Canadian journal of physiology and pharmacology最新文献

{"title":"Adaptive and maladaptive roles of different angiotensin receptors in the development of cardiac hypertrophy and heart failure.","authors":"Sukhwinder K Bhullar, Naranjan S Dhalla","doi":"10.1139/cjpp-2023-0226","DOIUrl":"10.1139/cjpp-2023-0226","url":null,"abstract":"<p><p>Angiotensin II (Ang II) is formed by the action of angiotensin-converting enzyme (ACE) in the renin-angiotensin system. This hormone is known to induce cardiac hypertrophy and heart failure and its actions are mediated by the interaction of both pro- and antihypertrophic Ang II receptors (AT1R and AT2R). Ang II is also metabolized by ACE 2 to Ang-(1-7), which elicits the activation of Mas receptors (MasR) for inducing antihypertrophic actions. Since heart failure under different pathophysiological situations is preceded by adaptive and maladaptive cardiac hypertrophy, we have reviewed the existing literature to gain some information regarding the roles of AT1R, AT2R, and MasR in both acute and chronic conditions of cardiac hypertrophy. It appears that the activation of AT1R may be involved in the development of adaptive and maladaptive cardiac hypertrophy as well as subsequent heart failure because both ACE inhibitors and AT1R antagonists exert beneficial effects. On the other hand, the activation of both AT2R and MasR may prevent the occurrence of maladaptive cardiac hypertrophy and delay the progression of heart failure, and thus therapy with different activators of these antihypertrophic receptors under chronic pathological stages may prove beneficial. Accordingly, it is suggested that a great deal of effort should be made to develop appropriate activators of both AT2R and MasR for the treatment of heart failure subjects.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"86-104"},"PeriodicalIF":2.1,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41119683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SCH772984 ameliorates lipopolysaccharide-induced hypoglycemia in mice through reversing MEK/ERK/Foxo1-mediated gluconeogenesis suppression.","authors":"Yirong Wang, Shuyun Qing, Jing Yang, Dehui Qian","doi":"10.1139/cjpp-2023-0133","DOIUrl":"10.1139/cjpp-2023-0133","url":null,"abstract":"<p><p>Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPS-induced glucose metabolism disorder is poorly understood. This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of extracellular signal-regulated kinase (ERK) inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption, and glycogenolysis were evaluated by pyruvate tolerance test, oral glucose tolerance test, and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice's blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 (mitogen-activated protein kinase), and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"33-41"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72013578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct cellular reprogramming techniques for cardiovascular regenerative therapeutics.","authors":"Xingyu He, Suchandrima Dutta, Jialiang Liang, Christian Paul, Wei Huang, Meifeng Xu, Vivian Chang, Ian Ao, Yigang Wang","doi":"10.1139/cjpp-2023-0088","DOIUrl":"10.1139/cjpp-2023-0088","url":null,"abstract":"<p><p>Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient's survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-13"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of a high-fat low-carbohydrate diet under different energy conditions on glucose homeostasis and fatty liver development in rats and on gluconeogenesis in the isolated perfused liver.","authors":"Mateus José de Oliveira, Evelyn Silva Moreira, Naiara Cristina Lucredi, Carla Indianara Bonetti, Anacharis Babeto de Sá-Nakanishi, Jurandir Fernando Comar, Adelar Bracht, Lívia Bracht","doi":"10.1139/cjpp-2023-0071","DOIUrl":"10.1139/cjpp-2023-0071","url":null,"abstract":"<p><p>The beneficial effects of high-fat low-carbohydrate (HFLC) diets on glucose metabolism have been questioned and their effects on liver metabolism are not totally clear. The aim of this work was to investigate the effects of an HFLC diet under different energy conditions on glucose homeostasis, fatty liver development, and hepatic gluconeogenesis using the isolated perfused rat liver. HFLC diet (79% fat, 19% protein, and 2% carbohydrates in Kcal%) was administered to rats for 4 weeks under three conditions: ad libitum (hypercaloric), isocaloric, and hypocaloric (energy reduction of 20%). Fasting blood glucose levels and total fat in the liver were higher in all HFLC diet rats. Oral glucose tolerance was impaired in isocaloric and hypercaloric groups, although insulin sensitivity was not altered. HFLC diet also caused marked liver metabolic alterations: higher gluconeogenesis rate from lactate and a reduced capacity to metabolize alanine, the latter effect being more intense in the hypocaloric condition. Thus, even when HFLC diets are used for weight loss, our data imply that they can potentially cause harmful consequences for the liver.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"42-54"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9965477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRIMA-1 synergizes olaparib-induced cell death in p53 mutant triple negative human breast cancer cell line via restoring p53 function, arresting cell cycle, and inducing apoptosis.","authors":"Mohamed Zaza, Mohammed H Rashed, Hesham Elrefaey, Memy H Hassan, Osama M Abo-Salem, El-Sayed M El-Sayed","doi":"10.1139/cjpp-2023-0031","DOIUrl":"10.1139/cjpp-2023-0031","url":null,"abstract":"<p><p>This study concerned with assessing the effect of restoring p53 using PRIMA-1 on the anti-cancer activity of olaparib against TP53-mutant triple negative breast cancer (TNBC) cells and exploring the optimum synergistic concentrations and the underlying mechanism. Human BC cell lines, MDA-MB-231 with mutated TP53 gene, and MCF-7 with wild-type TP53 gene were treated with olaparib and/or PRIMA-1. The IC₅₀ value for olaparib was significantly decreased by PRIMA-1 in MDA-MB-231 cells compared to MCF-7 cells. Contrary to MCF-7 cells, co-treatment with olaparib and PRIMA-1 had a synergistic anti-proliferative effect in MDA-MB-231 at all tested concentrations with the best synergistic combination at 45 and 8.5 µM, respectively, and furthermore PRIMA-1 enhanced olaparib-induced apoptosis. This synergistic apoptotic effect was associated with a significant boost in mRNA expression of TP53 gene, cell cycle arrest at G2/M phase, modulation of BRCA-1, BAX and Bcl2 proteins expressions, and induction of active caspase-3. These results present a clue for the utility of combined olaparib and PRIMA-1 in treatment of TP53-mutant TNBC invitro. PRIMA-1 triggers olaparib-induced MDA-MB-231 cell death in a synergistic manner via restoring TP53, decreasing BRCA-1 expression, cell cycle arrest, and enhancement of apoptosis via p53/BAX/Bcl2/caspase 3 pathway.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"55-68"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41192176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential benefits of therapeutic drug monitoring for beta-lactam antibiotics in augmented renal clearance patients: a case report.","authors":"Ibrahim El-Haffaf, Jean Laverdière, Martin Albert, Amélie Marsot, David Williamson","doi":"10.1139/cjpp-2023-0109","DOIUrl":"10.1139/cjpp-2023-0109","url":null,"abstract":"<p><p>Augmented renal clearance (ARC) is commonly described in critically ill patients, making drug pharmacokinetics even harder to predict in this population. This case report displays the value of therapeutic drug monitoring (TDM) of piperacillin/tazobactam (PTZ) in this population. We identified two patients with ARC and intermittent administration of PTZ who took part in a prospective, descriptive study conducted at Hôpital du Sacré-Cœur de Montréal. Both had plasma samples drawn at peak, middle, and end of their dosing intervals of PTZ. Minimal inhibitory concentrations (MICs) of 4 and 8 mg/L were chosen to evaluate therapeutic target attainment at middle and end of dosing interval. The first patient was a 52-year-old male with a renal clearance rate estimated at 147 mL/min who received 3.375 g PTZ every 6 h. The second patient, a 49-year-old male, had an estimated renal clearance rate of 163 mL/min and received the same regimen. Both patients had piperacillin concentrations above the target MICs at middle of the dosing interval, but they failed to reach a trough concentration above 8 mg/L. The present case report showcases two patients with subtherapeutic PTZ concentrations despite strict following of local administration protocols. This suboptimal administration could not only lead to treatment failure, but also to the selection and growth of resistant pathogens. Implementing TDM would offer the possibility to adjust drug regimens in real-time and prevent situations like these from occurring.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"69-74"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10261125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diabetic complications.","authors":"Omonzejie E Imaralu, Chandrakala Aluganti Narasimhulu, Pawan K Singal, Dinender K Singla","doi":"10.1139/cjpp-2023-0223","DOIUrl":"10.1139/cjpp-2023-0223","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) complications have remained a major cause of death among patients with diabetes. Hence, there is a need for effective therapeutics against diabetes-induced CVD complications. Since its discovery, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be involved in the pathology of various CVDs, with studies showing a positive association between plasma levels of PCSK9, hyperglycemia, and dyslipidemia. PCSK9 regulates lipid homeostasis by interacting with low-density lipoprotein receptors (LDLRs) present in hepatocytes and subsequently induces LDLR degradation via receptor-mediated endocytosis, thereby reducing LDL uptake from circulation. In addition, PCSK9 also induces pro-inflammatory cytokine expression and apoptotic cell death in diabetic-CVD. Furthermore, therapies designed to inhibit PCSK9 effectively reduces diabetic dyslipidemia with clinical studies reporting reduced cardiovascular events in patients with diabetes and no significant adverse effect on glycemic controls. In this review, we discuss the role of PCSK9 in the pathogenesis of diabetes-induced CVD and the potential mechanisms by which PCSK9 inhibition reduces cardiovascular events in diabetic patients.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"14-25"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the antibacterial and antioxidant potential of <i>Hedera helix</i> leaf extracts: recent findings.","authors":"Khaled Qabaha, Jehad Abbadi, Reem Yaghmour, Thameen Hijawi, Saleh A Naser, Fuad Al-Rimawi","doi":"10.1139/cjpp-2023-0264","DOIUrl":"10.1139/cjpp-2023-0264","url":null,"abstract":"<p><p><i>Hedera helix</i> L., a member of the Araliaceae family, is a commonly known decorative plant with recognized medicinal activities. In this study, the ethanolic extract from <i>H. helix</i> leaves was investigated for its total polyphenolic and flavonoid contents, as well as its antioxidant and antibacterial properties. The aim was to evaluate its potential for controlling certain infections by screening its antibacterial activity against selected pathogenic bacteria. The total phenolic and flavonoid contents of the extract were determined using colorimetric methods. The antioxidant activity was assessed through two assay methods: the 1, 1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging activity and the reducing power ferric reducing/antioxidant power (FRAP). The antibacterial activity against different pathogenic bacteria, including <i>Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia</i>, and <i>Pseudomonas aeruginosa</i>, was evaluated using the well diffusion method. The total phenolic and flavonoid contents of the <i>H. helix</i> extract were found to be 134.3 ± 4.9 mg gallic acid/g and 42.4 ± 3.6 mg catechin/g, respectively. The extract exhibited antioxidant activity, with a reducing power represented by an FRAP value of 9.5 ± 0.9 mmol Fe⁺²/g DW and a percentage inhibition of DPPH of 64.7 ± 3.8 at 80 µg/mL. The extract demonstrated antibacterial activity, inhibiting the growth of <i>K. pneumoniae</i> and <i>S. aureus</i> with zone of inhibition values of 18.5 and 23.2 mm, respectively, using 25 mg/well. However, <i>E. coli</i> and <i>P. aeruginosa</i> exhibited resistance to the extract. The findings of this study highlight the antibacterial and antioxidant properties of the ethanolic extract from <i>H. helix</i> leaves. The extract exhibited significant phenolic and flavonoid contents, as well as antioxidant activity. It also demonstrated antibacterial activity against selected pathogenic bacteria, suggesting its potential for controlling certain infections. Further research is warranted to identify the active compounds responsible for these activities and to explore their mechanisms of action.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"26-32"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41232566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Note of appreciation.","authors":"","doi":"10.1139/cjpp-2023-0346","DOIUrl":"10.1139/cjpp-2023-0346","url":null,"abstract":"","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":"102 1","pages":"i"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139073430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salvianolic acid B attenuates diabetic nephropathy through alleviating ADORA2B, NALP3 inflammasome, and NFκB activity","authors":"Ying Wang, Jiang Chang, Shubin Qiao, Ying Yang, Chuan Yun, Yongyan Li, Fa Wang","doi":"10.1139/cjpp-2023-0089","DOIUrl":"https://doi.org/10.1139/cjpp-2023-0089","url":null,"abstract":"Diabetic nephropathy is one of the microvascular complications of diabetes. This study is aimed at investigating the role and mechanisms of Salvianolic acid B (Sal B) in diabetic nephropathy. High glucose (HG)-induced human renal tubular epithelial HK-2 cells were treated with Sal B, BAY-60-6583(agonist of Adenosine 2B receptor) or PSB-603(antagonist of Adenosine 2B receptor) for 24 hours. Adenosine A2b-receptor (ADORA2B), NACHT, leucine-rich repeat (LRR) and pyrin (PYD) domains-containing protein 3 (NALP3), and nuclear factor Kappa B (NFκB) expressions, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were examined. Following 6-week of Sal B treatment, db/db mice blood and kidney tissue were harvested for biochemical detection with H&E, Masson’s, PAS and Sirius red staining and detection of ADORA2B, NALP3, NFκB, interleukin 1β (IL-1β) and Toll-like receptor 4 (TLR4) activity. NFκB, IL-1β and TLR4 as well as increased MMP levels and decreased intracellular ROS generation in HK-2 cells with HG exposure. Sal B-treated diabetic mice had the improvement in body weight, water intake, hyperglycemia, hyperlipidemia, liver and kidney function. Altogether, Sal B attenuates HG-induced kidney tubule cell injury and diabetic nephropathy in diabetic mice, providing clues to other novel mechanisms by which Sal B is beneficial in diabetic nephropathy.","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":"15 5","pages":""},"PeriodicalIF":2.1,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138585343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}