Canadian Journal Of Physiology And Pharmacology[JOURNAL]
Sun
200 papers
Alleviation of adipose-hepatic glycolipid dysregulation by acetate in experimental PCOS model is associated with NF-κB/NLRP3 repression.
Olaniyi K, Areloegbe S
Can J Physiol Pharmacol · 2023 Dec · PMID 37590975 · Publisher ↗
This study hypothesized that acetate breaks the vicious cycle driving adipose-hepatic metabolic dysregulation in a rat model of polycystic ovarian syndrome (PCOS), possibly by suppression of nuclear factor-kappaB (NF-κB)...
This study hypothesized that acetate breaks the vicious cycle driving adipose-hepatic metabolic dysregulation in a rat model of polycystic ovarian syndrome (PCOS), possibly by suppression of nuclear factor-kappaB (NF-κB)/NOD-like receptor protein 3 (NLRP3) inflammasome. Female Wistar rats (8-week-old) were randomly allocated into four groups of =6/group, which received vehicle, sodium acetate (200 mg), letrozole (1 mg/kg), and letrozole plus sodium acetate, respectively. The animals were treated by oral gavage, once daily for a period of 21 days. The PCOS animals were insulin-resistant, hyperandrogenic, and hypoestrogenic with decreased sex-hormone binding globulin. In addition, the hepatic tissue had increased lipid profile and decreased glycogen synthesis, while the adipose tissue showed decreased lipid profile with elevated glycogen synthesis. Besides, the results also showed increased malondialdehyde, γ-glutamyl transferase, lactate dehydrogenase, and inflammatory mediators with corresponding decrease in antioxidant defense in the hepatic and adipose tissues. Immunohistochemical evaluation also demonstrated severe expression with Bcl2-associated X protein/NLRP3 antibodies. Nonetheless, concomitant acetate supplementation attenuated these derangements. The present data collectively suggest that acetate ameliorates adipose-hepatic glycolipid dysregulation in experimental PCOS model by attenuating androgen excess and NF-κB/NLRP3 immunoreactivity.
Copaiba oil improves pulmonary nitric oxide bioavailability in monocrotaline-treated rats.
Campos-Carraro C, Turck P, de Lima-Seolin BG … +4 more , Teixeira RB, Zimmer A, Araujo ASDR, Belló-Klein A
Can J Physiol Pharmacol · 2023 Sep · PMID 37581356 · Publisher ↗
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...
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, = 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.
Alpha-lipoic acid enhances ischemic postconditioning-mediated improvement of myocardial infarction and apoptosis in diabetic rats with ischemia/reperfusion injury.
Gholami S, Badalzadeh R, Alihemmati A
Can J Physiol Pharmacol · 2023 Dec · PMID 37523770 · Publisher ↗
This work evaluated the combined effects of alpha-lipoic acid (ALA) and ischemic postconditioning (Post) on myocardial infarction and cell death in rats with chronic type-II diabetes following ischemia/reperfusion injury...
This work evaluated the combined effects of alpha-lipoic acid (ALA) and ischemic postconditioning (Post) on myocardial infarction and cell death in rats with chronic type-II diabetes following ischemia/reperfusion injury. The rats received a high-fat diet and were given one intraperitoneal injection of 35 mg/kg streptozotocin to induce chronic diabetes. They were then pretreated with ALA (100 mg/kg/day, orally) for 5 weeks before undergoing ischemia/reperfusion (I/R) insult. The hearts experienced 35 min regional ischemia through ligating the left anterior descending coronary artery, followed by 60 min reperfusion. The Post protocol involved 6 cycles of a 10/10 s algorithm, applied during the early stage of reperfusion. The use of Post alone did not significantly alter lactate dehydrogenase and infarct size levels, while ALA showed positive effects. Similar findings were observed for apoptotic changes with single treatments. However, the concurrent administration of ALA and Post significantly reduced the protein expressions of Bax, Bax/Bcl2, and cleaved caspase-3 while increasing Bcl2 expression. Additionally, the histopathological findings of the combined therapy were superior to those of single treatments. The concomitant use of ALA and Post effectively inhibited apoptosis, leading to cardiac recovery after I/R injury in diabetic conditions. This strategy could improve outcomes for preserving diabetic hearts following I/R insults.
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.
de Oliveira M, Moreira E, Lucredi N … +5 more , Bonetti C, de Sá-Nakanishi A, Comar J, Bracht A, Bracht L
Can J Physiol Pharmacol · 2024 Jan · PMID 37523769 · Publisher ↗
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...
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.
Molecular hydrogen: prospective treatment strategy of kidney damage after cardiac surgery.
Kalocayova B, Kura B, Vlkovicova J … +11 more , Snurikova D, Vrbjar N, Frimmel K, Hudec V, Ondrusek M, Gasparovic I, Sramaty R, Luptak J, Hulman M, LeBaron TW, Slezak J
Can J Physiol Pharmacol · 2023 Oct · PMID 37463517 · Publisher ↗
Cardiac surgery-associated acute kidney injury is a common post-operative complication, mostly due to increasing oxidative stress. Recently, molecular hydrogen (H gas) has also been applied to cardiac surgery due to its...
Cardiac surgery-associated acute kidney injury is a common post-operative complication, mostly due to increasing oxidative stress. Recently, molecular hydrogen (H gas) has also been applied to cardiac surgery due to its ability to reduce oxidative stress. We evaluated the potential effect of H 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% H 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, H 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 H. The administration of H had a protective effect on the kidneys of pigs after cardiac surgery, especially in terms of normalization of plasma biomarkers to control levels.
NLG-919 combined with cisplatin to enhance inhibitory effect on cell migration and invasion via IDO1-Kyn-AhR pathway in human nasopharyngeal carcinoma cell.
Zou X, Zhao D, Wen X … +1 more , Chen F
Can J Physiol Pharmacol · 2023 Nov · PMID 37459654 · Publisher ↗
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 th...
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.
Novel mediators regulating angiogenesis in diabetic foot ulcer healing.
Rai V, Le H, Agrawal DK
Can J Physiol Pharmacol · 2023 Oct · PMID 37459652 · Publisher ↗
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-treatabl...
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.
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.
Ibrahim KG, Chivandi E, Erlwanger KH … +1 more , Brooksbank RL
Can J Physiol Pharmacol · 2023 Nov · PMID 37433224 · Publisher ↗
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...
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 ( = 119) were allocated to four groups and gavaged with either 10 mL·kg body mass 0.5% dimethyl sulfoxide, 100 mg·kg body mass fenofibrate, fructose (20%, ), 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%, ) 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 ( > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations ( < 0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.
Sleep deprivation disturbs uterine contractility and structure in pregnant rats: role of matrix metalloproteinase 9 and transforming growth factor-β.
El-Malkey NF, Aref M, Goda NIA … +3 more , Hussien MH, Samy W, Hadhod S
Can J Physiol Pharmacol · 2023 Nov · PMID 37433223 · Publisher ↗
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 rem...
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.
Long-term potentiation and its neurotrophin-dependent modulation in the superior cervical ganglion of the rat are influenced by KCNQ channel function.
Arias ER, Sánchez-Tafolla BM, Terrón C … +4 more , Martínez LA, Zetina ME, Morales MA, Cifuentes F
Can J Physiol Pharmacol · 2023 Oct · PMID 37406358 · Publisher ↗
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...
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.
Sex hormone dose escalation for treating abnormal sleep in ovariectomized rats: in vitro GABA synthesis in sleep-related brain areas.
Carrasco-Nuñes N, Romano M, Cabeza M
Can J Physiol Pharmacol · 2023 Oct · PMID 37364372 · Publisher ↗
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...
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-E), 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-E 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-E plus P presence in the assay increased the activity of GAD in the studied brain tissues.
Detection of joining points for genomic DNA circularization in cell culture.
Maeda T
Can J Physiol Pharmacol · 2023 Sep · PMID 37339525 · Publisher ↗
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...
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.
Mechanical activation of vagal afferents involves opposing cation and TREK1 currents and NO regulation.
Park SJ, Zides CG, Beyak MJ
Can J Physiol Pharmacol · 2023 Oct · PMID 37311256 · Publisher ↗
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 stud...
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.
High salt-induced morphological and glycocalyx remodeling of human vascular smooth muscle cells is reversible but induces a high sodium salt-like sensitive memory.
Simon Y, Jacques D, Bkaily G
Can J Physiol Pharmacol · 2023 Sep · PMID 37290125 · Publisher ↗
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 sod...
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.
Vitamins E and A increase the passing of the P-gp substrate ivermectin into the brain in mice.
Tras B, Uney K, Parlak TM … +1 more , Tufan O
Can J Physiol Pharmacol · 2023 Sep · PMID 37235885 · Publisher ↗
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 age...
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 ( < 0.05). The high-dose vitamins E and A and their high-dose combination increased the brain concentration of ivermectin by 3, 2, and 2.7 times, respectively. This research is the first in vivo study to determine the interaction between P-gp substrates and vitamins E and A.
Opioid prescriptions and patients' health services utilization and cost before and during the COVID-19 pandemic: an exploratory population-based administrative data analysis.
Lopatina E, Thanh NX, Tanguay R … +2 more , Pereira JX, Wasylak T
Can J Physiol Pharmacol · 2023 Sep · PMID 37235884 · Publisher ↗
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 opi...
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.
Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model.
Yamamoto S, Sato I, Fujii M … +9 more , Kakimoto M, Honma K, Kirihara S, Nakayama H, Fukuoka T, Tamura S, Ueda M, Hirohata S, Watanabe S
Can J Physiol Pharmacol · 2023 Sep · PMID 37224568 · Publisher ↗
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, whic...
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.
Protective effects of diclofenac on liver graft preservation.
Chaabani R, Bejaoui M, Zaouali MA … +1 more , Ben Abdennebi H
Can J Physiol Pharmacol · 2023 Aug · PMID 37224567 · Publisher ↗
This study aims to evaluate the effect of diclofenac addition to the preservation solution Celsior on liver graft preservation. Liver from Wistar rats were cold flushed in situ, harvested, and then stored in Celsior solu...
This study aims to evaluate the effect of diclofenac addition to the preservation solution Celsior on liver graft preservation. Liver from Wistar rats were cold flushed in situ, harvested, and then stored in Celsior solution (24 h, 4 °C) supplemented or not with 50 mg/L of diclofenac sodium salt. Reperfusion was performed (120 min, 37 °C) using the isolated perfusion rat liver model. Perfusate samples were collected to evaluate transaminases' activities after cold storage and by the end of reperfusion. To evaluate liver function, bile flow, hepatic clearance of bromosulfophthalein, and vascular resistance were assessed. Diclofenac scavenging property (DPPH assay) as well as oxidative stress parameters (SOD and MPO activities and the concentration of glutathione, conjugated dienes, MDA, and carbonylated proteins) were measured. Transcription factors (PPAR-γ and NF-κB), inflammation (COX-2, IL-6, HMGB-1, and TLR-4), as well as apoptosis markers (Bcl-2 and Bax) were determined by quantitative RT-PCR. Enriching the preservation solution Celsior with diclofenac sodium salt attenuated liver injuries and improved graft function. Oxidative stress, inflammation, and apoptosis were significantly reduced in Celsior + Diclo solution. Also, diclofenac activated PPAR-γ and inhibited NF-κB transcription factors. To decrease graft damage and improve transplant recovery, diclofenac sodium salt may be a promising additive to preservation solution.
Sex- and enantiospecific differences in the formation rate of hydroxyeicosatetraenoic acids in rat organs.
Gerges SH, Alammari AH, El-Ghiaty MA … +2 more , Isse FA, El-Kadi AOS
Can J Physiol Pharmacol · 2023 Aug · PMID 37220651 · Publisher ↗
Hydroxyeicosatetraenoic acids (HETEs) are hydroxylated arachidonic acid (AA) metabolites that are classified into midchain, subterminal, and terminal HETEs. Hydroxylation results in the formation of R and S enantiomers f...
Hydroxyeicosatetraenoic acids (HETEs) are hydroxylated arachidonic acid (AA) metabolites that are classified into midchain, subterminal, and terminal HETEs. Hydroxylation results in the formation of R and S enantiomers for each HETE, except for 20-HETE. HETEs have multiple physiological and pathological effects. Several studies have demonstrated sex-specific differences in AA metabolism in different organs. In this study, microsomes from the heart, liver, kidney, lung, intestine, and brain of adult male and female Sprague-Dawley rats were isolated and incubated with AA. Thereafter, the enantiomers of all HETEs were analyzed by liquid chromatography-tandem mass spectrometry. We found significant sex- and enantiospecific differences in the formation levels of different HETEs in all organs. The majority of HETEs, especially midchain HETEs and 20-HETE, showed significantly higher formation rates in male organs. In the liver, the R enantiomer of several HETEs showed a higher formation rate than the corresponding S enantiomer (e.g., 8-, 9-, and 16-HETE). On the other hand, the brain and small intestine demonstrated a higher abundance of the S enantiomer. 19(S)-HETE was more abundant than 19(R)-HETE in all organs except the kidney. Elucidating sex-specific differences in HETE levels provides interesting insights into their physiological and pathophysiological roles and their possible implications for different diseases.
induces cardiovascular dysfunction.
Stanisic D, Jeremic N, Singh M … +3 more , Pushpakumar S, Mokshagundam SPL, Tyagi SC
Can J Physiol Pharmacol · 2023 Aug · PMID 37207360 · Publisher ↗
() is one of the most responsible periodontopathogenic bacteria in the development of periodontal disease (PD); however, its role in the development of other diseases still needs to be understood, specially its implicati...
() is one of the most responsible periodontopathogenic bacteria in the development of periodontal disease (PD); however, its role in the development of other diseases still needs to be understood, specially its implications in the causation of cardiovascular pathogenesis. The aim of this study is to determine whether there is a direct association between -induced PD with that of the development of cardiovascular disease, and whether a long-term administration of probiotic(s) could help improve the cardiovascular disease outcome. To test this hypothesis, we employed four different experimental groups of mice, designated as: : Wild-type (WT) mice (C57BL/6J); : GG (LGG) (WT mice treated with a probiotic; LGG), PD (WT mice treated with ), and : PD + LGG (WT mice treated with and LGG). PD was created by injecting 2 µL (i.e., 20 µg) of lipopolysaccharide (LPS) intragingivally between the 1st and 2nd mandibular molars, two times a week for a total period of 6 weeks. The PD (LGG) intervention was done orally employing 2.5 × 10 CFU/day for a continuous period of 12 weeks. Immediately before the mice were sacrificed, echocardiography of the heart was performed, and after sacrifice, we collected serum samples, hearts, and the periodontal tissue. Histological assessment, cytokine analysis, and zymography of the cardiac tissue were performed. Results revealed inflammation of the heart muscle in the PD group that was marked by infiltration of neutrophils and monocytes, followed by fibrosis. Cytokine analysis of the mice sera revealed significantly elevated levels of tumor necrosis factor-α, IL-1β, IL-6, and IL-17A in the PD group along with LPS-binding protein, and CD14. Most importantly, we observed elevated levels of mRNAs in the heart tissues of PD mice. Zymographic analysis demonstrated matrix remodeling as revealed by increasing content of MMP-9 in the heart tissues of PD mice. Interestingly, LGG treatment was able to mitigate most of the pathological effects. The findings suggest that could lead to cardiovascular system disorder and that probiotic intervention could alleviate, and most likely prevent bacteremia and its harmful effect(s) on the cardiovascular function.
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