Search Results (280)

F₄-Neuroprostanes (F₄-NeuroPs), oxidative metabolites of docosahexaenoic acid, act as bioactive lipid mediators enhancing sperm motility and induce capacitation-like changes in vitro. Their biological action is proposed to involve sperm ion channels, in particular ryanodine receptors (RyRs), which regulate intracellular calcium homeostasis. We evaluated the effects of dantrolene, a RyR inhibitor, on motility and vitality of a selected spermatozoa at different concentrations (10, 30, 50, 100 μM). Then sperm motility, acrosome integrity, and RyR localization following co-incubation with dantrolene (D50 or D100 μM) and 4-/10-F_4t-NeuroPs (7 ng) were investigated. Acrosomal status was assessed using Pisum sativum agglutinin (PSA) staining and RyR localization by immunofluorescence. D50 was identified as the minimum effective dose to induce significant reductions in sperm motility. F₄-NeuroPs significantly increased rapid progressive motility versus controls. Co-incubation with F₄-NeuroPs + D50 reduced rapid motility and increased in situ and circular movement. The acrosome staining appeared altered or absent to different percentages, and RyR localization was also seen in the midpiece. These findings suggested that F₄-NeuroPs enhance sperm motility via RyR-mediated pathways, as confirmed by dantrolene inhibition. Accordingly, our results underscore the physiological relevance of RyRs in sperm function and suggest new insights into lipid-based mechanisms regulating sperm motility. Full article

Background: The European League Against Rheumatism (EULAR), in collaboration with the European Scleroderma Trial and Research group (EUSTAR), published the first set of treatment recommendations for systemic sclerosis (SSc) in 2009, with subsequent updates in 2016 and 2023. Objectives: This study aimed to evaluate how rheumatologists’ clinical approaches to the treatment of SSc evolved following the 2016 update of the clinical management guidelines. Methods: Medication use for SSc was analyzed in a cohort of 378 patients. The patients were stratified based on enrollment before (233 patients) and after (145 patients) the guideline update, and medication usage was compared between the two groups. Results: Although all patients presented with Raynaud’s phenomenon (RP), only 35% received calcium channel blockers. Medications such as iloprost, phosphodiesterase type 5 (PDE-5) inhibitors, fluoxetine, and bosentan, recommended for the treatment of RP and digital ulcers, were not approved for SSc by the Republic Health Insurance Fund. Treatment for pulmonary arterial hypertension (PAH) was administered to only 16 patients (4.2%), including 2 who received bosentan, 10 who received PDE-5 inhibitors, and 4 who were treated with riociguat. The use of PDE-5 inhibitors increased following the 2016 update of the guidelines. Cyclophosphamide was consistently prescribed for interstitial lung disease (ILD), with an increased frequency observed after the guideline update. No significant differences were observed in the use of methotrexate for skin involvement, ACE inhibitors for scleroderma renal crisis, or antibiotics for gastrointestinal symptoms. Proton pump inhibitors (PPIs) were prescribed to 87.3% of patients with gastrointestinal involvement, with an increase in use of both PPIs and prokinetic agents following the guideline update. Conclusions: Rheumatologists’ adherence to the EULAR/EUSTAR guidelines varied considerably, with 25% to 100% of eligible patients receiving the recommended treatments. Concordance improved in the management of PAH, ILD, and gastrointestinal involvement after the 2016 guideline update. Full article

Cancer therapy-induced hypertension (HTN) is an increasingly recognized complication associated with a wide range of anticancer agents, including vascular endothelial growth factor (VEGF) inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and alkylating agents. The pathogenesis of HTN in this setting is multifactorial, involving mechanisms such as endothelial dysfunction, nitric oxide (NO) suppression, sympathetic nervous system activation, and vascular remodeling. Additional factors, including paraneoplastic syndromes, poorly controlled pain, mood disturbances, and overlapping cardiovascular risk factors like obesity and diabetes, further contribute to the complexity of diagnosis and management. Despite its prevalence and clinical implications, cancer therapy-induced HTN is often addressed using general population guidelines, with limited oncology-specific protocols available. Accurate blood pressure measurement and individualized treatment plans are critical to optimize outcomes and avoid interruptions to cancer therapy. Antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and calcium channel blockers have shown efficacy in both blood pressure control and, in some cases, oncologic outcomes. A multidisciplinary approach involving oncologists, cardiologists, and primary care providers is essential to navigate the interplay between cancer treatment and cardiovascular health. Ongoing research is needed to develop targeted guidelines and improve the long-term care of cancer patients affected by treatment-induced HTN. Full article

Calcium (Ca²⁺) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca²⁺ concentration is tightly regulated by a balance between Ca²⁺ mobilization mechanisms, including Ca²⁺ release from the intracellular stores in the sarcoplasmic/endoplasmic reticulum and Ca²⁺ entry via voltage-dependent, transient-receptor potential, and store-operated Ca²⁺ channels, and Ca²⁺ elimination pathways including Ca²⁺ extrusion by the plasma membrane Ca²⁺-ATPase and Na⁺/Ca²⁺ exchanger and Ca²⁺ re-uptake by the sarco(endo)plasmic reticulum Ca²⁺-ATPase and the mitochondria. Some cell membranes/organelles are multifunctional and have both Ca²⁺ mobilization and Ca²⁺ removal pathways. Also, the individual Ca²⁺ handling pathways could be integrated to function in a regenerative, capacitative, cooperative, bidirectional, or reciprocal feed-forward or feed-back manner. Disruption of these pathways causes dysregulation of the Ca²⁺ signaling dynamics and leads to pathological cardiovascular conditions such as hypertension, coronary artery disease, atherosclerosis, and vascular calcification. In the endothelium, dysregulated Ca²⁺ signaling impairs nitric oxide production, reduces vasodilatory capacity, and increases vascular permeability. In VSMCs, Ca²⁺-dependent phosphorylation of the myosin light chain and Ca²⁺ sensitization by protein kinase-C (PKC) and Rho-kinase (ROCK) increase vascular tone and could lead to increased blood pressure and hypertension. Ca²⁺ activation of matrix metalloproteinases causes collagen/elastin imbalance and promotes vascular remodeling. Ca²⁺-dependent immune cell activation, leukocyte infiltration, and cholesterol accumulation by macrophages promote foam cell formation and atherosclerotic plaque progression. Chronic increases in VSMCs Ca²⁺ promote phenotypic switching to mesenchymal cells and osteogenic transformation and thereby accelerate vascular calcification and plaque instability. Emerging therapeutic strategies targeting these Ca²⁺-dependent mechanisms, including Ca²⁺ channel blockers and PKC and ROCK inhibitors, hold promise for restoring Ca²⁺ homeostasis and mitigating vascular disease progression. Full article

The L-type calcium channels (LTCCs) function as the main entry points that convert myocyte membrane depolarization into calcium transients, which drive every heartbeat. There is increasing evidence to show that maladaptive remodeling of these channels is the cause of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Recent experimental, translational, and clinical studies have improved our understanding of the roles LTCC expression, micro-domain trafficking, and post-translational control have in disrupting excitation–contraction coupling, provoking arrhythmias, and shaping phenotype specific hemodynamic compromise. We performed a systematic search of the PubMed and Google Scholar databases (2015–2025, English) and critically evaluated 17 eligible publications in an effort to organize the expanding body of work. This review combines existing data about LTCC density and T-tubule architecture with β-adrenergic and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) signaling and downstream sarcoplasmic reticulum crosstalk to explain how HFrEF presents with contractile insufficiency and how HFpEF shows diastolic calcium overload and stiffening. Additionally, we highlight the emerging therapeutic strategies aimed at restoring calcium homeostasis such as CaMKII inhibitors, ryanodine receptor type 2 (RyR2) stabilizers, and selective LTCC modulators without compromising systolic reserve. The review establishes LTCC dysregulation as a single mechanism that causes myocardial dysfunction while remaining specific to each phenotype, thus offering clinicians and researchers a complete reference for current concepts and future precision therapy approaches in heart failure. Full article

Neuropathic pain resulting from injury to the somatosensory nervous system affects approximately 6.9–10% of the general population and significantly impacts quality of life. Common presentations include burning, stabbing, tingling, or electrical sensations, occurring spontaneously or through hyperalgesia or allodynia. Treatment approaches follow a tiered system. First-line therapies include gabapentinoids (e.g., gabapentin, pregabalin), which target voltage-gated calcium channels; tricyclic antidepressants (e.g., amitriptyline, nortriptyline); and serotonin-norepinephrine reuptake inhibitors such as duloxetine. Second-line options encompass topical agents (e.g., 5% lidocaine, 8% capsaicin), opioid-like medications (e.g., tramadol, tapentadol), and adjunctive therapies including psychological therapies and lifestyle interventions. For refractory cases, third-line treatments include NMDA receptor antagonists (e.g., ketamine, dextromethorphan), cannabinoids, and botulinum toxin type A, though these have more limited clinical evidence. Procedural interventions such as spinal cord stimulation and transcutaneous electrical nerve stimulation provide alternatives when pharmacological approaches fail. Despite advances in treatment options, many patients remain undertreated, highlighting the need for individualized, multimodal approaches and continued research into the complex pathophysiology of neuropathic pain conditions. Full article

Background and Objectives: Up to 40% of patients undergoing a coronary angiogram due to angina pectoris have no obstructive coronary artery disease, also known as angina with non-obstructive coronary arteries (ANOCA). ANOCA is associated with significant impairment in patients’ quality of life, increased risk of myocardial infarction and all-cause mortality. Approximately 25% of patients with ANOCA have persisting symptoms despite optimal medical therapy. There is a lack of in-depth knowledge regarding tailored treatment for patients with ANOCA due to a scarcity of trials designed to assess the effect of treatment modalities. The aim of this systematic review and meta-analysis is to give clinicians an overview of the efficacy of current treatment modalities for patients with ANOCA. Methods: PudMed/MEDLINE, Embase, the Cochrane Library and clinical trial registries were searched for randomised controlled and cohort studies regarding treatment modalities for ANOCA. The main outcome was change in angina pectoris frequency for each treatment modality. Secondary outcomes included changes in exercise capacity, quality of life, Canadian Cardiovascular Society (CCS) class, coronary flow reserve (CFR) and survival. Results: In total, 80 studies were included and used in the meta-analysis, of which ten studies met the current definition of ANOCA. Angina pectoris frequency improved significantly in the majority of the treatment modalities, with neuromodulation resulting in −3.35 standardised mean difference (SMD) (95% CI: −5.13; −1.56), trimetazidine in −1.74 SMD (−2.63; −0.85), traditional Chinese medicine in −1.55 SMD (−2.36; −0.75), beta-blockers in −1.32 SMD (−1.88; −0.77), enhanced external counterpulsation in −1.27 SMD (−2.04; −0.49), stem cell therapy in −1.04 SMD (−1.51; −0.57), lifestyle interventions in −0.86 SMD (−1.15; −0.57), RAAS-inhibitors in −0.83 SMD (−1.31; −0.35) and calcium channel blockers in −0.64 SMD (−0.92; −0.35). Conclusions: This meta-analysis into treatment modalities for patients with ANOCA shows a significant improvement in angina pectoris frequency in the majority of included treatment modalities. However, these results should be interpreted cautiously, as only ten of the studies included in the meta-analysis meet the current definition of ANOCA. This review underlines the importance of undertaking new studies with existing treatment modalities to determine the efficacy in patients with ANOCA. Full article

Neuropathic pain is a chronic and debilitating disorder of the somatosensory system that affects a significant proportion of the population and is characterized by abnormal responses such as hyperalgesia and allodynia. Voltage-gated ion channels, including sodium (Na_V), calcium (Ca_V), and potassium (K_V) channels, play a pivotal role in modulating neuronal excitability and pain signal transmission following nerve injury. This review intends to provide a comprehensive analysis of the molecular and cellular mechanisms by which dysregulation in the expression, localization, and function of specific Na_V channel subtypes (mainly Na_V1.7 and Na_V1.8) and their auxiliary subunits contributes to aberrant neuronal activation, the generation of ectopic discharges, and sensitization in neuropathic pain. Likewise, special emphasis is placed on the crucial role of Ca_V channels, particularly Ca_V2.2 and the auxiliary subunit Ca_Vα₂δ, whose overexpression increases calcium influx, neurotransmitter release, and neuronal hyperexcitability, thus maintaining persistent pain states. Furthermore, K_V channels (particularly K_V7 channels) function as brakes on neuronal excitability, and their dysregulation facilitates the development and maintenance of neuropathic pain. Therefore, targeting specific K_V channel subtypes to restore their function is also a promising therapeutic strategy for alleviating neuropathic pain symptoms. On the other hand, recent advances in the development of small molecules as selective modulators or inhibitors targeting voltage-gated ion channels are also discussed. These agents have improved efficacy and safety profiles in preclinical and clinical studies by attenuating pathophysiological channel activity and restoring neuronal function. This review seeks to contribute to guiding future research and drug development toward more effective mechanism-based treatments by discussing the molecular mechanisms underlying neuropathic pain and highlighting translational therapeutic opportunities. Full article

Mechanogated (MG) ion channels play a crucial role in mechano-transduction and immune cell regulation, yet their impact on blood cancers, particularly acute lymphoblastic leukemia (ALL), remains poorly understood. This study investigates the pharmacological effects of GsMTx4, an MG channel inhibitor, in human ALL cells both in vitro and in vivo. Unexpectedly, we found that GsMTx4 remarkably increased basal calcium (Ca²⁺) levels in ALL cells through constitutive Ca²⁺ entry and enhanced store-operated Ca²⁺ influx upon thapsigargin stimulation. This increase in basal Ca²⁺ signaling promoted ALL cell viability and proliferation in vitro. Notably, chelating intracellular Ca²⁺ with BAPTA-AM reduces GsMTx4-mediated leukemia cell viability and proliferation. However, in vivo, GsMTx4 decreases cytosolic Ca²⁺ levels in Nalm-6 GFP⁺ cells isolated from mouse blood, effectively countering leukemia progression and significantly extending survival in NSG mice transplanted with leukemia cells (median survival: GsMTx4 vs. control, 37.5 days vs. 29 days, p = 0.0414). Our results highlight the different properties of GsMTx4 activity in in vitro and in vivo models. They also emphasize that Ca²⁺ signaling is a key vulnerability in leukemia, where its precise modulation dictates disease progression. Thus, targeting Ca²⁺ channels could offer a novel therapeutic strategy for leukemia by exploiting Ca²⁺ homeostasis. Full article

With rapid societal changes and increasing stress levels, the abuse of psychoactive substances has emerged as a global health crisis. Studies indicate that the mitochondrial calcium uniporter (MCU) plays a pivotal role in neurotoxic damage induced by psychoactive substances. As the primary channel for mitochondrial Ca²⁺ uptake, MCU dysfunction can lead to Ca²⁺ overload, oxidative stress, and apoptosis, representing a crucial mechanism underlying neurotoxic damage. Psychoactive substances such as 3,4-Methylenedioxymethamphetamine (MDMA), cocaine, and morphine influence MCU function through multiple pathways, resulting in excessive Ca²⁺ accumulation and mitochondrial dysfunction, ultimately leading to neuronal injury. Although MCU inhibitors have demonstrated potential in alleviating Ca²⁺ overload and improving neural function in preliminary studies, their selectivity and long-term safety require further evaluation. Future research should explore the precise regulatory mechanisms of MCU in neurotoxic damage induced by psychoactive substances and develop more effective targeted therapeutic strategies. Full article

Background/Objectives: Fructose-1,6-bisphosphate (FBP) is an intermediate product of the glycolytic pathway with analgesic effect in acute inflammatory pain model via the production of adenosine. However, whether FBP is active in neuropathic pain is unknown. Therefore, we reason that it would be suitable to investigate the analgesic effect and mechanism of action of FBP in a model of chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain in mice. Methods: After CCI induction, mice received FBP, adenosine, A1 and/or A2A receptor antagonists, and/or inhibitors of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)/ATP sensitive K channels (KATP) signaling pathway. Results: FBP (up to 85%) and adenosine (up to 84%) inhibited the mechanical hyperalgesia (electronic aesthesiometer) induced by CCI with similar profiles. FBP analgesia was dependent on adenosine because adenosine A1 and A2A receptors antagonists diminished FPB activity (100% and 79%, respectively). FBP analgesia was also dependent on activating the NO/cGMP/PKG/KATP signaling pathway. Furthermore, FBP treatment increased the production of NO in cultured dorsal root ganglia (DRG) neurons (100% increase), whereas neuronal nitric oxide synthase (nNOS) inhibition decreased (up to 70%) the analgesic effect of FBP. We also observed that FBP reduced the calcium levels of transient receptor potential ankyrin 1 (TRPA1)⁺ DRG neurons (85%) and paw-flinching triggered by TRPA1 activation (38%). Conclusions: FBP reduced neuropathic pain by reducing DRG neuron activation. The mechanisms involved the activation of adenosine A1 and A2A receptors to trigger the analgesic NO/cGMP/PKG/KATP signaling pathway and reducing TRPA1⁺ DRG neuron activity. Full article

Unconventional heavy oil reservoirs are particularly susceptible to steam breakthrough, which significantly reduces crude oil production. Profile control is a crucial strategy used for stabilizing oil production and minimizing production costs in these reservoirs. Conventional plugging agent systems used in the thermal recovery of heavy oil currently fail to meet the high-temperature, high-strength, and deep profile control requirements of this process. Precipitation-type calcium salt blocking agents demonstrate long-term stability at 300 °C and concentrations up to 250,000 mg/L, making them highly effective for profile control and channeling blockage during the steam injection stages of heavy oil recovery. This study proposes two types of precipitation-type calcium salt blocking agents: CaSO₄ and CaCO₃ crystals. The precipitation behavior of these agents was investigated, and their dynamic growth patterns were examined. The calcium sulfate blocking agent exhibits a slower crystal precipitation rate, allowing for a single-solution injection, while the calcium carbonate blocking agent precipitates rapidly, requiring a dual-solution injection. Both systems incorporate scale inhibitors to delay the growth of calcium salt crystals, which aids in deep profile control. Through microscopic visualization experiments, the micro-blocking characteristics of the calcium salt blocking agent systems within pores were compared, elucidating the blocking positions of the precipitated calcium salts under porous conditions. Calcium sulfate crystals preferentially precipitate in and block larger pore channels, whereas calcium carbonate crystals are more evenly distributed throughout the pore channels, reducing the reservoir’s heterogeneity. The final single-core displacement experiment demonstrated the sealing properties of the precipitation-type calcium salt blocking agent systems. The developed precipitation-type calcium salt blocking agent systems exhibit excellent profile control performance. Full article

Mammalian spermatozoa undergo a series of physiological and biochemical changes in the oviduct that lead them to acquire the ability to fertilize eggs. During their transit in the oviduct, spermatozoa face a series of environmental changes that can affect sperm viability. A series of ion channels and transporters, as well as the sperm cytoskeleton, allow spermatozoa to remain viable and functional. Cl⁻ channels such as TMEM16A (calcium-activated chloride channel), CFTR (cystic fibrosis transmembrane conductance regulator), and ClC3 (chloride voltage-gated channel 3) are some of the ion transporters involved in maintaining cellular homeostasis. They are expressed in mammalian spermatozoa and are associated with capacitation, acrosomal reaction, and motility. However, little is known about their role in maintaining sperm volume. Therefore, this study aimed to determine the mechanism through which TMEM16A maintains sperm volume during capacitation. The effects of TMEM16A were compared to those of CFTR and ClC3. Spermatozoa were capacitated in the presence of specific TMEM16A, CFTR, and ClC3 inhibitors, and the results showed that only TMEM16A inhibition increased acrosomal volume, leading to changes within the acrosome. Similarly, only TMEM16A inhibition prevented actin polymerization during capacitation. Further analysis showed that TMEM16A inhibition also prevented ERK1/2 and RhoA activation. On the other hand, TMEM16A and CFTR inhibition affected both capacitation and spontaneous acrosomal reaction, whereas ClC3 inhibition only affected the spontaneous acrosomal reaction. In conclusion, during capacitation, TMEM16A activity regulates acrosomal structure through actin polymerization and by regulating ERK1/2 and RhoA activities. Full article

The COVID-19 pandemic, driven by the high transmissibility and immune evasion caused by SARS-CoV-2 and its variants (e.g., Alpha, Delta, Omicron), has led to massive casualties worldwide. As of November 2024, the International Committee on Taxonomy of Viruses (ICTV) has identified 14,690 viral species across 3522 genera. The increasing infectious and resistance to FDA and EMA-approved antivirals, such as 300-fold efficacy reduction in Nirmatrelvir against the SARS-CoV-2 3CLpro, highlight the need for mutation-stable antivirals, likewise targeting the essential host proteins like kinases, heat shock proteins, lipid metabolism proteins, immunological pathway proteins, etc. Unlike direct-acting antivirals, HDAs reduce the risk of resistance by targeting conserved host proteins essential for viral replication. The proposal for repurposing current FDA-approved drugs for host-directed antiviral (HDA) approach is not new, such as the Ouabain, a sodium-potassium ATPase inhibitor for herpes simplex virus (HSV) and Verapamil, a calcium channel blocker for influenza A virus (IAV), to name a few. Given the colossal potential of the mutation-stable HDA approach to exterminate the virus infection, it has been increasingly studied on SARS-CoV-2. This review aims to unravel the interaction between viruses and human hosts and their successfully proposed host-directed antiviral approach to provide insight into an alternative treatment to the rampant mutation in SARS-CoV-2. The benefits, limitations, and potential of host protein-targeted antiviral therapies and their prospects are also covered in this review. Full article

Background: Staphylococcus aureus is a highly lethal Gram-positive bacterium that is responsible for over one million deaths annually. As a member of the ESKAPE pathogens, its methicillin-resistant strains (MRSA) are prevalent worldwide and exhibit significant antimicrobial resistance (AMR). Bacterial efflux pumps play a pivotal role in the development of AMR by facilitating the expulsion of a range of antimicrobial agents. Methods: The S. aureus strain SA-1199B, which overexpresses NorA and carries a GrlA mutation, was utilized to comprehensively profile the mechanism of the compounds PQQ16P and PQK4F. To assess the toxicity and genotoxicity of these compounds, RAW macrophages, HEK 293T, and HepG2 cell lines were utilized. Female BALB/c mice were utilized to assess the in vivo synergism of EPIs with CPX, Results: NorA efflux pump inhibitors (EPIs), PQQ16P and PQK4F, enhanced the efficacy of the antibacterial ciprofloxacin (CPX) against resistant S. aureus strains. The mechanism of EPIs involved the inhibition of NorA efflux pump, without compromising bacterial membrane permeability, ATP levels, or mammalian calcium channels. Moreover, the EPIs significantly augmented the bactericidal and post-antibiotic effects of CPX, elevating its mutation prevention concentration without manifesting substantial toxicity to human cells. Furthermore, the EPIs reduced S. aureus invasiveness in macrophages, indicating a role for NorA in bacterial virulence. Notably, the in vivo synergism of these EPIs with CPX was observed in a mouse infection model. Conclusions: This study provides substantial evidence for the potential of employing EPIs in a combination with CPX to counteract AMR, both in vitro and in vivo. Full article