The interaction between KIF21A and KANK1 regulates dendritic morphology and synapse plasticity in neurons.

JOURNAL/nrgr/04.03/01300535-202501000-00029/figure1/v/2024-05-14T021156Z/r/image-tiff Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory. Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1; however, whether KIF21A modulates dendritic structure and function in neurons remains unknown. In this study, we found that KIF21A was distributed in a subset of dendritic spines, and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines. Furthermore, the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity. Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching, and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1, but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1. Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals' cognitive abilities. Taken together, our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.

The hidden costs of informal caregiving: a concept analysis.

BACKGROUND: "The hidden costs of informal caregiving" is an interdisciplinary concept. While caregivers make a significant contribution to the process of caregiving, they sacrifice their leisure time, and incur risks of dropping out of the job, impaired mental and physical health, and decreased well-being within the context of caregiving. Those invisible sacrifices are often overlooked and described as hidden costs of informal caregiving. However, the conceptualisation of hidden costs of informal caregiving has not yet been clarified and scientifically assessed. The research aimed to clarify the concept of hidden costs of informal caregiving and develop an operational definition. METHODS: Walker and Avant's concept analysis was conducted. Databases of CBM, CNKI, WanFang, VIP, PubMed, Embase, CINAHL, Web of Science, MEDLINE, Cochrane Library, Econlit, CINAHL and ProQuest were searched with the term "hidden costs of informal caregiving". Information about the uses of the concept, defining attributes, model cases, antecedents, consequences and empirical referents of hidden costs of informal caregiving was extracted and synthesized. RESULTS: A total of 25 articles were included. The six defining attributes of hidden costs of informal caregiving were identified as including "undertaken by informal caregivers", "the time costs of caregiving", "costs of career development" "physical well-being costs", "mental well-being costs" and "social relationship costs". Personal characteristics of the caregivers and care recipients, along with caregiving attributes, were among the antecedents. The consequences of hidden costs of informal caregiving resulted in negative influences which included poor quality of life, life-altering decisions, options for the type of care, some degree of economic hardship, decreased compliance with treatment plans and monetary value informal caregivers are willing to pay to be replaced. CONCLUSION: This concept analysis decisively illuminated the hitherto nebulous concept and expanded the contents of hidden costs of informal caregiving, which will foster a deeper appreciation of the invisible cost of caregivers. Moreover, it will provide a reference for the study of the hidden costs of informal caregiving in future, contribute to the development of assessment tools and theoretical models of hidden costs of informal caregiving, and create a basis for designing an evidence-based care program.

Reporting quality and risk of bias of randomized controlled trials of Chinese herbal medicine for multiple sclerosis.

Background: Multiple sclerosis (MS) is the most common non-traumatic disabling disease affecting young adults. A definitive curative treatment is currently unavailable. Many randomized controlled trials (RCTs) have reported the efficacy of Chinese herbal medicine (CHM) on MS. Because of the uncertain quality of these RCTs, the recommendations for routine use of CHM for MS remain inconclusive. The comprehensive evaluation of the quality of RCTs of CHM for MS is urgent. Methods: Nine databases, namely, PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Sinomed, Wanfang Database, China National Knowledge Infrastructure, and VIP Database, were searched from inception to September 2023. RCTs comparing CHM with placebo or pharmacological interventions for MS were considered eligible. The Consolidated Standards of Reporting Trials (CONSORT) and its extension for CHM formulas (CONSORT-CHM Formulas) checklists were used to evaluate the reporting quality of RCTs. The risk of bias was assessed using the Cochrane Risk of Bias tool. The selection criteria of high-frequency herbs for MS were those with cumulative frequency over 50% among the top-ranked herbs. Results: A total of 25 RCTs were included. In the included RCTs, 33% of the CONSORT items and 21% of the CONSORT-CHM Formulas items were reported. Eligibility title, sample size calculation, allocation concealment, randomized implementation, and blinded description in CONSORT core items were reported by less than 5% of trials. For the CONSORT-CHM Formulas, the source and authentication method of each CHM ingredient was particularly poorly reported. Most studies classified the risk of bias as "unclear" due to insufficient information. The top five most frequently used herbs were, in order, Radix Rehmanniae Preparata, Radix Rehmanniae Recens, Herba Epimedii, Scorpio, and Poria. No serious adverse effect had been reported. Conclusions: The low reporting of CONSORT items and the unclear risk of bias indicate the inadequate quality of RCTs in terms of reporting completeness and result validity. The CONSORT-CHM Formulas appropriately consider the unique characteristics of CHM, including principles, formulas, and Chinese medicinal substances. To improve the quality of RCTs on CHM for MS, researchers should adhere more closely to CONSORT-CHM Formulas guidelines and ensure comprehensive disclosure of all study design elements.

Development of a cost-effective confocal Raman microscopy with high sensitivity.

Confocal Raman microscopy is a powerful technique for identifying materials and molecular species; however, the signal from Raman scattering is extremely weak. Typically, handheld Raman instruments are cost-effective but less sensitive, while high-end scientific-grade Raman instruments are highly sensitive but extremely expensive. This limits the widespread use of Raman technique in our daily life. To bridge this gap, we explored and developed a cost-effective yet highly sensitive confocal Raman microscopy system. The key components of the system include an excitation laser based on readily available laser diode, a lens-grating-lens type spectrometer with high throughput and image quality, and a sensitive detector based on a linear charge-coupled device (CCD) that can be cooled down to -30 °C. The developed compact Raman instrument can provide high-quality Raman spectra with good spectral resolution. The 3rd order 1450 cm-1 peak of Si (111) wafer shows a signal-to-noise ratio (SNR) better than 10:1, demonstrating high sensitivity comparable to high-end scientific-grade Raman instruments. We also tested a wide range of different samples (organic molecules, minerals and polymers) to demonstrate its universal application capability.

Fermentation: improvement of pharmacological effects and applications of botanical drugs.

Fermentation is an important concoction technique for botanical drugs. Fermentation transforms and enhances the active ingredients of botanical drugs through specific microbiological processes, ultimately affecting their pharmacological effects. This review explores the use of fermented botanical drugs in areas such as anti-tumor, hypolipidemic, antioxidant, antimicrobial, cosmetology, and intestinal flora regulation. It elucidates the potential pharmacological mechanisms and discusses the benefits of fermentation technology for botanical drugs, including reducing toxic side effects, enhancing drug efficacy, and creating new active ingredients. This article also discussesdelves into the common strains and factors influencing the fermentation process, which are crucial for the successful transformation and enhancement of these drugs. Taken together, this study aimed to provide a reference point for further research and wider applications of botanical drug fermentation technology.

Maternal folic acid over-supplementation impairs cardiac function in mice offspring by inhibiting SOD1 expression.

BACKGROUND: Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. METHODS AND RESULTS: Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. CONCLUSIONS: Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.

The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China.

BACKGROUND: This study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs). METHODS: LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy. RESULTS: The baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy. CONCLUSION: Neoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Transcriptome analysis provides new insight into the mechanism of Bombyx mori under zinc exposure.

Zinc is a significant source of heavy metal pollution that poses risks to both human health and biodiversity. Excessive concentrations of zinc can hinder the growth and development of insects and trigger cell death through oxidative damage. The midgut is the main organ affected by exposure to heavy metals. The silkworm, a prominent insect species belonging to the Lepidoptera class and widely used in China, serves as a model for studying the genetic response to heavy metal stress. In this study, high-throughput sequencing technology was employed to investigate detoxification-related genes in the midgut that are induced by zinc exposure. A total of 11,320 unigenes and 14,723 transcripts were identified, with 553 differentially expressed genes (DEGs) detected, among which 394 were up-regulated and 159 were down-regulated. The Gene Ontology (GO) analysis revealed that 452 DEGs were involved in 18 biological process subclasses, 14 cellular component subclasses and 8 molecular functional subclasses. Furthermore, the KEGG analysis demonstrated enrichment in pathways such as Protein digestion, absorption and Lysosome. Validation of the expression levels of 9 detoxification-related DEGs through qRT-PCR confirmed the accuracy of the RNA-seq results. This study not only contributes new insights into the detoxification mechanisms mechanism of silkworms against zinc contamination, but also serves as a foundation basis for understanding the molecular detoxification processes in lepidopteran insects.

Coating seeds with biocontrol bacteria-loaded sodium alginate/pectin hydrogel enhances the survival of bacteria and control efficacy against soil-borne vegetable diseases.

Microbial seed coatings serve as effective, labor-saving, and ecofriendly means of controlling soil-borne plant diseases. However, the survival of microbial agents on seed surfaces and in the rhizosphere remains a crucial challenge. In this work, we embedded a biocontrol bacteria (Bacillus subtilis ZF71) in sodium alginate (SA)/pectin (PC) hydrogel as a seed coating agent to control Fusarium root rot in cucumber. The formula of SA/PC hydrogel was optimized with the highest coating uniformity of 90 % in cucumber seeds. SA/PC hydrogel was characterized using rheological, gel content, and water content tests, thermal gravimetric analysis, and Fourier transform infrared spectroscopy. Bacillus subtilis ZF71 within the SA/PC hydrogel network formed a biofilm-like structure with a high viable cell content (8.30 log CFU/seed). After 37 days of storage, there was still a high number of Bacillus subtilis ZF71 cells (7.23 log CFU/seed) surviving on the surface of cucumber seeds. Pot experiments revealed a higher control efficiency against Fusarium root rot in ZF71-SA/PC cucumber seeds (53.26 %) compared with roots irrigated with a ZF71 suspension. Overall, this study introduced a promising microbial seed coating strategy based on biofilm formation that improved performance against soil-borne plant diseases.

A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation.

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

Effects of soy protein isolate interaction with brown rice starch on the multiscale structure of brown rice bread.

BACKGROUND: Gluten-free bread (GFB) has technical bottlenecks such as hard texture, rough taste and low nutrition in practical production. In order to solve these problems, this study used germinated brown rice starch as the main raw material, and investigated the effects of soybean isolate protein (SPI) on the multiscale structure of germinated brown rice starch and bread quality. RESULTS: A gluten-free rice bread process simulation system was established, and the interaction between SPI and starch in the simulation system was characterized. The result shows that the interaction forces between SPI and germinated brown rice starch were mainly represented by hydrogen bonds, and with the addition of SPI, the crystallinity of starch showed a downward trend. At the same time, when the amount of SPI was 3%, the appearance quality was the best and the specific volume of bread was 1.08 mL g-1. When the amount of SPI was 6%, the texture quality was the best. Compared with the bread without SPI, the hardness of the bread with 6% SPI was reduced by 0.13 times, the springiness was increased by 0.03 times, the color was the most vibrant, the L* value being 1.02 times the original, and the baking loss was reduced to 0.98 times the original. CONCLUSIONS: The interaction force between SPI and germinated brown rice starch and its effect on bread quality were clarified, and these results inform choices about providing a theoretical basis for the subsequent development of higher-quality GFB. © 2024 Society of Chemical Industry.

Efficient RNA interference method by feeding in Brachionus plicatilis (Rotifera).

Rotifers are small, ubiquitous invertebrate animals found throughout the world and have emerged as a promising model system for studying molecular mechanisms in the fields of experimental ecology, aquatic toxicology, and geroscience. However, the lack of efficient gene expression manipulation techniques has hindered the study of rotifers. In this study, we used the L4440 plasmid with two reverse-oriented T7 promoters, along with RNase-deficient E. coli HT115, to efficiently produce dsRNA and thereby present an efficient feeding-based RNAi method in Brachionus plicatilis. We targeted Bp-Ku70 & Ku80, key proteins in the DNA double-strand breaks repair pathway, and then subjected rotifers to UV radiation. We found that the mRNA expression, fecundity, as well as survival rate diminished significantly as a result of RNAi. Overall, our results demonstrate that the feeding-based RNAi method is a simple and efficient tool for gene knockdown in B. plicatilis, advancing their use as a model organism for biological research.

Matrine-loaded self-adhesive swelling microneedle for inflammation regulation to improve eczema treatment.

Eczema is a common chronic dermatological disease. Conventional treatments exhibit limited efficacy due to fast drug release resulting in short-term relief. Development of a new treatment strategy that enables sustained drug release and long-term maintenance on the skin surface is necessary. A self-adhesive swelling microneedle patch (SDSMNs) was designed and constructed using a two-step casting method. The adhesive substrate was prepared by blending gelatin and dopamine via oxidation of NaIO4, so it could adhere onto the skin surface as well as withstand repeated bending movement without detachment. The swelling needles were fabricated using polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), which could swell by absorbing interstitial fluid and release the drug in a controlled manner. SDSMNs also showed desirable antibacterial activities toward E. coli and S. aureus. The adhesive microneedles loaded with matrine (MAT-SDSMNs), an anti-inflammatory Chinese medicine, dramatically relieved eczema symptoms through IL-17 mediated inflammation responses. The use of MAT-SDSMNs significantly decreased the infiltration of inflammation cells and level of inflammatory cytokines, reduced the skin thickness, and increased collagen deposition fraction compared with conventional ointment or subcutaneous injection. The results suggested that MAT-SDSMNs can improve eczema treatment by regulating the local inflammatory microenvironment, providing a simple, self-administered sustainable strategy for eczema treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00235-z.

[Clinical anatomy of the free latissimus dorsi myocutaneous flap and its application in the restoration of giant defects of the head and neck].

PURPOSE: To investigate the feasibility and effect of free latissimus dorsi myocutaneous flap in the reconstruction of giant head and neck defects. METHODS: Free latissimus dorsi myocutaneous flap on the cadaver was simulated dissected, and measured by Image-Pro Plus 6.0 to assess the feasibility of repairing giant head and neck defects. Between May 2011 and September 2022, seven patients with giant head and neck defects of different causes repaired with the latissimus dorsi myocutaneous flap were retrospectively analyzed. RESULTS: The diameter of the initiating thoracodorsal artery was (4.03±0.56) mm, and the mean lengths of the arteriolar and venous pedicles of the latissimus dorsi myocutaneous flaps obtained from human specimens were (85.5±10.5) mm and (104±4.2) mm, respectively. Among 7 patients, 5 cases had scalp defects, the remaining 2 cases had neck defects. There were no substantial postoperative problems in the donor site, and all seven latissimus dorsi myocutaneous flaps were successfully transplanted. CONCLUSIONS: For the treatment of considerable head and neck deformities, the latissimus dorsi myocutaneous flap is an optimal muscle flap due to its abundance of tissue, enough length of vascular pedicles, and sufficient venous drainage.

Bacterial infection-biased abundance of proteins in the skin mucus of obscure puffer (Takifugu Obscurus).

The skin mucus of fish is equipped with immunological and antimicrobial peptides that confer protection against invading pathogens. The skin mucus has been studied in fish however information regarding its immunological roles in bacterial infection is rare. This study highlighted the proteins and peptides in the skin mucus of Obscure puffer Takifugu obscurus that quantitatively altered against Aeromonas hydrophila infection. We infected the fish through bath immersion, intraperitonially, and treated with PBS (control) then compared the level of proteins in the skin mucus among the groups using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The Tandem Mass Tag (TMT) based quantification showed that 4896 proteins were Deferentially Quantified Proteins (DQPs), based on 19,751 unique peptides. Of which 170 were depleted (decreased in abundance) and 69 were abundant in comparison of Bath Treated (BT) vs Control (C) groups. Similarly, 76 DQPs were depleted and 70 were abundant in comparison of Treated (T) vs BT groups. Further, 126 DQPs were depleted, and 34 were abundant in comparison to T vs C groups. The DQPs we report were mostly immunological and were involved in unique biological functions and pathways. The interesting protein we report, where some of the proteins are for the first time in fish, shows the protein-rich structure of the mucus of fish, which may act as a biomarker to be targeted for bacterial disease therapy in fish and ultimately hint to the way of making resistance in fish against bacterial pathogens.

Bioequivalence study of two formulations of afatinib dimaleate tablets in healthy subjects under fasting conditions: A randomized, open-label, single-dose, crossover trial.

OBJECTIVE: To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles. MATERIALS AND METHODS: This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120 hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit. RESULTS: Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC0-t, 90.26 - 105.52% for Cmax, and 93.49 - 104.05% for AUC0-∞. CONCLUSION: The 90% CI for the geometric mean ratios (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.

Female-specific association between the APOE E4 allele and age at diagnosis of glaucoma in UK Biobank.

OBJECTIVE: To explore the impact of the apolipoprotein E (APOE) E4 allele in the gender-specific aging process in glaucoma by illustrating the interaction between risk factors, including the APOE E4 allele, gender and intraocular pressure (IOP), for age at diagnosis (AAD) of glaucoma. DESIGN: A cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis. Data were analyzed in December 2023. PARTICIPANTS: 2,236 glaucoma patients and 103,232 controls. METHODS: We evaluated multivariable-adjusted associations of AAD of glaucoma, APOE E4 allele (0: absence; 1: presence), and IOP using linear mixed model (LMM) analyses across groups stratified by AAD of mean age of menopause (50 years) and gender. MAIN OUTCOMES MEASURES: AAD of glaucoma, APOE E4 allele and IOP. RESULTS: Glaucoma patients were older and had a higher percentage of males and a higher mean IOP compared to controls (all P < 0.001). Further stratifying the glaucoma patients by AAD of 50 and gender, lower IOP (Model 1 adjusted by age, ßIOP=-0.096±0.041, P=0.019) and positive APOE E4 allele (Model 2 adjusted by age and IOP, ße4=1.093±0.488, P=0.026) were associated with an older AAD in females with an AAD < 50 years under univariate LMM. In multivariate LMM adjusted by age (Model 3), the effect size of both factors increased in the multivariate model as the beta-value increased. (ßIOP=-0.111±0.040, P=0.007; ße4=1.235±0.485, P=0.012) (Model 1 vs Model 3: P=0.011). In females with an AAD ≥50 years, only positive APOE E4 allele (adjusted by age and IOP, ße4=-1.121±0.412, P=0.007) was associated with a younger AAD. In males, only higher IOP was associated with an older AAD in those with an AAD ≥50 years (ßIOP=0.088±0.032, P=0.006). CONCLUSIONS: APOE E4 allele may initially delay and later accelerate the development of glaucoma in females around the transition period of 50 years, which is the mean age of menopause, and importantly, this is independent of IOP. Understanding the specific transition states and modifiable factors within each age phase is crucial for developing interventions or strategies that promote healthy aging.

Fucoxanthin Inhibits the Proliferation and Metastasis of Human Pharyngeal Squamous Cell Carcinoma by Regulating the PI3K/Akt/mTOR Signaling Pathway.

Human pharyngeal squamous cell carcinoma (HPSCC) is the most common malignancy in the head and neck region, characterized by high mortality and a propensity for metastasis. Fucoxanthin, a carotenoid isolated from brown algae, exhibits pharmacological properties associated with the suppression of tumor proliferation and metastasis. Nevertheless, its potential to inhibit HPSCC proliferation and metastasis has not been fully elucidated. This study represents the first exploration of the inhibitory effects of fucoxanthin on two human pharyngeal squamous carcinoma cell lines (FaDu and Detroit 562), as well as the mechanisms underlying those effects. The results showed dose-dependent decreases in the proliferation, migration, and invasion of HPSCC cells after fucoxanthin treatment. Further studies indicated that fucoxanthin caused a significant reduction in the expression levels of proteins in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, as well as the downstream proteins matrix metalloproteinase (MMP)-2 and MMP-9. Specific activators of PI3K/AKT reversed the effects of fucoxanthin on these proteins, as well as on cell proliferation and metastasis, in FaDu and Detroit 562 cells. Molecular docking assays confirmed that fucoxanthin strongly interacted with PI3K, AKT, mTOR, MMP-2, and MMP-9. Overall, fucoxanthin, a functional food component, is a potential therapeutic agent for HPSCC.

How to trace etomidate in illegal E-cigarettes from authentic human hair: identification, quantification and multiple-factor analysis.

PURPOSE: The abusive consumption of illegal E-cigarettes containing etomidate (ET) can have a significant impact on public mental and physical well-being. The purpose of this study is to establish a rapid quantitative method using ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) for the targeted screening of etomidate (ET) and its metabolite etomidate acid (ETA) in hair samples. METHODS: A 1 mL methanol solution containing the internal standard ET-d5 at a concentration of 50 pg/mg was added to 20 mg of hair and milled below 4 °C. After centrifugation, 5 µL of the supernatant was injected into a UHPLC-MS/MS system. RESULTS: The limit of detection (LOD) and limit of quantification (LOQ) were determined to be 1 pg/mg and 10 pg/mg, respectively, for ET, and 10 pg/mg and 25 pg/mg, respectively, for ETA. Calibration curves for all analytes showed good linearity (r > 0.997), indicating a reliable method. Accuracies were between 92.12% and 110.72%. Intra-day and inter-day precision for all analytes at all concentration levels were below 10.13%. Analyte recoveries ranged from 86.90% to 101.43%, with a matrix effect ranging from -18.55% to -14.93%. CONCLUSIONS: The validated method was successfully used to analyze 105 hair samples from suspected ET users. Of these, 50 tested positive for ET and 43 tested positive for ETA above the LOQ. This demonstrates the effectiveness of the developed UHPLC-MS/MS method in detecting ET and ETA in hair samples, which could be instrumental in addressing the issue of illegal E-cigarette abuse and its impact on public health.