Search Results (1,607)

Background: Apigenin (4′,5,7-trihydroxyflavone), a flavonoid with potential cardiovascular benefits, has unclear mechanisms of action. This study investigates its effects on vascular function in Spontaneously Hypertensive Rats (SHRs). Methods: Mesenteric vascular beds (MVBs) were isolated from SHRs and perfused with increasing doses of apigenin after pre-contraction with phenylephrine. To explore the mechanisms, different MVBs were pre-perfused with antagonists and inhibitors, including indomethacin, L-NAME, and potassium channel blockers (tetraethylammonium, a non-specific potassium channel blocker; glibenclamide, an ATP-sensitive potassium channel blocker; 4-aminopyridine, a voltage-gated potassium channel blocker; charybdotoxin a selective intermediate-conductance calcium-activated potassium channel blocker; and apamin, a selective small-conductance calcium-activated potassium channel blocker). Results: Apigenin induced a dose-dependent reduction in perfusion pressure in MVBs with intact endothelium, an effect abolished by endothelium removal. L-NAME reduced apigenin-induced vasodilation by approximately 40%. The vasodilatory effect was blocked by potassium chloride and tetraethylammonium. The inhibition of small and intermediate calcium-activated potassium channels with charybdotoxin and apamin reduced apigenin-induced vasodilation by 50%, and a combination of these blockers with L-NAME completely inhibited the effect. Conclusions: Apigenin promotes vasodilation in resistance arteries through endothelial nitric oxide and calcium-activated potassium channels. These findings suggest that apigenin could have therapeutic potential in cardiovascular disease, warranting further clinical research. Full article

Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects. Full article

This article reviews the contemporary understanding of the functional role of connexins in intercellular communications, their involvement in maintaining cellular and tissue homeostasis, and in aging-associated respiratory disease pathogenesis. Connexins are discussed as potential therapeutic targets. The review particularly focuses on the involvement of gap junction connexins and hemichannels in the transfer of calcium ions, metabolite molecules, ATP, and mitochondria through the cell membrane. Various disorders in the regulation of intercellular communication can heavily contribute to the pathogenesis of multiple diseases, including respiratory system diseases. A deeper understanding of molecular mechanisms underlying the activities of various connexins in gap junction channels will enable the prospective development of therapeutic approaches by either inhibiting or stimulating the activities of a certain connexin, while considering its critical functions in intercellular communications on the whole. Full article

We have previously reported that the calcineurin inhibitor macrolide immunosuppressant Tacrolimus (TAC, FK506) can promote the migration and invasion of the human-derived extravillous trophoblast cells conducive to preventing implantation failure in immune-complicated gestations manifesting recurrent implantation failure. Although the exact mode of action of TAC in promoting implantation has yet to be elucidated, the integral association of its binding protein FKBP12 with the inositol triphosphate receptor (IP3R) regulated intracellular calcium [Ca²⁺]i channels in the endoplasmic reticulum (ER), suggesting that TAC can mediate its action through ER release of [Ca²⁺]i. Using the immortalized human-derived first-trimester extravillous trophoblast cells HTR8/SVneo, our data indicated that TAC can increase [Ca²⁺]I, as measured by fluorescent live-cell imaging using Fluo-4. Concomitantly, the treatment of HTR8/SVneo with TAC resulted in a major dynamic reorganization in the actin cytoskeleton, favoring a predominant distribution of cortical F-actin networks in these trophoblasts. Notably, the findings that TAC was unable to recover [Ca²⁺]i in the presence of the IP3R inhibitor 2-APB indicate that this receptor may play a crucial role in the mechanism of action of TAC. Taken together, our results suggest that TAC has the potential to influence trophoblast migration through downstream [Ca²⁺]i-mediated intracellular events and mechanisms involved in trophoblast migration, such as F-actin redistribution. Further research into the mono-therapeutic use of TAC in promoting trophoblast growth and differentiation in clinical settings of assisted reproduction is warranted. Full article

This study focuses on the reservoir scaling and the under-injection issues of the water injection well during the water injection development of an ultra-low permeability reservoir in Xinjiang due to the complex composition of injected water. Microfluidic experiments were applied to visualize the flow channel changes during water flooding, indoor core flooding experiments were employed to analyze the permeability and ion concentration, and nuclear magnetic resonance (NMR) was used to evaluate the pore structure damage. Together, these experiments were used to clarify the scaling and precipitation characteristics as the injected water met the formation water in porous media and the effects on reservoir damage. The research results showed that the poor compatibility of the injected water with the formation water could easily produce calcium carbonate scaling. The scaling products exhibited a unique network structure of blocks and a radial distribution, mainly composed of calcium carbonate and aluminosilicate. The scaling in the porous media exhibited the characteristics of unstable crystal precipitation, migration, and repeated scaling following water mixing, while the scale crystal growth occurred in the pores and the throats. According to the scaling characteristics, the damage to the reservoir permeability by scaling can be divided into the induction, damage, and stabilization stages. The filling and clogging of the scale crystals enhanced the pore structure heterogeneity, with the median pore radius reduced by 21.61% and the permeability reduced by 50%. Full article

Neurodevelopmental disorders (NDDs) are a group of conditions affecting brain development, with variable degrees of severity and heterogeneous clinical features. They include intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), often coexisting with epilepsy, extra-neurological comorbidities, and multisystemic involvement. In recent years, next-generation sequencing (NGS) technologies allowed the identification of several gene pathogenic variants etiologically related to these disorders in a large cohort of affected children. These genes encode proteins involved in synaptic homeostasis, such as SNARE proteins, implicated in calcium-triggered pre-synaptic release of neurotransmitters, or channel subunit proteins, such as post-synaptic ionotropic glutamate receptors involved in the brain’s fast excitatory neurotransmission. In this narrative review, we dissected emerged molecular mechanisms related to NDDs and epilepsy due to defects in pre- and post-synaptic transmission. We focused on the most recently discovered SNAREopathies and AMPA-related synaptopathies. Full article

In this paper, well Keshen 221 was taken as the research object. The stagnant water–rock static experiment showed that, after 8 weeks of the residual water–rock static reaction, the pore size of the inner profile of the rock slice increased from 5 μm to 90 μm, and calcium carbonate crystals were deposited in the hole. Combined with the microscopic visualization model, it is observed that the reservoir blockage mostly occurs at the pore throat diameter, and the small fracture (30 μm) is blocked first, then the large fracture (50 μm). So, it is inferred that the blockage of the reservoir flow channel is caused by the migration of the crystals precipitated by the interaction between the stagnant water and the reservoir rock. On this basis, the TOUGHREACT reservoir model was further constructed to simulate the scaling of the stagnant water in the reservoir matrix and used to compare the scaling of the fractures with 7% and 30% porosity and the retained water at 0.658 m and 768 m. The pre-results of reservoir scaling show that the scaling is more serious when the fractures occur in the far well zone than when the fractures occur in the well entry zone. At the same location, the deposition of large fractures is six times that of small fractures, and the scaling is more severe in large fractures. Full article

This study investigates the role of calcium ions in the release of action potentials by comparing two models based on the framework: the standard HH model and a HH + Ca model that incorporates calcium ion channels. Purkinje cells’ responses to four types of electrical current stimuli—constant direct current, step current, square wave current, and sine current—were simulated to analyze the impact of calcium on action potential characteristics. The results indicate that, under the constant direct current stimulation, the action potential firing frequency of both models increased with the escalating current intensity, while the delay time of the first action potential decreased. However, when the current intensity exceeded a specific threshold, the peak amplitude of the action potential gradually diminished. The HH + Ca model exhibited a longer delay in the first action potential compared to the HH model but maintained an action potential release under stronger currents. In response to the step current, both models showed an increased action potential frequency with a higher current, but the HH + Ca model generated subthreshold oscillations under weak currents. With the square wave current, the action potential frequency increased, though the HH + Ca model experienced suppression under high-frequency weak currents. Under the sine current, the action potential frequency rose, with the HH + Ca model showing less depression near the sine peak due to calcium’s role in modulating membrane potential. These findings suggest that calcium ions contribute to a more stable action potential release under varying stimuli. Full article

Introduction: We sought to determine by systematic review the independent effect of overweight/obesity on cutaneous microvascular reactivity in adults as measured by laser-Doppler fluxmetry. Methods: CINAHL Complete, SPORTSDiscus, Embase, Medline, and Cochrane Library were searched until March 2024 to identify studies investigating cutaneous microvascular reactivity in an overweight/obese but otherwise healthy group versus a lean/healthy weight. Reporting is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Quality appraisal of included studies was performed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Results: Nineteen eligible articles reported on 1847 participants. Most articles reported impaired cutaneous microvascular reactivity in cohorts with overweight/obesity compared to cohorts with lean/healthy weight. Investigating reactivity via post-occlusive reactive hyperaemia (PORH) and iontophoresis of acetylcholine (ACh) has shown significance. No significant differences were reported between groups in response to local heating or to iontophoresis of methacholine or insulin, while findings of the effect of obesity on iontophoresis of sodium nitroprusside (SNP) were mixed. Conclusions: The pathophysiology of impaired cutaneous microvascular reactivity in overweight/obesity requires further investigation; however, impaired function of vasoactive substances, endothelial dysfunction, sensory nerves, and calcium-activated potassium channels may be implicated. Identifying these impaired microvascular responses should inform possible therapy targets in overweight and obesity.activated potassium channels may be implicated. Identifying these impaired microvascular responses should inform possible therapy targets in overweight and obesity. Full article

Previous studies have observed alterations in excitation–contraction (EC) coupling during end-stage heart failure that include action potential and calcium (Ca²⁺) transient prolongation and a reduction of the Ca²⁺ transient amplitude. Underlying these phenomena are the downregulation of potassium (K⁺) currents, downregulation of the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA), increase Ca²⁺ sensitivity of the ryanodine receptor, and the upregulation of the sodium–calcium (Na⁼-Ca²⁺) exchanger. However, in human heart failure (HF), debate continues about the relative contributions of the changes in calcium handling vs. the changes in the membrane currents. To understand the consequences of the above changes, they are incorporated into a computational human ventricular myocyte HF model that can explore the contributions of the spontaneous Ca²⁺ release from the sarcoplasmic reticulum (SR). The reduction of transient outward K⁺ current (I_to) is the main membrane current contributor to the decrease in RyR2 open probability and L-type calcium channel (LCC) density which emphasizes its importance to phase 1 of the action potential (AP) shape and duration (APD). During current-clamp conditions, RyR2 hyperphosphorylation exhibits the least amount of Ca²⁺ release from the SR into the cytosol and SR Ca²⁺ fractional release during a dynamic slow–rapid–slow (0.5–2.5–0.5 Hz) pacing, but it displays the most abundant and more lasting Ca²⁺ sparks two-fold longer than a normal cell. On the other hand, under voltage-clamp conditions, HF by decreased SERCA and upregulated I_NCX show the least SR Ca²⁺ uptake and EC coupling gain, as compared to HF by hyperphosphorylated RyR2s. Overall, this study demonstrates that the (a) combined effect of SERCA and NCX, and the (b) RyR2 dysfunction, along with the downregulation of the cardiomyocyte’s potassium currents, could substantially contribute to Ca²⁺ mishandling at the spark level that leads to heart failure. Full article

The cytosolic calcium concentration ([Ca²⁺]_cyt) in yeast cells is maintained at a low level via the action of different transporters sequestrating these cations in the vacuole. Among them, the vacuolar Ca²⁺ ATPase Pmc1 crucially contributes to this process. Its inactivation in Ogataea yeasts was shown to cause sodium dodecyl sulfate (SDS) hypersensitivity that can be alleviated by the inactivation of the plasma membrane high-affinity Ca²⁺ channel Cch1. Here, we show that SDS at low concentrations induces a rapid influx of external Ca²⁺ into cells, while the plasma membrane remains impermeable for propidium iodide. The inactivation of Pmc1 disturbs efficient adaptation to this activity of SDS. The inactivation of Cch1 partially restores the ability of pmc1 mutant cells to cope with an increased [Ca²⁺]_cyt that correlates with the suppression of SDS hypersensitivity. At the same time, Cch1 is unlikely to be directly involved in SDS-induced Ca²⁺ influx, since its inactivation does not decrease the amplitude of the rapid [Ca²⁺]_cyt elevation in the pmc1-Δ mutant. The obtained data suggest that the effects of CCH1 inactivation on SDS sensitivity and coping with increased [Ca²⁺]_cyt are related to an additional Cch1 function beyond its direct involvement in Ca²⁺ transport. Full article

Developmental and Epileptic Encephalopathies (DEEs) represent a clinically and genetically heterogeneous group of rare and severe epilepsies. DEEs commonly begin early in infancy with frequent seizures of various types associated with intellectual disability and leading to a neurodevelopmental delay or regression. Disease-causing genomic variants have been identified in numerous genes and are implicated in over 100 types of DEEs. In this context, genes encoding voltage-gated ion channels (VGCs) play a significant role, and part of the large phenotypic variability observed in DEE patients carrying VGC mutations could be explained by the presence of genetic modifier alleles that can compensate for these mutations. This review will focus on the current knowledge of the compensatory effect of DEE-associated voltage-gated ion channels and their therapeutic implications in DEE. We will enter into detailed considerations regarding the sodium channels SCN1A, SCN2A, and SCN8A; the potassium channels KCNA1, KCNQ2, and KCNT1; and the calcium channels CACNA1A and CACNA1G. Full article

Several attempts have been made to elucidate the pathogenesis of drug-induced gingival overgrowth (DIGO), which is triggered by the chronic use of certain drugs that fall into three main categories: anticonvulsants, immunosuppressants, and calcium channel blockers. Previous research suggests that cytokines and impaired cellular functions play a role in DIGO. Of particular interest are macrophages, immune cells that can switch between M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes in response to exogenous signals and stimuli. An imbalance between M1 and M2 macrophage populations may underlie DIGO. M1 may contribute to the initial tissue damage in DIGO, while M2 may then attempt to repair the damage with anti-inflammatory mechanisms. To test the hypothesis that drugs associated with DIGO could influence macrophage polarization, human monocytes (precursors of macrophages) were induced to differentiate into M0-naïve macrophages and then exposed to drugs: diphenylhydantoin, gabapentin, mycophenolate, and amlodipine. Quantitative real-time PCR amplification was used to measure the expression of specific genes associated with macrophage polarization. All of the drugs tested induced M0 macrophages to overexpress genes typical of the M1 phenotype, such as CCL5, CXCL10, and IDO1. This investigation provides the first evidence of a link between drugs that cause DIGO and M1 pro-inflammatory macrophage polarization. The knowledge gained from this research could be valuable for future DIGO treatment strategies. Full article

Background: The increased popularity and ubiquitous use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of diabetes, heart failure, and obesity has led to significant concern for increased risk for perioperative aspiration, given their effects on delayed gastric emptying. This concern is highlighted by many major societies that have published varying guidance on the perioperative management of these medications, given limited data. We conducted a scoping review of the available literature regarding the aspiration risk and aspiration/regurgitant events related to GLP-1 RAs. Methods: A librarian-assisted search was performed using five electronic medical databases (PubMed, Embase, and Web of Science Platform Databases, including Web of Science Core Collection, KCI Korean Journal Database, MEDLINE, and Preprint Citation Index) from inception through March 2024 for articles that reported endoscopic, ultrasound, and nasogastric evaluation for increased residual gastric volume retained food contents, as well as incidences of regurgitation and aspiration events. Two reviewers independently screened titles, abstracts, and full text of articles to determine eligibility. Data extraction was performed using customized fields established a priori within a systematic review software system. Results: Of the 3712 citations identified, 24 studies met eligibility criteria. Studies included four prospective, six retrospective, five case series, and nine case reports. The GLP-1 RAs reported in the studies included semaglutide, liraglutide, lixisenatide, dulaglutide, tirzepatide, and exenatide. All studies, except one case report, reported patients with confounding factors for retained gastric contents and aspiration, such as a history of diabetes, cirrhosis, hypothyroidism, psychiatric disorders, gastric reflux, Barrett’s esophagus, Parkinson’s disease, dysphagia, obstructive sleep apnea, gastric polyps, prior abdominal surgeries, autoimmune diseases, pain, ASA physical status classification, procedural factors (i.e., thyroid surgery associated with risk for nausea, ketamine associated with nausea and secretions), and/or medications associated with delayed gastric emptying (opioids, anticholinergics, antidepressants, beta-blockers, calcium channel blockers, DPP-IV inhibitors, and antacids). Of the eight studies (three prospective and five retrospective) that evaluated residual contents in both GLP-1 users and non-users, seven studies (n = 7/8) reported a significant increase in residual gastric contents in GLP-1 users compared to non-users (19–56% vs. 5–20%). In the three retrospective studies that evaluated for aspiration events, there was no significant difference in aspiration events, with one study reporting aspiration rates of 4.8 cases per 10,000 in GLP-1 RA users compared to 4.6 cases per 10,000 in nonusers and the remaining two studies reporting one aspiration event in the GLP-1 RA user group and none in the non-user group. In one study that evaluated for regurgitation or reflux by esophageal manometry and pH, there was no significant difference in reflux episodes but a reduction in gastric acidity in the GLP-1 RA user group compared to the non-user group. Conclusions: There is significant variability in the findings reported in the studies, and most of these studies include confounding factors that may influence the association between GLP-1 RAs and an increased risk of aspiration and related events. While GLP-1 RAs do increase residual gastric contents in line with their mechanism of action, the currently available data do not suggest a significant increase in aspiration and regurgitation events associated with their use and the withholding of GLP-1 RAs to reduce aspiration and regurgitation events, as is currently recommended by many major societal guidelines. Large randomized controlled trials (RCTs) may be helpful in further elucidating the impact of GLP-1 RAs on perioperative aspiration risk. Full article

Background: Even though beta-blockers had been used as a first-line therapy for hypertension, since the late 1960s, the Eighth Joint National Committee, JNC 8, decided to recommend them no longer. This decision was based on relatively weak evidence from previous studies, which found that first-line beta-blockers were less effective in reducing stroke and heart failure, the main outcomes of hypertension. Despite the general perception, the most common events caused by hypertension are death and MI, not stroke or heart failure. Therefore, this study aimed to clarify beta-blocker efficacy by incorporating the data from all relevant beta-blocker trials, using the composite outcome of major cardiovascular events. Method: A search was conducted on MEDLINE, PubMed, Embase, and the Cochrane Library, restricted to published, peer-reviewed, human, meta-analysis, and controlled clinical trials. The term words used were “beta-blockers or adrenergic beta antagonists”, “hypertension”, and “death or coronary heart disease or stroke or congestive heart failure or myocardial infarction”. For this research, we selected six randomized controlled trials, and three meta-analyses were also chosen. Results: The results showed that beta-blockers were as effective as other first-line medications in younger hypertensive patients. On the other hand, in the patients aged above 60, the results were mixed. Beta-blockers were more effective than diuretics, but inferior to angiotensin receptor blockers. Also, beta-blockers were as safe and effective as angiotensin-converting enzyme inhibitors in reducing coronary heart disease, myocardial infarction, heart failure, and sudden death. However, beta-blockers were inferior to calcium channel blockers in reducing strokes. Conclusions: Beta-blockers were found to be the most effective in many aspects except for strokes. Further studies are needed to assess beta-blockers’ effectiveness in treating primary hypertension. Full article