Inverted Sandwich-Type e-LCR Aided by Lambda Exonuclease-RecJf Combination Enables Ultrasensitive Detection of Low-Frequency EGFR-L858R Mutation in NSCLC.

Highly sensitive detection of low-frequency EGFR-L858R mutation is particularly important in guiding targeted therapy of nonsmall-cell lung carcinoma (NSCLC). To this end, a ligase chain reaction (LCR)-based electrochemical biosensor (e-LCR) with an inverted sandwich-type architecture was provided by combining a cooperation of lambda exonuclease-RecJf exonuclease (λ-RecJf exo). In this work, by designing a knife-like DNA substrate (an overhang ssDNA part referred to the "knife arm") and introducing the λ-RecJf exo, the unreacted DNA probes in the LCR were specially degraded while only the ligated products were preserved, after which the ligated knife-like DNA products were hybridized with capture probes on the gold electrode surface through the "knife arms", forming the inverted sandwich-type DNA structure and bringing the methylene blue-label close to the electrode surface to engender the electrical signal. Finally, the sensitivity of the e-LCR could be improved by 3 orders of magnitude with the help of the λ-RecJf exo, and due to the mutation recognizing in the ligation site of the employed ligase, this method could detect EGFR-L858R mutation down to 0.01%, along with a linear range of 1 fM-10 pM and a limit detection of 0.8 fM. Further, the developed method could distinguish between L858R positive and negative mutations in cultured cell samples, tumor tissue samples, and plasma samples, whose accuracy was verified by the droplet digital PCR, holding a huge potential in liquid biopsy for precisely guiding individualized-treatment of NSCLC patients with advantages of high sensitivity, low cost, and adaptability to point-of-care testing.

De novo mutations promote inflammation in children with STAT3 gain-of-function syndrome by affecting IL-1ß expression.

STAT3 gain-of-function syndrome, characterized by early-onset autoimmunity and primary immune regulatory disorder, remains poorly understood in terms of its immunological mechanisms. We employed whole-genome sequencing of familial trios to elucidate the pivotal role of de novo mutations in genetic diseases. We identified 37 high-risk pathogenic loci affecting 23 genes, including a novel STAT3 c.508G>A mutation. We also observed significant down-regulation of pathogenic genes in affected individuals, potentially associated with inflammatory responses regulated by PTPN14 via miR378c. These findings enhance our understanding of the pathogenesis of STAT3 gain-of-function syndrome and suggest potential therapeutic strategies. Notably, combined JAK inhibitors and IL-6R antagonists may offer promising treatment avenues for mitigating the severity of STAT3 gain-of-function syndrome.

Response Properties of Electrorheological Composite Hydrophilic Elastomers Based on Different Morphologies of Magnesium-Doped Strontium Titanate.

As smart materials, electrorheological elastomers (EREs) formed by pre-treating active electrorheological particles are attracting more and more attention. In this work, four Mg-doped strontium titanate (Mg-STO) particles with spherical, dendritic, flake-like, and pinecone-like morphologies were obtained via hydrothermal and low-temperature co-precipitation. XRD, SEM, Raman, and FT-IR were used to characterize these products. The results showed that Mg-STOs are about 1.5-2.0 µm in size, and their phase structures are dominated by cubic crystals. These Mg-STOs were dispersed in a hydrogel composite elastic medium. Then, Mg-STO/glycerol/gelatin electrorheological composite hydrophilic elastomers were obtained with or without an electric field. The electric field response properties of Mg-doped strontium titanate composite elastomers were investigated. We concluded that dendritic Mg-STO composite elastomers are high-performance EREs, and the maximum value of their energy storage was 8.70 MPa. The significant electrorheological performance of these products is helpful for their applications in vibration control, force transducers, smart structures, dampers, and other fields.

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.

PathoDuet: Foundation models for pathological slide analysis of H&E and IHC stains.

Large amounts of digitized histopathological data display a promising future for developing pathological foundation models via self-supervised learning methods. Foundation models pretrained with these methods serve as a good basis for downstream tasks. However, the gap between natural and histopathological images hinders the direct application of existing methods. In this work, we present PathoDuet, a series of pretrained models on histopathological images, and a new self-supervised learning framework in histopathology. The framework is featured by a newly-introduced pretext token and later task raisers to explicitly utilize certain relations between images, like multiple magnifications and multiple stains. Based on this, two pretext tasks, cross-scale positioning and cross-stain transferring, are designed to pretrain the model on Hematoxylin and Eosin (H&E) images and transfer the model to immunohistochemistry (IHC) images, respectively. To validate the efficacy of our models, we evaluate the performance over a wide variety of downstream tasks, including patch-level colorectal cancer subtyping and whole slide image (WSI)-level classification in H&E field, together with expression level prediction of IHC marker, tumor identification and slide-level qualitative analysis in IHC field. The experimental results show the superiority of our models over most tasks and the efficacy of proposed pretext tasks. The codes and models are available at https://github.com/openmedlab/PathoDuet.

The changes of coagulation profiles in Kawasaki disease and its associations with clinical classification, intravenous immunoglobulin responsiveness and coronary artery involvement.

Coagulation disorders are common in Kawasaki disease (KD). The main objectives of the present study were to probe the associations of coagulation profiles with clinical classification, IVIG responsiveness, coronary artery abnormalities (CAAs) in the acute episode of KD. A total of 313 KD children were recruited and divided into six subgroups, including complete KD (n = 217), incomplete KD (n = 96), IVIG-responsive KD (n = 293), IVIG-nonresponsive KD (n = 20), coronary artery noninvolvement KD (n = 284) and coronary artery involvement KD (n = 29). Blood samples were collected within 24-h pre-IVIG therapy and 48-h post-IVIG therapy. Coagulation profiles, conventional inflammatory mediators and blood cell counts were detected. Echocardiography was performed during the period from 2- to 14-day post-IVIG infusion. In addition, 315 sex- and age-matched healthy children were enrolled as the controls. (1) Before IVIG therapy, coagulation disorders were more prone to appear in KD patients than in healthy controls, and could be overcome by IVIG therapy. FIB and DD significantly increased in the acute phase of KD, whereas reduced to normal levels after IVIG therapy. (2) PT and APTT were significantly longer in patients with complete KD when compared with their incomplete counterparts after IVIG therapy. (3) The larger δDD, δFDP and the smaller δPT, δINR predicted IVIG nonresponsiveness. (4) The higher δDD and δFDP correlated with a higher risk for CAAs (DD: r = -0.72, FDP: r = -0.54). Coagulation disorders are correlated with complete phenotype, IVIG nonresponsiveness and CAA occurrence in the acute episode of KD, and can be rectified by synergistic effects of IVIG and aspirin.

Vacancy-Induced Anionic Electrons in Single-Metal Oxides and Their Possible Applications in Ammonia Synthesis.

Realizating of a low work function (WF) and room-temperature stability in electrides is highly desired for various applications, such as electron emitters, catalysts, and ion batteries. Herein, a criterion based on the electron localization function (ELF) and projected density of states (PDOS) in the vacancy of the oxide electride [Ca24Al28O64]4+(4e-) (C12A7) was adopted to screen out 13 electrides in single-metal oxides. By creating oxygen vacancies in nonelectride oxides, we find out 9 of them showed vacancy-induced anionic electrons. Considering the thermodynamic stability, two electrides with ordered vacancies, Nb3O3 and Ce4O3, stand out and show vacancy-induced zero-dimensional anionic electrons. Both exhibit low WFs, namely 3.1 and 2.3 eV for Nb3O3 and Ce4O3, respectively. In the case of Nb3O3, the ELF at oxygen vacancies decreases first and then increases during the decrease in the total number of electrons in self-consistent calculations due to Nb's multivalent state. Meanwhile, Ce4O3 displays promise for ammonia synthesis due to its low hydrogen diffusion barrier and low activation energy. Further calculations revealed that CeO with disordered vacancies at low concentrations also exhibits electride-like properties, suggesting its potential as a substitute for Ce4O3.

Epidemiological trends of subarachnoid hemorrhage at global, regional, and national level: a trend analysis study from 1990 to 2021.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke characterized by high mortality and low rates of full recovery. This study aimed to investigate the epidemiological characteristics of SAH between 1990 and 2021. METHODS: Data on SAH incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021 were obtained from the Global Burden of Disease Study (GBD) 2021. Estimated annual percentage changes (EAPCs) were calculated to evaluate changes in the age-standardized rate (ASR) of incidence and mortality, as well as trends in SAH burden. The relationship between disease burden and sociodemographic index (SDI) was also analyzed. RESULTS: In 2021, the incidence of SAH was found to be 37.09% higher than that in 1990; however, the age-standardized incidence rates (ASIRs) showed a decreased [EAPC: -1.52; 95% uncertainty interval (UI) -1.66 to -1.37]. Furthermore, both the number and rates of deaths and DALYs decreased over time. It was observed that females had lower rates compared to males. Among all regions, the high-income Asia Pacific region exhibited the highest ASIR (14.09/100,000; 95% UI 12.30/100,000 - 16.39/100,000) in 2021, with an EPAC for ASIR < 0 indicating decreasing trend over time for SAH ASIR. Oceania recorded the highest age-standardized mortality rates (ASMRs) and age-standardized DALYs rates among all regions in 2021 at values of respectively 8.61 (95% UI 6.03 - 11.95) and 285.62 (95% UI 209.42 - 379.65). The burden associated with SAH primarily affected individuals aged between 50 - 69 years old. Metabolic risks particularly elevated systolic blood pressure were identified as the main risk factors contributing towards increased disease burden associated with SAH when compared against environmental or occupational behavioral risks evaluated within the GBD framework. CONCLUSIONS: The burden of SAH varies by gender, age group, and geographical region. Although the ASRs have shown a decline over time, the burden of SAH remains significant, especially in regions with middle and low-middle SDI levels. High systolic blood pressure stands out as a key risk factor for SAH. More specific supportive measures are necessary to alleviate the global burden of SAH.

In Vitro Protective Effect of Pea-Derived Peptides (PPs) via the Keap1/Nrf2 Signaling Pathway on Alpha-Gliadin-Sensitizing Peptide Induced Cacao-2 Cells.

SCOPE: Celiac disease (CD) is an allergic intestinal disease caused mainly by gliadin in wheat, which is widespread in the population and currently lacks effective treatment. α-Gliadin peptides cause cellular damage by substantially increasing cellular reactive oxygen species (ROS) levels. METHODS AND RESULTS: This study investigates the protective effect of 11 pea-derived peptides (PPs) on ɑ-gliadin peptide (P31-43) treated Caco-2 cells. Results show that cells treated with PP2, PP5, and PP6 peptides significantly reduce the cell mortality caused by P31-43. Three PPs significantly reduce the P31-43-induced decrease in ROS levels to control levels, and there is no difference between them and the vitamin C (Vc) group. The results in terms of antioxidant-related enzymes show that PPs significantly decrease superoxide dismutase activity (SOD), glutathione reductases (GR), and glutathione (GSH)/oxidized glutathione (GSSG) levels, thus significantly enhancing the antioxidant level of cells. By studying the key proteins of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) pathway, it is found that PPs activate the Keap1/Nrf2 signaling pathway. CONCLUSION: The study finds that peptides from peas can effectively alleviate ɑ-gliadin peptide-induced cell damage. The discovery of these food-derived peptides provides novel potential solutions for the prevention and treatment of CD.

Selective recognition and enrichment of C70 over C60 using an anthracene-based nanotube.

Selective recognition and enrichment of fullerenes (e.g., C60 and C70) remains challenging due to the same diameter and geometrical similarity. Herein, we report a hexagonal anthracene-based nanotube (1) through a one-pot Suzuki-Miyaura cross-coupling reaction. With anthracene-based side walls and pyridine linkers, 1 features a nano-scale tubular cavity measuring 1.2 nm in diameter and 0.9 nm in depth, along with pH-responsive properties. Interestingly, the electron-rich 1 shows high binding affinity (K a ≈ 106 M-1) and selectivity (K s ≈ 140) to C70 over C60 in toluene, resulting from their different contribution of π-π interactions with the host. The protonation of 1 simultaneously alters the electronic properties within the nanotube, resulting in the release of the fullerene guests. Lastly, the selective recognition and pH stimuli-responsive properties of the nanotube have been utilized to enrich C70 from its low-content mixtures of fullerenes in chloroform.

Sex differences in PD-L1-induced analgesia in paclitaxel-induced peripheral neuropathy mice depend on TRPV1-based inhibition of CGRP.

AIMS: Paclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel-induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions. METHODS: Male and female C57BL/6 mice (5-6 weeks and 12 months, weighing 18-30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD-L1. On day 14 after PTX administration, PD-L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno-associated virus 9 (AAV9)-Trpv1-RNAi (5 µL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD-L1, TRPV1 and CGRP were measured via Western blotting, RT-PCR, and immunofluorescence staining. The levels of TNF-α and IL-1ß were measured via RT-PCR. RESULTS: TRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX-induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD-L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717-fold and 2.303-fold, respectively. PD-L1 and CGRP were partly co-localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD-L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9-mediated spinal cord specific decreased TRPV1 expression. CONCLUSIONS: PTX-induced nociceptive behaviors and the analgesic effect of PD-L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex-specific therapeutic approaches.

Programmable "triple attack" cancer therapy through in situ activation of disulfiram toxification combined with phototherapeutics.

Effectively and completely eliminating residual tumor cells is the key to reducing the risk of tumor metastasis and recurrence. Designing an "ideal" nanoplatform for programmable cancer therapy has great prospects for completely eliminating residual tumor cells. Herein, an intelligent nanoplatform of disulfiram (DSF)-loaded CuS-tannic acid nanohexahedrons (denoted as "DSF-CuS@TA") with thermal- and pH-sensitive degradation, as well as near-infrared (NIR-II) phototherapeutics properties, was constructed. And then, it was employed for in situ DSF toxification activation programmable "triple attack" cancer therapy. After accumulating in the tumor, DSF-CuS@TA first releases the loaded Cu(DTC)2, and simultaneously degrades and releases Cu2+ and DSF under mildly acidic stimulation to trigger instant intratumoral Cu(DTC)2 chelation, thereby achieving the "first strike." Next, under irradiation by a NIR-II laser, light energy is converted into heat to generate NIR-II photothermal therapy, thereby achieving the second strike. Subsequently, under thermal stimulation, DSF-CuS@TA degrades further, triggering the chelation of Cu(DTC)2 for a second time to reach the third strike. As expected, in vitro and in vivo studies showed that the synergistic integration of DSF-based programmed chemotherapy and NIR-II phototherapeutics could achieve effective tumor removal. Therefore, we propose a novel type of programmed therapy against cancer by designing a nanoplatform via "nontoxicity-to-toxicity" chemical chelation transformation.

Kinetically controlled synthesis of low-strain disordered micro-nano high voltage spinel cathodes with exposed {111} facets.

High-voltage LiNi0.5Mn1.5O4 (LNMO) is one of the most promising cathode candidates for rechargeable lithium-ion batteries (LIBs) but suffers from deteriorated cycling stability due to severe interfacial side reactions and manganese dissolution. Herein, a micro-nano porous spherical LNMO cathode was designed for high-performance LIBs. The disordered structure and the preferred exposure of the {111} facets can be controlled by the release of lattice oxygen in the high-temperature calcination process. The unique configuration of this material could enhance the structural stability and play a crucial role in inhibiting manganese dissolution, promoting the rapid transport of Li+, and reducing the volume strain during the charge/discharge process. The designed cathode exhibits a remarkable discharge capacity of 136.7 mA h g-1 at 0.5C, corresponding to an energy density of up to 636.4 W h kg-1, unprecedented cycling stability (capacity retention of 90.6% after 500 cycles) and superior rate capability (78.9% of initial capacity at 10C). The structurally controllable preparation strategy demonstrated in this work provides new insights into the structural design of cathode materials for LIBs.

Photoinduced copper catalyzed nitrogen-to-alkyl radical relay Sonogashira-type coupling of o-alkylbenzamides with alkynes.

This report describes a copper-catalyzed, photoinduced N-to-alkyl radical relay Sonogashira-type reactions at benzylic sites in o-alkylbenzamides with alkynes. The process employs an N-to-alkyl radical mechanism, initiated through the copper-catalyzed reductive generation of nitrogen radicals. Radical translocation is facilitated by a 1,5-hydrogen atom transfer (1,5-HAT), leading to the formation of translocated carbon radicals. These radicals are then subjected to copper-catalyzed alkynylation. The methodology exhibits broad sub-strate scope and applicability to the synthesis of complex natural products.

Sub-chronic toxicity of the active fraction of a modified Huang-Lian-Jie-Du Decoction.

A traditional Chinese herbal medicine formula named Huang-Lian-Jie-Du Decoction (HLJDD) has been used to cure various inflammatory diseases with a long history. However, one component of HLJDD Gardeniae fructus has remarkable liver and kidney toxicities. Therefore, it was altered with Dictamni cortex to form a modified HLJDD (MHLJDD). In this study, we aimed to evaluate the sub-chronic toxicity of the active fraction of MHLJDD (MHLJDD-F) in rats. Adult rats of both sexes were intragastrically administered with vehicle or MHLJDD-F (at the dose of 170, 340, and 680 mg/kg/day) once daily for 90 days. Half of the rats from each group were kept for an additional 30-day period to observe the drug withdrawal effect. The signs of toxicity and mortality of the rats were observed, and the body weight and food consumption were recorded. Blood was collected for hematological and biochemical analyses and major organs were weighed and harvested for histopathological examinations. The results revealed that no systemic toxicity of MHLJDD-F was found during the experiments. Organ coefficients and pathological alterations of major organs were comparable to the control rats. The no-observed adverse effect level (NOAEL) of MHLJDD-F was found up to 680 mg/kg/day. All these results demonstrated that long-term oral administration of MHLJDD-F did not cause significant toxicity, which is worthy to be widely applied as a new herbal medicine in pre-clinical and clinical studies.

Treatment of a patient with severe cerebral malaria during the COVID-19 pandemic in China: A case report.

BACKGROUND: On June 30, 2021, China received certification from the World Health Organization for malaria elimination. However, this certification does not signify the absence of malaria within China. Due to the increasing frequency of international exchanges and collaborations, the threat of imported malaria persists in China. Consequently, the prevention and control of imported malaria have become a primary focus for our country to maintain its malaria elimination status. CASE SUMMARY: Herein, we present a case report of a 53-year-old Chinese man who worked in Africa for nearly two years. He was diagnosed with malaria in the Democratic Republic of the Congo between November 19 and November 23, 2022. After receiving effective treatment with oral antimalarial drugs, his condition improved, allowing him to return to China. He was later admitted to our hospital on January 12, 2023, during the coronavirus disease 2019 pandemic in Huangshi, China. Through a thorough evaluation of the patient's symptoms, clinical signs, imaging and laboratory test results, and epidemiological data, he was rapidly diagnosed with severe cerebral malaria. The patient underwent successful treatment through a series of intensive care unit interventions. CONCLUSION: The successful treatment of this imported case of severe cerebral malaria provides a valuable reference for managing patients with similar malaria infections and has significant clinical implications.

Memantine alleviates cognitive impairment and hippocampal morphology injury in a mouse model of chronic alcohol exposure.

Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.

Identifying influencing factors of metabolic syndrome in patients with major depressive disorder: A real-world study with Bayesian network modeling.

BACKGROUND: The bidirectional relationships between metabolic syndrome (MetS) and major depressive disorder (MDD) were discovered, but the influencing factors of the comorbidity were barely investigated. We aimed to fully explore the factors and their associations with MetS in MDD patients. METHODS: The data were retrieved from the electronic medical records of a tertiary psychiatric hospital in Beijing from 2016 to 2021. The influencing factors were firstly explored by univariate analysis and multivariate logistic regressions. The propensity score matching was used to reduce the selection bias of participants. Then, the Bayesian networks (BNs) with hill-climbing algorithm and maximum likelihood estimation were preformed to explore the relationships between influencing factors with MetS in MDD patients. RESULTS: Totally, 4126 eligible subjects were included in the data analysis. The proportion rate of MetS was 32.6 % (95 % CI: 31.2 %-34.1 %). The multivariate logistic regression suggested that recurrent depression, uric acid, duration of depression, marriage, education, number of hospitalizations were significantly associated with MetS. In the BNs, number of hospitalizations and uric acid were directly connected with MetS. Recurrent depression and family history psychiatric diseases were indirectly connected with MetS. The conditional probability of MetS in MDD patients with family history of psychiatric diseases, recurrent depression and two or more times of hospitalizations was 37.6 %. CONCLUSION: Using the BNs, we found that number of hospitalizations, recurrent depression and family history of psychiatric diseases contributed to the probability of MetS, which could help to make health strategies for specific MDD patients.

Preparation of Pueraria lobata Root-Derived Exosome-Like Nanovesicles and Evaluation of Their Effects on Mitigating Alcoholic Intoxication and Promoting Alcohol Metabolism in Mice.

Purpose: Pueraria lobata (P. lobata), a dual-purpose food and medicine, displays limited efficacy in alcohol detoxification and liver protection, with previous research primarily focused on puerarin in its dried roots. In this study, we investigated the potential effects and mechanisms of fresh P. lobata root-derived exosome-like nanovesicles (P-ELNs) for mitigating alcoholic intoxication, promoting alcohol metabolism effects and protecting the liver in C57BL/6J mice. Methods: We isolated P-ELNs from fresh P. lobata root using differential centrifugation and characterized them via transmission electron microscopy, nanoscale particle sizing, ζ potential analysis, and biochemical assays. In Acute Alcoholism (AAI) mice pre-treated with P-ELNs, we evaluated their effects on the timing and duration of the loss of the righting reflex (LORR), liver alcohol metabolism enzymes activity, liver and serum alcohol content, and ferroptosis-related markers. Results: P-ELNs, enriched in proteins, lipids, and small RNAs, exhibited an ideal size (150.7 ± 82.8 nm) and negative surface charge (-31 mV). Pre-treatment with 10 mg/(kg.bw) P-ELNs in both male and female mice significantly prolonged ebriety time, shortened sobriety time, enhanced acetaldehyde dehydrogenase (ALDH) activity while concurrently inhibited alcohol dehydrogenase (ADH) activity, and reduced alcohol content in the liver and serum. Notably, P-ELNs demonstrated more efficacy compared to P-ELNs supernatant fluid (abundant puerarin content), suggesting alternative active components beyond puerarin. Additionally, P-ELNs prevented ferroptosis by inhibiting the reduction of glutathione peroxidase 4 (GPX4) and reduced glutathione (GSH), and suppressing acyl-CoA synthetase long-chain family member 4 (ACSL4) elevation, thereby mitigating pathological liver lipid accumulation. Conclusion: P-ELNs exhibit distinct exosomal characteristics and effectively alleviate alcoholic intoxication, improve alcohol metabolism, suppress ferroptosis, and protect the liver from alcoholic injury. Consequently, P-ELNs hold promise as a therapeutic agent for detoxification, sobriety promotion, and prevention of alcoholic liver injury.