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BACKGROUND: Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. METHODS: A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. RESULTS: DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). CONCLUSIONS: Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.

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OBJECTIVES: To compare the level of knowledge of depression, recognition ability and attitudes towards depression among urban and rural residents in Beijing. DESIGN: A cross-sectional study. SETTING: Six districts in Beijing, China, 2021. PARTICIPANTS: A total of 6463 participants aged 18 years and above who had lived for more than 6 months over the last year in Beijing were selected in this study. OUTCOME: The awareness and recognition of depression and the views of residents towards people with depression. RESULTS: A total of 2554 urban and 2043 rural residents completed the survey. Urban residents of Beijing exhibited a higher average total score on the Depression Knowledge Questionnaire [(20.4±3.3) vs (18.7±3.5), p<0.001] and a higher rate of correctly identifying individuals with depression (47.9% vs 36.6%, p<0.001) than their counterparts in rural areas. Residents who correctly identified people with depression had higher scores on the Depression Knowledge Questionnaire. Depression knowledge varied significantly among urban and rural residents. The multivariate linear regression analysis revealed that rural residents scored significantly lower on measures of depression knowledge compared with urban residents (B=-0.83, 95%CI=-1.03 to -0.63, p<0.001). Older individuals (aged 50+) showed lower understanding compared with the 18-49 age group, with significant negative regression coefficients (Urban: B=-1.06, Rural: B=-1.35, both p<0.001). Higher educational levels were positively associated with greater depression knowledge (Urban: B=1.40, Rural: B=1.21, both p<0.001). Employment was linked to higher knowledge levels than unemployment (Urban: B=-0.60, Rural: B=-0.58, both p=0.00). A monthly income of 8000 yuan or more correlated with better depression understanding than lower incomes (Urban: B=0.81, Rural: B=1.04, both p<0.001). Additionally, in urban areas, unmarried residents scored higher in depression knowledge than those divorced (B=-0.55, p=0.04). Residents in urban areas had relatively positive attitudes towards individuals with depression. CONCLUSIONS: Rural residents of Beijing had lower levels of knowledge and recognition of depression and more negative attitudes towards individuals with depression than those from urban areas. The health authority needs to focus on the poor level of knowledge and increase mental health resources in rural areas as a priority site for future psychological popularisation efforts.

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INTRODUCTION: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. OBJECTIVES: This study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. METHODS: Clinical study, Western blotting, publicly available databasesand bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. RESULTS: The protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin-proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. CONCLUSIONS: LAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC.

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A novel cooperative pseudo[3]rotaxane system was successfully constructed by the inclusion complexation of two identical amine naphthotubes with a bis-pyridinium/isoquinolinium guest. Single crystal structure analysis revealed that weak Csp3-H⋯O hydrogen bonds between the two hosts are responsible for the positive cooperativity during the formation of pseudo[3]rotaxanes. Moreover, intermolecular charge-transfer interactions between the electron-rich host and the electron-poor guests were observed. The pseudo[3]rotaxanes showed pH-controllable association/dissociation processes with naked-eye color changes in solution.

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BACKGROUND: Environmental endocrine disruptors (EEDs) are a class of new pollutants that are diffusely used in the medical industry and animal husbandry. In view of toxicity concerns, elevated levels of EEDs in the environment and food, which cause potential harm to human beings and ecosystems, must be monitored. Determination of EEDs contaminants to ensure environment and food safety has became a major concern worldwide, it is also a challenging task because of their trace level and probable matrices interference. Thus, developing rapid adsorption and efficient analysis methods for EEDs is apparently necessary. RESULTS: A magnetic conjugated micro-porous polymer (Fe3O4@TbDt) was designed and synthesized, which was endowed with large specific surface area, rich functional groups and magnetic responsiveness. The material showed high extraction efficiency for EEDs via magnetic solid-phase extraction (MSPE). The quantum chemistry calculations showed the adsorption mechanism of Fe3O4@TbDt on EEDs mainly included electrostatic interactions, van der waals forces (N-H … π interaction, C-H … π interaction), and multiple hydrogen bonds. Finally, a trace analysis method for nine EEDs was established combined with HPLC-MS/MS under optimized MSPE conditions. The method showed a good linearity (R2 ≥ 0.996), low limits of detection (0.25-5.1 ng L-1), high precision (RSD of 1.1-8.2 %, n = 6). The applicability of this method was investigated by analyzing four water samples and two dairy products, and satisfactory recovery rates (82.1-100.7 %) were obtained. The proposed method showed the potential for the analysis of EEDs residues in food and environmental samples. SIGNIFICANCE: The developed MSPE method based on conjugated micro-porous polymers (CMPs) is simple, green, and efficient compared to existing techniques. The application of CMPs provides a new idea for preparing versatile sample pre-treatment materials. What's more, this work has certain reference value for addressing of EEDs residues in the environment and food.

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Skyrmion Hall effect (SkHE) remains an obstacle for the application of magnetic skyrmions. While methods have been established to cancel or compensate SkHE in artificial antiferromagnets and ferrimagnets, eliminating intrinsic SkHE in ferromagnets is still a big challenge. Here, we propose a strategy to eliminate SkHE by intercalating nonmagnetic elements into van der Waals bilayer ferromagnets featuring in-plane ferromagnetism. The in-plane magnetism, along with a delicate balance among exchange interactions, Dzyaloshinskii-Moriya interactions (DMI), and magnetocrystalline anisotropy, creates interlayer bimerons/quadmerons, whose polarity can be controlled by DMI. Opposite DMI in the upper and lower layers results in opposite polarity and topological charge number Q-locking of topological spin texture, therefore, eliminating the SkHE. By intercalating Sr (Ba) in bilayer VSe2, we identify ten topological magnetic structures with zero topological charge number. Furthermore, we present a phase diagram illustrating diverse magnetic configurations achievable within the bimagnetic atomic layer, offering valuable guidance for future investigations.

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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.

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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.

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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.

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Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and < 70 years), and comparisons were made based on the type of camrelizumab-based therapy (monotherapy, combined chemotherapy, or combined anti-VEGF therapy). A total of 185 patients were administered camrelizumab-based immunotherapy, 55 (30%) of whom were ≥ 70 years old. A total of 146 (78.9%) patients received camrelizumab-based combination treatment. The incidence of all-grade AEs was 56.8% (105 patients), while that of irAEs was 36.8% (68 patients). There was no difference in the percentage of patients experiencing any grade or grade ≥ 3 AEs between age groups. However, the frequency of irAEs (both any grade and grade ≥ 3) significantly differed by age group (P = 0.001 and 0.009, respectively). The results of multivariable analysis revealed that age ≥ 70 years was the only independent risk factor for irAEs. The results of subgroup analysis revealed that the incidence of irAEs was higher in older patients treated with camrelizumab-chemotherapy, while the incidence rates were similar between age groups in the monotherapy and combination anti-VEGF treatment subgroups. Immune-related diabetes mellitus occurred more frequently among older adults. The spectrum of irAEs showed that combination immunotherapy had more widely effects on the organ system than monotherapy. In this study, older (≥ 70 years) patients had a higher risk of all-grade and high-grade irAEs when receiving camrelizumab chemotherapy combination treatment. Notably, long-term random glucose monitoring should be performed during ICI-based immunotherapy in older cancer patients.

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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.

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Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work aimed to investigate the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.

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The Japanese eel (Anguilla japonica), a flagship anguillid species for conservation, is known for its long-distance-oriented migration. However, our understanding of the genetic architecture underlying long-distance migration and population genomic characteristics of A. japonica is still limited. Here, we generated a high-quality chromosome-level genome assembly and conducted whole-genome resequencing of 218 individuals to explore these aspects. Strong signals of selection were found on genes involved in long-distance aerobic exercise and navigation, which might be associated with evolutionary adaptation to long-distance migrations. Low genetic diversity was detected, which might result from genetic drift associated with demographic declines. Both mitochondrial and nuclear genomic datasets supported the existence of a single panmictic population for Japanese eel, despite signals of single-generation selection. Candidate genes for local selection involved in functions like development and circadian rhythm. The findings can provide insights to adaptative evolution to long-distance migration and inform conservation efforts for A. japonica.

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Petroleum pollution has become a prominent global environmental problem, restricting the coordinated development of the economy and the ecological environment. Although bioremediation has the advantages of low carbon, high efficiency, and safety, the complexity and severity of the pollution makes it difficult to achieve the remediation purpose with a single bioremediation. Ecological remediation based on bioremediation can integrate carbon neutrality and ecological environmental protection, synergistically promote pollution reduction and carbon reduction, ensure the sustainability of soil and sediment to fulfil ecosystem service functions, and ultimately achieve soil health and sediment health. Therefore, the transition from bioremediation to ecological restoration is the optimal choice for environmental management and ecosystem maintenance at this stage. Here, we first analyzed the micro-removal mechanism of petroleum hydrocarbons in different bioremediation techniques and discussed the types and characteristics of different bioremediation techniques from an ecological point of view. Based on this, the necessity of bioremediation for ecological restoration was analyzed in detail. Finally, a reasonable outlook on the development of ecological remediation is given to provide theoretical support for optimizing ecological remediation of petroleum pollution.

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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.

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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.

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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.

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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.

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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.

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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.

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