Amino acids-based deep eutectic solvents as additives for improved enantioseparation in capillary electrophoresis.

In this study, several amino acids deep eutectic solvents were prepared using L-valine and L-leucine as hydrogen bond acceptors, and L-lactic acid and glycerol as hydrogen bond donors. These amino acids' deep eutectic solvents were first used as buffer additives to construct several synergistic systems along with maltodextrin in capillary electrophoresis for the enantioseparations of four racemic drugs. Compared with single maltodextrin system, the separations of model drugs in the synergistic systems were significantly improved. Some key parameters affecting chiral separation such as maltodextrin concentration, deep eutectic solvent concentration, buffer pH, and applied voltage were optimized. In order to further understand the specific mechanism of the amino acids deep eutectic solvents in improving chiral separation, we first calculated the binding constants of maltodextrin with enantiomers using the capillary electrophoresis method in the two separation modes, respectively. We also used molecular simulation to calculate the binding free energy of maltodextrin with enantiomers. It is the first time that amino acids deep eutectic solvents were used for enantioseparation in capillary electrophoresis, which will greatly promote the development of deep eutectic solvents in the field of chiral separation.

Impact of Undertreatment of Depression on Suicide Risk Among Children and Adolescents With Major Depressive Disorder: A Microsimulation Study.

Undertreatment of depression is common among children and adolescents, but evidence of the impact of undertreatment of depression on risk of suicide is limited due to the low base rate of suicide in the population and lack of sufficient data sources. We developed a microsimulation model that uses evidence from multiple sources to study the impact of different durations of antidepressant treatment on suicide risk in a synthesized sample that is nationally representative of children and adolescents with major depressive disorder. Compared with receiving no treatment, suicide rate and risk of suicide attempt both decreased with increasing duration of antidepressant treatment (for 12 weeks, suicide rate ratios = 0.78 (95% credible interval (CrI): 0.58, 1.15), 36 weeks, 0.65 (95% CrI: 0.44, 0.90), and 52 weeks, 0.63 (95% CrI: 0.45, 0.72); for suicide attempt: 12 weeks, suicide risk ratios = 0.68 (95% CrI: 0.62, 0.69), 36 weeks, 0.56 (95% CrI: 0.52, 0.57), and 52 weeks, 0.55 (95% CrI: 0.51, 0.56). The suicide rate and risk of suicide attempt were lower in children than in adolescents. Males had a lower risk of suicide attempt but higher suicide rate than females. The findings from the microsimulation model show that completion of 12-36 weeks of antidepressant treatment may reduce suicide attempt and suicide among children and adolescents with major depressive disorder.

Mechanistic Observation of Interactions between Macrophages and Inorganic Particles with Different Densities.

Many different types of inorganic materials are processed into nano/microparticles for medical utilization. The impact of selected key characteristics of these particles, including size, shape, and surface chemistries, on biological systems, is frequently studied in clinical contexts. However, one of the most important basic characteristics of these particles, their density, is yet to be investigated. When the particles are designed for drug delivery, highly mobile macrophages are the major participants in cellular levels that process them in vivo. As such, it is essential to understand the impact of particles' densities on the mobility of macrophages. Here, inorganic particles with different densities are applied, and their interactions with macrophages studied. A set of these particles are incubated with the macrophages and the outcomes are explored by optical microscopy. This microscopic view provides the understanding of the mechanistic interactions between particles of different densities and macrophages to conclude that the particles' density can affect the migratory behaviors of macrophages: the higher the density of particles engulfed inside the macrophages, the less mobile the macrophages become. This work is a strong reminder that the density of particles cannot be neglected when they are designed to be utilized in biological applications.

Two new alkaloids from Dendrobium nobile Lindl. exhibited neuroprotective activity, and dendrobine alleviated Aß1-42 -induced apoptosis by inhibiting CDK5 activation in PC12 cells.

Dendrobium nobile Lindl. is registered in the Chinese Pharmacopoeia as a traditional medicine. Phytochemical investigation of the ethanol extract of D. nobile Lindl. stems yielded three alkaloid compounds, including two new compounds dendroxine B (2) and denrine B (3) as well as one known compound dendrobine (1). Here, we identified the structure of these compounds using spectroscopic analyses and compared them with those described in previous studies. Compounds 1-3 were found to show protective effect against amyloid-ß 1-42 (Aß1-42 )-induced neurotoxicity in rat pheochromocytoma (PC12) cells, among which dendrobine exhibited the most significant neuroprotective effect. Hoechst 33342/propidium iodide staining indicated that dendrobine ameliorated Aß1-42 -induced apoptosis. Moreover, quantitative real-time polymerase chain reaction and western blot analysis analysis demonstrated that dendrobine suppressed the activation of cyclin-dependent kinase 5 (CDK5), upregulated Bcl-2 expression, and downregulated Bax, cyto-c, and caspase-3 expression. Molecular docking analysis and surface plasmon resonance assay suggested that dendrobine directly bound to CDK5 protein with a KD value of 2.05 × 10-4 M. In summary, alkaloids are the neuroprotective constituents of D. nobile Lindl., and dendrobine protected PC12 cells against Aß1-42 -induced apoptosis by inhibiting CDK5 activation.

[Research progress of effect of anxiolytic traditional Chinese medicines and formulas on neurotransmitters].

Anxiety disorders are a common mental illness that seriously endangered physical and mental health of human beings. The etiology of anxiety disorders is closely related to the abnormality of monoamines neurotransmitters, amino acids neurotransmitters and neuropeptides. The long-term use of anti-anxiety chemical drugs has some adverse effects, such as constipation, muscle relaxation, lethargy, tolerance and withdrawal symptoms. However, traditional Chinese medicines have advantages of multi-component, multi-target coordination, with less adverse reactions. Therefore, it is a promising prospect to develop novel anti-anxiety drugs from traditional Chinese medicines and formulas. This article reviewed some traditional Chinese medicines and formulas that can relieve anxiety symptoms. These include traditional Chinese medicines(Panax ginseng, Lycium ruthenium, Morus alba, Bupleurum plus dragon bone oyster soup, Chailong Jieyu Pills, and Naogongtai Formulas) with the effect on monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine; traditional Chinese medicines(Rehmannia glutinosa, Ziziphus jujuba Mill. var. spinosa, Jielv Anshen Decoction, Baixiangdan Capsules, Antianxietic Compound Prescription Capsules) with the effect on amino acid neurotransmitters, such as glutamic acid, γ-aminobutyrc acid; and traditional Chinese medicines(P. ginseng, Xiaoyao San, Shuyu Ningxin Decoction)with the effect on neuropeptide Y pathway, with the aim to provide theoretical basis for the further development of some novel and more effective anti-anxiety therapeutics from traditional Chinese medicine and formulas.

Activation of the hippocampal AC-cAMP-PKA-CREB-BDNF signaling pathway using WTKYR in depression model rats.

Depression, also called "depression disorder," is characterized by a significant and persistent low mood. It has become a major refractory disease in the 21st century. In recent years, Chinese medicine has shown some important clinical value in the treatment of depression. Among them, the Warming and "Tonifying" Kidney-Yang Recipe (WTKYR) has been demonstrated to have obvious effects in the clinical treatments of depression; however, the mechanism remains unclear. This study is based on the adenylyl cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding protein (CREB)-brain derived neurotrophic factor (BDNF) signaling pathway, aiming to investigate the mechanism of WTKYR. The results showed that WTKYR can upregulate AC-cAMP-PKA-CREB-BDNF in the hippocampus of depression model rats and alleviate its depressive symptoms, which may be the mechanism of WTKYR.

Paper-based SERS analysis with smartphones as Raman spectral analyzers.

SERS (Surface Enhanced Raman Spectroscopy) can realize fingerprint recognition of molecular samples with high detection accuracy and sensitivity. However, rapid and convenient measurement of the Raman spectra of analytes for a point-of-care test (POCT) has put forward a high demand for portable Raman spectrometers, as well as reliable SERS substrates. Hereby, we first utilize a smartphone as a miniaturized Raman spectral analyzer, which has the revolutionary advantages of a friendly human-machine interface, fast measurement time, and good sensitivity. Meanwhile, a paper-based SERS chip was prepared based on commonly used filter paper and silver nanoparticles (AgNP), which was successfully used to detect low concentrations of typical SERS analyte model molecules including rhodamine 6G and crystal violet. The current method of smartphone-based SERS spectroscopy as a POCT device will greatly promote the application of Raman technology in a variety of scenarios, such as safety inspections, pesticide residue detection, water pollution monitoring, and so on. Coupled with paper-based SERS chips with advantages of facile preparation, low cost and good reliability, the current work proves to have a great potential for industrial production and for meeting the vast marketing demand of Raman based POCT technology.

Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway.

Hericium erinaceus is a culinary-medicinal mushroom used traditionally in Eastern Asia to improve memory. In this work, we investigated the neuroprotective and neuritogenic effects of the secondary metabolites isolated from the MeOH extract of cultured mycelium of H. erinaceus and the primary mechanisms involved. One new dihydropyridine compound (6) and one new natural product (2) together with five known compounds (1,3-5,7) were obtained and their structures were elucidated by spectroscopic analysis, including 2D NMR and HRMS. The cell-based screening for bioactivity showed that 4-chloro-3,5-dimethoxybenzoic methyl ester (1) and a cyathane diterpenoid, erincine A (3), not only potentiated NGF-induced neurite outgrowth but also protected neuronally-differentiated cells against deprivation of NGF in PC12 pheochromocytoma cells. Additionally, compound 3 induced neuritogenesis in primary rat cortex neurons. Furthermore, our results revealed that TrkA-mediated and Erk1/2-dependant pathways could be involved in 1 and 3-promoted NGF-induced neurite outgrowth in PC12 cells.

Picrotoxane Sesquiterpene Glycosides and a Coumarin Derivative from Coriaria nepalensis and Their Neurotrophic Activity.

Two picrotoxane sesquiterpene lactone glycosides, nepalactones A (1) and B (2), and one new coumarin, nepalarin (3), were isolated from the root barks of the poisonous plant Coriarianepalensis. Their structures were elucidated via HRESIMS and 1D and 2D NMR spectroscopic analyses, and further verified via transformation methods. In addition, compounds 1-3 and five semisynthetic congeners (1a-e) were assayed for the activity to induce neurite outgrowth in rat pheochromocytoma (PC12) cells. As a result, nepalactone A derivative 1c and nepalarin (3) significantly enhanced nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells.

Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells.

One new meroterpenoid, named hericenone K (11), along with 10 known compounds (1-10), ergosterol peroxide (1), cerevisterol (2), 3ß,5α,9α-trihydroxy-ergosta-7,22-dien-6-one (3), inoterpene A (4), astradoric acid C (5), betulin (6), oleanolic acid (7), ursolic acid (8), hemisceramide (9), and 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran (10), was isolated from the fruiting bodies of the mushroom Hericium erinaceus. Their structures were characterized on the basis of spectroscopic methods, as well as through comparison with previously reported data. Compounds 3-6, 8, and 9 were isolated from Hericium species for the first time. Compounds 10 and 11 was suggested to be racemic by the CD spectrum data and specific rotations, which ware resolved by chiral HPLC into respective enantiomers. Compounds 1-3, (±)-10, (-)-10 and (+)-10 in the presence of NGF (20 ng/mL) exerted a significant increase in neurite-bearing cells.

Striatoids A-F, Cyathane Diterpenoids with Neurotrophic Activity from Cultures of the Fungus Cyathus striatus.

Six new highly oxygenated polycyclic cyathane-xylosides, named striatoids A-F (1-6), were isolated from the cultures of the basidiomycete Cyathus striatus. Their structures were established by comprehensive spectroscopic analysis including 2D NMR (HMBC, HSQC, ROESY, (1)H-(1)H-COSY) and HRESIMS experiments. Compounds 2 and 3 possess an unusual 15,4'-ether ring system. The isolated compounds dose-dependently enhanced nerve growth factor (NGF)-mediated neurite outgrowth in rat pheochromocytoma (PC-12) cells.

Risk of incident gout following exposure to recombinant zoster vaccine in US adults aged ≥65 years.

OBJECTIVE: Assess the risk of incident gout following exposure to recombinant zoster vaccine (RZV). METHODS: This case-only, self-controlled risk interval study included a cohort of US fee-for-service Medicare (Part A, B, and D) beneficiaries aged ≥65 years. The exposure was receipt of at least one dose of the two-dose RZV regimen in 2018 or 2019. The risk and control windows were days 1-30 and days 31-60, respectively, following vaccination. Incident gout was defined as the first episode of gout during the risk or control window, with no evidence of gout in the last 365 days. We estimated the relative risk (RR) and 95 % confidence interval (CI) of incident gout in the risk window relative to the control window, using conditional Poisson regression models. Sensitivity analyses included a dose-compliant subanalysis of individuals who received dose 2 60-183 days after dose 1; dose-specific analysis; seasonality adjustment; and COVID-19 adjustment for potential detection bias due to the pandemic. RESULTS: The 1290 RZV-exposed individuals with incident gout were primarily White (86.98 %), male (61.16 %), and aged 70-79 years (55.82 %). The RR of incident gout was 1.00 (95 % CI 0.90, 1.12). In the dose-compliant sensitivity analysis (n = 959 cases of incident gout), the RR of incident gout was 0.99 (95 % CI 0.87, 1.13). The findings were unchanged in the dose-specific, seasonality, and COVID-19 sensitivity analyses. CONCLUSION: The findings suggest that RZV is not significantly associated with an increased risk of incident gout in the Medicare population aged ≥65 years.

Recognition and management of children and adolescents with conduct disorder: a real-world data study from four western countries.

BACKGROUND: Conduct disorders (CD) are among the most frequent psychiatric disorders in children and adolescents, with an estimated worldwide prevalence in the community of 2-4%. Evidence-based psychological outpatient treatment leads to significant improvement in about two-thirds of cases. However, there seems to be considerable variation in rates of CD diagnoses and implementation of evidence-based interventions between nations. The aim of this study was to compare administrative prevalence and treatment patterns for CD in children and adolescents seen in health care systems across four Western countries (Denmark, Germany, Norway, and the USA). METHODS: Cross-sectional observational study using healthcare data to identify children and adolescents (aged 0-19 years) with an ICD-10 code for CD within the calendar year 2018. Within each country's study population, the prevalence of CD, psychiatric comorbidity, psychopharmacological treatment, and psychiatric hospitalisation was calculated. RESULTS: The prevalence of diagnosed CD differed 31-fold between countries: 0.1% (Denmark), 0.3% (Norway), 1.1% (USA) and 3.1% (Germany), with a male/female ratio of 2.0-2.5:1. The rate of psychiatric comorbidity ranged from 69.7 to 86.1%, with attention-deficit/hyperactivity disorder being most common. Between 4.0% (Germany) and 12.2% (USA) of youths with a CD diagnosis were prescribed antipsychotic medication, and 1.2% (Norway) to 12.5% (Germany) underwent psychiatric hospitalisation. CONCLUSION: Recognition and characteristics of youths diagnosed with CD varied greatly by country. In some countries, the administrative prevalence of diagnosed CD was markedly lower than the average estimated worldwide prevalence. This variation might reflect country-specific differences in CD prevalence, referral thresholds for mental health care, diagnostic tradition, and international variation in service organisation, CD recognition, and availability of treatment offers for youths with CD. The rather high rates of antipsychotic prescription and hospitalisation in some countries are remarkable, due to the lack of evidence for these therapeutic approaches. These findings stress the need of prioritising evidence-based treatment options in CD. Future research should focus on possible reasons for inter-country variation in recognition and management of CD, and also address possible differences in patient-level outcomes.

Enhanced EPR effects by tumour stromal cell mimicking nanoplatform on invasive pituitary adenoma.

Rapid advances in nanomedicine have enabled potential applications in cancer therapy. The enhanced permeability and retention (EPR) effect is the primary rationale for the passive targeting of nanoparticles in oncology. However, growing evidence indicates that the accumulation of nanomaterials via the EPR effect could be more efficient. Inspired by our clinical observation of the Gap Junction connecpion between folliculostellate cells and pituitary adenoma cells, we designed a novel drug delivery system that targets tumours by coating folliculostellate cell (FS) membranes onto PLGA nanoparticles (NPs). The resulting FSNPs, inheriting membrane proteins from the folliculostellate cell membrane, significantly enhanced the EPR effect compared to nanoparticles without cancer cell membranes. We further demonstrated that mitotane encapsulation improved the therapeutic efficacy of mitotane in both heterotopic and orthotopic pituitary adenoma models. Owing to its significant efficacy, our FS cell membrane-coated nanoplatforms has the potential to be translated into clinical applications for the treatment of invasive pituitary adenoma.

Use of chiral ionic liquid as additive for synergistic enantioseparation of basic drugs in capillary electrophoresis.

This work presents a synergistic system for enantioseparation in capillary electrophoresis (CE) with a chiral ionic liquid (CIL) based on D-10-camphorsulfonic acid as additive and carboxymethyl-ß-cyclodextrin (CM-ß-CD) as the chiral selector. The proposed method showed excellent enantioseparation performance towards sixteen chiral drugs. In contrast to the single CM-ß-CD system, the notably improved resolution (Rs) and selectivity factor (α) of model drugs were observed in synergistic system. Several key parameters such as CIL concentration, CM-ß-CD concentration, buffer pH and separation voltage were investigated, after which Statistical Product and Service Solutions (SPSS) was used to prove the potential synergistic effect. The nuclear magnetic resonance (NMR) results further demonstrated the function of the CIL and the superiority of synergistic system. Finally, chiral impurity determination of chlorpheniramine maleate sample was successfully carried out using the established method.

Influence of Healthy Brand and Diagnosticity of Brand Name on Subjective Ratings of High- and Low-Calorie Food.

Brand names on food packaging and the diagnosticity of brand names have notable effects on consumer preferences. However, their effects on healthy food consumption are not clear. The objective of this study was to investigate the effect of healthy brands and the diagnosticity of brand names on consumers' subjective ratings of different calorie foods. In two studies, participants viewed 32 pictures of high- and low-calorie food product packaging from healthy and unhealthy brands and rated their feelings and willingness to pay online. Study 1 used real brand names, and Study 2 used fictional brand names and added press releases to manipulate diagnosticity. The present study demonstrated that participants perceived foods from healthy brands as healthier but less delicious and were more willing to buy low-calorie foods from healthy brands. Moreover, only when the brand name was of high diagnosticity were high-calorie foods rated as more likable, and did the willingness to pay for low-calorie foods increase. Collectively, these findings highlight the influence of the healthy brand on consumers' subjective ratings of food. It is also inspiring for healthy food marketing.

Paper-based lateral flow assay for the point-of-care detection of neurofilament light chain.

Neurofilament light chain (NF-L) is a protein found in neurons of the nervous system and is widely used as a biomarker for neurological disorders. However, the current methods for detecting NF-L levels are complicated, expensive, and require specialized equipment, making it challenging to implement in a point-of-care (POC) setting. In this study, we developed a gold nanoshell (AuNS)-assisted lateral flow assay (LFA) based test strip for the POC detection of NF-L at a low ng/mL level (8 ng/mL = 117.65 pM). The test strip is a simple, rapid, and cost-effective method for detecting NF-L, making it suitable for use in a POC setting for the diagnosis and treatment of various neurological disorders. With its ease of use and reliability, the paper-based LFA is a valuable tool for the diagnosis and management of neurological conditions.Clinical Relevance- The AuNS-assisted LFA test strip developed in this study offers a rapid, cost-effective, and simple method for detecting NF-L levels, making it of great interest to practicing clinicians for the diagnosis of various neurological diseases such as HIV-associated dementia (HID), Amyotrophic Lateral Sclerosis (ALS), and Creutzfeldt-Jakob disease (CJD).

Integrated RPA-CRISPR/Cas12a system towards Point-of-Care H. pylori detection.

The rapidly advanced CRISPR/Cas biosensing technology provides unprecedent potential for the development of novel biosensing systems. It provides a new approach for realizing rapid, sensitivity and highly specific pathogen nucleic acid detection, with the capability to combine other technologies, including Polymerase Chain Reaction or isothermal amplifications. The detection of Helicobacter pylori (H. pylori), one of the most common human pathogens to cause various gastroduodenal diseases, has also been explored with the assistance of CRISPR/Cas systems. However, gaps still remain for the development of end-user friendly sensing systems.In this study, a combined RPA-CRISPR/Cas12a biosensing system has been established. It shown the capability to quantitively detect the presence of H. pylori genome DNA with 4 orders of magnitude linear range, and sensitivity of 1.4 copies/µL. The overall reaction can be done within 45 mins at room temperature, which eliminates the needs for heating instrumentation. In addition, with the addition of pullulan as a protective reagent, the potential of storing CRISPR/Cas12a system reagents by using a freeze-dry approach has also been demonstrated.Clinical Relevance - This study represents a novel exploration to applying CRISPR/Cas12a-based biosensing technology to the detection of pathogen DNA with improved potential for the development of Point-of-Care diagnostics. This critical aspect of our technology will contribute to address the newly emerged pathogenic threats and support public health systems.

RNA reporter based CRISPR/Cas12a biosensing platform for sensitive detection of circulating tumor DNA.

CRISPR/Cas biotechnology provides an exceptional platform for biosensor development. To date, the reported CRISPR/Cas biosensing systems have shown extraordinary performance for nucleic acids, small molecules, small proteins and microorganism detection. The CRISPR/Cas12a biosensing system, as a typical example, has been well established and applied for both nucleic acids and non-nucleic acids target detection. However, all established CRISPR/Cas12a biosensing systems are based on DNA reporters, which potentially limits further application.In this study, we established an RNA reporter based CRISPR/Cas12a biosensing system. A basic biosensing system was evaluated, and the limit of detection was found to be 1 nM. Afterwards, we optimized this biosensing system using both temperature and chemical enhancers. The final optimal biosensing system (with DTT & 37°C) shows fluorescence signal increased by a factor of ~10 compared with the basic system. The optimal biosensing system was further applied for the detection of circulating tumor DNA (ctDNA), which shows over 4 orders of magnitude detection range from 1pM to 25 nM, with the limit of detection of 1pM. This RNA reporter based CRISPR/Cas12a biosensing system provides an effective platform for nucleic acids quantification.Clinical Relevance- This research provides a novel approach for ctDNA diagnostics, which is an attractive biomarker for noninvasive monitoring of tumor growth, response, and spread.

Comparison of Intergrowth-21st and Fenton growth standards to evaluate and predict the postnatal growth in eastern Chinese preterm infants.

Objectives: The aim of this article was to compare the differences between Intergrowth-21st (IG-21) and Fenton growth standards in the classification of intrauterine and extrauterine growth restriction (EUGR) in eastern Chinese preterm infants, and detect which one can better relate to neonatal diseases and predict the physical growth outcomes at 3-5 years old. Methods: Premature infants admitted to a tertiary pediatric hospital in Shanghai, China, from 2016 to 2018 were enrolled. Prenatal information, neonatal diseases during hospitalization, and anthropometric data (weight, height, and head circumference) at birth and at discharge were collected and analyzed. Physical growth outcomes (short stature, thinness, and overweight) were examined by telephone investigations in 2021 at age 3-5 years. Results: The medium gestational age and birth weight of the included 1,065 preterm newborns were 33.6 weeks and 1,900 g, respectively. The IG-21 curves diagnosed more newborns with small for gestational age (SGA) (19% vs. 14.7%) and fewer newborns with longitudinal EUGR on height (25.5% vs. 27.9%) and head circumference (17.9% vs. 24.7%) compared to Fenton curves. Concordances between Fenton and IG-21 standards were substantial or almost perfect in the classification of SGA and longitudinal EUGR, but minor in cross-sectional EUGR. EUGR identified by Fenton curves was better related to neonatal diseases than IG-21 curves. There were no statistical significances in the prediction of short stature, thinness, and overweight at 3-5 years old between the two charts. Conclusions: IG-21 growth standards are not superior to Fenton in assessing preterm growth and development in the eastern Chinese population.