Melatonin Release Research Articles

The Reindeer Circadian Clock Is Rhythmic and Temperature-compensated But Shows Evidence of Weak Coupling Between the Secondary and Core Molecular Clock Loops.

Circadian rhythms synchronize the internal physiology of animals allowing them to anticipate daily changes in their environment. Arctic habitats may diminish the selective advantages of circadian rhythmicity by relaxing daily rhythmic environmental constraints, presenting a valuable opportunity to study the evolution of circadian rhythms. In reindeer, circadian control of locomotor activity and melatonin release is weak or absent, and the molecular clockwork is reportedly non-functional. Here we present new evidence that the circadian clock in cultured reindeer fibroblasts is rhythmic and temperature-compensated. Compared with mouse fibroblasts, however, reindeer fibroblasts have a short free-running period, and temperature cycles have an atypical impact on clock gene regulation. In reindeer cells, Per2 and Bmal1 reporters show rapid responses to temperature cycles, with a disintegration of their normal antiphasic relationship. The antiphasic Per2-Bmal1 relationship re-emerges immediately after release from temperature cycles, but without complete temperature entrainment and with a marked decline in circadian amplitude. Experiments using Bmal1 promoter reporters with mutated RORE sites showed that a reindeer-like response to temperature cycles can be mimicked in mouse or human cell lines by decoupling Bmal1 reporter activity from ROR/REV-ERB-dependent transcriptional regulation. We suggest that weak coupling between core and secondary circadian feedback loops accounts for the observed behavior of reindeer fibroblasts in vitro. Our findings highlight diversity in how the thermal environment affects the temporal organization of mammals living under different thermoenergetic constraints.

Formulation and evaluation of melatonin as fast dissolving oral strips using combined polymers

Background and objective: Fast-dissolving oral thin film (FDOF) is a novel and most advanced form of solid dosage form that dissolves or disintegrates in 1 minute when put in the mouth without water or chewing. Pre-gastric absorption of FODFs from the mouth, pharynx, and esophagus as saliva flows down into the stomach would improve the therapeutic benefit of the drug as oral films disintegrated in the mouth. The study is designed and purposed to use most water soluble, best type and concentration of polymers to be selected for use in combination to formulate melatonin oral thin films. Different types of synthetic water soluble polymers were utilized the preparation of films (hydroxypropyl methyl cellulose HPMC15M, sodium carboxy methyl cellulose NACMC). Methods: Solvent casting method was performed for preparation of twelve placebo films at the beginning, to obtain and select suitable polymer type and concentration for use in combination to be formulated for drug loading. The films were evaluated for their characteristics like mechanical properties (thickness and folding endurance), surface pH and disintegration time. Percentage of release and assay of melatonin was taken. Comparison studies were performed on melatonin films from this study with melatonin oral disintegrating tablets release profiles. Best batch could be selected. Drug-excipient compatibility carried out as pre formulation study to see whether there is interaction between the drug and excipients used. Results: Results from FT-IR showed no interaction between melatonin and polymers used, the prepared formulations were clear, transparent, non-sticky and easily removed from the plate surface with the thickness ranging from (0.04-0.07) mm depending on the polymer concentration. The times required for the films to disintegrate was ranging from 21-26 seconds, and the majority of melatonin was released within first 2 minutes within the dosage form. Conclusion: Melatonin can be formulated as fast dissolving oral films using combination of water-soluble polymers by solvent casting method to obtain ease of administration without using water during administration, fast onset of action resulted from rapid disintegration.

Melatonin Bioavailability After Oral Administration of a New Delayed-Release Form in Healthy Male Volunteers.

Two main types of galenic formulation, immediate release and prolonged release, have been developed to optimize melatonin bioavailability. We recently described the kinetic profile of a prolonged-release form generating a peak of plasma melatonin 1 h (Tmax) after intake, followed by a prolonged decay over time. We have developed a new oral form of melatonin with the aim of producing a melatonin peak several hours after intake. The objective is to investigate melatonin bioavailability after administration of this new delayed-release form (DR form). In this single-centre open-label study, 12 healthy male volunteers received one tablet of the DR form containing 1.9 mg melatonin, 10 mg zinc and 200 mg lemon balm extract (Melissa officinalisL aerial parts). Blood samples were collected for 12 h, beginning at 8:00 am. Plasma concentrations of melatonin and 6-sulfatoxymelatonin (6-SMT), the main hepatic melatonin metabolite, were determined by radioimmunoassay. A progressive increase in plasma melatonin concentrations was observed from 20 min and a peak about 3 h after intake (Cmax 740 ± 824 pg/mL; Tmax 179 ± 60min). Concentrations remained high between 140 and 220 min, the concentration remaining physiologically significant (over 100pg/mL) up to 7 h after intake. The DR form was well tolerated. The melatonin release profile was consistent with what was anticipated for the DR form. The DR form generated a 2 h delayed Tmax compared with a prolonged-release form previously evaluated. This suggests that the DR form is suitable for the treatment of certain sleep disorders such as short sleep duration or early awakening. Registration number: NCT05419466.

Melatonin-coated nanofiber cell sheets promote periodontal regeneration through ROS scavenging and preservation of stemness

Mesenchymal stem cell (MSC)-based cell sheet engineering holds great promise for periodontal tissue engineering and restoring damaged tissues. However, achieving optimal regenerative outcomes remains a challenge. This study introduces a novel approach that integrates melatonin-coated nanofiber fragments (mNFs) into dental follicle stem cell sheets (mNF-CSs) to enhance their regenerative potential. The mNF-CSs were engineered using electrospun poly-L-lactic acid (PLLA) nanofiber sheets fragmented into mNFs and coated with melatonin, a potent antioxidant and osteogenic agent. The mNF-CSs exhibited a homogenous morphology with sustained melatonin release over 21 days, providing a prolonged antioxidative effect critical for tissue regeneration. In vitro experiments demonstrated that mNF-CSs significantly reduced intracellular reactive oxygen species (ROS) levels and upregulated antioxidative proteins such as SOD1 and SOD2, resulting in improved cell viability, maintenance of stemness, and enhanced osteogenic differentiation potential of dental follicle stem cells (DFCs). In vivo studies using both a nude mouse and a rat periodontal defect model demonstrated that mNF-CSs promoted alveolar bone repair and periodontal tissue regeneration, with enhanced retention of MSCs at the defect site and increased expression of periodontal tissue-related markers. Transcriptome analysis revealed the upregulation of genes associated with biomineralization, odontogenesis, and autophagy pathways in mNF-CSs, suggesting their ability to modulate crucial cellular processes for tissue regeneration. Overall, mNF-CSs offer a promising strategy for enhancing periodontal tissue engineering applications, providing a platform for improving bone grafts and regenerative medicine strategies in the context of periodontal diseases.

Melatonin loaded nanostructured lipid carriers for the treatment of uveal melanoma

Uveal melanoma, a highly aggressive intraocular tumor and the second most common form of ocular malignancy, currently lacks effective therapeutic options. Therefore, this study addresses an unmet medical need by developing nanostructured lipid carriers (NLC) as a potential delivery system for melatonin (MEL) to target uveal melanoma. NLC were optimized for ophthalmic administration by the addition of a cationic surfactant to increase mucoadhesivity to the negatively charged ocular surface. MEL-loaded NLC (MEL-NLC) exhibited suitable particle size (<200 nm), good colloidal stability (5 months), and sustained MEL release. In vitro cytotoxicity assays demonstrated antiproliferative activity against uveal melanoma cells while maintaining corneal cell viability, further confirmed by in vitro HET-CAM test and in vivo ocular tolerance studies. Additionally, inflammation studies were performed since inflammation constitutes one of the main hallmarks of cancer development and progression. Consequently, MEL-NLC displayed anti-inflammatory properties. Furthermore, preliminary biodistribution results suggested their ability to reach the posterior segment of the eye, mainly the retina and the ciliary body, positioning them as a promising strategy for uveal melanoma treatment.

Antitumoral melatonin-loaded nanostructured lipid carriers.

Aim: Cancer constitutes the second leading cause of death worldwide, with conventional therapies limited by significant side effects. Melatonin (MEL), a natural compound with antitumoral properties, suffers from instability and low solubility. To overcome these issues, MEL was encapsulated into nanostructured lipid carriers (MEL-NLC) containing rosehip oil to enhance stability and boost its antitumoral activity.Methods: MEL-NLC were optimized by a design of experiments approach and characterized for their physicochemical properties. Stability and biopharmaceutical behavior were assessed, along with interaction studies and in vitro antitumoral efficacy against various cancer cell lines.Results: Optimized MEL-NLC exhibited desirable physicochemical characteristics, including small particle size and sustained MEL release, along with long-term stability. In vitro studies demonstrated that MEL-NLC selectively induced cytotoxicity in several cancer cell lines while sparing healthy cells.Conclusion: MEL-NLC represent a promising alternative for cancer, combining enhanced stability and targeted antitumoral activity, potentially overcoming the limitations of conventional treatments.

Bioactive Peptides in Dairy Milk: Highlighting the Role of Melatonin.

Melatonin, an endogenous indolamine derived from tryptophan, is primarily synthesized by the pineal gland in mammals and regulated by a complex neural system. Its release follows a circadian rhythm, which is crucial for regulating physiological processes in response to light-dark cycles in both humans and animals. In this review, we report that the presence of this hormone in bovine milk, with significant differences in concentration between daytime and nighttime milking, has increased interest in milk as a natural source of bioactive molecules. Melatonin lowers cortisol levels at night, reduces body temperature and blood pressure, coinciding with decreased alertness and performance, acts as an antioxidant and anti-inflammatory agent, modulates the immune system, offers neuroprotective benefits, and supports gastrointestinal health by scavenging free radicals and reducing oxidative stress in dairy cows. Many factors influence the release of melatonin, such as the intensity of artificial lighting during nighttime milking, the frequency of milkings, milk yield, and genetic differences between animals. Nocturnal milking under low-intensity light boosts melatonin, potentially reducing oxidative damage and mastitis risk. Additionally, ultra-high temperature (UHT) treatment does not significantly affect the melatonin content in milk. However, further research on its stability during milk processing and storage is crucial for ensuring product efficacy. In some countries, nighttime milk with naturally elevated melatonin content is already commercialized as a natural aid for sleep. Thus, naturally melatonin-rich milk may be a promising alternative to synthetic supplements for promoting better sleep and overall well-being.

Effects of Functional Pinealectomy on Immunity, Hematopoietic, Gastrointestinal and Urinary Systems in Experimentally Malnutritioned Rats

Objective: The aim of this study was to demonstrate morphological changes in immunity, hematopoietic, gastrointestinal and urinary systems in different melatonin (MEL) release situations in a rat model of protein energy malnutrition (PEM). Methods: A total of 32 adult male Wistar rats were assigned into four equal groups: normal control; PEM light/dark; PEM light, called functional pinealectomy (Px); and PEM dark. PEM was produced with a 50% restricted diet, Px was produced by keeping rats in continuous light environment for 24 hours, and complete blood count and serum albumin level were analyzed at the end of the 6-week experimental period. Measurements of weights of body and some visceral organs were obtained, biochemical and morphological parameters were analyzed in addition to measurements of malondialdehyde (MDA), total glutatione (GSH), tumor necrosis factor (TNF)-α and interleukin-10 (IL-10) in tissue samples. Results: A reduction in the weights of body and visceral organs of animals in the PEM groups was accompanied by hypoalbuminemia, anemia, leukopenia and lymphopenia, and higher MDA, GSH, TNF-α and IL-10 levels in visceral tissues. There was a significant decrease in parenchymal cells of the liver and spleen, duodenal villi, lymphoid structures and kidney glomeruli, but there was an increase in the spleen capsule thickness and renal Bowman’s space, sinusoidal congestion and fat accumulation in the liver. Importantly, these findings were milder in the PEM dark group, while they were prominent in the PEM light group. Conclusions: This study suggests that MEL has a protective role in reducing the negative effects of PEM, making it a potential therapeutic agent for further investigation.

A sponge-like nanofiber melatonin-loaded scaffold accelerates vascularized bone regeneration via improving mitochondrial energy metabolism

Electrospun nanofibers have been widely employed in bone tissue engineering for their ability to mimic the micro to nanometer scale network of the native bone extracellular matrix. However, the dense fibrous structure and limited mechanical support of these nanofibers pose challenges for the treatment of critical size bone defects. In this study, we propose a facile approach for creating a three-dimensional scaffold using interconnected electrospun nanofibers containing melatonin (Scaffold@MT). The hypothesis posited that the sponge-like Scaffold@MT could potentially enhance bone regeneration and angiogenesis by modulating mitochondrial energy metabolism. Melatonin-loaded gelatin and poly-lactic-acid nanofibers were fabricated using electrospinning, then fragmented into shorter fibers. The sponge-like Scaffold@MT was created through a process involving homogenization, low-temperature lyophilization, and chemical cross-linking, while maintaining the microstructure of the continuous nanofibers. The incorporation of short nanofibers led to a low release of melatonin and increased Young's modulus of the scaffold. Scaffold@MT demonstrated positive biocompatibility by promoting a 14.2 % increase in cell proliferation. In comparison to the control group, Scaffold@MT significantly enhanced matrix mineralization by 3.2-fold and upregulated the gene expression of osteoblast-specific markers, thereby facilitating osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Significantly, Scaffold@MT led to a marked enhancement in the mitochondrial energy function of BMMSCs, evidenced by elevated adenosine triphosphate (ATP) production, mitochondrial membrane potential, and protein expression of respiratory chain factors. Furthermore, Scaffold@MT promoted the migration of human umbilical vein endothelial cells (HUVECs) and increased tube formation by 1.3 times compared to the control group, accompanied by an increase in vascular endothelial growth factor (VEGFA) expression. The results of in vivo experiments indicate that the implantation of Scaffold@MT significantly improved vascularized bone regeneration in a distal femur defect in rats. Micro-computed tomography analysis conducted 8 weeks post-surgery revealed that Scaffold@MT led to optimal development of new bone microarchitecture. Histological and immunohistochemical analyses demonstrated that Scaffold@MT facilitated bone matrix deposition and new blood vessel formation at the defect site. Overall, the utilization of melatonin-loaded nanofiber sponges exhibits significant promise as a scaffold that promotes bone growth and angiogenesis, making it a viable option for the repair of critical-sized bone defects.

3D printing of melatonin-loaded esophageal stents for treatment of corrosive esophagitis

Corrosive esophagitis (CE) is a severe disease caused by accidental or suicidal ingestion of corrosive chemical agents, leading to serious esophageal stenosis or fibrosis. However, the effective and safe treatment of CE is lacking. Here, a melatonin esophagus stent (MES) was prepared using the stereolithography three-dimensional (3D) printing technology with melatonin, polyethylene glycol diacrylate (PEGDA), polyethylene glycol (PEG) 400, and other additives. The MESs with the Roman columns, caduceus, Pagoda, and mace morphologies were designed and printed, respectively. Pagoda MESs exhibited good mechanical properties, retained in the esophagus for more than 24 h, and showed rapid melatonin release. MESs had high in vitro and in vivo safety. More importantly, the implanted MES was broken down into fragments in the gastrointestinal tract and then completely evacuated from the rat body. The CE rat model was established by injecting a strong alkaline solution into the esophagus. The Pagoda MES was conveniently implanted at the injury position, which remarkably alleviated the CE symptoms, reduced inflammation, and prevented esophagus stenosis and fibrosis. 3D-printed Pagoda MESs hold promise for the treatment of CE.

Insomnia Guidelines—The European Update 2023

The last ten years have seen the development and publication of numerous national and international guidelines devoted to the diagnosis and treatment of insomnia. These include guidelines by the American College of Physicians (ACP), the American Academy of Sleep Medicine (AASM), the British Sleep Society (BSS), the German Sleep Society (GSS), and the European Sleep Research Society (ESRS). Though coming from very diverse authors and backgrounds, these guidelines by and large agree concerning the therapeutic recommendations: cognitive behavioral treatment of insomnia (CBT-I), a multicomponent psychotherapeutic intervention, is unequivocally recommended as a first-line treatment. In this report, we will focus on the most recent guideline update from the ESRS, which was published in November 2023. After suggesting a careful diagnostic procedure, CBT-I, both applied face to face (F2F) or digitally (dCBT-I), is again recommended as a first-line treatment based on the available evidence. Hypnotic medications like benzodiazepines (BZ), benzodiazepine receptor agonists (BZRA), sedating antidepressants, and others are approved for short-term-treatment of up to four weeks. Orexin receptor antagonists (i.e., daridorexant) and prolonged release melatonin are considered as options for longer-term treatment when carefully considering the advantages and disadvantages. Both light therapy and exercise regimens were viewed as promising; however, they still lack convincing evidence for the time being. Given the fact that not every patient responds satisfactorily or even remits following CBT-I or other treatment options, the research agenda calls for the development and evaluation of new therapeutic avenues and combination therapies.

Digital automation of transdermal drug delivery with high spatiotemporal resolution

Transdermal drug delivery is of vital importance for medical treatments. However, user adherence to long-term repetitive drug delivery poses a grand challenge. Furthermore, the dynamic and unpredictable disease progression demands a pharmaceutical treatment that can be actively controlled in real-time to ensure medical precision and personalization. Here, we report a spatiotemporal on-demand patch (SOP) that integrates drug-loaded microneedles with biocompatible metallic membranes to enable electrically triggered active control of drug release. Precise control of drug release to targeted locations (<1 mm2), rapid drug release response to electrical triggers (<30 s), and multi-modal operation involving both drug release and electrical stimulation highlight the novelty. Solution-based fabrication ensures high customizability and scalability to tailor the SOP for various pharmaceutical needs. The wireless-powered and digital-controlled SOP demonstrates great promise in achieving full automation of drug delivery, improving user adherence while ensuring medical precision. Based on these characteristics, we utilized SOPs in sleep studies. We revealed that programmed release of exogenous melatonin from SOPs improve sleep of mice, indicating potential values for basic research and clinical treatments.

Melatonin and calcium phosphate crystal-loaded poly(L-lactic acid) porous microspheres reprogram macrophages to improve bone repair.

The bone immune microenvironment can influence the occurrence and progression of bone defects. To date, research on promoting macrophage M2 polarization to improve bone injury repair has been insufficient. In this study, we designed an injectable poly(L-lactic acid) (PLLA) porous microsphere that forms calcium phosphate crystals on its surface by binding to melatonin, followed by bionanomimetic mineralization in vitro. The microsphere is injectable and degradable, and its release of melatonin (MT) and calcium phosphate (CaP) crystals promotes macrophage M2 polarization, reprogramming of macrophages, and enhanced osteogenesis. After LPS stimulation, the proportion of M2-polarized macrophages in the MS@CaP@MT group was 39.2 ± 2.7%, significantly higher than that in other groups (P < 0.05). Further, in the MS@CaP@MT group, rats exhibited bone mineral densities of 129.4 ± 12.8 mg cc-1 at 2 weeks and 171.6 ± 13.6 mg cc-1 at 4 weeks in the defect area, which were significantly higher than those in other groups (P < 0.05). Using an animal model of femoral condylar defects, we demonstrated that MT PLLA porous microspheres loaded with calcium phosphate crystals can improve the immune microenvironment and form a microsphere-centered osteogenesis model. This significantly accelerates bone defect repair and provides a potential strategy for bone defect treatment.

Near-infrared activated liposomes for neuroprotection in glaucoma.

Neurodegenerative diseases have a profound impact on vision, leading to conditions such as glaucoma, optic neuropathy, and diabetic retinopathy, affecting millions worldwide. These diseases are characterized by the degeneration of retinal ganglion cells (RGCs), resulting in a progressive loss of visual acuity and field, with the threat of irreversible blindness. However, existing treatments, such as eye drops, direct injections, and laser surgeries face significant challenges due to limited efficacy and potential infection. The inefficiency of traditional corneal drug delivery methods is a major obstacle in treating vision neurodegenerative diseases. To address these challenges, we developed a remotely triggered on-demand liposomal delivery system to treat glaucomatous neurodegeneration in mice. We utilized the localized surface plasmon resonance (LSPR) effect of gold nanorods (AuNRs) under near-infrared (NIR) light (808 nm) to control the release of cyclodextrin-encapsulated melatonin from thermally responsive liposomal nanocarriers in the vitreous humor. Due to the transparency of the eye's cornea, NIR light can penetrate deep tissues, enabling on-demand drug delivery to the retina. By enhancing the drug's solubility and stability through cyclodextrin encapsulation, this remotely activated melatonin/HPβCD AuNRs liposomes delivery system can decrease intraocular pressure (IOP) elevation by (24 ± 7)%, enhance the survival rate of RGCs by (77 ± 6)%, and decrease glial fibrillary acidic protein (GFAP) activation by (75 ± 6)% at depth in an acute experimental glaucoma model. This NIR-triggered drug delivery system presents the potential of a promising minimally photo-triggered therapeutic option for glaucoma treatment.

Melatonin-loaded mesoporous zinc- and gallium-doped hydroxyapatite nanoparticles to control infection and bone repair.

Effective treatment of infected bone defects resulting from multi-drug resistant bacteria (MDR) has emerged as a significant clinical challenge, highlighting the pressing demand for potent antibacterial bone graft substitutes. Mesoporous nanoparticles have been introduced as a promising class of biomaterials offering significant properties for treating bone infections. Herein, we synthesize antibacterial mesoporous hydroxyapatite substituted with zinc and gallium (Zn-Ga:mHA) nanoparticles using a facile sol-gel method. The resulting mesoporous nanoparticles are applied for the controlled release of melatonin (Mel). Zn-Ga:mHA nanoparticles with an average particle size of 36 ± 3 nm and pore size of 10.6 ± 0.4 nm reveal a Mel loading efficiency of 58 ± 1%. Results show that 50% of Mel is released within 20 h and its long-term release is recorded up to 50 h. The Zn-Ga:mHA nanoparticles exhibit highly effective antibacterial performance as reflected by a 19 ± 1% and 8 ± 2% viability reduction in Escherichia coli and Staphylococcus bacteria, respectively. Noticeably, Mel-loaded Zn-Ga:mHA nanoparticles are also cytocompatible and stimulate in vitro osteogenic differentiation of human mesenchymal stem cells (hMSCs) without any osteoinductive factor. In vivo studies in a rabbit skull also show significant regeneration of bone during 14 days. In summary, Mel-loaded Zn-Ga:mHA nanoparticles provide great potential as an antibacterial and osteogenic component in bone substitutes like hydrogels, scaffolds, and coatings.

Insight into molecular structures and dynamical properties of niosome bilayers containing melatonin molecules: a molecular dynamics simulation approach.

Niosomes represent vesicular carriers capable of encapsulating both hydrophobic and hydrophilic drugs within their inner core or bilayer shell. They are typically composed of non-ionic synthetic surfactants such as sorbitan monostearate (Span60) with the addition of cholesterol (Chol). The physical properties and stability of niosomal vesicles strongly depend on the composition of their bilayers, which plays a significant role in determining the efficiency of drug encapsulation and release in drug delivery systems. In this study, we have explored the interactions between melatonin (Mel) molecules and the niosome bilayer, as well as their resulting physical properties. Molecular dynamics simulations were employed to investigate melatonin-inserted niosome bilayers, both with and without the inclusion of cholesterol. The simulation results revealed that cholesterol notably influences the location of melatonin molecules within the niosome bilayers. In the absence of cholesterol, melatonin tends to occupy the region around the Span60 tail groups. However, in the presence of cholesterol, melatonin is found in the vicinity of the Span60 head groups. Melatonin molecules in niosome bilayers without cholesterol exhibit a more ordered orientation when compared to those in bilayers containing 50 mol% cholesterol. The bilayer structure of the Span60/Mel and Span60/Chol/Mel systems exhibited a liquid-disordered phase (Ld). In contrast, the Span60/Chol bilayer system displays a liquid-ordered phase (Lo) with less fluidity. This study reveals that melatonin induces a disorderly bilayer structure and greater lateral expansion, whereas cholesterol induces an orderly bilayer structure and a more condensed effect. Cholesterol plays a crucial role in condensing the bilayer structure with stronger interactions between Span60 and cholesterol. The addition of 50 mol% cholesterol in the Span60 bilayers not only enhances the stability and rigidity of niosomes but also facilitates the easier release of melatonin from the bilayer membranes. This finding is particularly valuable in the context of preparing niosomes for drug delivery systems.

Designing an effective dissolution test for bilayer tablets tailored for optimal melatonin release in sleep disorder management.

This project aims to investigate the release performance of bilayer tablet (BL-Tablet) designed with both fast and slow-release technology, targeting sleep disorders. The tablet incorporates Melatonin, extracts of Eschscholzia californica and Melissa officinalis. In order to validate the effectiveness of the extended-release profile, an advanced dissolution test was herein proposed. This new method utilizes biorelevant intestinal fluid media and incorporates a stomach-to-intestine fluid changing (SIFC) system. To demonstrate the advantages of employing this method for assessing the controlled release profile of active ingredients, the dissolution results were compared with those obtained using the conventional EU Pharmacopoeia approach. Furthermore, the comparative analysis was extended to include a monolayer tablet version (ML-Tablet) lacking the slow-release technology. Technological characterization and bioaccessibility studies, including intestinal permeability test, were conducted as well to assess the pharmacological performance and bioavailability of active ingredients. The dissolution data recovered revealed that the two dissolution methods did not exhibit any significant differences in the release of ML-Tablet's. However, the dissolution profile of the BL-Tablet exhibited notable differences between the two methods particularly when assessing the behavior of the slow-release layer. In this scenario, both methods initially exhibited a similar release pattern within the first approximately 0.5 h, driven by the fast-release layer of the tablet. Following this, distinct gradual and sustained releases were observed, spanning 2.5 h for the EU Pharmacopoeia method and 8 h for the new SIFC-biorelevant dissolution method, respectively. Overall, the novel method demonstrated a substantial improvement compared to conventional EU Pharmacopoeia test in evaluating the performance of a controlled slow-release technology. Remarkably, the prolonged release technology did not have an adverse impact on melatonin intestinal absorption, and, consequently, maintaining its potential bioavailability of around 78%. Concluding, this research provides valuable insights into how the innovative dissolution test can assist formulators in developing controlled release formulations.

The Effects of Sleep on Human Physiology and Its Regulation

Sleep is an essential aspect of human biology and is crucial for maintaining overall health and cognitive functioning. The significance of sleep, its effects on bodily and cognitive function, and the underlying mechanisms were covered in this essay. One of the primary functions of sleep is to facilitate physical restoration. During sleep, the body engages in critical processes such as immune system regulation, metabolic waste clearance, and cell repair. The brain also undergoes restoration during sleep, consolidates memories, enhances learning, and promotes creativity. Insufficient sleep can lead to physical symptoms such as fatigue and reduced concentration, as well as emotional instability and fluctuations in mood. The mechanisms of sleep regulation are multifaceted, incorporating both physiological and neurological processes. The body's circadian rhythm plays a crucial role in sleep regulation. Sleep quality can be influenced by various environmental and psychological factors. Exposure to artificial light, especially before bedtime, can inhibit the release of melatonin. Stress, anxiety, and depression can also disrupt sleep patterns, making it difficult to obtain restful sleep. In conclusion, sleep is a crucial aspect of human biology that impacts both physical and cognitive function. Further research into sleep regulation and its impact on academic success may provide opportunities for new therapeutic approaches for sleep-related disorders.

Short-Wavelength Light-Blocking Filters and Oral Melatonin Administration in Patients With Retinitis Pigmentosa: Protocol for a Randomized Controlled Trial.

The medical community is beginning to recognize that retinitis pigmentosa (RP), due to its disabling progression, eventually leads to a reduction in the patient´s quality of life, a direct economic impact, and an increase in the burden on the health care system. There is no curative treatment for the origin of the disease, and most of the current interventions fail in reducing the associated negative psychological states, such as anxiety and depression, which lead to increased variability of vision and pose a continuous threat to the patient's independence. The aim of this study is to assess the effect of oral melatonin (OM) administration alone and combined with short-wavelength light (SWL)-blocking filters on patients with RP and test their effectiveness in improving the level of stress and sleep problems in many of these patients. We have developed a low-cost therapy protocol for patients with RP with sleep disorders and negative psychological stress. Patients will be randomized to receive a combined intervention with SWL-blocking filters and OM, SWL-blocking filters alone, or OM alone. There will also be a nonintervention arm as a control group. This study will be conducted across 2 retinal units in patients with RP with sleep disorders and high perceived stress and anxiety score reports. Patients will be assessed in the preintervention period, weekly during the 4 weeks of intervention, and then at 6 months postintervention. The primary outcomes are the differences in changes from baseline to postintervention in hormone release (α-amylase, cortisol, and melatonin) and sleep quality, as measured with the visual analog scale. Secondary outcome measures include clinical macular changes, as measured with optical coherence tomography and optical coherence tomography angiography; retinal function, as measured using the visual field and best-corrected visual acuity; sleep data collected from personal wearables; and several patient-reported variables, such as self-recorded sleep diaries, quality of life, perceived stress, and functional status. This project is still a study protocol and has not yet started. Bibliographic research for information for its justification began in 2020, and this working group is currently seeking start-up funding. As soon as we have the necessary means, we will proceed with the registration and organization prior to the preliminary phase. In this feasibility randomized clinical controlled trial, we will compare the effects of SWL blocking alone, administration of OM alone, and a combined intervention with both in patients with RP. We present this study so that it may be replicated and incorporated into future studies at other institutions, as well as applied to additional inherited retinal dystrophies. The goal of presenting this protocol is to aid recent efforts in reducing the impact of sleeping disorders and other psychological disorders on the quality of life in patients with RP and recovering their self-autonomy. In addition, the results of this study will represent a significant step toward developing a novel low-cost therapy for patients with RP and validating a novel therapeutic target. PRR1-10.2196/49196.

On-demand electrically controlled melatonin release from PEDOT/SNP composite improves quality of chronic neural recording.

Long-time and high-quality signal acquisition performance from implantable electrodes is the key to establish stable and efficient brain-computer interface (BCI) connections. The chronic performance of implantable electrodes is hindered by the inflammatory response of brain tissue. In order to solve the material limitation of biological interface electrodes, we designed sulfonated silica nanoparticles (SNPs) as the dopant of Poly (3,4-ethylenedioxythiophene) (PEDOT) to modify the implantable electrodes. In this work, melatonin (MT) loaded SNPs were incorporated in PEDOT via electrochemical deposition on nickel-chromium (Ni-Cr) alloy electrode and carbon nanotube (CNT) fiber electrodes, without affecting the acute neural signal recording capacity. After coating with PEDOT/SNP-MT, the charge storage capacity of both electrodes was significantly increased, and the electrochemical impedance at 1kHz of the Ni-Cr alloy electrodes was significantly reduced, while that of the CNT electrodes was significantly increased. In addition, this study inspected the effect of electrically triggered MT release every other day on the quality and longevity of neural recording from implanted neural electrodes in rat hippocampus for 1 month. Both MT modified Ni-Cr alloy electrodes and CNT electrodes showed significantly higher spike amplitude after 26-day recording. Significantly, the histological studies showed that the number of astrocytes around the implanted Ni-Cr alloy electrodes was significantly reduced after MT release. These results demonstrate the potent outcome of PEDOT/SNP-MT treatment in improving the chronic neural recording quality possibly through its anti-inflammatory property.