El-Haffaf I, Marsot A, Paillault A
… +6 more, Giang V, Williams V, Smith M, Albert M, Chassé M, Williamson D
Can J Physiol Pharmacol
· 2025 Dec · PMID 41086445
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In this study, we evaluate the exposure and pharmacokinetic/pharmacodynamic target attainment of meropenem in critically ill patients. We conducted a prospective observational study in two Canadian intensive care units (...In this study, we evaluate the exposure and pharmacokinetic/pharmacodynamic target attainment of meropenem in critically ill patients. We conducted a prospective observational study in two Canadian intensive care units (ICUs) from January 2021 to December 2023. We included adult patients admitted in the ICU who received meropenem. On study days 1, 4, and 7 of antimicrobial therapy, three blood samples were collected: 1 h after end of infusion, at the middle, and at the end of the dosing interval. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector. The pharmacokinetic profile of meropenem was evaluated, as well as the attainment of serum concentrations above minimum inhibitory concentrations of 2, 4, and 8 mg/L at midpoint and at trough. We enrolled 28 patients and analyzed 167 meropenem concentrations. We observed large interindividual variability, but intraindividual variability was low. At midpoint, 52% of concentrations were below the target concentration of 8 mg/L, while this proportion increased to 73% for trough concentrations. Patients who failed to reach therapeutic concentrations all had normal to increased renal function. The majority of ICU patients who received meropenem were underexposed for a target concentration of 8 mg/L, with notable interindividual variability but low intraindividual variability. More aggressive dosing administration protocols are warranted to facilitate target attainment of meropenem.
Can J Physiol Pharmacol
· 2026 Jan · PMID 41086444
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Generation of reactive oxygen species (ROS) is a physiological product of cell activity that is mainly generated by the mitochondria as well as by transmembrane NADPH oxidases (NOX1-5) present at the plasma and nuclear e...Generation of reactive oxygen species (ROS) is a physiological product of cell activity that is mainly generated by the mitochondria as well as by transmembrane NADPH oxidases (NOX1-5) present at the plasma and nuclear envelope membranes. The level of basal intracellular ROS is regulated by endogenous antioxidants such as glutathione (GSH), and the endogenous and exogenous antioxidant taurine. These two antioxidants are present in all types of cells and more particularly in the heart and the vascular system. They regulate and control intrcellular normal ROS levels in order to prevent an increase that induces dysfunction of the cardiovascular system. There are also exogenous antioxidants that are present in many types of food such as vitamin C, vitamin E, and resveratrol. These exogenous antioxidants are necessary to complement the effect of endogenous antioxidants. However, according to the literature, it is difficult to generalize about the beneficial effect of exogenous antioxidants in preventing cardiovascular disease. This does not necessarily seem to be the case for endogenous antioxidants. In this review, we will discuss the advantages and disadvantages of using exogenous and endogenous antioxidants, and suggest the potential application of one of them.
Ros-Madrid I, Cano-Mármol R, Ferrer-Gomez M
… +1 more, Ramos-Molina B
Can J Physiol Pharmacol
· 2025 Dec · PMID 41086442
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Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), exert a wide range of beneficial effects beyond glycemic control, largely mediated by their anti-inflammatory properties. Chron...Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), exert a wide range of beneficial effects beyond glycemic control, largely mediated by their anti-inflammatory properties. Chronic low-grade inflammation is a common pathological mechanism underlying metabolic, cardiovascular, hepatic, and neurodegenerative diseases. GLP-1RAs reduce systemic and tissue-specific inflammation through both direct and indirect mechanisms, including inhibition of nuclear factor kappa B signaling, reduction of proinflammatory cytokines, and modulation of immune cell activity, such as that of macrophages and microglia. In type 2 diabetes and obesity, GLP-1RAs improve insulin sensitivity and endothelial function by attenuating inflammation. In metabolic dysfunction-associated steatotic liver disease, GLP-1RAs reduce hepatic steatosis and fibrosis by modulating inflammation in hepatocytes and Kupffer cells. In cardiovascular disease, they mitigate atherosclerosis progression and improve vascular health. GLP-1RAs also exert direct nephroprotective effects by reducing renal inflammation, oxidative stress, and glomerular hyperfiltration in both diabetic and nondiabetic models. GLP-RAs have been also associated with the preservation of cognitive and motor function. Preclinical studies suggest that these neuroprotective effects may involve the attenuation of neuroinflammation and reduced aggregation of pathological proteins. Overall, these pleiotropic actions position incretin-based therapies as promising tools for the management of complex chronic diseases with an inflammatory component.
Can J Physiol Pharmacol
· 2025 Dec · PMID 41061280
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Despite the known association between hypertension and nonalcoholic fatty liver disease (NAFLD), the cut-off values of blood pressure for identifying risk of NAFLD have not yet been determined. The aim of this study was...Despite the known association between hypertension and nonalcoholic fatty liver disease (NAFLD), the cut-off values of blood pressure for identifying risk of NAFLD have not yet been determined. The aim of this study was to determine the diagnostic performance and optimal cut-off values of blood pressure for detecting NAFLD defined by fatty liver index (FLI). This cross-sectional study included 1227 participants aged 35-55 years. NAFLD was determined by FLI with a cut-off value of ≥60. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic ability of blood pressure parameters for screening FLI-defined NAFLD and to determine their cut-off values. The results of this study showed that systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly correlated with FLI values. The prevalence of NAFLD defined by FLI was 23.5% in men and 18.2% in women. The ROC curve analysis showed a good ability of blood pressure for the prediction of FLI-defined NAFLD. The optimal cut-off values of SBP and DBP were 136 and 88 mmHg in men and 137 and 85 mmHg in women, respectively. Thus, high-normal blood pressure is associated with the risk of NAFLD defined by FLI in both men and women.
Tipparaju SM, Manickam R, Oliveira G
… +2 more, Sadana P, Sutariya V
Can J Physiol Pharmacol
· 2025 Nov · PMID 41060702
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The Guest Editors provide highlights and overview of the eCollection which was based on the International Academy of Cardiovascular Sciences-North American Section (IACS-NAS) 2023 annual meeting. The overall impact gener...The Guest Editors provide highlights and overview of the eCollection which was based on the International Academy of Cardiovascular Sciences-North American Section (IACS-NAS) 2023 annual meeting. The overall impact generated by the papers published in eCollection with emphasis on cutting edge topics including FDA-Adverse Event Reporting System (FAERS), ChatGPT and physician recommendation, small molecule research, sarcopenia and aging, metabolism, and orphan receptors and weight loss. The editorial overview provides insights into the continued success of the eCollection.
Martins B, de Deus I, Gutierres V
… +7 more, Souza M, da Silva T, Fagundes M, das Mercês A, Lima W, Ceron C, Paula-Gomes S
Can J Physiol Pharmacol
· 2025 Dec · PMID 41056570
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This study aimed to evaluate the effects of insulin therapy on oxidative stress markers, matrix metalloproteinases (MMPs) 2 and 9 activities, and cardiac remodeling in alloxan-induced diabetic rats. Forty-two male Wistar...This study aimed to evaluate the effects of insulin therapy on oxidative stress markers, matrix metalloproteinases (MMPs) 2 and 9 activities, and cardiac remodeling in alloxan-induced diabetic rats. Forty-two male Wistar rats were randomly allocated into three groups ( ≤ 14 animals), for 30 days: control (CON; saline, IP); diabetes mellitus (DM; alloxan 60 mg/kg, IP); and insulin-treated diabetic (DINS; NPH insulin 4 U, twice daily, IP). After the treatment, the animals were anesthetized and euthanized, and plasma and heart were collected for biochemical, histological, and enzymatic analysis. Compared to DM, the DINS exhibited improved body and heart masses, as well as reduced food intake. Insulin significantly decreased glycemia, triglycerides, and total cholesterol. The antioxidant defenses were enhanced (increased catalase activity and concentrations of reduced glutathione), while the oxidative damage was reduced (decreased protein carbonyls and thiobarbituric acid reactive substance concentrations). Histological analysis revealed a reduction in the inflammatory nuclei and collagen deposition. MMP-2 and MMP-9 activities were lower in the DINS compared to the DM. The insulin treatment attenuated oxidative stress, modulated MMP activity, and collagen accumulation in the heart of diabetic rats. These findings support the potential role of insulin in mitigating diabetes-induced cardiac remodeling through redox balance.
Can J Physiol Pharmacol
· 2025 Dec · PMID 41056565
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Angiogenesis, the formation of new blood vessels, is crucial in ischemic heart disease to improve blood supply to the heart. Meanwhile, in cancer, inhibiting angiogenesis can limit tumor growth by reducing oxygen and nut...Angiogenesis, the formation of new blood vessels, is crucial in ischemic heart disease to improve blood supply to the heart. Meanwhile, in cancer, inhibiting angiogenesis can limit tumor growth by reducing oxygen and nutrients. Calcium ions, key in cellular functions like proliferation and migration, play an important role in this process. Transient Receptor Potential Cation Channel, Vanilloid Subfamily Member 4 (TRPV4), a calcium-permeable channel, is highly expressed in endothelial cells lining blood vessels. This study explored the connection between TRPV4 and angiogenesis using an aortic ring assay. Aortic rings from 3-day-old C57Bl/6 pups were exposed to TRPV4 agonist (GSK1016790) and antagonist (HC067047) and standard growth media (control) after which maximal length and number of new sprouts were measured. The study found that the antagonist significantly reduced the number and length of new micro vessels, while the agonist increased sprout length. These findings highlight TRPV4's role in vascular remodeling, suggesting it could be a therapeutic target for treating diseases related to impaired blood flow and abnormal angiogenesis.
Can J Physiol Pharmacol
· 2025 Dec · PMID 41037821
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Aquaporin-3 (AQP3) is expressed in the basolateral membrane of the renal principal cell, contributing to vasopressin-mediated water reabsorption and urine concentration. We reported that post-translational acetylation of...Aquaporin-3 (AQP3) is expressed in the basolateral membrane of the renal principal cell, contributing to vasopressin-mediated water reabsorption and urine concentration. We reported that post-translational acetylation of lysine 282 of AQP3 promotes water permeability. In this study, we hypothesized that AQP3 acetylation may improve polyuria in a mouse model of lithium-induced nephrogenic diabetes insipidus (Li-NDI). Wild type, AQP3 acetylation (K282Q), and deacetylation (K282R) mimetic mice were fed a lithium-containing diet or a control diet for 14 days. Body masses and spot urines were collected overtime, while urine flow and osmolality, plasma osmolality, and kidneys were collected on day 14 of the diets. All Li-NDI mice had greater urine output and water intake compared to control fed mice, and unexpectedly, this was exacerbated in female Li-NDI AQP3-acetylation and AQP3-deacetylation mice. After 14 days of lithium diet, acetylated AQP3 was almost undetectable in the kidneys of WT mice, and AQP3 localization in acetylated and deacetylated mice was minimal. In the setting of LI-NDI, the significant loss of AQP3 was not prevented in acetylated-AQP3 mice and in female mice mutation of K282 resulted in a worsened Li-NDI phenotype, suggesting that this lysine is critical for promoting sex-specific AQP3-water permeability.
Şen GC, Aydın M, Öner O
… +3 more, Yıldız S, Akbaş E, Öztürk L
Can J Physiol Pharmacol
· 2025 Dec · PMID 40997344
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Chronic sleep restriction (SR) disrupts blood glucose regulation, leading to glucose intolerance and insulin resistance. Regular exercises, however, are known to enhance glycemic control. This study aimed to evaluate the...Chronic sleep restriction (SR) disrupts blood glucose regulation, leading to glucose intolerance and insulin resistance. Regular exercises, however, are known to enhance glycemic control. This study aimed to evaluate the regulatory effects of three distinct exercise protocols on blood glucose alterations caused by chronic rapid eye movement SR. Thirty-four Sprague-Dawley rats were allocated into five groups: control (CTRL), SR, SR plus aerobic exercise (SR + Ex), SR plus resistance exercise (SR + Ex), and SR plus combined exercises (SR + Ex). Except for the control group, all rats underwent 18 h of SR daily for 8 weeks using a modified multi-platform model. Exercise protocols included 30 min of swimming and/or vertical ladder climbing (15 repetitions/day) performed 3 days per week for 8 weeks. Following the intervention, glucose and insulin tolerance tests were conducted. Chronic SR increased blood glucose levels, while aerobic and/or resistance exercises effectively reduced or prevented this elevation. Glucose tolerance was significantly improved in all exercise groups compared to the sedentary group (intraperitoneal glucose tolerance test blood glucose 120 min: SR + Ex = 95 ± 7.7, SR + Ex = 100 ± 7.3, SR + Ex = 90 ± 12.6, SR = 119 ± 14.5 mg/dL; < 0.05). Regular exercise may mitigate adverse metabolic effects of SR.
Todorović D, Stojanović M, Jakovljević Uzelac J
… +7 more, Mutavdžin Krneta S, Radisavljevic N, Gopčević K, Medić A, Labudović Borović M, Stankovic S, Djuric D
Can J Physiol Pharmacol
· 2025 Nov · PMID 40991665
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Hyperhomocysteinemia can induce significant alterations in the cardiovascular system, and vitamin B6 is one of the primary cofactors of enzymes involved in homocysteine metabolism. The aim of this study was to examine th...Hyperhomocysteinemia can induce significant alterations in the cardiovascular system, and vitamin B6 is one of the primary cofactors of enzymes involved in homocysteine metabolism. The aim of this study was to examine the effects of vitamin B6 in hyperhomocysteinemic conditions on cardiovascular biomarkers in sera, oxidative stress parameters, metabolic enzymes activities, and histological changes in rat heart and aorta. Male Wistar albino rats were divided into four groups ( = 10, per group): C: 0.9% NaCl 0.2 mL/day s.c. + 0.9% NaCl 0.5 mL i.p; H: D, L-homocysteine 0.45 mmol/g b.w./day s.c. + 0.9% NaCl 0.5 mL i.p; CB6: 0.9% NaCl 0.2 mL/day s.c. + vitamin B6 7 mg/kg b.w. i.p.; and H-B6: D, L-homocysteine 0.45 mmol/g b.w./day s.c. + vitamin B6 7 mg/kg b.w. i.p. Substances were applied s.c. for 2 weeks and i.p for 4 weeks. Level of homocysteine, activity of superoxide dismutase, concentration of malondialdehyde, and right ventricle wall thickness were significantly lower in HB6 group compared to H group, while lactate dehydrogenase activity was higher in HB6 group compared to all other groups. These findings suggest the potential beneficial effects of vitamin B6 supplementation on cardiovascular system in patients with hyperhomocysteinemia.
Can J Physiol Pharmacol
· 2025 Nov · PMID 40829189
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The present study was designed to investigate the role of PERK in CVD risk associated with polycystic ovarian syndrome (PCOS) in experimental rat model, and the therapeutic benefits of probiotics. Eight-weeks-old female...The present study was designed to investigate the role of PERK in CVD risk associated with polycystic ovarian syndrome (PCOS) in experimental rat model, and the therapeutic benefits of probiotics. Eight-weeks-old female Wistar rats were assigned into four groups ( = 6): Control (CTRL), Probiotics (PROB), Letrozole (PCOS), and PCOS + PROB. Daily administration of letrozole (1 mg/kg) for 21 days was used to induce PCOS; thereafter, probiotics (3 × 10 CFU) was administered daily for 6 weeks. Biochemical parameters and histological evaluations were performed with appropriate techniques. The present findings revealed that animals with PCOS were characterized with phenotypic features such as hyperandrogenemia and multiple cysts in the ovaries. In addition, PCOS rats manifested insulin resistance and increase in glucose regulatory protein (GRP78), together with increased levels of circulating corticosterone, cardiac triglyceride, inflammatory mediators (NF-κB and TNF-α), TGF-β1, Caspase-6, and HDAC2, while a decrease in HIF-1α and NrF2 was observed when compared with control animals. These were accompanied by elevated level of PERK. However, treatment with probiotics reversed these systemic, endocrine, metabolic, and cardiac anomalies. The present study suggests that probiotics attenuates CVD risk profile in experimental PCOS rat model by suppression of PERK/HDAC2-dependent pathway.
Rivera-Ruedas A, Medina-Vilchis A, Romero-Tovar J
… +2 more, Cristóbal-Mondragón G, la Rosa VD
Can J Physiol Pharmacol
· 2025 Oct · PMID 40743563
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Pharmacological targeting of ion channels represents a crucial avenue for pain management. The KCNQ family of ion channels plays a significant role in controlling neuronal excitability and the generation and propagation...Pharmacological targeting of ion channels represents a crucial avenue for pain management. The KCNQ family of ion channels plays a significant role in controlling neuronal excitability and the generation and propagation of pain-related nerve impulses, mitigating excessive electrical signaling and limiting the transmission of pain signals. Eugenol has a variety of biological activities, including analgesic and anti-inflammatory properties. When used in conjunction with the anti-inflammatory drug diclofenac, eugenol demonstrates enhanced analgesic efficacy in animal models. We investigated the effects of eugenol on KCNQ ion channels. Eugenol acts as a KCNQ2/3 activator, shifting the voltage dependency to negative potentials, most of the activation can be explained by the effect on the KCNQ3, molecular docking simulation and mutagenesis experiments suggest that the binding pocket of eugenol is located at the top of the voltage-sensing domain. We also show that eugenol is a weak activator of the TRPV1 channel yet inhibits the capsaicin and acidic pH-activated current. Diclofenac also inhibits the TRPV1 channel current. In cells co-expressing KCNQ2/3 and TRPV1, eugenol and diclofenac limit the extent of membrane depolarization. Altogether, we report a new target for eugenol that adds to its wide array of biological activities, including its role in modulating acute pain.
Incretin therapies have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests that these agents modulate key pathways involved in cardiovascular, renal, hepatic, neuropsychiatric, and rep...Incretin therapies have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests that these agents modulate key pathways involved in cardiovascular, renal, hepatic, neuropsychiatric, and reproductive health. In this narrative review, we examine the role of incretin-based therapies in chronic kidney disease, heart failure with preserved ejection fraction, metabolic dysfunction-associated steatotic liver disease, neurodegenerative and cognitive disorders, substance use disorder, obstructive sleep apnea, knee osteoarthritis, and polycystic ovary syndrome. The mechanisms underlying these benefits appear to extend beyond glucose and weight regulation, including anti-inflammatory, neuroprotective, and cardiorenal effects. We summarize key clinical trial data, highlight knowledge gaps, and discuss future directions for integrating incretin-based therapies into broader clinical practice.
Gurusamy N, Almalki B, Katragadda S
… +3 more, Murray J, Speth R, Robison L
Can J Physiol Pharmacol
· 2025 Aug · PMID 40334279
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Ketone bodies, particularly β-hydroxybutyrate (BHB), play an important role in the epigenetic regulation of gene expression in cardiac tissues, impacting both cardiac health and disease. This review explores the multifac...Ketone bodies, particularly β-hydroxybutyrate (BHB), play an important role in the epigenetic regulation of gene expression in cardiac tissues, impacting both cardiac health and disease. This review explores the multifaceted influence of ketone bodies on epigenetic mechanisms, including histone acetylation, DNA methylation, ubiquitination, sirtuins activation, and RNA modulation. By acting as endogenous histone deacetylase inhibitors, ketone bodies enhance histone acetylation, thereby promoting the expression of genes involved in antioxidant defenses, anti-inflammatory responses, and metabolic regulation. Furthermore, BHB affects DNA methylation patterns by altering the availability of key metabolites such as S-adenosylmethionine. Ketogenic diet, which elevates BHB levels, has been shown to modulate gene expression, such as increasing FOXO3a and metallothionein 2, and improve cardiac function. This review highlights the therapeutic potential of ketone bodies in managing cardiac diseases through their epigenetic effects, underscoring the need for further research to elucidate the detailed molecular pathways and long-term impacts of these metabolic interventions.
Can J Physiol Pharmacol
· 2025 Aug · PMID 40327889
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Stromal interaction molecule 1 (STIM1) is a Ca sensor in the endoplasmic reticulum (ER) membrane. The protein plays a crucial role in store-operated Ca entry (SOCE) by transducing ER Ca depletion signals to Ca release-ac...Stromal interaction molecule 1 (STIM1) is a Ca sensor in the endoplasmic reticulum (ER) membrane. The protein plays a crucial role in store-operated Ca entry (SOCE) by transducing ER Ca depletion signals to Ca release-activated Ca channel protein 1 (ORAI1) at the plasma membrane. Myotubularin related protein 7 (MTMR7) is a lipid phosphatase that dephosphorylates phosphoinositides. Using yeast two-hybrid analysis, immunoprecipitation and fluorescence microscopy, we discovered that MTMR7 interacts with STIM1 at the ER. These observations identified MTMR7 as a novel STIM1-binding protein that bridges myotubularins and phosphoinositide signaling with SOCE. Our research revealed a novel link between Ca signaling and phosphoinositide biology, positioning MTMR7 as a potential marker or drug target for SOCE related human pathophysiology.
Can J Physiol Pharmacol
· 2025 Oct · PMID 40305875
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Anaplastic lymphoma kinase (ALK) inhibitors have transformed treatment for ALK-rearranged malignancies, particularly non-small cell lung cancer, by disrupting oncogenic signalling. However, hematologic adverse effects, i...Anaplastic lymphoma kinase (ALK) inhibitors have transformed treatment for ALK-rearranged malignancies, particularly non-small cell lung cancer, by disrupting oncogenic signalling. However, hematologic adverse effects, including hemolysis, have emerged as concerns, especially with alectinib. This study evaluates the prevalence of hemolytic events associated with ALK inhibitors using FDA Adverse Event Reporting System (FAERS) data. A retrospective pharmacovigilance analysis was conducted using FAERS data (2013-2023). Disproportionality analysis with OpenVigil 2.1 assessed associations between ALK inhibitors and hemolysis-related events. Reporting odds ratios (RORs) were calculated, with statistical significance defined as ROR > 2.00 and a lower 95% confidence interval (CI) bound > 1.00. Alectinib exhibited strong associations with hemolysis (ROR 24.01, 95% CI: 17.88-32.24; 45 reports) and bilirubin increase (ROR 18.86, 95% CI: 15.92-22.34; 138 reports). Crizotinib and ceritinib showed weaker signals, while brigatinib and lorlatinib had no significant associations. The findings highlight alectinibs potential hemolytic risk, necessitating hematologic monitoring. Proposed mechanisms include immune-mediated hemolysis, direct cytotoxicity, and metabolic variability. Routine hemoglobin and bilirubin assessments, along with clinical vigilance, are essential. Further studies are needed to elucidate mechanisms of causality and optimize patient safety.
Lourenço L, da Silva Lopes Salles É, Emídio R
… +3 more, Paffaro Junior V, Soncini R, Zavan B
Can J Physiol Pharmacol
· 2025 Aug · PMID 40305874
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Obesity induced by a high-fat diet (HFD) is a growing global health concern, often linked to numerous metabolic and respiratory disorders. This study investigates the impact of a maternal HFD on the respiratory physiolog...Obesity induced by a high-fat diet (HFD) is a growing global health concern, often linked to numerous metabolic and respiratory disorders. This study investigates the impact of a maternal HFD on the respiratory physiology of adult offspring, emphasizing the potential for fetal programming to exacerbate airway responsiveness. Adult male offspring from dams fed a HFD or a control diet during gestation were submitted to ventilatory mechanical analysis following bronchoconstrictor and bronchodilator challenge. Offspring from the HFD group demonstrated increased body weight, elevated blood glucose levels, heightened airway responsiveness to methacholine-induced bronchoconstriction, and impaired bronchodilator efficacy compared to controls. These findings underscore the potential long-term impact of maternal nutrition on offspring respiratory health. The study also highlights the necessity of identifying critical therapeutic targets for managing respiratory dysfunction in populations exposed to maternal obesity, intending to improve treatment outcomes and prevent related respiratory complications.
Sepsis is an organ dysfunction caused by the body's dysfunctional response to infection, which is one of the most important causes of death in critically ill patients. It is characterized by high morbidity, high mortalit...Sepsis is an organ dysfunction caused by the body's dysfunctional response to infection, which is one of the most important causes of death in critically ill patients. It is characterized by high morbidity, high mortality, and high treatment costs. Currently, the treatment of sepsis relies mainly on supportive therapy, and there is a lack of targeted intervention ways. Studying the pathogenesis of sepsis and exploring new therapeutic targets are of great theoretical and clinical importance. Calcium-sensitive receptor (CaSR) is a cell membrane receptor belonging to the family of G protein-coupled receptors and is widely distributed in various tissues and organs. Research indicates that CaSR plays a role in mitigating sepsis-induced organ dysfunction, exhibiting tissue-specific protective effects in certain tissues while inducing inflammatory responses in others. Elucidating these dual effects and the underlying signaling pathways could facilitate the development of targeted therapies for sepsis-related organ damage. This review summarizes recent literature and evidence on CaSR signaling in sepsis-induced organ dysfunction. In addition, we provide an up-to-date schematic of the most important and likely molecular signaling pathways associated with CaSR in sepsis.
We previously demonstrated that naringin (NAR) protects against liver damage in streptozotocin (STZ)-induced diabetes in rats. The aim of this study was to elucidate whether NAR is also able to protect the functioning, b...We previously demonstrated that naringin (NAR) protects against liver damage in streptozotocin (STZ)-induced diabetes in rats. The aim of this study was to elucidate whether NAR is also able to protect the functioning, biogenesis and dynamics of the liver mitochondria in diabetic rats (DM). The activities of isocitrate dehydrogenase and malate dehydrogenase from the Krebs cycle, complex I-III from electron chain and adenosine triphosphate synthase were decreased in DM rats, effects that were blocked by NAR. The gene expression of mitofusin-2 and GTPase dynamin-related protein 1, markers of mitochondrial fusion and fission, were decreased in DM rats, which was prevented by NAR. Total glutathione was decreased and protein carbonyl contents as well as the activity of the antioxidant enzymes were increased in DM rats. All these changes were blocked by NAR. In conclusion, NAR protects the liver mitochondria from DM rats avoiding changes in the activity of Krebs cycle, the respiratory chain and the oxidative phosphorylation as well as preventing alterations in the fusion-fission processes. These effects are mediated, at least in part, by decreasing oxidative stress and anomalies in the enzymatic antioxidant system. Further studies are necessary to validate efficacy and safety of NAR for human use.
Neuropathic pain severely impacts quality of life and effective treatments are needed. To address this, the present study investigated the antihyperalgesic mechanisms of levetiracetam administered at the supraspinal leve...Neuropathic pain severely impacts quality of life and effective treatments are needed. To address this, the present study investigated the antihyperalgesic mechanisms of levetiracetam administered at the supraspinal level, together with its effects on ion channel activities. The ventral posterolateral nucleus of the thalamus was selected as the location for micro-injection. Thermal hyperalgesia and mechanical allodynia were assessed via in vivo experiments using the Hargreave's and e-Von Frey apparatus, respectively. Levetiracetam displayed statistically meaningful time and dose-dependent effects in the chronic constriction injury model, with statistical probability values less than 0.05. It was discovered that the antihyperalgesic effects were more pronounced in mechanical allodynia. Electrophysiological studies conducted through whole-cell patch clamp recordings indicated that levetiracetam tended to activate or increase the permeability of one or more channels for ion flow that are active only at hyperpolarized membrane potentials (-130 to -90 mV), suggesting the potential participation of hyperpolarization-activated cyclic nucleotide-gated, inwardly-rectifying K, or G protein-gated inwardly-rectifying K channels. The findings could guide future drug development studies towards levetiracetam and its derivatives as effective treatments for neuropathic pain.