Search Results (152)

Objective: Pain response scores were evaluated by associating pain biomarkers with several parameters affecting radiotherapy (RT)-induced pain response in patients with bone metastases. Methods: A newly developed ‘revised pain and response scale’ based on standardized scales was used for pain scoring. TRPV1, β-endorphin (bEP), neurotensin (NT), and orexin A (OXA) biomarkers were determined by ELISA before and after RT. Results: Pain response rates were 44.75% (n = 47) poor response, 10.5% (n = 11) moderate response, 44.75% (n = 47) good response. NLR before RT was higher in patients with poor response than those with good response (4.0 (1.3–36.7) vs. 2.6 (1.2–11.4), respectively (p = 0.036). NLR after RT was lower in patients with good response than in patients with poor response (3.1 (1.2–10.8) and 3.9 (0.8–37.2), respectively (p = 0.047). There was a significant correlation between response scores and NT, bEP, and TRPV1. In patients with good response, NT and bEP decreased, while TRPV1 increased, both of which were significant. Pre-RT and post-RT values were, respectively, NT: 631.4 (39.7–2863.0) vs. 400.3 (79.1–1479.0) p = 0.006) and bEP: 92.1 (18.7–228.8) vs. 49.1 (13.3–135.6) p ≤ 0.001). TRPV1 values: 321.7 (48.1–1100.7) vs. 352.8 (119.3–1510.9) p ≤ 0.001). Conclusions: The study found no difference in pain response scores between the different fractionation treatments. Significant changes in NT, bEP, and TRPV1 levels were seen in patients with a ‘good response’. Pain response ratings were potentially least affected by OXA. Changes in NT, TRPV1, and bEP levels represent RT’s pain response efficacy and patients’ pain perception. These pain biomarkers may be included in guidelines as part of pain response monitoring strategies in the future. Full article

The relationship between sleep and epilepsy involves complex interactions between thalamocortical circuits, circadian mechanisms, and sleep architecture that fundamentally influence seizure susceptibility and cognitive outcomes. Epileptic activity disrupts essential sleep oscillations, particularly sleep spindles generated by thalamic circuits. Thalamic epileptic spikes actively compete with physiological sleep spindles, impairing memory consolidation and contributing to cognitive dysfunction in epileptic encephalopathy. This disruption explains why patients with epilepsy often experience learning difficulties despite adequate seizure control. Sleep stages show differential seizure susceptibility. REM sleep provides robust protection through enhanced GABAergic inhibition and motor neuron suppression, while non-REM sleep, particularly slow-wave sleep, increases seizure risk. These observations reveal fundamental mechanisms of seizure control within normal brain physiology. Circadian clock genes (BMAL1, CLOCK, PER, CRY) play crucial roles in seizure modulation. Dysregulation of these molecular timekeepers creates permissive conditions for seizure generation while being simultaneously disrupted by epileptic activity, establishing a bidirectional relationship. These mechanistic insights are driving chronobiological therapeutic approaches, including precisely timed antiseizure medications, sleep optimization strategies, and orexin/hypocretin system interventions. This understanding enables a paradigm shift from simple seizure suppression toward targeted restoration of physiological brain rhythms, promising transformative epilepsy management through sleep-informed precision medicine. Full article

Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior. This report first describes evidence in animals that exposure in adults and during adolescence to rewarding substances, such as the drugs alcohol, nicotine and cocaine and palatable fat-rich food, stimulates the expression of MCH as well as HCRT and their intracellular molecular systems. It also increases reward-seeking and emotional behavior, leading to excess consumption and abuse of these substances and neurological conditions, completing this positive feedback loop. Next, this review focuses on the model involving embryonic exposure to these rewarding substances. In addition to revealing a similar positive feedback circuit, this model greatly advances our understanding of the diverse changes that occur in these neuropeptide/molecular systems in the embryo and how they relate, perhaps causally, to the disturbances in behavior early in life that predict a later increased risk of developing substance use disorders. Studies using this model demonstrate in animals that embryonic exposure to these rewarding substances, in addition to stimulating the expression of peptide neurons, increases the intracellular molecular systems in neuroprogenitor cells that promote their development. It also alters the morphology, migration, location and neurochemical profile of the peptide neurons and causes them to develop aberrant neuronal projections to forebrain structures. Moreover, it produces disturbances in behavior at a young age, which are sex-dependent and occur in females more than in males, that can be directly linked to the neuropeptide/molecular changes in the embryo and predict the development of behavioral disorders later in life. These results supporting the close relationship between the brain and behavior are consistent with clinical studies, showing females to be more vulnerable than males to developing substance use disorders with co-occurring emotional conditions and female offspring to respond more adversely than male offspring to prenatal exposure to rewarding substances. It is concluded that the continued consumption of or exposure to rewarding substances at any stage of life can, through such peptide brain systems, significantly increase an individual’s vulnerability to developing neurological disorders such as substance use disorders, anxiety, depression, or cognitive impairments. Full article

The lateral hypothalamic area (LHA) serves as a central integrative hub for the regulation of energy homeostasis and motivational behaviors, including feeding and arousal. Recent advances in single-cell transcriptomics have revealed remarkable molecular heterogeneity within the LHA, identifying more than 30 distinct neuronal subtypes, such as GABAergic (LHA^Vgat), glutamatergic (LHA^Vglut2), orexin, melanin-concentrating hormone (MCH), and leptin receptor-expressing (LHA^Lepr) neurons. These neuronal populations sense peripheral metabolic signals—such as leptin, insulin, and glucose—both directly and indirectly, and they coordinate appropriate physiological and behavioral responses through local circuits and reciprocal connections with other hypothalamic nuclei. Furthermore, the LHA interfaces with extrahypothalamic regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and lateral habenula (LHb), thereby linking metabolic state to reward processing and behavioral prioritization. In this review, we summarize and integrate recent molecular and functional findings to present a comprehensive view of the LHA as a dynamic, multifunctional center in the central regulation of metabolism. A deeper understanding of these mechanisms may offer new therapeutic avenues for addressing obesity and related metabolic disorders. Full article

Sleep disorders, such as insomnia and narcolepsy, significantly impact quality of life. They are often associated with long-term health consequences, including cardiovascular disease, immune dysfunction, and cognitive impairment. While traditional treatments, such as sedatives and hypnotics, can be effective, they are limited by issues of tolerance and dependence. The orexinergic system, particularly the orexin 1 receptor (OXR1), has emerged as a promising therapeutic target due to its central role in regulating sleep–wake cycles. In this study, we investigate the molecular interactions of three OXR1 antagonists—daridorexant, lemborexant, and suvorexant—using an integrated computational approach combining molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and the molecular fractionation with conjugate caps (MFCC) methodology. The MFCC approach enabled the precise quantification of interaction energies between ligands and key receptor residues, providing detailed insights into the contributions of specific amino acids to binding stability. Our results reveal that residues such as GLU204, HIS216, and ASN318 play critical roles in stabilizing ligand–receptor interactions, with a marked decrease in binding energy magnitude as dielectric constants increase. Daridorexant exhibited the strongest interaction energy, driven by hydrogen bonds and hydrophobic contacts, while lemborexant and suvorexant showed distinct stabilization patterns mediated by hydrophobic interactions. These findings provide a robust molecular basis for the rational design of next-generation OXR1 antagonists with improved efficacy and safety profiles. By elucidating drug–receptor interactions at the atomic level, this research underscores the impact of integrated computational approaches in drug discovery. It supports the development of precise targeted therapies for sleep disorders. Full article

Background: Nutraceuticals have emerged as promising alternatives to conventional pharmacological treatments for managing joint pain and low-grade inflammation in physically active individuals. However, few clinical studies have evaluated the combined metabolic, inflammatory, and neuroendocrine effects of multi-ingredient supplements. This study aimed to evaluate the effects of Flector Softgel FS Integratore, a multi-component food supplement, on joint pain, inflammatory markers, metabolic health, and orexin-A levels in physically active adults. Methods: In this randomized, controlled, low-intervention study, 25 adult participants (aged 30–60 years and amateur athletes engaging in at least 3 sessions/week of moderate physical activity) were assigned to either a treatment group (n = 15 received Flector Softgel FS for 14 days) or a placebo group (n = 10). The supplement contained 500 mg of Cannabis sativa seed oil (THC-free), 250 mg of Boswellia serrata extract, 250 mg of fish oil, 160 mg of omega-3 fatty acids, and 0.6 mg of undenatured type II collagen (UC-II). Pain was assessed using the Visual Analog Scale (VAS). Metabolic parameters, inflammatory cytokines (IL-6, IL-8, TNF-α, IFN-γ, and IL-10), and serum orexin-A levels were measured before and after the intervention. Results: Compared with the placebo, the treatment group showed a significant reduction in VAS scores (p < 0.001), as well as improvements in BMI, insulin, and lipid profiles, and a decrease in pro-inflammatory cytokines (IL-6, IL-8, TNF-α, and IFN-γ). A reduction in orexin-A levels was also observed in the treatment group (p < 0.001), with a positive correlation between orexin-A and perceived pain. No adverse effects were reported. Conclusions: Flector Softgel FS Integratore may be effective in reducing joint pain and systemic inflammation while supporting metabolic health in active adults. These effects may involve indirect modulation of orexin-A, though the exact mechanisms remain to be clarified. Despite the promising results, conclusions regarding efficacy in comparison with NSAIDs should be approached with caution in the absence of a pharmacological control group. Further studies with larger samples and a longer duration are needed. Full article

Sleep disturbance is common among people with cognitive impairment and, when present, is an important target for intervention because it potentially leads to negative outcomes and cognitive decline. Given this association, sleep represents a potential public health target, although evidence for efficacy is lacking. For this study, a systematic review and meta-analysis was undertaken of controlled clinical trials of pharmacological and non-pharmacological interventions to improve sleep in mild cognitive impairment and dementia. A total of 144 trials involving 13,471 participants (median 50 per trial) were included. To measure sleep, 68 trials used subjective measures exclusively, and 41 used only objective measures, while 35 used a combination. In all, 287 discrete sleep outcome measures were reported. Bright light therapy was the most frequently examined non-pharmacological intervention, but results were equivocal. Other non-pharmacological interventions (such as physical activity, cognitive behavioural therapy for insomnia, music, and continuous positive airway pressure) showed promise but require further evidence. Results for melatonin, the most frequently examined pharmacological intervention, were inconclusive, but lower doses may be more effective. Other pharmacological interventions (such as trazadone and orexin-receptor antagonists) demonstrated effectiveness in a small number of trials but require further evidence. Overall, there is insufficient evidence upon which to base clinical decisions regarding the treatment of sleep disturbance in this population. Existing research is marked by wide heterogeneity, which limits opportunities for data synthesis. A core outcome set is urgently required to ensure that future research provides more coherent and reliable evidence to improve outcomes for people with cognitive impairment and sleep disturbance. Full article

Sudden unexpected death in epilepsy (SUDEP) is sudden, unexpected, witnessed or unwitnessed, nontraumatic, non-drowning death that occurs in a person with epilepsy. SUDEP is the leading cause of epilepsy-related death in adults with epilepsy, with an incidence of about 1.2 per 1000 person-years in the general epilepsy population. Recent studies have shown similar prevalence in the pediatric population too. Although the precise mechanism remains unclear, well-documented cases of SUDEP suggest that a generalized tonic clonic seizure-induced, centrally mediated change in cardiorespiratory function leads to terminal apnea and cardiac arrest. Risk factors include generalized tonic clonic seizure frequency, duration of epilepsy, nocturnal seizure, and certain genetic syndromes. Orexin, adenosine, and serotonin neurotransmission have been explored as novel drug targets to mitigate SUDEP risk. Neurostimulation and resective epilepsy surgery have been reported to have beneficial effects on long-term SUDEP risk as well. Future studies may aim to clarify the role of sleep and other comorbidities in SUDEP pathophysiology. Full article

Insomnia is the most prevalent sleep disorder, estimated to affect at least one-third of the global population. There are a variety of treatment options available for both acute and chronic insomnia. Currently, the pharmacological arsenal for treating insomnia includes short- or intermediate-acting benzodiazepine hypnotics, non-benzodiazepine hypnotic sedatives, melatonin receptor agonists, orexin receptor antagonist, and sedating antidepressants. Diphenhydramine, a first-generation antihistamine, is commonly used in the treatment of allergies and dermatitis. This review examines the preclinical and clinical efficacy and safety evidence of diphenhydramine in treating short-term insomnia. Additionally, it provides expert consensus on its implementation as an over-the-counter medication for this condition. The available evidence indicates that diphenhydramine is an effective treatment for acute insomnia in adults, offering a safe and affordable option for most patients suffering from this condition. Experts concur that there is strong evidence supporting the recommendation of diphenhydramine for the treatment of acute insomnia in adults. Full article

Air pollution plays a key role in sleep disorders and neurodegeneration. Alzheimer’s disease (AD), Parkinson’s disease (PD), and/or transactive response DNA-binding protein TDP-43 neuropathology have been documented in children and young adult forensic autopsies in the metropolitan area of Mexico City (MMC), along with sleep disorders, cognitive deficits, and MRI brain atrophy in seemingly healthy young populations. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) reach urbanites’ brains through nasal/olfactory, lung, gastrointestinal tract, and placental barriers. We documented Fe UFPM/NPs in neurovascular units, as well as lateral hypothalamic nucleus orexinergic neurons, thalamus, medullary, pontine, and mesencephalic reticular formation, and in pinealocytes. We quantified ferromagnetic materials in sleep and arousal brain hubs and examined their motion behavior to low magnetic fields in MMC brain autopsy samples from nine children and 25 adults with AD, PD, and TDP-43 neuropathology. Saturated isothermal remanent magnetization curves at 50–300 mT were associated with UFPM/NP accumulation in sleep/awake hubs and their motion associated with 30–50 µT (DC magnetic fields) exposure. Brain samples exposed to anthropogenic PM pollution were found to be sensitive to low magnetic fields, with motion behaviors that were potentially linked to the early development and progression of fatal neurodegenerative diseases and sleep disorders. Single-domain magnetic UFPM/NPs in the orexin system, as well as arousal, sleep, and autonomic regions, are key to neurodegeneration, behavioral and cognitive impairment, and sleep disorders. We need to identify children at higher risk and monitor environmental UFPM and NP emissions and exposures to magnetic fields. Ubiquitous ferrimagnetic particles and low magnetic field exposures are a threat to global brain health. Full article

The peptidergic systems are involved in neuroblastoma. Peptides (angiotensin II, neuropeptide Y, neurotensin, substance P) act as oncogenic agents in neuroblastoma, whereas others (adrenomedullin, corticotropin-releasing factor, urocortin, orexin) exert anticancer effects against neuroblastoma. This plethora of peptidergic systems show the functional complexity of the mechanisms regulated by peptides in neuroblastoma. Peptide receptor antagonists act as antineuroblastoma agents since these compounds counteracted neuroblastoma cell growth and migration and the angiogenesis promoted by oncogenic peptides. Other therapeutic approaches (signaling pathway inhibitors, focal adhesion kinase inhibitors, peptide receptor knockdown, acetic acid analogs) that also counteract the beneficial effects mediated by the oncogenic peptides in neuroblastoma are discussed, and future research lines to be developed in neuroblastoma (interactions between oncogenic and anticancer peptides, combination therapy using peptide receptor antagonists and chemotherapy/radiotherapy) are also suggested. Although the data regarding the involvement of the peptidergic systems in neuroblastoma are, in many cases, fragmentary or very scarce for a particular peptidergic system, taken together, they are quite promising with respect to potentiating and developing this research line with the aim of developing new therapeutic strategies to treat neuroblastoma in the future. Peptidergic systems are potential and promising targets for the diagnosis and treatment of neuroblastoma. Full article

Cancer cachexia, often observed in patients with advanced-stage cancer, is characterized by the loss of body weight and appetite. The Japanese herbal medicine Ninjinyoeito (NYT), which is composed of 12 crude herbal components, has been used as a therapeutic in Japan to improve anorexia and fatigue, which are commonly observed in cancer patients with cachexia. We have previously reported that Citrus unshiu peel (CUP) contained in NYT can enhance food intake by activating the orexin 1 receptor (OX1R). Using the CellKey™ system, which offers detection of OXR activity in intracellular impedance changes, NYT and CUP were found to activate OX1R, which in turn was inhibited by SB-674042, a selective OX1R antagonist. Among the flavonoids contained in CUP, nobiletin and hesperidin, but not naringin, activated OX1R. Furthermore, some monoterpenes contained in CUP, including limonene and linalool, but not terpineol, activated OX1R. In addition, nobiletin and limonene synergistically activated OX1R when added simultaneously. However, neither NYT nor CUP induced OX2R activity. The results collectively suggested that the CUP contained in NYT activates OX1R, but not OX2R, and that flavonoids and monoterpenes in CUP can synergistically activate OX1R. These findings could provide evidence supporting the therapeutic potential of NYT in cancer patients with cachexia. Full article

Objective: This study aims to evaluate the effects of different nutritional strategies, specifically intermittent fasting (IF) combined with high-intensity interval training (HIIT) versus a low-calorie diet (LCD), on body composition, physical performance, and the orexinergic system in postmenopausal women. Methods: A randomized controlled trial involving thirty postmenopausal women (mean age 57.50 ± 6.50 years) was conducted over eight weeks, comparing the two dietary approaches alongside an 8-week HIIT program. Body composition was assessed using bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA). Performance metrics included handgrip strength and the 6-min walking test (6MWT). Salivary samples were analyzed for Orexin-A (OX-A) levels pre- and post-intervention. Results: Significant improvements in health metrics, such as heart rate (HR) and endurance, were found, with mean HR changes showing a significant difference (F = 5.943, p = 0.033) between the groups at T1. Orexin-A levels reflected significant metabolic regulation shifts in relation to other variables, showing a change from baseline to post-intervention values at T1 (F = 10,931, p = 0.033). Flexibility (sit and reach) significantly improved by 6% (p < 0.05), as well as ${\mathrm{VO}}_2$ max (10%, p < 0.05), both highlighted as key predictors of overall health outcomes. Additionally, Cohen’s d analyses indicated that the dietary groups exhibited notable differences in endurance, with the LCD group showing a Cohen’s d of −0.90, suggesting a large effect size compared with the control group. Conclusions: The combination of IF and HIIT is an effective nutritional strategy for enhancing body composition and physical performance in postmenopausal women, potentially mediated by changes in the orexinergic system. Further research is warranted to explore long-term effects and underlying mechanisms. Full article

Objective: To narratively review currently available antidepressants and future potential antidepressants as monotherapy for the treatment of depressive disorders. Methods: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), dopamine reuptake inhibitor (bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were reviewed according to the results from Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study and systematic reviews. For the rest of the antidepressants, a PubMed/Medline search was conducted with priority for systematic reviews. For drugs in development for depressive disorders, PubMed, Google, and Clinicaltrials.gov databases were used. Results: The STAR*D Study demonstrated that sertraline, venlafaxine, and bupropion monotherapy had similar efficacy in patients with major depressive disorder (MDD) who failed citalopram. A network meta-analyses of randomized, placebo-controlled trials found that SSRIs, SNRIs, bupropion, TCAs, mirtazapine, and agomelatine had similar relative efficacy compared to placebo, but had different acceptability. Gepirone had more failed/negative studies and smaller effect size relative to placebo compared to other antidepressants. The combination of dextromethorphan and bupropion, ketamine infusion, and intranasal esketamine had faster onset of action but similar effect size compared to monoamine-based antidepressants as monotherapy. Brexanolone and zuranolone are effective in postpartum depression (PPD), but the effect size of zuranolone in MDD as monotherapy or adjunctive therapy was very small. Psychedelics, glutamate receptor-related agents, kappa opioid receptor antagonists, orexin receptor antagonists, new anti-inflammatory agents, and biomarker-based antidepressant therapy have been under investigation for depressive disorders. Psychedelics showed faster onset of action, large effect size, and long durability. Conclusions: Monoamine-based antidepressants likely continue to be the mainstream antidepressants for depressive disorder. NMDA receptor antagonists and neurosteroid antidepressants will play a bigger role with the improvement of accessibility. Psychedelics may become a game changer if phase III studies validate their efficacy and safety in depressive disorders. Full article

Prader-Willi syndrome (PWS) is a rare genetic disorder. The main characteristics are muscular hypotonia, failure to thrive and feeding problems in infancy, which switch to hyperphagia in early childhood and continue into adulthood. Due to hyperphagia, the risk of developing morbid obesity is high without treatment. PWS is considered a hypothalamic disease, and within the hypothalamus the arcuate nucleus (AC) is of central importance for controlling metabolism, hunger, and satiety. The AC has been studied in several animal models as well as in humans, including PWS. The function of AC is regulated by several neuropeptides and proteins produced within the central nervous system such as oxytocin, orexin, tachykinins as well as the hypothalamic hormones, regulating the adeno-hypophyseal hormones, also acting as neurotransmitters. Additionally, there are many peripheral hormones among which insulin, leptin, adiponectin, ghrelin, and glucagon-like peptide (GLP-1) are the most important. High levels of adiponectin and ghrelin have consistently been reported in PWS, but dysregulation and deviating levels of many other factors and hormones have also been demonstrated in both individuals with PWS and in animal models. In this review, we focus on the role of AC and peptides and proteins produced within the central nervous system in the regulation of hunger and satiety in PWS. Full article