Hypnotic effect of AR-001 through adenosine A1 receptor.

Insomnia is one of the most common sleep disorders, affecting 10-15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N2-Ethyl-N4-(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A1 receptor and may have therapeutic potential for insomnia.

A novel TAp73-inhibitory compound counteracts stemness features of glioblastoma stem cells.

Glioblastoma (GB) is the most common and fatal type of primary malignant brain tumor for which effective therapeutics are still lacking. GB stem cells, with tumor-initiating and self-renewal capacity, are mostly responsible for GB malignancy, representing a crucial target for therapies. The TP73 gene, which is highly expressed in GB, gives rise to the TAp73 isoform, a pleiotropic protein that regulates neural stem cell biology; however, its role in cancer has been highly controversial. We inactivated TP73 in human GB stem cells and revealed that TAp73 is required for their stemness potential, acting as a regulator of the transcriptional stemness signatures, highlighting TAp73 as a possible therapeutic target. As proof of concept, we identified a novel natural compound with TAp73-inhibitory capacity, which was highly effective against GB stem cells. The treatment reduced GB stem cell-invasion capacity and stem features, at least in part by TAp73 repression. Our data are consistent with a novel paradigm in which hijacking of p73-regulated neurodevelopmental programs, including neural stemness, might sustain tumor progression, pointing out TAp73 as a therapeutic strategy for GB.

Reciprocal Coupling of Circadian Clocks in the Compound Eye and Optic Lobe in the Cricket Gryllus bimaculatus.

The circadian system comprises multiple clocks, including central and peripheral clocks. The central clock generally governs peripheral clocks to synchronize circadian rhythms throughout the animal body. However, whether the peripheral clock influences the central clock is unclear. This issue can be addressed through a system comprising a peripheral clock (compound eye clock [CE clock]) and central clock (the optic lobe [OL] clock) in the cricket Gryllus bimaculatus. We previously found that the compound eye regulates the free-running period (τ) and the stability of locomotor rhythms driven by the OL clock, as measured by the daily deviation of τ at 30°C. However, the role of the CE clock in this regulation remains unexplored. In this study, we investigated the importance of the CE clock in this regulation using RNA interference (RNAi) of the period (per) gene localized to the compound eye (perCE-RNAi). The perCE-RNAi abolished the compound eye rhythms of the electroretinogram (ERG) amplitude and clock gene expression but the locomotor rhythm driven by the OL clock was maintained. The locomotor rhythm of the tested crickets showed a significantly longer τ and greater daily variation of τ than those of control crickets treated with dsDsRed2. The variation of τ was comparable with that of crickets with the optic nerve severed. The τ was considerably longer but was comparable with that of crickets with the optic nerve severed. These results suggest that the CE clock regulates the OL clock to maintain and stabilize τ.

A method of impressing flabby ridge.

Flabby ridge remained a challenge in dental clinical practice to obtain an accurate impression for edentulous patients. During the traditional impression making process, the excessive and displaceable soft tissue are usually compressed. In this article, we presented an impression method by using a modified special stock tray, impression compound and polyvinyl siloxane impression materials.•the suitable stock tray was modified with holes about 5 mm diameter in the corresponding area to the crest of the flabby ridge.•the primary impression was made by position the modified tray with the softened compound impression on the edentulous ridge, avoiding the area of the flabby ridge.•the final accurate impression was obtained by using the light body polyvinyl siloxane impression material.

Application of MXene composites for target gas detection in food safety.

Food contamination has long plagued agriculture, posing significant health risks to consumers. The use of volatile gases for food safety detection has proven highly effective, with composite gas sensors that leverage the two-dimensional material MXene exhibiting notable advancements in detecting various target gases. This paper reviews the progress of MXene-based composite gas sensors in the detection of food safety-related gases. The review begins by examining MXene material synthesis methods and then presents an overview of techniques aimed at enhancing MXene-based sensor detection capabilities. Recently, advancements in MXene composite gas sensors tailored for food safety gases have been highlighted. Finally, challenges encountered in gas-sensing applications of MXene-based composites are outlined, alongside predictions for their future development, aiming to offer insights for the application and advancement of intelligent gas sensors for target gases in food safety.

Identification of key physicochemical properties and volatile flavor compounds for the sensory formation of roasted tilapia.

Tilapia is suitable for industrial roasting production because of its good flavor and processing adaptability. In this study, the key physicochemical properties and volatile compounds for sensory formation of roasted tilapia were identified after roasting condition optimization. The highest sensory score was obtained at 215 °C, 45 min, and 4% oil. During roasting, the a*, b*, hardness, chewiness, and oxidation of proteins and lipids significantly increased, the moisture content decreased, and the myofibrillar protein aggregation was observed by scanning electron microscope. After identification and quantification by headspace-gas chromatography-ion mobility spectrometry, 10 compounds with odor active value ≥1 were selected as characteristic flavor compounds. The correlation network indicated that the sensory formation mainly resulted from Maillard reaction, myofibrillar protein aggregation, and improvement of pleasant volatile flavor compounds induced by oxidation of proteins and lipids and water loss. This study provides an important theoretical basis and technical support for roasted tilapia production.

Characterization of the key aroma compounds in different varieties of hops by application of the Sensomics approach.

Aroma is a crucial indicator of hop quality. This study analyzed the differences in aroma compound composition among six hop varieties from three regions: North America, Europe, and Asia. Descriptive analysis and sensomic approaches including gas chromatography-olfactometry/aroma extract dilution analysis, odour activity value calculation and aroma recombination were used for the detailed characterization and comparative analysis of hop aroma. A total of 55 aroma-active compounds were identified. Among them, linalool, geraniol, ß-myrcene, 2-undecanone, and methyl decanoate contributed significantly to hop aroma. Orthogonal partial least squares discriminant analysis revealed that, except for the SAAZ and XinYuan hops with some similarities in their aroma composition, the remaining hops exhibited unique aroma characteristics. A total of 16 compounds, including methyl 5-methylhexanoate and (E)-ß-farnesene, were identified as differentiating aroma compounds in the six hop samples. This study enriches the knowledge on hop flavour with different origins and provides valuable insights into its application.

Identification of a novel xanthine oxidoreductase inhibitor for hyperuricemia treatment with high efficacy and safety profile.

Hyperuricemia is with growing incidence and of high risk to develop into gout and other metabolic diseases. The key enzyme catalyzing uric acid synthesis, xanthine oxidoreductase (XOR) is a vital target for anti-hyperuricemic drugs, while XOR inhibitors characterized as both potent and safe are currently in urgent need. In this study, a novel small molecule compound, CC15009, was identified as a specific XOR inhibitor. CC15009 exerted strongest in vitro XOR inhibitory activity among current XOR inhibitors. It also showed favorable dose-dependent uric acid-lowering effects in two different XOR substrate-induced hyperuricemic mouse models, which was significantly superior than the current first-line drug, allopurinol. Mechanically, the direct binding of CC15009 against XOR was confirmed by molecular docking and SPR analysis. The inhibition mode was competitive and reversible. Besides, the potential antioxidant activity of CC15009 was indicated by its strong inhibitory activity against the oxidized isoform of XOR, which reduced ROS generation as the byproduct. Regarding the safety concerns of current XOR inhibitors, especially in cardiovascular risks, the safety of CC15009 was comprehensively evaluated. No significant abnormality was observed in the acute, subacute toxicity tests and mini-AMES test. Notably, there was no obvious inhibition of CC15009 against cardiac ion channels, including hERG, Nav1.5, Cav1.2 at the concentration of 30 µM, indicating its lower cardiovascular risk. Taken together, our results supported CC15009 as a candidate of high efficacy and safety profile to treat hyperuricemia through direct XOR inhibition.

Improvements in Therapy Experience with Evoked Compound Action Potential Controlled, Closed-Loop Spinal Cord Stimulation - Primary Outcome of the ECHO-MAC Randomized Clinical Trial.

Spinal cord stimulation (SCS) is a well-established treatment for chronic neuropathic pain. However, over- or under-delivery of the SCS may occur because the spacing between the stimulating electrodes and the spinal cord is not fixed; spacing changes with motion and postural shifts may result in variable delivery of the SCS dose, and in turn a sub-optimal therapy experience for the patient. The evoked compound action potential (ECAP)-a measure of neural activation - may be used as a control signal to adapt SCS parameters in real-time to compensate for this variability. In this prospective, multicenter, randomized, single-blind, crossover trial, reduction in overstimulation intensity was used as a perceptual measure to evaluate a novel ECAP-controlled, closed-loop (CL) SCS algorithm relative to traditional open-loop (OL) SCS. The primary outcome used a Likert scale to assess sensation during activities of daily living with CL versus OL SCS. Of the 42 subjects in the Intent-to-Treat Analysis set, 97.6% had a reduction in sensation with CL versus OL SCS. The primary objective was met as the lower confidence limit (87.4%) exceeded the performance goal of 50% (p < 0.001). A total of 88.1% (37/42) of subjects preferred CL and 11.9% (5/42) preferred OL SCS. SCS dose consistency during CL SCS was demonstrated by the reduced variability in ECAP amplitude with CL SCS (SD: 8.72 µV) relative to OL SCS (SD: 19.95 µV). Together, these results demonstrate that the ECAP-controlled, CL algorithm reduces or eliminates unwanted sensation, and thereby provides a more preferred and consistent SCS experience. PERSPECTIVE: Patients with chronic pain need durable and dependable options for pain relief. SCS is an important therapy option, and new technology advancements could improve long-term therapy use. Closed-loop SCS offers a preferred and more consistent therapy experience for patients that could lead to increased therapy utilization and reliable therapy outcomes.

Effects of compound emulsifiers on the characteristics and stability of nano-emulsions from pollock bones.

To improve the stability of pollock bone broth, compound emulsifiers were employed and evaluated in nano-emulsions from pollock bones (PBNs). The microstructure, creaming index, particle size, zeta potential, and viscosity of PBNs were characterized and the stability of PBNs was investigated. It revealed that the concentration of compound emulsifiers is one of the principal factors for particle size, zeta potential, and viscosity of PBNs, and 0.9% of sodium caseinate and sucrose fatty acid ester (CS-SE) can make the PBN display good stability. Its particle size changed from 81.17 ± 1.33 nm to 19.62 ± 0.21 nm when the temperature ranged from 40 °C to 80 °C, and its creaming index could reach a maximum (90.83%) among all PBNs in 4 months of freeze-thaw assays. PBN stability could be improved by the compound emulsifier (CS-SE), which offers a theoretical basis for the application of pollock bone broth.

Modulation of energetic and lipid pathways by curcumin as a potential chemopreventive strategy in human prostate cancer cells.

In Western industrialized countries, prostate cancer (PCa) is the second most common malignant disease and prevalent cause of death for men. Epidemiological studies have shown that curcumin (CUR) either prevents PCa initiation or delays its progression to a more aggressive and treatment-refractory form, thus reducing related mortality. Our previous studies have proven the anticancer, antioxidant, and anti-inflammatory properties of CUR on PCa cells. However, there are few reports of the effect of CUR on energy and lipid pathways in PCa. Herein, we show that CUR can modulate the two metabolic energy pathways, increasing glycolytic reserve and reducing oxidative phosphorylation. Moreover, through the regulation of key enzymes and proteins, CUR affected the lipid pathway in PC-3 to a greater extent compared to the healthy PNT-2 cells. According to molecular docking investigations, the CUR activity in PCa may be mediated by the direct binding to the pyruvate dehydrogenase (PDHA1) enzyme, which is essential for regulating the appropriate mitochondrial activity. Taken together, our results shed light on the mechanism of action of CUR in the PCa cell metabolism and provide evidence of its potential value as an anticancer metabolic modulator, paving opportunities for novel therapeutic strategies.

A novel compound heterozygous variant of MYO7A in Usher syndrome type 1.

Usher syndrome (USH) is a recessive genetic disorder manifested by congenital sensorineural hearing loss and progressive retinitis pigmentosa, which leads to audiovisual impairment. We report a patient with Usher syndrome type 1 with new compound heterozygous MYO7A variants. A total of four members from the USH family were included. Medical history and retinal examinations were taken and genomic DNA from peripheral blood was extracted in the proband and other members. 381 retinal disease-associated genes were screened using targeted sequence capture array technology and Sanger sequencing was used to confirm the screening results. Scanning laser ophthalmoscope showed bone spicule pigmentary deposits in the mid-peripheral retina and whitish and thin retinal blood vessels especially in the arterioles. Optical coherence tomography showed that the centrality of the macular ellipsoid band disappeared in both eyes, and only remained near the fovea. Visual field examination suggested a progressive loss of the visual field in a concentric pattern in both eyes. The electroretinography showed a significant decrease in the amplitudes of a- and b-waves in the scotopic and photopic condition. DNA sequencing identified the compound heterozygous variants including c.1003+1G>A: p.(?) and c.5957_5958del: p.G1987Lfs*50 of MYO7A, with the latter being novel. In this study, we found a novel compound heterozygous variant in MYO7A, which enriched the mutation spectrum and expanded our understanding of the heterogeneity of phenotype and genotype of Usher syndrome type 1.

Natural and synthetic 5-(3'-indolyl)oxazoles: Biological activity, chemical synthesis and advanced molecules.

5-(3'-Indolyl)oxazole moiety is a privileged heterocyclic scaffold, embedded in many biologically interesting natural products and potential therapeutic agents. Compounds containing this scaffold, whether from natural sources or synthesized, have demonstrated a wide array of biological activities. This has piqued the interest of synthetic chemists, leading to a large number of reported synthetic approaches to 5-(3'-indolyl)oxazole scaffold in recent years. In this review, we comprehensively overviewed the different biological activities and chemical synthetic methods for the 5-(3'-indolyl)oxazole scaffold reported in the literatures from 1963 to 2024. The focus of this study is to highlight the significance of 5-(3'-indolyl)oxazole derivatives as the lead compounds for the lead discovery of anticancer, pesticidal, antimicrobial, antiviral, antioxidant and anti-inflammatory agents, to summarize the synthetic methods for the 5-(3'-indolyl)oxazole scaffold. In addition, the reported mechanism of action of 5-(3'-indolyl)oxazoles and advanced molecules studied in animal models are also reviewed. Furthermore, this review offers perspectives on how 5-(3'-indolyl)oxazole scaffold as a privileged structure might be exploited in the future.

Catechin and flavonoid glycosides from the Ulmus genus: Exploring their nutritional pharmacology and therapeutic potential in osteoporosis and inflammatory conditions.

This review investigates the therapeutic effects of Ulmus species extracts, traditionally used as tea ingredients in East Asia, on bone health and inflammatory conditions. Through the analysis of 9757 studies, narrowing down to 56 pertinent ones, we evaluated the safety and efficacy of Ulmus extracts. The focus was on catechin glycosides (CG) and flavonoid glycosides (FG), key compounds identified for their potential benefits. The research highlights the extracts' role in enhancing bone mineral density (BMD) by stimulating osteoblast activity and suppressing osteoclast differentiation, suggesting a protective effect against osteoporosis. Furthermore, the extracts demonstrated significant anti-inflammatory properties by modulating inflammatory markers and pathways. The findings confirm the historical use of Ulmus extracts in East Asia for health benefits and recommend further exploration into functional foods and nutraceuticals. The review calls for more rigorous research, including clinical trials, to establish optimal use and integration into modern health solutions. It underscores the potential of Ulmus extracts in promoting bone health and managing inflammation, advocating for a bridge between traditional practices and contemporary scientific validation. In conclusion, Ulmus extracts, a material long consumed as tea ingredients in East Asia, exhibit significant potential for improving bone health and reducing inflammation. This review calls for additional research to explore their full therapeutic capabilities, emphasizing the need for optimized extraction methods and clinical trials. It reinforces the importance of bridging traditional knowledge with contemporary scientific approaches to health and dietary solutions, promoting overall wellness.

Case report: Comprehensive exploration of a novel PFKM mutation in glycogen storage disease Type VII.

Glycogen Storage Disease Type VII (GSD VII) is a rare glycogen metabolism disorder resulting from mutations in the PFKM gene, inherited in an autosomal recessive manner. It is characterized by exercise intolerance, muscle cramps, myoglobinuria, compensatory hemolysis, and later onset de novo myasthenia and mild myopathy, contributing to its clinical heterogeneity and diagnostic challenges. Here, we report a rare case of a 17-year-old Chinese woman exhibiting substantial muscle weakness and compensated hemolysis. Muscle biopsies showed glycogen deposition, and blood tests showed hyperuricemia and significantly elevated creatine kinase. Whole genome sequencing (WGS) and whole exome sequencing (WES) identified two compound heterozygous mutations in the PFKM (NM_000289.6) gene: c.626G>A and c.1376G>A in exons 7 and 15, respectively. According to the clinical presentation, diagnostic examination, and WES results, the patient was finally diagnosed with GSDVII. The discovery of these two new PFKM mutations expands the genetic spectrum, and understanding the clinical manifestations of these mutations is critical to preventing diagnostic delays and timely intervention and treatment.

Coinoculation of autochthonous starter cultures: A strategy to improve the flavor characteristics and inhibit biogenic amines of Harbin dry sausage.

The effects of separately coinoculating Lactiplantibacillus plantarum S8 (LP) with Staphylococcus carnosus L8 (LP + SC), Pichia kudriavzevii M6 (LP + PK), and S. carnosus L8 and P. kudriavzevii M6 (LP + SC + PK) on the flavor characteristics and biogenic amines (BAs) production in Harbin dry sausages were investigated. The coinoculated sausages exhibited higher free amino acids (FAAs) content than the noninoculated and LP sausages. Moreover, inoculated dry sausages exhibited lower BA contents (174.45, 239.43, 190.24, and 206.7 mg/kg for the LP, LP + SC, LP + PK, and LP + PK + SC sausages, respectively) than the noninoculated sausage (339.73 mg/kg). Meanwhile, the LP + PK and LP + SC + PK sausages had the highest contents of esters (996.70 µg/kg) and alcohols (603.46 µg/kg), respectively. A sensory evaluation demonstrated that the LP + SC + PK sausage had the highest fermented odor and the lowest fatty odor. Pearson correlation analysis revealed that FAAs were correlated with most key volatile compounds and BAs. This study provides new insights into flavor development and BA inhibition in dry sausages through coinoculation.

Efficacy and feasibility analysis of compound fluocinolone acetonide cream combined with guaiazulene in the treatment of neurodermatitis.

OBJECTIVE: To evaluate the effectiveness and feasibility of combined treatment with compound fluocinolone acetonide cream and guaiazulene in patients with neurodermatitis. METHODS: A prospective study was conducted on 92 outpatient patients diagnosed with neurodermatitis at our dermatology department from January 2022 to December 2023. Using a random number table, these patients were evenly divided into a control group and an experimental group, with 46 individuals in each group. The control group received treatment with compound fluocinolone acetonide alone, while the experimental group additionally received oral guaiazulene tablets. Clinical symptom and sign scores, Visual Analog Scale (VAS) scores, skin lesion itching scores, comprehensive efficacy, treatment onset time, adverse reactions, and quality of life were monitored, recorded, and compared. RESULTS: In the 2-week treatment period, patients in the experimental group showed significant improvement in skin symptoms and signs, with scores significantly lower than those in the control group (P < 0.05). After treatment, VAS and skin lesion itching scores in the experimental group were significantly reduced (P < 0.05), demonstrating a more pronounced therapeutic advantage compared to the control group (P < 0.05). Although the effective rate in the experimental group was as high as 86.96%, there was no significant advantage compared to the control group, and the difference in treatment efficacy was not significant (P > 0.05). The treatment onset time in the experimental group was significantly shorter than that in the control group (P < 0.05), and the incidence of adverse reactions was lower (P < 0.05). The quality of life in the experimental group improved significantly after treatment, with DLQI scores lower than those in the control group (P < 0.05). CONCLUSION: Combined treatment with compound fluocinolone acetonide cream and guaiazulene demonstrates excellent efficacy and feasibility in the management of neurodermatitis. Compared to standard treatment alone, it yields superior clinical outcomes.

Review on Catalytic Meinwald Rearrangement of Epoxides.

The past few decades have witnessed tremendous development within epoxides. Among the many known reactions involving epoxide, Meinwald rearrangements represent one of the most important and attractive approaches, which can transform epoxides into versatile carbonyl compounds. Given the high efficiency of this protocol, substantial efforts have been made by researchers by utilizing multiple catalyst systems. This review provides an overview of recent advances in the Meinwald rearrangement (from 2014 onward), along with detailed discussions on mechanistic insights. This review aims to highlight the importance and value of these methodologies, thereby promoting further investigation and application.

Developement of lactic acid fermentation of jackfruit (Artocarpus heterophyllus) seed drink and its physicochemical and sensory properties.

The objective of this study was to create a plant-based drink from jackfruit seed. Firstly, jackfruit seed powder was hydrolyzed step by step with 0.2% α-amylase for 60 min and 0.3% glucoamylase for 90 min. The sample then was fermented with Lactiplantibacillus plantarum (L. plantarum) at 37 °C for 15 h. The findings indicated that hydrolysis and lactic acid fermentation enhanced the polyphenol, flavonoid, and antioxidant activity of jackfruit seed drink. Jackfruit seed drink was a favorable matrix for L. plantarum delivery. Moreover, the product underwent fermentation and reached the viability density of L. plantarum of 8.15 Log CFU/mL. The overall sensory liking score was rated between 5 and 5.5/7 points. Throughout the 35 days of storage period at 4-6 °C, the number of L. plantarum uncharged, whereas the bioactive compound and antioxidant activity of the product diminished by nearly 20-50% compared to the sample before storage. Overall, this research highlights the potential of the the fermented jackfruit seed drink as a probiotic plant-based drink with massive biological function and sensory appeal.

Elucidating the Potential Role of Microorganisms in Postmortem Biotransformation: A Comparison of Clonazolam and its Metabolite in Postmortem and DUID Cases.

Clonazolam is a designer triazolobenzodiazepine first synthesized in 1971 and primarily used for its anxiolytic and sedative effects. It became a drug of misuse in 2012 and is known for its high potency and long duration of effects. Previous studies of nitrobenzodiazepines such as nitrazepam, clonazepam, flunitrazepam, and their metabolites have demonstrated that bacterial species native to the gastrointestinal tract and active during postmortem (PM) decomposition are capable of affecting positivity and compound-to-metabolite ratios. Further studies have not been performed with clonazolam; however, it possesses the nitro functional group necessary for this biotransformation. To understand whether clonazolam may be similarly affected, PM (n = 288) and driving under the influence of drugs (DUID, n = 54) cases positive for 8-aminoclonazolam reported by NMS Labs from 2020 to 2023 were selected for inclusion in this study. Concentrations of clonazolam and 8-aminoclonazolam were evaluated, and concurrent identification of parent drug and metabolite occurred less frequently in PM cases (n = 1, 0.30% of cases) than in DUID cases (n = 21, 38% of cases). The clonazolam concentration in one PM case was 13 ng/mL. In DUID cases the median clonazolam concentration was 4.0 ng/mL and ranged from 2.0-10 ng/mL. 8-Aminoclonazolam had median concentrations of 13 and 19 ng/mL and ranges of 2.0-580 and 2.8-59 ng/mL for PM and DUID cases, respectively. Due to the everchanging landscape of the DBZD market, in vitro studies of PM microbial biotransformation of clonazolam are unavailable. The data reported herein provide valuable information in the absence of such studies and represent an alternative method of investigating this phenomenon as a potential cause of parent nitrobenzodiazepine to metabolite conversion.