Canadian journal of physiology and pharmacology最新文献

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.

Stromal interaction molecule 1 (STIM1) is a Ca²⁺ sensor in the endoplasmic reticulum (ER) membrane. The protein plays a crucial role in store-operated Ca²⁺ entry (SOCE) by transducing ER Ca²⁺ depletion signals to Ca²⁺ release-activated Ca²⁺ 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 Ca²⁺ signaling and phosphoinositide biology, positioning MTMR7 as a potential marker or drug target for SOCE related human pathophysiology.

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.

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.

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.

NAD⁺ is an important cofactor involved in regulating many biochemical processes in cells. An imbalance in NAD⁺/NADH ratio is linked to many diseases. NAD⁺ is depleted in diabetes, cardiovascular and neurodegenerative diseases, and in aging, and is increased in tumor cells. NAD⁺ is generated in cells via the de novo, Preiss-Handler, and salvage pathways. Most of the cellular NAD⁺ is generated through Nampt activation, a key rate-limiting enzyme that is involved in the salvage pathway. Restoration of NAD⁺/NADH balance offers therapeutic advantages for improving tissue homeostasis and function. NAD⁺ is known to benefit and restore the body's physiological mechanisms, including DNA replication, chromatin and epigenetic modifications, and gene expression. Recent studies elucidate the role of NAD⁺ in cells utilizing transgenic mouse models. Translational new therapeutics are positioned to utilize the NAD⁺ restoration strategies for overcoming the drawbacks that exist in the pharmacological toolkit. The present review highlights the significance of Nampt-NAD⁺ axis as a major player in energy metabolism and provides an overview with insights into future strategies, providing pharmacological advantages to address current and future medical needs.

The lack of polygenic scores (PGSs) developed for body mass index (BMI) in children may be problematic because the genetic architecture characterizing BMI changes throughout life. This study aims to describe the genetic susceptibility to obesity in children and to compare two PGSs based on data from adults and children and their association with BMI and discrimination of obesity. The study sample comprises 717 participants aged 4-13 years. Adult- and child-based PGSs were evaluated by examining (1) mean BMI across polygenic score risk categories, (2) the capacity to identify obesity with logistic regression, and (3) the linear association with BMI z-scores using linear regression. Increases in one standardized unit of adult-based PGS were related to a stronger increase in BMI z-score (β = 0.24-0.39) than PGS derived in children (β = 0.21-0.30). The association between obesity and the child score was higher (OR = 1.75-2.33) than that for the adult score (OR = 1.74-2.06) for the age group 4-7 years. The inverse was observed for the age group 8-13 years (OR_child 1.56-1.79 vs. OR_adult 1.78-2.54). Both adult- and child-based PGSs show strong associations with BMI and risk of obesity, with the adult-based score standing out from 8 years old.

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.

Doxorubicin is a commonly used chemotherapy that rapidly accumulates in skeletal muscle and disrupts nitric oxide (NO) formation. However, studies investigating these effects have largely been performed in tumour-free models, therefore it remains unknown whether intramuscular accumulation and disruptions to NO content persist during tumour growth. Female C57bl/6 mice (n = 8/group) were randomly assigned to true control, doxorubicin control, tumour only, or tumour plus doxorubicin groups. Tumours were grown for 21, 24, or 28 days using E0771 cells. Doxorubicin was administered as a single 10 mg/kg intraperitoneal dose on day 21. Doxorubicin accumulation was similar in muscle with and without tumours present. Doxorubicinol, a metabolite of doxorubicin, was elevated (p < 0.05) in 24-day tumour + doxorubicin compared to doxorubicin alone. NO was similar across all groups in muscle; however, tumour NO was 15-fold higher at day 21 compared to 24, or 28 days (p < 0.05). The results confirm that doxorubicin is sequestered in skeletal muscle when a tumour is present, which may impact bioavailability. Tumour growth transiently increased intramuscular doxorubicinol, potentially exacerbating the toxicity of the drug. Earlier stage tumour growth appeared to profoundly elevate NO, which could suggest temporal angiogenesis and vasodilation to facilitate growth.