Canadian Journal Of Physiology And Pharmacology[JOURNAL]
Sun
200 papers
Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta.
Bojić MG, Treven M, Pandey KP … +10 more , Tiruveedhula VVNPB, Santrač A, Đukanović Đ, Vojinović N, Amidžić L, Škrbić R, Scholze P, Ernst M, Cook JM, Savić MM
Can J Physiol Pharmacol · 2024 Mar · PMID 37909404 · Publisher ↗
Hypotensive influences of benzodiazepines and other GABA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABA receptors in peripheral blood vessels, besides any mechanisms...
Hypotensive influences of benzodiazepines and other GABA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABA 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 receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABA 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 αβ3γ2 GABA 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 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.
Direct cellular reprogramming techniques for cardiovascular regenerative therapeutics.
He X, Dutta S, Liang J … +6 more , Paul C, Huang W, Xu M, Chang V, Ao I, Wang Y
Can J Physiol Pharmacol · 2024 Jan · PMID 37903419 · Publisher ↗
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...
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.
Unveiling the antibacterial and antioxidant potential of leaf extracts: recent findings.
Qabaha K, Abbadi J, Yaghmour R … +3 more , Hijawi T, Naser SA, Al-Rimawi F
Can J Physiol Pharmacol · 2024 Jan · PMID 37850568 · Publisher ↗
L., a member of the Araliaceae family, is a commonly known decorative plant with recognized medicinal activities. In this study, the ethanolic extract from leaves was investigated for its total polyphenolic and flavonoi...
L., a member of the Araliaceae family, is a commonly known decorative plant with recognized medicinal activities. In this study, the ethanolic extract from 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 , and , was evaluated using the well diffusion method. The total phenolic and flavonoid contents of the 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/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 and with zone of inhibition values of 18.5 and 23.2 mm, respectively, using 25 mg/well. However, and exhibited resistance to the extract. The findings of this study highlight the antibacterial and antioxidant properties of the ethanolic extract from 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.
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.
Zaza M, Rashed MH, Elrefaey H … +3 more , Hassan MH, Abo-Salem OM, El-Sayed ESM
Can J Physiol Pharmacol · 2024 Jan · PMID 37818839 · Publisher ↗
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 c...
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 IC 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.
The impact of ionizing radiation compared to drug-induced immunological changes.
Hussien S
Can J Physiol Pharmacol · 2023 Dec · PMID 37767909 · Publisher ↗
Ionizing radiation (IR) activates several signaling pathways. This study shows the impact of acute low-dose IR on crucial cytokines involved in cell-mediated immunity. The immunomodulatory effects of 0.25 and 0.5 Gray (G...
Ionizing radiation (IR) activates several signaling pathways. This study shows the impact of acute low-dose IR on crucial cytokines involved in cell-mediated immunity. The immunomodulatory effects of 0.25 and 0.5 Gray (Gy) gamma rays and standard immunomodulatory drugs (cyclophosphamide) on blood counts and significant pro-inflammatory cytokines implicated in various inflammatory conditions were tested in 20 rats. Examined was the effect of acute low doses on critical cytokines, which could be utilized as an alternative to current immunosuppressive drugs. One day post-irradiation, serum levels of interferon-gamma (INF-γ), tumor necrosis factor-alpha, and interleukin-2/1-beta were measured. A 0.25 Gy exposure did not affect the detected cytokines or blood cell count compared to the nonirradiated group. On the other hand, 0.5 Gy raises the majority of the immunologically examined cytokines except for INF-γ. Except for INF-γ, cyclophosphamide reduces all of the cytokines examined. As a result, low-dose IR has a less negative influence on essential inflammatory cytokines, permitting its use. More research is needed to determine how low amounts could be used in different immunological disorders.
Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diabetic complications.
Imaralu OE, Aluganti Narasimhulu C, Singal PK … +1 more , Singla DK
Can J Physiol Pharmacol · 2024 Jan · PMID 37748207 · Publisher ↗
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 discov...
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.
RAD54B inhibits vascular endothelial senescence via suppression of CHK1/p53/p21 pathway.
Mai Y, Lin T, Zhang L … +6 more , Yang W, Liu S, Wang M, Liu P, Li Z, Luo W
Can J Physiol Pharmacol · 2024 Feb · PMID 37748205 · Publisher ↗
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 agin...
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 HO, 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 HO and delayed replicative endothelial senescence. Mechanistically, silencing RAD54B compensatorily increased the expression of RAD51/XRCC4, which remained unchanged in HO-induced senescence. RAD54B lacking the SNF2 domain could still reverse the increasing expression of p53/p21 induced by HO. 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.
Adaptive and maladaptive roles of different angiotensin receptors in the development of cardiac hypertrophy and heart failure.
Bhullar SK, Dhalla NS
Can J Physiol Pharmacol · 2024 Feb · PMID 37748204 · Publisher ↗
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 b...
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.
The non-nutritive sweetener sucralose increases β-arrestin signaling at the constitutively active orphan G protein-coupled receptor GPR52.
Power ME, Fernandez NR, Oni OP … +2 more , Kalia A, Rourke JL
Can J Physiol Pharmacol · 2024 Feb · PMID 37748201 · Publisher ↗
Non-nutritive sweeteners are popular food additives owing to their low caloric density and powerful sweetness relative to natural sugars. Their lack of metabolism contributes to evidence proclaiming their safety, yet sev...
Non-nutritive sweeteners are popular food additives owing to their low caloric density and powerful sweetness relative to natural sugars. Their lack of metabolism contributes to evidence proclaiming their safety, yet several studies contradict this, demonstrating that sweeteners activate sweet taste G protein-coupled receptors (GPCRs) and elicit deleterious metabolic functions through unknown mechanisms. We hypothesize that activation of GPCRs, particularly orphan receptors due to their abundance in metabolically active tissues, contributes to the biological activity of sweeteners. We quantified the response of 64 orphans to the sweeteners saccharin and sucralose using a high-throughput β-arrestin-2 recruitment assay (PRESTO-Tango). GPR52 was the sole receptor that significantly responded to a mixture of sucralose and saccharin. Subsequent experiments revealed sucralose as the activating sweetener. Activation of GPR52 was concentration-dependent, with an EC of 0.23 mmol/L and an Emax of 3.43 ± 0.24 fold change at 4 mmol/L. GPR52 constitutively activates CRE pathways; however, we show that sucralose-induced activation of GPR52 does not further activate this pathway. Identification of this novel sucralose-GPCR interaction supports the notion that sucralose elicits off-target signaling through the activation of GPR52, calling into question sucralose's assumed lack of bioactivity.
Considerations for choosing an optimal animal model of cardiovascular disease.
Parikh M, Pierce GN
Can J Physiol Pharmacol · 2024 Feb · PMID 37748198 · Publisher ↗
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 atheroscler...
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- rat as a model of cardiovascular disease is discussed.
Thyroid hormone induces restrictive cardiomyopathy in β1-adrenoceptor knockout mice.
da Silveira A, Seara F, Lustrino D … +6 more , Mecawi A, Antunes-Rodrigues J, Kettelhut Í, Chakur-Brum P, Reis L, Olivares E
Can J Physiol Pharmacol · 2023 Dec · PMID 37747059 · Publisher ↗
The purpose of this study was to characterize the role of β-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac hypertrophy. T was administered at 0.5 mg·kg·day fo...
The purpose of this study was to characterize the role of β-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac hypertrophy. T was administered at 0.5 mg·kg·day for 10 days in β1-KO and WT groups, while control groups received vehicle alone. Echocardiography and myocardial histology was performed; cardiac and serum ANGI/ANGII and ANP and cardiac levels of p-PKA, p-ERK1/2, p-p38-MAPK, p-AKT, p-4EBP1, and ACE were measured. WT showed decreased IVST and increased LVEDD versus WT ( < 0.05). β1-KO exhibited lower LVEDD and higher relative IVST versus β1-KO, the lowest levels of ejection fraction, and the highest levels of cardiomyocyte diameter ( < 0.05). Cardiac ANP levels decreased in WT versus β1-KO ( < 0.05). Cardiac ACE expression was increased in T-treated groups ( < 0.05). Phosphorylated-p38 MAPK levels were higher in WT versus WT or β1-KO p-4EBP1 was elevated in β1-KO animals, and p-ERK1/2 was up-regulated in β1-KO. These findings suggest that β-AR signaling is crucial for TiCH.
MiR-122 knockdown regulates vascular smooth muscle cells phenotypic switching through enhanced FOXO3 expression.
Zhang L, Huang Q, Pu Y … +6 more , Xiao X, Song B, Zhang X, Yang Y, Zhang Y, Gong F
Can J Physiol Pharmacol · 2023 Dec · PMID 37747048 · Publisher ↗
Vascular smooth muscle cells (VSMCs) phenotypic switching is identified as enhanced dedifferentiation, proliferation, and migration ability of VSMCs, in which microRNAs have been identified as important regulators of the...
Vascular smooth muscle cells (VSMCs) phenotypic switching is identified as enhanced dedifferentiation, proliferation, and migration ability of VSMCs, in which microRNAs have been identified as important regulators of the process. The present study is aimed to explore the pathophysiological effect of miR-122 on VSMC phenotypic modulation. Here, the result showed that the decreased miR-122 expression was found in VSMCs subjected to platelet-derived growth factor-BB (PDGF-BB) treatment. Next, we investigated the response of miR-122 knockdown in VSMCs with PDGF-BB stimulation. MiR-122 silencing showed increased proliferation and migration capability, whereas attenuated the differentiation markers expression. The above results were reversed by miR-122 overexpression. Finally, we further demonstrated that FOXO3 was an important target for miR-122. Collectively, we demonstrated that miR-122 silencing promoted VSMC phenotypic modulation partially through upregulated FOXO3 expression that indicated miR-122 may be a novel therapeutic target for neointimal formation.
Caloric restriction improves inflammation in different tissues of the Wistar rats with obesity and 2K1C renovascular hypertension.
Pizzo T, Valverde A, Orzari L … +8 more , Terciotti L, de Lima R, Costa do Bomfim F, Esquisatto M, de Andrade T, Corezola do Amaral M, de Oliveira C, Felonato M
Can J Physiol Pharmacol · 2023 Dec · PMID 37746936 · Publisher ↗
Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile i...
Renovascular hypertension (RHV) is the cause of high blood pressure due to left renal ischemia, and obesity and hypertension cause an inflammatory response. This work analyzed the inflammatory and tissue repair profile in renal, hepatic, and cardiac tissues in an animal model of RVH associated with a high-fat diet and caloric restriction. The expressions of RORγ-t, IL-17, T-bet, and TNF-α decreased and IFN-γ increased in the right kidney. In relation to the left kidney, caloric restriction decreased the expression of IFN-γ. In the liver, caloric restriction decreased RORγ-t, IL-17, and T-bet. Hypertension associated with obesity decreased the expression of IFN-γ, while caloric restriction increased. In the right kidney, hypertension and obesity, associated or not with caloric restriction, increased the area of collagen fibers. In the heart and liver, caloric restriction reduced the area of collagen fibers. Caloric restriction increased vascular endothelial growth factor, reduced levels of growth transformation factor-β1 (TGF-β), and increased collagen I in the left kidney. Hypertension/obesity, submitted or not having caloric restriction, increased TGF-β in liver. The results suggest that caloric restriction has beneficial effects in lowering blood pressure and regulating tissue proinflammatory cytokines. However, there was no change in the structure and composition of tissue repair markers.
Tumour adaptation to immune factors: old and new ideas for cancer immunotherapy.
Malyshev I, Budanova O, Kuznetsova L
Can J Physiol Pharmacol · 2023 Nov · PMID 37728163 · Publisher ↗
The tumour is fully functional in the zone of action of immune mediators. Moreover, the tumour needs immune system mediators to survive. "Adaptation" refers to a tumour's ability to withstand the effect of harmful elemen...
The tumour is fully functional in the zone of action of immune mediators. Moreover, the tumour needs immune system mediators to survive. "Adaptation" refers to a tumour's ability to withstand the effect of harmful elements. This gives birth to a new form of antitumour therapy: blocking tumour adaptability pathways. In this review, we will look at (i) tumour adaptation mechanisms as a result of pro-tumour immunoediting, (ii) how understanding tumour-adaptive mechanisms has led to ideas for developing cancer immunotherapies, and (iii) prospects for using the adaptation theory to substantiate new approaches to tumour growth inhibition. By considering the cancer problem through the lens of adaptability, a unique strategy for enhancing the efficacy of immunotherapy was proposed. The new approach is to utilise antisense treatment to erase the structural trace of adaptation in tumour cells or to disadapt tumour cells by "turning off" the immune system before initiating immunotherapy.
Effect of oral versus parenteral vitamin D3 supplementation on nuclear factor-κB and platelet aggregation in type 2 diabetic patients.
Habiba E, Ali S, Ghanem Y … +2 more , Sharaki O, Hewedy W
Can J Physiol Pharmacol · 2023 Nov · PMID 37721213 · Publisher ↗
Platelet hyperactivity is one of the key factors implicated in the development and progression of diabetic vascular complications. Activated platelets mediate leukocyte recruitment that further enhances inflammatory resp...
Platelet hyperactivity is one of the key factors implicated in the development and progression of diabetic vascular complications. Activated platelets mediate leukocyte recruitment that further enhances inflammatory responses in vascular wall ultimately resulting in atherosclerotic complications. Since vitamin D insufficiency is highly prevalent in diabetics, we aimed to evaluate the effect of three dosage forms of vitamin D supplementation on lipid profile, NF-κB, platelet aggregation, and platelet calcium content in type 2 diabetic patients. Type 2 diabetic patients were randomized to receive daily (4000 IU/day) or weekly (50 000 IU/week) oral vitamin D3 for 3 months. Another group received a single parenteral dose (300 000 IU) of vitamin D3, whereas the control group received their antidiabetic drug(s) alone. Serum 25(OH)D, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, NF-κB, and platelet aggregation were measured at the beginning and 3 months after vitamin D supplementation. Platelet calcium content was evaluated by measuring the fluorescence intensity of Rhod-2-stained platelets by confocal fluorescence microscopy. Results showed that serum 25(OH)D3 levels significantly increased in all vitamin D3-treated groups. However, the mean level for parenteral treated group was significantly lower than oral-treated groups. Oral and parenteral treatment were also able to decrease NF-κB level, platelet aggregation, and platelet calcium content. However, both oral doses of vitamin D3 were superior to the single parenteral dose. In conclusion, restoring normal levels of vitamin D is an important determinant to maintain normal platelet function and reduce inflammation. Nevertheless, further long-term studies are still needed.
Potential benefits of therapeutic drug monitoring for beta-lactam antibiotics in augmented renal clearance patients: a case report.
El-Haffaf I, Laverdière J, Albert M … +2 more , Marsot A, Williamson D
Can J Physiol Pharmacol · 2024 Jan · PMID 37713726 · Publisher ↗
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...
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.
A novel cuproptosis-related gene prognostic signature in colon adenocarcinoma.
Su Y, Zhang K
Can J Physiol Pharmacol · 2023 Nov · PMID 37698225 · Publisher ↗
Cuproptosis is the latest cell death type caused by enhanced mitochondrial-dependent energy metabolism. This study plans to establish a survival prognosis model for colon adenocarcinoma (COAD) patients based on cuproptos...
Cuproptosis is the latest cell death type caused by enhanced mitochondrial-dependent energy metabolism. This study plans to establish a survival prognosis model for colon adenocarcinoma (COAD) patients based on cuproptosis-related genes (CRGs). We investigated the genetic alterations of CRGs in COAD based on The Cancer Genome Atlas database and validated in the GSE41328 dataset. Our results showed that LIPT1, PDHA1, GLS, and CDKN2A had significantly higher expression in COAD tissues than in normal tissues, while FDX1, DLD, and MTF1 had significantly lower expression in COAD tissues than in normal tissues (|(log2(fold change))| > 2, < 0.05). DLD (hazard ratio (HR): 0.658; 95% confidence interval (CI): 0.445, 0.974; = 0.037) and CDKN2A (HR: 1.785; 95% CI: 1.200, 2.654; = 0.004) expressions were linked with overall survival throughout a log-rank test. CRG prognostic scores exhibited an area under the curve of 0.737, 0.646, and 0.633 at 1, 3, and 5 years. Patients with a high-risk factor suffered from poor prognosis (HR = 1.514; 95% CI: 1.022, 2.243; = 0.0386). An independent validation dataset (GSE41328 ( = 20)) confirmed the above results. The CRGs' signature may be used as a prognostic predictor for COAD patients, providing unique insights into anticancer therapy.
α-Tocopherol reduces VLDL secretion through modulation of intracellular ER-to-Golgi transport of VLDL.
Clay R, Siddiqi S, Siddiqi SA
Can J Physiol Pharmacol · 2023 Nov · PMID 37683292 · Full text
Avoiding hepatic steatosis is crucial for preventing liver dysfunction, and one mechanism by which this is accomplished is through synchronization of the rate of very low density lipoprotein (VLDL) synthesis with its sec...
Avoiding hepatic steatosis is crucial for preventing liver dysfunction, and one mechanism by which this is accomplished is through synchronization of the rate of very low density lipoprotein (VLDL) synthesis with its secretion. Endoplasmic reticulum (ER)-to-Golgi transport of nascent VLDL is the rate-limiting step in its secretion and is mediated by the VLDL transport vesicle (VTV). Recent in vivo studies have indicated that α-tocopherol (α-T) supplementation can reverse steatosis in nonalcoholic fatty liver disease, but its effects on hepatic lipoprotein metabolism are poorly understood. Here, we investigated the impact of α-T on hepatic VLDL synthesis, secretion, and intracellular ER-to-Golgi VLDL trafficking using an in vitro model. Pulse-chase assays using [H]-oleic acid and 100 µmol/L α-T demonstrated a disruption of early VLDL synthesis, resulting in enhanced apolipoprotein B-100 expression, decreased expression in markers for VTV budding, ER-to-Golgi VLDL transport, and reduced VLDL secretion. Additionally, an in vitro VTV budding assay indicated a significant decrease in VTV production and VTV-Golgi fusion. Confocal imaging of lipid droplet (LD) localization revealed a decrease in overall LD retention, diminished presence of ER-associated LDs, and an increase in Golgi-level LD retention. We conclude that α-T disrupts ER-to-Golgi VLDL transport by modulating the expression of specific proteins and thus reduces VLDL secretion.
Astaxanthin prevents nephrotoxicity through pathway.
Lorestani F, Movahedian A, Mohammadalipour A … +2 more , Hashemnia M, Aarabi MH
Can J Physiol Pharmacol · 2024 Feb · PMID 37683291 · Publisher ↗
Renal toxicity is one of the side effects of methotrexate (MTX). Therefore, this study explored the use of astaxanthin (AST), as a natural carotenoid, against MTX-induced nephrotoxicity emphasizing the changes in oxidati...
Renal toxicity is one of the side effects of methotrexate (MTX). Therefore, this study explored the use of astaxanthin (AST), as a natural carotenoid, against MTX-induced nephrotoxicity emphasizing the changes in oxidative stress and the expression of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (). During the 10 days of the experiment, male Wistar rats in different groups received MTX (10 mg/kg) on days 6, 8, and 10 and three doses of AST (25, 50, and 75 mg/kg) during the entire course. Renal failure caused by MTX was observed in significant histopathological changes and a significant increase in serum levels of creatinine, urea, and uric acid ( < 0.05). Oxidative change induced by MTX injection was also observed by remarkably increasing the tissue level of malondialdehyde (MDA) and decreasing the activity of superoxide dismutase (SOD) and catalase ( < 0.001). AST decreases the adverse effects of MTX by upregulating the expression of genes ( < 0.01) and decreasing the tissue level of MDA ( < 0.01). Also, AST significantly reduced the amount of creatinine, urea, and uric acid in the serum and improved the activity of SOD and catalase in the kidney tissue ( < 0.05). Thus, AST may protect the kidney against oxidative stress caused by MTX.
Simultaneous intervention against oxidative stress and inflammation by targeting Nrf2/ARE and NLRP3 inflammasome pathway mitigates thioacetamide-induced liver fibrosis in rat.
Dwivedi DK, Sahu C, Jena GB
Can J Physiol Pharmacol · 2023 Oct · PMID 37665062 · Publisher ↗
Liver fibrosis is a typical pathological state/stage involved in most chronic liver diseases and its persistence results in cirrhosis. Inflammasomes are cytoplasmic sensors that induce inflammation in response to stress....
Liver fibrosis is a typical pathological state/stage involved in most chronic liver diseases and its persistence results in cirrhosis. Inflammasomes are cytoplasmic sensors that induce inflammation in response to stress. Glibenclamide (GLB) is an USFDA-approved drug for type 2 diabetes and is reported to possess anti-inflammatory activity by inhibiting inflammatory cytokines. Dimethyl fumarate (DMF) is an USFDA-approved drug for multiple sclerosis and has been reported to activate the Nrf2/ARE pathway to maintain the cellular antioxidant balance. A total of 36 rats were randomized into six groups ( = 6 each). The rats were injected with thioacetamide (TAA) 200 mg/kg, intraperitoneally every third day for eight consecutive weeks to induce liver fibrosis and oral treatment of GLB 0.5 mg/kg/day and DMF 25 mg/kg/day, and their combinations were provided for the last four consecutive weeks. Treatment with GLB, DMF, and GLB+DMF significantly protected against TAA-mediated oxidative stress and inflammatory conditions by improving hepatic function test, triglycerides, hydroxyproline, and histopathological alterations, by inhibiting the NLRP3 inflammasome signaling and fibrogenic markers, and by activating Nrf2/ARE pathway in Wistar rats. The present results suggest that simultaneous Nrf2/ARE activation and NLRP3 inflammasome inhibition could significantly contribute to developing a novel therapy for patients with liver fibrosis.
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