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- Effect of oral versus parenteral vitamin D3 supplementation on nuclear
factor-κB and platelet aggregation in type 2 diabetic patients-
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Authors: Esraa Habiba, Samia Ali, Yehia Ghanem, Ola Sharaki, Wafaa Hewedy
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
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.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-09-18T07:00:00Z
DOI: 10.1139/cjpp-2022-0359
- A novel cuproptosis-related gene prognostic signature in colon
adenocarcinoma-
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Authors: Yongqin Su, Kun Zhang
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
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, p
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-09-12T07:00:00Z
DOI: 10.1139/cjpp-2023-0118
- Simultaneous intervention against oxidative stress and inflammation by
targeting Nrf2/ARE and NLRP3 inflammasome pathway mitigates
thioacetamide-induced liver fibrosis in rat-
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Authors: Durgesh Kumar Dwivedi, Chittaranjan Sahu, G.B. Jena
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
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 (n = 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.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-09-02T07:00:00Z
DOI: 10.1139/cjpp-2023-0018
- Copaiba oil improves pulmonary nitric oxide bioavailability in
monocrotaline-treated rats-
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Authors: Cristina Campos-Carraro, Patrick Turck, Bruna Gazzi de Lima-Seolin, Rayane Brinck Teixeira, Alexsandra Zimmer, Alex Sander da Rosa Araujo, Adriane Belló-Klein
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Oxidative stress is involved in increased pulmonary vascular resistance (PVR) and right ventricular (RV) hypertrophy, characteristics of pulmonary arterial hypertension (PAH). Copaiba oil, an antioxidant compound, could attenuate PAH damage. This study’s aim was to determine the effects of copaiba oil on lung oxidative stress, PVR, and mean pulmonary arterial pressure (mPAP) in the monocrotaline (MCT) model of PAH. Male Wistar rats (170 g, n = 7/group) were divided into four groups: control, MCT, copaiba oil, and MCT + copaiba oil (MCT-O). PAH was induced by MCT (60 mg/kg i.p.) and, after 1 week, the treatment with copaiba oil (400 mg/kg/day gavage) was started for 14 days. Echocardiographic and hemodynamic measurements were performed. RV was collected for morphometric evaluations and lungs and the pulmonary artery were used for biochemical analysis. Copaiba oil significantly reduced RV hypertrophy, PVR, mPAP, and antioxidant enzyme activities in the MCT-O group. Moreover, increased nitric oxide synthase and decreased NADPH oxidase activities were observed in the MCT-O group. In conclusion, copaiba oil was able to improve the balance between nitric oxide and reactive oxygen species in lungs and the pulmonary artery and to reduce PVR, which could explain a decrease in RV hypertrophy in this PAH model.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-08-15T07:00:00Z
DOI: 10.1139/cjpp-2023-0028
- Molecular hydrogen: prospective treatment strategy of kidney damage after
cardiac surgery-
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Authors: Barbora Kalocayova, Branislav Kura, Jana Vlkovicova, Denisa Snurikova, Norbert Vrbjar, Karel Frimmel, Vladan Hudec, Matej Ondrusek, Ivo Gasparovic, Rastislav Sramaty, Jaroslav Luptak, Michal Hulman, Tyler W. LeBaron, Jan Slezak
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Cardiac surgery-associated acute kidney injury is a common post-operative complication, mostly due to increasing oxidative stress. Recently, molecular hydrogen (H2 gas) has also been applied to cardiac surgery due to its ability to reduce oxidative stress. We evaluated the potential effect of H2 application on the kidney in an in vivo model of simulated heart transplantation. Pigs underwent cardiac surgery within 3 h while connected to extracorporeal circulation (ECC) and subsequent 60 min of spontaneous reperfusion of the heart. We used two experimental groups: T—pigs after transplantation and TH—pigs after transplantation treated with 4% H2 mixed with air during inhalation of anesthesia and throughout oxygenation of blood in ECC. The levels of creatinine, urea and phosphorus were measured in plasma. Renal tissue samples were analyzed by Western blot method for protein levels of nuclear factor erythroid 2–related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), and superoxide dismutase (SOD1). After cardiac surgery, selected plasma biomarkers were elevated. However, H2 therapy was followed by the normalization of all these parameters. Our results suggest activation of Nrf2/Keap1 pathway as well as increased SOD1 protein expression in the group treated with H2. The administration of H2 had a protective effect on the kidneys of pigs after cardiac surgery, especially in terms of normalization of plasma biomarkers to control levels.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-07-18T07:00:00Z
DOI: 10.1139/cjpp-2023-0098
- NLG-919 combined with cisplatin to enhance inhibitory effect on cell
migration and invasion via IDO1–Kyn–AhR pathway in human
nasopharyngeal carcinoma cell-
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Authors: Xiaofeng Zou, Deming Zhao, Xin Wen, Feihong Chen
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
As a common aggressive head and neck cancer, nasopharyngeal carcinoma (NPC) received cisplatin treatment as a first-line chemotherapy. Platinum-induced resistance is a major limitation of current treatment strategy in the advanced NPC. Increased indoleamine 2,3-dioxygenase (IDO1) activities are found in cisplatin-resistant NPC cells versus cisplatin-sensitive NPC cells. As an IDO1 immunosuppressant, NLG-919 has entered clinical phase I to treat advanced solid tumors. To reverse cisplatin resistance, we investigated the combinatory application of cisplatin and NLG-919 in NPC treatment. In vitro biological studies on cisplatin-resistant and cisplatin-sensitive NPC cells were taken to imply that the combination of NLG-919 and cisplatin got a stronger impact on the induction of cell apoptosis and the inhibition of cell migration, exploring superior effect of antitumor over single drug. We proved that the mechanism of the combined therapy could inhibit the activity of IDO1, blocking amino acid tryptophan conversion to kynurenine through the kynurenine pathway, which further inhibited the aryl hydrocarbon receptor expression. Our study underscored the combination of cisplatin and NLG-919 as a potent therapeutic way for the reversal of cisplatin resistance.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-07-17T07:00:00Z
DOI: 10.1139/cjpp-2023-0079
- Novel mediators regulating angiogenesis in diabetic foot ulcer healing
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Authors: Vikrant Rai, Hoangvi Le, Devendra K. Agrawal
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
A non-healing diabetic foot ulcer (DFU) is a debilitating clinical problem amounting to socioeconomic and psychosocial burdens. DFUs increase morbidity due to prolonged treatment and mortality in the case of non-treatable ulcers resulting in gangrene and septicemia. The overall amputation rate of the lower extremity with DFU ranges from 3.34% to 42.83%. Wound debridement, antibiotics, applying growth factors, negative pressure wound therapy, hyperbaric oxygen therapy, topical oxygen, and skin grafts are common therapies for DFU. However, recurrence and nonhealing ulcers are still major issues. Chronicity of inflammation, hypoxic environment, poor angiogenesis, and decreased formation of the extracellular matrix (ECM) are common impediments leading to nonhealing patterns of DFUs. Angiogenesis is crucial for wound healing since proper vessel formation facilitates nutrients, oxygen, and immune cells to the ulcer tissue to help in clearing out debris and facilitate healing. However, poor angiogenesis due to decreased expression of angiogenic mediators and matrix formation results in nonhealing and ultimately amputation. Multiple proangiogenic mediators and vascular endothelial growth factor (VEGF) therapy exist to enhance angiogenesis, but the results are not satisfactory. Thus, there is a need to investigate novel pro-angiogenic mediators that can either alone or in combination enhance the angiogenesis and healing of DFUs. In this article, we critically reviewed the existing pro-angiogenic mediators followed by potentially novel factors that might play a regulatory role in promoting angiogenesis and wound healing in DFUs.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-07-17T07:00:00Z
DOI: 10.1139/cjpp-2023-0193
- Sleep deprivation disturbs uterine contractility and structure in pregnant
rats: role of matrix metalloproteinase 9 and transforming growth factor-β
-
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Authors: Nanees F. El-Malkey, Mohammed Aref, Nehal I. A. Goda, Marwa H. Hussien, Walaa Samy, Shimaa Hadhod
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Sleep deprivation (SD) during pregnancy can impact the delivery procedure, with prolongation of the labor duration. Matrix metalloproteinase-9 (MMP9) and transforming growth factor-β (TGF-β) are regulators of uterine remodeling. Their dysregulation is vital for abnormal placentation and uterine enlargement in complicated pregnancies. Therefore, this study aims to explore the outcome of SD throughout pregnancy on ex vivo uterine contractility, MMP9 and TGF-β, and uterine microscopic structure. A total of 24 pregnant rats were divided into two groups. From the first day of pregnancy, animals were exposed to partial SD/6 h/day. Uterine in vitro contractile responses to oxytocin, acetylcholine, and nifedipine were assessed. Additionally, uterine levels of superoxide dismutase and malondialdehyde and uterine mRNA expression of MMP9, TGF-β, and apoptotic biomarkers were analyzed. The results showed that SD significantly reduced uterine contractile responses to oxytocin and acetylcholine, while it augmented the relaxing effect of nifedipine. In addition, it significantly increased oxidative stress status, MMP9, TGF-β, and apoptotic biomarkers' mRNA expression. All were accompanied by degeneration of endometrial glands, vacuolization with apoptotic nuclei, and increased area% of collagen fibers. Finally, increased uterine MMP9 and TGF-β mRNA expression during SD clarified their potential role in modulating uterine contractility and structure.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-07-11T07:00:00Z
DOI: 10.1139/cjpp-2023-0120
- Neonatal administration of fenofibrate had no developmental programming
effect on the lipid profile and relative leucocyte telomere lengths of
adolescent rats fed a high-fructose diet postnatally-
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Authors: Kasimu Ghandi Ibrahim, Eliton Chivandi, Kennedy Honey Erlwanger, Richard Leslie Brooksbank
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n = 119) were allocated to four groups and gavaged with either 10 mL·kg−1 body mass 0.5% dimethyl sulfoxide, 100 mg·kg−1 body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-07-11T07:00:00Z
DOI: 10.1139/cjpp-2022-0528
- Long-term potentiation and its neurotrophin-dependent modulation in the
superior cervical ganglion of the rat are influenced by KCNQ channel
function-
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Authors: Erwin R. Arias, Berardo M. Sánchez-Tafolla, Carlos Terrón, Luis A. Martínez, Maria E. Zetina, Miguel A. Morales, Fredy Cifuentes
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-07-05T07:00:00Z
DOI: 10.1139/cjpp-2022-0552
- Sex hormone dose escalation for treating abnormal sleep in ovariectomized
rats: in vitro GABA synthesis in sleep-related brain areas-
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Authors: Nayely Carrasco-Nuñes, Marta Romano, Marisa Cabeza
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
No data in the literature have evaluated sex hormone dose escalation for treating abnormal sleep of ovariectomized rats—nor studies on the role of sex hormones in GABA synthesis of rats' sleep-related areas. The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol (ET), progesterone (PT), and the mixture of both (EPT) to restore normal sleep in a model of menopause in rats. The second purpose was to describe the in vitro activity of glutamate decarboxylase (GAD) in sleep-related brain areas in the presence or absence of sex hormones. A weekly dose-escalation design of ET, PT, or EPT was implemented in ovariectomized rats (six per group). Dose escalation continued until the dose at which 100% of the rats exhibited a state of “complete somnolence.” Doses that were not toxic or did not show side effects were considered. For in vitro experiments, sleep-related brain areas were separated and incubated with radiolabeled glutamate. Estradiol (17β-E2), progesterone (P), and pyridoxal phosphate (PLP) were added to this assay, and GAD activity was determined. Under the same conditions, a second test was carried out, but the P antagonist RU486 was added to assess the role of P in GAD activity. Ovariectomy increased periodic awakenings compared to those determined for the SHAM group. The EPT for ovariectomized rats was very effective by the fifth week in decreasing arousal and achieving a similar sleep behavior to the SHAM-control group. Rats tolerated the ET, PT, and EPT well to the maximum planned dose (0.66 mg/kg and 4.4 mg/kg, respectively). No lethal events occurred; the MTD was reached. The in vitro studies indicated that the presence of 17β-E2 plus P in the assay triggered the activity of isotype 65 GAD in all the studied brain areas. RU486 in the incubation medium blocked such activity; however, the action of isotype 67 GAD was not blocked by RU486. A dose-escalation model was determined; the MTD coincided with the maximum dose of ET and PT used. However, the EPT combination restored normal sleep in the menopause model compared to the SHAMs without toxic effects. The in vitro model demonstrated that 17β-E2 plus P presence in the assay increased the activity of GAD65 in the studied brain tissues.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-06-26T07:00:00Z
DOI: 10.1139/cjpp-2022-0524
- Detection of joining points for genomic DNA circularization in cell
culture-
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Authors: Toyoki Maeda
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
We previously reported on extrachromosomal circular DNA extracted from mouse brain. We attempted to reconfirm the formation of circular DNA from this region in a culture system. From a circular DNA-enriched fraction of a mouse embryonic tumor-derived cell line capable of inducing neuronal differentiation, circular DNA in the same region was isolated by nested inverse polymerase chain reaction as performed previously. We attempted to amplify and identify some junctions that were evidence of circularization. In this analysis, we captured several junctions that indicated circularization in cultured cells induced to differentiate into neurons. We observed that some of the sequences shared the same point of attachment, indicating that there exist genomic sequences that are amenable to binding toward circularization. Cells were X-ray-irradiated to determine whether any transformation occurred in DNA circularization. Consequently, circularization junctions occurred after differentiation-induced stimulation and before and after X-ray irradiation. This finding indicated that circularization junctions can be formed from this region without being inhibited by X-ray irradiation and irrespective of cell differentiation stage. Furthermore, the presence of circular DNA was confirmed in which genomic fragments from different chromosomes were replaced. These findings suggest that extrachromosomal circular DNA contributes to the interchromosomal translocation of genomic fragments.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-06-20T07:00:00Z
DOI: 10.1139/cjpp-2022-0461
- Mechanical activation of vagal afferents involves opposing cation and
TREK1 currents and NO regulation-
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Authors: Sung Jin Park, Carter G. Zides, Michael J. Beyak
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Vagal afferents convey signals of mechanical stimulation in the gut to the brain, which is essential for the regulation of food intake. However, ion channels sensing mechanical stimuli are not fully understood. This study aimed to examine the ionic currents activated by mechanical stimulation and a possible neuro-modulatory role of nitric oxide on vagal afferents. Nodose neuronal currents and potentials, and intestinal afferent firing by mechanical stimulation were measured by whole-cell patch clamp, and in vitro afferent recording, respectively. Osmotically activated cation and two-pore domain K+ currents were identified in nodose neurons. The membrane potential displayed a biphasic change under hypotonic stimulation. Cation channel-mediated depolarization was followed by a hyperpolarization mediated by K+ channels. The latter was inhibited by l-methionine (TREK1 channel inhibitor) and l-NNA (nitric oxide synthase inhibitor). Correspondingly, mechanical stimulation activated opposing cation and TREK1 currents. NOS inhibition decreased TREK1 currents and potentiated jejunal afferent nerve firing induced by mechanical stimuli. This study suggested a novel activation mechanism of ion channels underlying adaptation under mechanical distension in vagal afferent neurons. The guts’ ability to perceive mechanical stimuli is vital in determining how it responds to food intake. The mechanosensation through ion channels could initiate and control gut function.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-06-13T07:00:00Z
DOI: 10.1139/cjpp-2022-0345
- High salt-induced morphological and glycocalyx remodeling of human
vascular smooth muscle cells is reversible but induces a high sodium
salt-like sensitive memory-
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Authors: Yanick Simon, Danielle Jacques, Ghassan Bkaily
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
Our recent work showed that short-term treatment (1–2 days) with high sodium salt had no effect on the morphology of human vascular smooth muscle cells (hVSMCs). However, chronic (long-term treatment, 6–16 days) high sodium salt (CHSS) induced hypertrophy and decreased the relative density of the glycocalyx in hVSMCs. Whether this CHSS effect is reversible at both the morphological and the intracellular calcium and sodium levels is unknown. In the present study, we tested the hypothesis that the effect of CHSS on the morphological and functional levels of hVSMCs is reversible. However, it induced an irreversible increase in the sensitivity of the cells following short-term treatment with high extracellular Na+. We tested the effects of the removal of CHSS treatment on the morphology and intracellular sodium and calcium of hVSMCs. Our results showed that restoring average sodium concentration (145 mM) modeled back the relative density of the glycocalyx, the intracellular resting calcium and sodium levels, and the whole cell and nuclear volumes of hVSMCs. In addition, it induced a permanent remodeling of hVSMCs’ response to a short-term increase in the extracellular level of sodium salt by developing spontaneous cytosolic and nuclear calcium waves. Our results showed that CHSS is reversible at both the morphological and basal intracellular ionic levels. However, it maintained a high sensitivity to short-term elevation of extracellular sodium. These results suggest that even if chronic high salt is corrected, it induces a high sodium salt-like sensitive memory.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-06-08T07:00:00Z
DOI: 10.1139/cjpp-2023-0087
- Opioid prescriptions and patients’ health services utilization and cost
before and during the COVID-19 pandemic: an exploratory population-based
administrative data analysis-
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Authors: Elena Lopatina, Nguyen X. Thanh, Robert Tanguay, John X. Pereira, Tracy Wasylak
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
The objective was to explore percentages of the population treated with prescribed opioids and costs of opioid-related hospitalizations and emergency department (ED) visits among individuals treated with prescription opioids and costs of all opioid-related hospitalizations and ED visits in the province (i.e., provincial costs) before and during the coronavirus disease 2019 (COVID-19) pandemic in Alberta, Canada. In administrative data, we identified individuals treated with prescription opioids and opioid-related hospitalizations and ED visits among those individuals and among all individuals in the province between 2015/16 and 2021/22 fiscal years. Services used were counted on an item-by-item basis and costed using case-mix approaches. Annually, from 9.98% (2020/21–2021/22) to 14.52% (2017/18) of the provincial population was treated with prescription opioids. Between 2015/16 and 2021/22, annual costs of opioid-related hospitalizations and ED visits among individuals treated with prescription opioids were ∼$5 and ∼$2 million, respectively. In 2020/21–2021/22, the provincial costs of opioid-related hospitalizations (∼$14 million) and ED visits (∼$7.0 million) were almost twice the costs observed in 2015/16 and immediately before the pandemic (2019/20). Our findings suggest that increases in the opioid-related utilization of inpatient and ED services between 2015/16 and 2021/22, including the drastic increases observed during the COVID-19 pandemic, were likely driven by unregulated substances.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-05-26T07:00:00Z
DOI: 10.1139/cjpp-2022-0544
- Vitamins E and A increase the passing of the P-gp substrate ivermectin
into the brain in mice-
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Authors: Bunyamin Tras, Kamil Uney, Tugba Melike Parlak, Oznur Tufan
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
This study aimed to determine the effect of administration of oral vitamins A and E at different doses on plasma and brain concentrations of ivermectin in mice. The study was carried out on 174 Swiss Albino male mice aged 8–10 weeks. After leaving six mice for method validation, the remaining mice were randomly divided into seven groups with equal numbers of animals. Mice received ivermectin (0.2 mg/kg, subcutaneous) alone and in combination with low (vitamin A: 4000 IU/kg; vitamin E: 35 mg/kg) and high (vitamin A: 30 000 IU/kg; vitamin E: 500 mg/kg) oral doses of vitamins A and E. The plasma and brain concentrations of ivermectin were measured using high-performance liquid chromatography-fluorescence detector. We determined that high doses of vitamins A and E and their combinations increased the passing ratio of ivermectin into the brain significantly. The high-dose vitamin E and the combination of high-concentration vitamins E and A significantly increased the plasma concentration of ivermectin (P
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-05-26T07:00:00Z
DOI: 10.1139/cjpp-2023-0078
- Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on
atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model-
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Authors: Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoru Tamura, Minoru Ueda, Satoshi Hirohata, Shogo Watanabe
Abstract: Canadian Journal of Physiology and Pharmacology, Ahead of Print.
The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRβ, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRβ-specific agonist. We aimed to examine whether OBG specifically affects LXRβ in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (−) group, and (IV) OBG (+) group. All groups’ rats were intraperitoneally administered L-NAME. The L-NAME/OBG group’s rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) group’s rats were administered OBG, while the OBG (−) group’s rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRβ-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.
Citation: Canadian Journal of Physiology and Pharmacology
PubDate: 2023-05-24T07:00:00Z
DOI: 10.1139/cjpp-2022-0532
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