ROR = 3.5, 95% CI: 3.3-3.7), while methylphenidate showed greater ROR for arrhythmias (ROR = 2.8, 95% CI: 2.6-3.0) and palpitations (ROR = 3.1, 95% CI: 2.9-3.3). Reboxetine had signals for palpitations (ROR = 3.0, 95% CI: 2.8-3.2) and myocardial infarction (ROR = 2.7, 95% CI: 2.5-2.9), whereas atomoxetine revealed signals for hypertension (ROR = 2.9, 95% CI: 2.7-3.1) and syncope (ROR = 2.5, 95% CI: 2.3-2.7). Time-trend analysis revealed temporal variability in the cardiovascular risks connected with NDRIs. Our research elucidates cardiovascular safety profiles for NDRIs, highlighting the necessity for continuous pharmacovigilance. The observed variations in adverse events emphasize the need for ongoing surveillance to mitigate potential cardiovascular risks and enhance patient safety and treatment outcomes.

Sarcopenia, a disorder marked by muscle loss and dysfunction, is a global health concern, particularly in aging populations. Sarcopenia is intricately related to various health conditions, including obesity, dysphagia, and frailty, which underscores the complexity. Despite recent advances in metabolomics and other omics data for early detection and treatment, the precise characterization and diagnosis of sarcopenia remains challenging. In the present review we provide an overview of the complex metabolic mechanisms that underlie sarcopenia, with particular emphasis on protein, lipid, carbohydrate, and bone metabolism. The review highlights the importance of leucine and other amino acids in promoting muscle protein synthesis and clarifies the critical role played by amino acid metabolism in preserving muscular health. In addition, the review provides insights regarding lipid metabolism on sarcopenia, with an emphasis on the effects of inflammation and insulin resistance. The development of sarcopenia is largely influenced by insulin resistance, especially with regard to glucose metabolism. Overall, the review emphasizes the complex relationship between bone and muscle health by highlighting the interaction between sarcopenia and bone metabolism. Furthermore, the review outlines various therapeutic approaches and potential biomarkers for diagnosing sarcopenia. These include pharmacological strategies such as hormone replacement therapy and anabolic steroids as well as lifestyle modifications such as exercise, nutrition, and dietary changes.

Lysophosphatidic acid (LPA) is a bioactive lipid that is mainly produced by the secreted lysophospholipase D, autotaxin (ATX), and signals through at least six G protein-coupled receptors (LPA1-6). Extracellular LPA is degraded through lipid phosphate phosphatases (LPP1, LPP2, and LPP3) at the plasmamembrane, terminating LPA receptor signaling. The ATX-LPA-LPP3 pathway is critically involved in a wide range of physiological processes, including cell survival, migration, proliferation, angiogenesis, and organismal development. Similarly, dysregulation of this pathway has been linked to many pathological processes, including cardiovascular disease. This review summarizes and interprets current literature examining the regulation and role of the ATX-LPA-LPP3 axis in heart disease. Specifically, the contribution of altered LPA metabolism via ATX and LPP3 and resulting changes to LPA receptor signaling in obesity cardiomyopathy, cardiac mitochondrial dysfunction, myocardial infarction/ischemia-reperfusion injury, hypertrophic cardiomyopathy, and aortic valve stenosis is discussed.

Cyclophosphamide (CYP) is combined with cytoprotective agents to minimize its toxicity in the bladder, which is mediated by reactive oxygen species (ROS). Using multiple antioxidant mechanisms, nebivolol protects from oxidative stress in distinctive conditions. We hypothesized that nebivolol would attenuate both molecular and functional alterations induced by CYP in the bladder. Male C57BL/6 were pretreated or not with nebivolol (10 mg/kg/day, gavage), which was given 5 days before a single injection of CYP (300 mg/kg; i.p.). Molecular and functional parameters were assessed at 24 h in the bladder. Nebivolol prevented increases in ROS generation and lipoperoxidation as well as reduction of superoxide dismutase activity induced by CYP. Increased voiding frequency, decreased voiding interval, and reduced bladder capacity were found in CYP-treated mice. These responses were prevented by nebivolol. An augmented number of urinary spots and smaller urinary volumes were detected in CYP-injected mice, and nebivolol partially prevented these responses. The reduction of ROS levels is the primary mechanism by which nebivolol attenuates the deleterious effects of CYP in the bladder. The association of nebivolol with other cytoprotective agents could be an option to prevent CYP-associated oxidative damage to the bladder during chemotherapy.

The purpose of this study was to determine the relationship between triptans (sumatriptan, rizatriptan, and zolmitriptan) and cardiovascular (CV) adverse events with data from the FDA Adverse Event Reporting System (FAERS). FAERS database was used to collect data on triptans from 1997 to 2023. Disproportionality methods were utilized to quantify triptan-associated CV events and to identify the potential risk. The reporting odds ratio was used to identify the risk signals. CV outcomes related to age, sex, clinical results, and other factors were also examined for triptans; 820 reports involving the triptans were recognized as CV adverse events out of total of 12 699 reports that were gathered from on FAERS database. Women reported more CV adverse events with rizatriptan and zolmitriptan as compared to men. The CV adverse event risk was highest among individuals aged 18-64. Clinical outcome analysis showed that sumatriptan carries a higher CV risk than rizatriptan and zolmitriptan, and most deaths and serious cases have been documented for sumatriptan. The patients prescribed sumatriptan or zolmitriptan were at a higher risk of reporting CV events for chest pain and chest discomfort, compared to rizatriptan. This finding may provide support for the clinical observation and risk evaluation of triptan treatment.

5-Fluorouracil (5-FU) is a first-line treatment for colorectal cancer, but side effects such as severe diarrhea are common in clinical use and have been linked to its induction of normal cell senescence. Chloramphenicol (CAP) is an antibiotic commonly used to treat typhoid or anaerobic infections, but its senescence-related aspects have not been thoroughly investigated. Here, we used 5-FU to induce senescence in human umbilical vein endothelial cells (HUVECs) and investigated the relationship between CAP and cellular senescence at the cellular level. In a model of cellular senescence induced by 5-FU treatment, we discovered that CAP treatment reversed the rise in the percentage of senescence-associated galactosidase (SA-β-gal)-positive cells and decreased the expression of senescence-associated proteins (p16), senescence-associated genes (p21), and senescence-associated secretory phenotypes (SASPs: IL-6, TNF-α). In addition, CAP subsequently restored the autophagic process inhibited by 5-FU and upregulated the levels of autophagy-related proteins. Mechanistically, we found that CAP restored autophagic flux by inhibiting the mTOR pathway, which in turn alleviated FU-induced cellular senescence. Our findings suggest that CAP may help prevent cellular senescence and restore autophagy, opening up new possibilities and approaches for the clinical management of colorectal cancer.

Medicinal signaling cells (MSC) hold promise for regenerative medicine due to their ability to repair damaged tissues. However, their effectiveness can be affected by how long they are cultured in the lab. This study investigated how passage number influences key properties for regenerative medicine of pig bone marrow MSC. The medicinal signiling cells derived from pig bone marrow (BM-MSC) were cultured in D-MEM High Glucose supplemented with 15% foetal bovine serum until the 25th passage and assessed their growth, viability, ability to differentiate into different cell types (plasticity), and cell cycle activity. Our findings showed that while the cells remained viable until the 25th passage, their ability to grow and differentiate declined after the 5th passage. Additionally, cells in later passages spent more time in a resting phase, suggesting reduced activity. In conclusion, the number of passages is a critical factor for maintaining ideal MSC characteristics. From the 9th passage BM-MSC exhibit decline in proliferation, differentiation potential, and cell cycle activity. Given this, it is possible to suggest that the use of 5th passage cells is the most suitable for therapeutic applications.