Gut microbiota-astrocyte axis: new insights into age-related cognitive decline.

With the rapidly aging human population, age-related cognitive decline and dementia are becoming increasingly prevalent worldwide. Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota, microbial metabolites, and the functions of astrocytes. The microbiota-gut-brain axis has been the focus of multiple studies and is closely associated with cognitive function. This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases. This article also summarizes the gut microbiota components that affect astrocyte function, mainly through the vagus nerve, immune responses, circadian rhythms, and microbial metabolites. Finally, this article summarizes the mechanism by which the gut microbiota-astrocyte axis plays a role in Alzheimer's and Parkinson's diseases. Our findings have revealed the critical role of the microbiota-astrocyte axis in age-related cognitive decline, aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.

Single-cell RNA Sequencing Identifies a Novel Subtype of Microglia with High Cd74 Expression that Facilitates White Matter Inflammation During Chronic Cerebral Hypoperfusion.

Vascular dementia (VaD) causes progressive cognitive decline in the elderly population, but there is short of available therapeutic measures. Microglia-mediated neuroinflammation is vigorously involved in the pathogenesis of VaD, but the traditional classification of microglial M1/M2 phenotypes remains restrictive and controversial. This study aims to investigate whether microglia transform into novel subtypes in VaD. Chronic cerebral hypoperfusion (CCH) rat model was constructed to mimic VaD. Microglia were isolated via magnetic-activated cell sorting and analyzed by single-cell RNA sequencing (scRNA-seq) and bioinformatics. The findings inferred from scRNA-seq and bioinformatics were further validated through in vivo experiments. In this study, microglia were divided into eight clusters. The proportion of MG5 cluster was significantly increased in the white matter of the CCH group compared with the Sham group and was named chronic ischemia-associated microglia (CIAM). Immunity- and inflammation-related genes, including RT1-Db1, RT1-Da, RT1-Ba, Cd74, Spp1, C3, and Cd68, were markedly upregulated in CIAM. Enrichment analysis illustrated that CIAM possessed the function of evoking neuroinflammation. Further studies unveiled that Cd74 is associated with the most abundant GO terms involved in inflammation as well as cell proliferation and differentiation. In addition, microglia-specific Cd74 knockdown mediated by adeno-associated virus decreased the abundance of CIAM in the white matter, thereby mitigating inflammatory cytokine levels, alleviating white matter lesions, and improving cognitive impairment for CCH rats. These findings indicate that Cd74 is the core molecule of CIAM to trigger neuroinflammation and induce microglial differentiation to CIAM, suggesting that Cd74 may be a potential therapeutic target for VaD.

Propofol Protects the Blood-Brain Barrier After Traumatic Brain Injury by Stabilizing the Extracellular Matrix via Prrx1: From Neuroglioma to Neurotrauma.

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs.

Impact and implications of national centralized drug procurement in China.

The national centralized drug procurement (NCDP) policy, known as the "4 + 7" policy in China, has transformed pharmaceutical procurement and access by leveraging healthcare institutions' collective buying power to reduce drug prices substantially. This policy has profoundly impacted drug pricing mechanisms, healthcare expenditures, market dynamics, and the quality of available drugs. This commentary evaluates the efficacy, challenges, and broader implications of the NCDP, summarizes the current state of post-marketing monitoring of selected generic drugs for centralized procurement, and presents relevant considerations.

The evaluation and enhancement strategies of core competencies for older adult caregivers in integrated medical and older adult care institutions.

The study aimed to understand the main skills of older adult caregivers and find ways to improve these skills. We selected participants using a method called random cluster sampling, where caregivers from 17 different medical and nursing care facilities across seven districts in Hangzhou were chosen. We collected 492 valid questionnaires and conducted interviews with 150 people. To analyze the data, we used T-tests and Analysis of Variance (ANOVA) to identify what factors affect caregivers' skills. We also performed multiple regression analysis to explore these factors in more depth. The analysis showed that age (p = 0.041), annual income (p < 0.001), and having a training certificate (p < 0.001) significantly influence the skills of older adult caregivers. Specifically, caregivers' age and whether they had a training certificate were linked to how competent they were, with income being a very strong factor. The study highlighted a gap between the caregivers' current skills and the skills needed for high-quality care. This gap shows the need for training programs that are specifically tailored to the caregivers' diverse needs and cultural backgrounds. Medical and eldercare facilities should adjust their work and educational programs accordingly. It's also important to look at how caregivers are paid to make sure their salary reflects their skills and the quality of care they provide. Finally, it's crucial to integrate a comprehensive training program that leads to certification within eldercare organizations.

Effect of Efavirenz on the Pharmacokinetics of SHR6390 in Healthy Volunteers.

Purpose: SHR6390 is an oral, potent and selective small-molecule CDK4/6 inhibitor for the treatment of human breast, ovarian and colon cancer. Previous studies have shown that SHR6390 in combination with rifampicin, a potent inducer of CYP3A4, significantly reduces exposure levels. Therefore, we further investigated the effect of efavirenz, a moderate CYP3A4 inducer, on a single oral dose of SHR6390 in healthy volunteers. Patients and Methods: Twenty healthy subjects were enrolled in this single-center, open, single-dose, self-controlled DDI study. On Day 1, subjects received a single oral dose of 150mg SHR6390; on Day 8-26, subjects received 600 mg efavirenz orally at night, with a single dose of 150 mg SHR6390 on Day 22. Blood samples for pharmacokinetic analyses were collected. Results: The geometric mean ratios of the maximum concentration(Cmax) and the area under the concentration curve from zero to infinity (AUC0-inf) between combination therapy and SHR6390 monotherapy (combination therapy/SHR6390 monotherapy) and their 90% confidence intervals were 0.562 (0.482, 0.654) and 0.328 (0.278, 0.386), respectively. This indicates that the Cmax and AUC0 inf of SHR6390 decreased by approximately 43.8% and 67.2%, respectively. Oral administration of 150 mg SHR6390 alone or together with efavirenz was safe and tolerable in healthy subjects. Conclusion: It is suggested that under the action of the moderate CPY3A4 inducer efavirenz, the exposure AUC of SHR6390 exhibits a moderate level of induction. It is recommended to avoid concomitant administration of moderate inducers of CYP3A4 during treatment with SHR6390. Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20211571/ https://classic.clinicaltrials.gov, NCT04973020.

Effects of Transglutaminase-Induced ß-Conglycinin Gels on Intestinal Morphology and Intestinal Flora in Mice at Different High-Intensity Ultrasound Pretreatment Time.

TGase-7S gels prepared after different HIU pretreatment times were used to intervene in healthy mice to analyze their effects on growth characteristics and intestinal morphology, and 16S rRNA high-throughput sequencing was applied to fecal samples to investigate the effects of the gel on the structure and diversity of intestinal flora in mice. The results showed that the intestinal tissues of mice in different treatment groups showed better integrity, and the intake of gel increased the length of small intestinal villi in mice, among which the 30-gel group had the highest value of villi length (599.27 ± 44.28) µm (p < 0.05) and showed the neatest and tightest arrangement, indicating that the intake of gel did not have adverse effects on the intestinal tract. The effect of gel ingestion on the diversity of the intestinal microbial community structure was more significant, positively promoting the growth of beneficial bacteria such as Desferriobacterium, Synechococcus, and Bifidobacterium. In addition, the ingestion of the gel improved the intestinal health of mice by altering the physiological functions of the intestinal flora and modulating their participation in various metabolic pathways. The above findings provide some theoretical value for the safety of 7S gel in food applications.

Self-assembled flower-like carbon nanosheets for magnetic solid-phase extraction of microcystins from aquatic organism.

Adsorbents with good dispersibility and high efficiency are crucial for magnetic solid-phase extraction (MSPE). In this study, flower-like magnetic nanomaterials (F-Ni@NiO@ZnO2-C) were successfully prepared by calcination of metal-organic framework (MOF) precursors that was stacked by two-dimensional (2D) nanosheet. The synthesized F-Ni@NiO@ZnO2-C has a flower-like layered structure with a large amount of pore space, promoting the rapid diffusion of targets. In addition, Zn2+ doped in MOF precursors was still retained that further produced strong metal chelation with targets. The unique structure of F-Ni@NiO@ZnO2-C was used as MSPE adsorbent, and combined with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for extraction of three microcystins (MCs) detection, including microcystin-LR (MC-LR), microcystin-RR (MC-RR), microcystin-YR (MC-YR). The resulting method has a detection limit of 0.2-1.0 pg mL-1, a linear dynamic range of 0.6-500.0 pg mL-1 and has good linearity (R ≥ 0.9996). Finally, the established method was applied to the highly selective enrichment of MCs in biological samples, successfully detecting trace amounts of MCs (8.4-15.0 pg mL-1) with satisfactory recovery rates (83.7-103.1 %). The results indicated that flower-like magnetic F-Ni@NiO@ZnO2-C was a promising adsorbent, providing great potential for the determination of trace amounts of MCs in biological samples.

Mechanistic insights into sulfadimethoxine degradation via microbially driven Fenton reactions.

Biodegradation, while cost-effective, is hindered by the requirement for specialized microorganisms and co-contaminants. Innovative biological technologies like the microbially driven Fenton reaction, hold promise for enhancing degradation efficiency. However, the intricate biochemical processes and essential steps for effective degradation in such systems have remained unclear. In this study, we harnessed the potential of the microbially driven Fenton reaction by employing Shewanella oneidensis MR-1 (MR-1). Our approach showcased remarkable efficacy in degrading a range of contaminants, including sulfadimethoxine (SDM), 4,4'-dibromodiphenyl ether (BDE-15) and atrazine (ATZ). Using SDM as a model contaminant of emergent contaminants (ECs), we unveiled that biodegradation relied on the generation of hydroxyl radicals (•OH) and involvement of oxidoreductases. Transcriptomic analysis shed light on the pivotal components of extracellular electron transfer (EET) during both anaerobic and aerobic periods. The presence of reactive oxidizing species induced cellular damage and impeded DNA repair, thereby affecting the Mtr pathway of EET. Moreover, the formation of vivianite hindered SDM degradation, underscoring the necessity of maintaining iron ions in the solution to ensure sustainable and efficient degradation. Overall, this study offers valuable insights into microbial technique for ECs degradation, providing a comprehensive understanding of degradation mechanisms during aerobic/anaerobic cycling.

Directional Femoral Ultrasound-Guided Compression Technique Using in Percutaneous Mechanical Thrombectomy for Acute Deep Vein Thrombosis: A Retrospective Cohort Study.

OBJECTIVE: The study aimed to investigate the early results of directional femoral ultrasound-guided compression technique (UCT) using in percutaneous mechanical thrombectomy (PMT) for acute deep vein thrombosis (DVT). METHODS: Consecutive single-center patients with acute iliofemoral DVT who underwent PMT from January 2020 to December 2021 were included. Directional femoral UCT was used to adjust the PMT catheter into the residual thrombus in the inguinal region by ultrasound compression to improve the thrombus clearance rate. Patients were retrospectively analyzed and divided into 2 groups based on PMT with or without directional femoral UCT. The primary efficacy outcome was the incidence of post-thrombotic syndrome (PTS) at 24-month follow-up. The secondary efficacy outcomes included common femoral venous thrombus removal grade, total thrombus removal grade, venous primary patency rate, and incidence of moderate-to-severe PTS at 24-month follow-up. The safety outcomes included complications, major bleeding events, and death at 24-month follow-up. RESULTS: A total of 96 patients were included in the study: 42 patients underwent PMT with directional femoral UCT and 54 patients underwent PMT without UCT. There was no significant difference in baseline characteristics between the 2 groups. The percentages of patients achieved common femoral venous thrombus removal grade 3 and total thrombus removal grade 3 were significantly higher in the PMT with UCT group than those in the PMT without UCT group (p<0.001). The 24-month primary patency rate was significantly higher in the PMT with UCT group than that in the PMT without UCT group (90.0% vs 71.2%, p=0.027). The incidence of PTS was significantly lower in the PMT with UCT group (10.0%) than that in the PMT without UCT group (28.8%) (p=0.027). CONCLUSION: PMT with directional femoral UCT could improve the thrombus clearance rate and primary patency rate of acute iliofemoral DVT and might decrease the incidence of PTS compared to traditional PMT treatment without UCT. CLINICAL IMPACT: Residual thrombus in common femoral vein is a difficult problem associated with higher incidence of PTS. Few studies have focused on common femoral venous thrombus clearance. PMT with directional femoral UCT could improve the thrombus clearance rate and primary patency rate of acute iliofemoral DVT, and might decrease the incidence of PTS compared to traditional PMT treatment without UCT. Directional femoral UCT is recommended in PMT treatment of acute iliofemoral DVT.

Effects of orthokeratology on corneal reshaping and the delaying of axial eye growth in children.

Purpose: To investigate the inhibition of myopia progression and axial elongation in children wearing orthokeratology (OK) lenses, as well as to evaluate the status of corneal reshaping, this study explores the relationship between changes in central corneal curvature (K-value) and e-value induced by OK lenses and axial elongation. Methods: In this study, it is planned to select children aged 8-15 who wear orthokeratology lenses at the Pediatric Ophthalmology and Strabismus Clinic of the Second Affiliated Hospital of Dalian Medical University. All children will undergo slit lamp examination, visual acuity assessment, computerized refraction, intraocular pressure measurement, biometry, and corneal topography examination before lens wear and at 1 month, 3 months, and 6 months after lens wear in the pediatric ophthalmology clinic. Based on age (lower age group (8 < age ≤12 years); higher age group (12 < age ≤15 years)) and baseline equivalent spherical (SE) value (mild myopia group (-1.00 D < SE ≤ -3.25D); moderate myopia group (-3.25 D < SE ≤ -6.00 D)), four groups will be formed by pairing these factors. Suitable data will be selected according to inclusion and exclusion criteria, and different groups will be included. Data will be organized, and statistical analysis will be performed using SPSS software to obtain the results. The expected results will be discussed and analyzed. Results: After wearing OK lenses, all four groups achieved good visual acuity at follow-up. At 6 months, there were no significant differences in visual acuity among the four groups (P = 0.149, >0.05). There were no significant differences in refractive error among the four groups (P = 0.066, >0.05). Baseline axial length differed significantly among the four groups (P = 0.000, <0.001), with the LM group having longer axial length than the LL group (P < 0.001, paired samples t-test), and the HM group having longer axial length than the HL group (P < 0.001, paired samples t-test). However, there were no significant differences in axial length change compared to baseline among the groups at 1 month, 3 months, and 6 months (P 1 = 0.053; P 3 = 0.557; P 6 = 0.329, >0.05). Significant differences were observed in corneal flat K-value change compared to baseline among the four groups at 1 month, 3 months, and 6 months (P 1 = 0.001, P 3 = 0.001, P 6 = 0.004, <0.05). There were no significant differences in e-value change among the groups at 1 and 3 months (P 1 = 0.205, P 3 = 0.252, >0.05), but significant differences were found in e-value change compared to baseline at 6 months (P 6 = 0.010, <0.05). Multiple regression analysis with changes in central corneal flat K-value and e-value as independent variables and axial elongation as the dependent variable showed a correlation between e-value change at 6 months and axial elongation (P = 0.004, <0.05), indicating a negative correlation. Conclusion: Orthokeratology (OK) lenses effectively improve myopic children's vision by reshaping the cornea, leading to reduced central corneal curvature and flattening of its anterior surface. The effectiveness of OK lenses is not significantly affected by age or initial myopia severity. Children of varying ages and myopia levels experience similar levels of axial length control with OK lens wear. Changes in corneal shape due to OK lenses affect axial elongation, with greater changes in corneal morphology associated with smaller increases in axial length.

Effect of primary osteoblast-derived extracellular vesicles on osteoclast differentiation. / åŽŸä»£æˆéª¨ç»†èƒžæ¥æºçš„ç»†èƒžå¤–å›Šæ³¡å¯¹ç ´éª¨ç»†èƒžåˆ†åŒ–çš„å½±å“.

OBJECTIVES: To investigate the effect of osteoblast-derived extracellular vesicles (OB-EVs) on the proliferation and differentiation of osteoclasts, and to explore the possible molecular mechanism of extracellular vesicles involved in the communication between osteoblasts and osteoclasts, and to elucidate the specific mechanism of extracellular vesicles interfering with alveolar bone homeostasis. METHODS: Primary osteoblasts were isolated from newborn mouse calvarial bone and induced by dexamethasone, ß glycerin phosphate and ascorbic acid. Osteogenic feature was tested by alkaline phosphatase (ALP) and alizarin red S staining. Extracellular vesicles were isolated by ultracentrifugation from the supernatant of cell culture. The vesicle morphology was observed by transmission electron microscopy, and the characteristic markers of tumor susceptibility gene 101 (TSG101), ALG-2 interacting protein X (Alix) and cluster of differentiation 9 (CD9) on the surface of extracellular vesicles were identified by Western blotting. Cell counting kit 8 (CCK-8) assay was used to determine the proliferation effect of OB-EVs on mouse mononuclear macrophage RAW264.7 cells. Furthermore, the expression level of specific markers of osteoclast differentiation in RAW264.7 cells was detected by Western blotting after the combined effect of OB-EVs and nuclear factor kappa B receptor activating factor ligand (RANKL). The number of osteoclasts was observed and compared with OB-EVs-treated mouse bone marrow-derived macrophages (BMMs) by tartrate-resistant acid phosphatase (TRAP) staining, and the effect of OB-EVs on osteoclast differentiation was determined. RESULTS: The extracted OB-EVs showed a double-layer cup-like structure with a diameter of 30-150 nm, and TSG101, Alix and CD9 were positively expressed. RAW264.7 cells were stimulated with OB-EVs, and the results of CCK-8 assay showed that high concentration of OB-EVs (more than 20 µg/mL) inhibited cell proliferation (P<0.05). Western blot analysis showed that the expression of osteoclast differentiation marker proteins such as c-Fos, activated T cell nuclear factor (NFATc1) and c-Jun N-terminal kinase (JNK) in RAW264.7 cells was significantly increased, and the promoting effect was enhanced with the increase of OB-EVs concentration (P<0.05). In addition, the combination of OB-EVs and RANKL on BMM showed that the number of TRAP-positive cells was significantly higher than that of the RANKL induction group alone (P<0.05). CONCLUSIONS: High concentration of OB-EVs can inhibit the proliferation of RAW264.7 cells, and OB-EVs can promote the differentiation of osteoclast precursor cells into osteoclasts.

Patients' perceptions matter: Risk communication and psychosocial factors in orthodontics.

INTRODUCTION: Effective risk communication is essential for achieving patient-centered oral health care, but the limited understanding of patients' subjective perceptions of orthodontic-related risks hinders this process. This study aimed to investigate adults' awareness, concerns, and risk-avoidance behaviors about long-term orthodontic risks, exploring their relationship with psychosocial factors. METHODS: We included 498 adult patients (mean age, 27.3 ± 6.8 years; women, 75.5%) during their initial visits to the orthodontic department at a hospital in Chengdu, China. Participants' understanding of orthodontic risks was gauged before and after exposure to the Oral Health Education Comics (OHEC), a specifically designed digital tool. Concurrently, we used logistic regression models to investigate the associations between patients' depression, anxiety, self-esteem, perfectionism, and dentofacial esthetics with risk perceptions. RESULTS: Approximately 79.5% of participants initially reported low awareness of orthodontic risks, with most knowledge from online sources. Notably, the percentage of participants with high awareness increased to 64.8% after OHEC. The negative facial soft-tissue change was most concerning for participants: 53.4% showed high concerns, and 28.1% showed high avoidance. Furthermore, linear regression indicated positive associations between depression (ß = 0.42 [95% confidence interval {CI}, 0.07-0.77]) and anxiety (ß = 0.76 [95% CI, 0.35-1.18]) with orthodontic risk concerns, whereas risk avoidance was positively associated with depression (ß = 0.62 [95% CI, 0.27-0.97]), anxiety (ß = 1.09 [95% CI, 0.68-1.50]), and perfectionism (ß = 0.24 [95% CI, 0.02-0.46]). CONCLUSIONS: Findings emphasize the imperative of streamlined risk communication in orthodontics. By incorporating comprehensible tools such as OHEC and integrating psychosocial evaluations, more refined patient-practitioner communication and psychosomatic-based dental care can be achieved.

Effects of mixed enzymolysis alone or combined with acetylation or carboxymethylation on the role of jujube kernel fibre as a biosorbent for wastewater treatment.

Jujube kernel fibre (JKF) could serve as a renewable, abundant, low-cost, and environmentally friendly adsorbent for wastewater if its adsorption capacities are improved. However, data on the modification of JKF, especially on the combination of biological and chemical modifications, are scarce. Therefore, for the first time, we studied the effect of mixed enzymolysis alone or combined with acetylation or carboxymethylation on the structure and adsorption capacities of JKF. After these modifications, the microstructure of JKF became more porous, and its soluble fibre and extractable polyphenol contents, surface area and adsorption capacities for nitrite, copper, and lead ions were all significantly improved (P < 0.05). Meanwhile, mixed enzymatic hydrolysis and acetylation treated JKF showed the highest surface hydrophobicity (43.57) and oil-adsorption ability (4.47 g g-1), while mixed enzymatic hydrolysis and carboxymethylation treated JKF exhibited the highest water adsorption ability (10.66 g g-1), water expansion ability (8.50 mL g-1), and lead and copper ion chelating abilities. Additionally, mixed enzymatic hydrolyzed JKF had the highest nitrite-ion-adsorption ability (10.57 µmol g-1). It can be concluded that mixed enzymolysis combined with carboxymethylation is an optimal way to increase the hydration properties and heavy-metal-adsorption capacity of JKF, while mixed enzymolysis combined with acetylation is an effective approach to enhance the oil-adsorption capacity of JKF.

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer.

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

The mysteries of pharmacokinetics and in vivo metabolism of Oroxylum indicum (L.) Kurz: A new perspective from MSOP method.

The pharmacological effects of flavonoids in Oroxylum indicum (L.) Kurz against inflammation, bacterial, and oxidation have been well-documented. Additionally, it is commonly consumed as tea. However, the in vivo mechanism of its main compounds has not been well elucidated. In this study, a highly selective and sensitive UHPLC-Q-TOF-MS method combined with Mass Spectrum-based Orthogonal Projection (MSOP) theory and four-step analytical strategy was established and validated to identify metabolites in rats following oral administration Oroxylum indicum (L.) Kurz extract. Furthermore, a sensitive LC-MS/MS method was developed and validated for the first time to analyze the pharmacokinetics of ten main flavonoids in rats. Notably, a total of 47 metabolites were identified in blood, bile, urine, and feces samples. The maximum plasma concentration (Cmax) values for oroxin A, oroxin B, baicalin, chrysin, baicalein, scutellarein, apigenin, quercetin oroxylin A and isorhamnetin were 2945.1 ± 11.23 ng/mL, 3123.9 ± 16.37 ng/mL, 130.40 ± 27.52 ng/mL, 117.20 ± 28.54 ng/mL, 64.12 ± 19.33 ng/mL, 97.22 ± 24.27 ng/mL, 145.22 ± 29.92 ng/mL, 45.19 ± 18.84 ng/mL, 67.32 ± 15.78 ng/mL and 128.44 ± 26.42 ng/mL. A double peak was observed in the drug-time curve of apigenin, due to enterohepatic recirculation. This study demonstrated that MSOP method provided more technical support for the identification of flavonoid metabolites in complex system than traditional methods.

Tension Induced Photoluminescence Enhancement in an Organic Single Crystal.

Organic single crystals possess distinct advantages due to their highly ordered molecular structures, resulting in improved stability, enhanced carrier mobility, and superior optical characteristics. However, their mechanical rigidity and brittleness impede the applications in flexible and wearable optoelectronic devices. Here, photoluminescence (PL) emission from 2,6-diphenylanthracene (DPA) single crystals is studied under tensile strain, which shows PL enhancement by more than two times with a strain of ≈1.42%. Such a tension induced PL enhancement is reversible, exhibiting no clear optical degradations during 100 cycles of bending and recovery processes. Theoretical calculations reveal that the deformation of molecular structure under strain induces a decrease of the dihedral between anthracene and benzene moieties in DPA molecules. Further, the increased molecular conjugation enhances the molecular oscillator strength, leading to the brightened PL emission. Meanwhile, with the decreased dihedral, the molecular vibrations in DPA crystals are suppressed, which can reduce the non-radiative decay rate. In contrast, no tension induced PL enhancement is observed in polycrystalline DPA thin films as the strain can be released via the grain boundaries. This study highlights the superior optical performance of DPA single crystals under strain field, which will provide new possibilities for DPA-based flexible devices.

Hospice Enrollment and Central Nervous System-Active Medication Prescribing to Medicare Decedents with Dementia.

This study explores the extent to which hospice enrollment is associated with CNS­active medication exposure among Medicare decedents with Alzheimer disease and related dementias.

Multi-omics reveals the molecular mechanism of muscle quality changes in common carp (Cyprinus carpio) under two aquaculture systems.

Preliminary experiments in our laboratory have demonstrated that common carp (Cyprinus carpio) cultivated for two months in land-based container recirculating aquaculture systems (C-RAS) exhibit superior muscle quality compared to those raised in traditional pond systems (TP). To elucidate the molecular mechanisms underlying muscle quality variations in common carp cultured under two aquaculture systems, transcriptomic and metabolomic analyses were performed on muscle tissues of specimens aged 11 to 23 months. Comparison of muscle histological sections between the two groups indicated a significantly lower long diameter of muscle fibers in the C-RAS group compared to the TP group (P < 0.01). Conversely, the muscle fiber density was significantly higher in the C-RAS group than in the TP group (P < 0.05). Transcriptomic and metabolomic analyses identified 3390 differentially expressed genes (DEGs)-1558 upregulated and 1832 downregulated-and 181 differentially expressed metabolites (DEMs)-124 upregulated and 57 downregulated-between the groups. Based on integrated transcriptomic and metabolomic analyses, the significant differences focus on metabolic pathways involving glycolysis/gluconeogenesis, arginine and proline metabolism, arginine biosynthesis, and purine metabolism. The study revealed that the muscle quality of common carp in two aquaculture systems is primarily regulated through improvements in energy metabolism, amino acid metabolism, fatty acid metabolism, and purine metabolism. These metabolic processes play significant roles in promoting muscle fiber hyperplasia and hypertrophy, enhancing muscle flavor, and increasing muscle antioxidant capacity. This study provides new insights into the molecular and metabolic pathways that control muscle quality in common carp under different environmental factors.

The development of 177Lu-DOTA-CC-PSMA following a unified "Click Chemistry" protocol of synthesizing metal nuclide-conjugated radiopharmaceuticals.

BACKGROUND: Currently, the synthesis pathway of metal nuclide-labeled radiopharmaceuticals is mainly divided into two steps: first, connecting the chelator with the target molecule, and second, labeling the metal nuclide to the chelator. However, the second step of the reaction to label the metal nuclide requires high temperature (90-100 °C), which tends to denature and inactivate the target molecule, leading to loss of biological activities, especially the targeting ability. A feasible solution may be the click chemistry labeling method, which consists of reacting a metal nuclide with a chelating agent to generate an intermediate and then synthesizing a radiopharmaceutical agent via the click chemistry intermediate and the target molecule-alkyne compound. In this study, through the click chemistry of 177Lu-DOTA-N3 with prostate-specific membrane antigen (PSMA)-alkyne compound, 177Lu-labeled PSMA-targeted molecular probe was synthesized and evaluated for its potential to be cleared from the bloodstream and rapidly distributed to tissues and organs, achieving a high target/non-target ratio. 177Lu-PSMA-617 was utilized as an analogue for comparison in terms of synthesizing efficiency and PSMA-targeting ability. RESULTS: A novel 177Lu-labeled PSMA radioligand was successfully synthesized through the click chemistry of 177Lu-DOTA-N3 with PSMA-alkyne compound, and abbreviated as 177Lu-DOTA-CC-PSMA, achieving a radiochemical yield of 77.07% ± 0.03% (n = 6) and a radiochemical purity of 97.62% ± 1.49% (n = 6) when purified by SepPak C18 column. Notably, 177Lu-DOTA-CC-PSMA was characterized as a hydrophilic compound that exhibited stability at room temperature and commendable pharmacokinetic properties, such as the superior uptake (19.75 ± 3.02%ID/g at 0.5 h) and retention (9.14 ± 3.16%ID/g at 24 h) within xenografts of 22Rv1 tumor-bearing mice. SPECT/CT imaging indicated that radioactivity in both kidneys and bladder was essentially eliminated after 24 h, while 177Lu-DOTA-CC-PSMA was further enriched and retained in PSMA-expressing tumors, resulting in the high target/non-target ratio. CONCLUSION: This study demonstrated the potential of click chemistry to unify the synthesis of metal radiopharmaceuticals, and 177Lu-DOTA-CC-PSMA was found for rapid clearance and appropriate chemical stability as a PSMA-targeted radioligand.