📋 Browse Articles

Because the prognostic value of lipoprotein(a) [Lp(a)] levels in Japanese patients remains unclear, we assessed their distribution and association with long-term outcomes in ST-segment elevation myocardial infarction (STEMI). In our retrospective analysis of 868 consecutive patients with STEMI, the median serum Lp(a) level was 15.75 mg/dL at admission, and the median follow-up was 736.5 days. Using restricted cubic spline analysis, we stratified patients into high (≥47.26 mg/dL) and low (<47.26 mg/dL) Lp(a) groups. The high Lp(a) group had a higher proportion of older and female patients, with lower body weight, estimated glomerular filtration rate, and stent use, and higher dyslipidemia prevalence than those in the low Lp(a) group. The 5-year cumulative incidence of the composite primary endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or any revascularization) was significantly higher in the high Lp(a) group, primarily because of a high rate of any revascularization. Patients with elevated Lp(a) levels demonstrated higher rates of any revascularization for both de novo and restenotic lesions than those with lower levels. After adjusting for confounders, a high Lp(a) level was identified as an independent predictor of the primary endpoint (hazard ratio:1.932; 95% confidence interval:1.255-2.974). In Japanese patients with STEMI, elevated Lp(a) levels were independently associated with worse long-term outcomes. Show less

Dementia involves progressive cognitive decline, impairing daily and social activities. As no current drugs can reverse this decline, preventive strategies using functional compounds are gaining attention. Rutin, a flavonoid with neuroprotective and vascular benefits, has limited bioavailability due to poor water solubility. Although enzymatic glycosylation improves its solubility, it contains multiple compounds with differing numbers of sugar units and is not a single compound. To address this, EubioQuercetin®, a novel water-soluble rutin (wsRutin) formulation, was developed using L-arginine and ascorbic acid, without enzymatic processing. Here, we evaluated the neuroprotective effects of quercetin and isorhamnetin, the major metabolites of rutin, and compared the cognitive effects of rutin suspension and wsRutin solution in mice. Quercetin and isorhamnetin suppressed glutamate-, menadione- and H Show less

An original dataset based on a national quota sample in the Czech Republic (n = 490, M = 46.09 y/o, 45.7% women) was used to assess susceptibility to medical (COVID-19) and political (Russian invasion of Ukraine) disinformation. Susceptibility to disinformation was assessed using 30 items addressing contemporary topics. To identify the latent structure underlying these items, an exploratory factor analysis (principal-axis factoring with direct oblimin rotation) was conducted. EFA yielded four correlated factors: one specific to COVID-19 hoaxes/misinformation (F1) and three others pertaining to the political (F2), economic (F3), and moral/ethical (F4) dimensions of the Russian war. In order to identify response patterns, all 30 items from 490 participants were subjected to Latent Profile Analysis (LPA) in which the EFA factors served to interpret the five resulting types: a neutral No Strong Opinion type (48%); two disinformation-resilient types-Rational Pro-Ukrainians (22%) and Anti-Russians (7%); and two disinformation-susceptible types-Pro-Russians (15%) and the Generally Disinformed (9%). The discussion addresses the sizable No Strong Opinion type and the correlation between COVID-19 hoaxes and propaganda disinformation (r = 0.47), which supports the 'monological belief system' concept. The identified types can be further followed prospectively and retrospectively within an ongoing panel study. Show less

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first clinical-stage small-molecule TREM2 agonist, has been proposed to function as a transmembrane molecular glue and positive allosteric modulator (PAM). Whether it directly engages the extracellular ligand-recognition surface of TREM2 remains unknown. Here, we used a deep learning-based blind docking algorithm to map potential VG-3927 binding sites across TREM2 and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed direct interaction of VG-3927 with TREM2 under optimized PEG-400 buffer conditions and independently demonstrated binding of Aβ Show less

The maternal perinatal environment shapes brain development and long-term neurodevelopmental trajectories. Probiotic supplementation during this period has emerged as a promising strategy to support healthy neurodevelopmental outcomes through modulation of immune and synaptic plasticity pathways. However, the persistence and specificity of molecular effects in the offspring brain, particularly with respect to sex and brain region, remain poorly understood. We conducted two independent mouse experiments using different probiotic strains and exposure windows to evaluate the long-term transcriptional effects of maternal probiotic supplementation. Time-mated C57BL/6JRj dams received a multi-species probiotic (Ecologic® Panda) from gestational day (GD) 6 until birth, whereas BALB/cJRj dams received Multi-species supplementation induced broad and persistent transcriptional changes in hippocampus and hypothalamus, with generally larger effects in males. Altered transcripts included markers of synaptic plasticity ( These findings highlight that short, targeted maternal probiotic supplementation during the perinatal period is associated with persistent molecular signatures in the adult offspring brain across genetic backgrounds, converging on neuroimmune-related pathways. Show less

Yoga is increasingly incorporated into clinical practice for managing a wide range of mental and physical health conditions, especially those related to stress, and has shown beneficial effects on inflammatory processes and neuroendocrine regulation. Its influence on cytokines such as interleukin-6 and tumor necrosis factor-α, as well as its modulatory action on the hypothalamic pituitary adrenal axis, suggests a potential role in reducing systemic inflammation and improving stress resilience. Despite these promising indications, there is limited scientific evidence from India evaluating yoga's impact on biological markers of stress and inflammation. The present study was undertaken to assess the effects of a structured yoga program on selected biomarkers in 60 adult volunteers who underwent evaluations before and after 3 months of practice. The intervention consisted of a daily 1-h yoga session conducted 6 days a week and included postures, breathing practices, and relaxation techniques. Assessments focused on brain-derived neurotrophic factor, interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein, cortisol, and perceived stress levels. Findings indicated an increase in brain-derived neurotrophic factor and reductions in inflammatory markers, cortisol, and perceived stress. These outcomes suggest that regular yoga practice can positively influence neurotrophic activity, reduce inflammation, and lower stress, supporting its value as a complementary approach to improving overall health and well-being. Show less

Supercritical fluid chromatography is traditionally employed for nonpolar and moderately polar analytes, while the analysis of ionic compounds remains a recognized limitation of the technique. Moreover, some polar lipids may contain a chromatographically challenging ionic group, which can interact with the metal surfaces of the instrument and column, resulting in poor peak shape and loss of sensitivity. Here, we introduce a novel ultrahigh-performance supercritical fluid chromatography-mass spectrometry (UHPSFC/MS) method using a bioinert column, enabling the separation of lipids with a broad polarity range from nonpolar to ionic species. The UHPSFC/MS method was optimized using 79 lipid species across 41 lipid subclasses, achieving a total run time of 7.5 min, including the column equilibration. The comparison of the separation with conventional and bioinert columns revealed a substantial improvement in peak shapes for ionic lipid classes, such as PS, LPS, PA, LPA, CerP, and SPBP. Additionally, we introduce a combination of the modified chloroform-free extraction followed by a hexane elimination step. The optimized methodology was applied for the untargeted analysis of human plasma and erythrocyte-rich fraction to achieve highly confident identification of 657 lipid species across 37 lipid subclasses in human blood. The method follows the recommendations for validation of (bio)analytical methods, and its accuracy was confirmed by quantitative analysis of the reference material NIST SRM 1950, with the determined concentrations in agreement with the consensus values from ring trials. The current methodology represents a novel high-throughput and comprehensive quantitative lipidomic method for biological samples. The modified MTBE extraction enhances workflow efficiency by reducing concentrations of nonpolar lipids, which enables injection of more concentrated lipid extracts while minimizes ion source contamination. Moreover, the findings highlight the potential for the development of bioinert components specifically designed for SFC platforms, enabling broader applicability of the technique. Show less

BuYang HuanWu Decoction (BYHW), a classical herbal formula first documented in Yilin Gaicuo (1830), is officially listed in the Chinese Pharmacopoeia for the treatment of stroke and sequelae attributed to "qi deficiency and blood stasis." Vertebral artery stenosis (VAS) is a leading cause of posterior circulation ischemic stroke-a condition for which BYHW has been traditionally prescribed. However, the molecular mechanism underlying its therapeutic effects against VAS remains poorly understood. This study aimed to systematically predict the therapeutic targets of BYHW against VAS using network pharmacology and to experimentally validate its core mechanism of action, with a focus on the AGE-RAGE/NF-κB signaling axis. Potential targets of BYHW and VAS-related genes were retrieved from TCMSP and DisGeNET databases for network construction and enrichment analysis. Key predictions were validated in vitro using ox-LDL/AGEs-stimulated human umbilical vein endothelial cells (HUVECs) and RAW 264.7 macrophages, and in vivo using ApoE Network analysis identified 62 common targets and six core hubs (IL-6, IL-10, FOS, MAPK1, AKT1, and CTNNB1), with the AGE-RAGE signaling pathway being the most significantly enriched. In vitro, BYHWE inhibited ox-LDL/AGEs-induced endothelial inflammation, oxidative stress, and macrophage foam cell formation by suppressing the AGE-RAGE/NF-κB axis. In vivo, BYHWE administration (2 g/kg/day for 4 weeks) significantly attenuated atherosclerotic plaque burden by 34.7% and reduced macrophage infiltration in ApoE This study provides the first evidence that BYHW alleviates VAS through multi-target modulation of the AGE-RAGE/NF-κB pathway, thereby protecting endothelial function and stabilizing plaques. These findings offer a mechanistic explanation for its traditional use in stroke-related disorders and support its therapeutic potential for atherosclerotic vertebral artery stenosis. Show less

Digital literacy has become a core competency for nursing professionals, enabling them to adapt to modern healthcare environments and engage effectively with emerging technologies. It is closely linked to innovative behavior, which is essential for problem solving and advancing nursing practice. Despite its importance, limited research has examined differences in digital literacy among undergraduate nursing students and how these differences influence innovation. A cross-sectional study was conducted using a convenience sample of 450 undergraduate nursing students from four universities in Anhui Province, China. Participants completed a general information questionnaire, the Undergraduate Digital Literacy Scale, and the Innovative Behavior Scale. Latent profile analysis (LPA) was employed to classify students into distinct digital literacy profiles, while logistic regression and one-way ANOVA were used to explore factors influencing profile membership and the relationship between digital literacy and innovative behavior. Three latent profiles were identified: a "Low Digital Literacy" group (34.1%), a "Moderate Digital Literacy" group (15.9%), and a "High Digital Literacy" group (50.0%). Significant differences were observed across profiles in relation to gender, age, academic year, and frequency of artificial intelligence (AI) use in the past 6 months. Importantly, students with higher digital literacy consistently exhibited stronger innovative behavior ( Digital literacy among undergraduate nursing students is heterogeneous and shaped by demographic and experiential factors. Targeted educational interventions tailored to distinct literacy profiles are needed to bridge gaps, promote equity, and strengthen innovation. By integrating AI and advanced digital tools into nursing curricula, educators can enhance students' competencies and better prepare them to thrive in an increasingly digital and intelligent healthcare landscape. Show less

Cisplatin is a widely used chemotherapeutic agent for triple-negative breast cancer (TNBC), but resistance remains a major challenge. Understanding the molecular alterations driving this resistance is essential for identifying therapeutic targets. In this study, we employed an integrated proteomics and lipidomics approach to elucidate key pathways associated with cisplatin resistance. Employing high-resolution mass spectrometry, we conducted a comparative analysis between cisplatin-resistant (cisR) and cisplatin-sensitive (cisS) TNBC cell lines to discover resistance-associated alterations in protein and lipid expression. Proteomic analysis revealed overexpression of extracellular matrix (ECM) remodeling proteins, COL6A1, COL6A2, COL6A3, and VTN, that support epithelial-mesenchymal transition (EMT) and chemoresistance. Membrane-associated proteins such as TIMP2, MMP14, and APP were also elevated, indicating enhanced invasive and pro-survival signaling. Lipidomic alterations, including upregulation of FABP3, FABP4, LPL, and downregulation of PLA2G4A, indicated increased lipid uptake, metabolic rewiring, and membrane restructuring. Notably, elevated long-chain phosphatidylcholines and decreased sphingomyelins suggested increased membrane rigidity and reduced cisplatin permeability. Additionally, dysregulation of CDK activity through CCND2, CCND3, and CCNB2 overexpression indicated accelerated cell cycle progression and evasion of DNA damage checkpoints. Together, this integrative analysis highlights ECM remodeling, cytoskeletal dynamics, and lipid metabolism as major contributors to cisplatin resistance and identifies potential therapeutic markers for TNBC. Show less

Osteoporosis frequently affects older women and is strongly linked to their daily routines, which include both sedentary behavior (SEB) and physical activities (PA) of different intensities. This study investigates the dose-response relationship of different SEB and PA patterns among community-dwelling older women and assesses the potential impact of time reallocation on osteoporosis risk through an isotemporal substitution analysis. In this study, 1,106 older women aged between 60 and 70 years in Tianjin participated. Their moderate to vigorous physical activity (MVPA), light physical activity (LPA), and SEB were objectively assessed using an accelerometer. The connection between MVPA, LPA, SEB, and osteoporosis was assessed using binary logistic regression models and isotemporal substitution models. The osteoporosis group and non-osteoporosis group comprised 461 and 645 subjects respectively, accounting for 41.68 and 58.32% of the total cohort. The osteoporosis group had significantly higher daily SEB compared to the non-osteoporosis group ( PA and SEB in older women exhibit a significant dose-response relationship with osteoporosis. Avoiding prolonged sitting and increasing PA duration both offer protective effects against osteoporosis in older women, with achieving a certain level of MVPA being the most effective protective measure. Show less

Microglial decline in the dentate gyrus is an important mechanism in the development of depression-like behaviors in stressed animals. Reversing this decline with low-dose lipopolysaccharide (LPS) can produce rapid antidepressant effects, yet the underlying mechanisms remain incompletely understood. Our previous work identified a critical role for astrocytic P2Y1 receptor (P2Y1R) activation and subsequent dentate gyrus extracellular signal-regulated kinase 1/2 (ERK1/2)-brain-derived neurotrophic factor (BDNF) signaling in the antidepressant effect of low-dose LPS. This study elucidates the signaling cascade linking astrocytic P2Y1R mobilization to the antidepressant effect of low-dose LPS. We found that low-dose LPS promoted glutamate release through ATP-triggered astrocytic P2Y1R signaling. Blockade of N-methyl-D-aspartic acid (NMDA) receptors, but not metabotropic receptors, and the GluN2B subtype of NMDA receptors abolished the antidepressant effect of low-dose LPS. GluN2B knockdown also abolished the reversal effect of low-dose LPS on CUS-induced depression-like behaviors and impairment of dentate gyrus ERK1/2-BDNF signaling. Moreover, chelating intracellular Ca Show less

The innate immune response and cytokine milieu in airway mucosa, mediated by bronchial epithelial cells, are critical in determining susceptibility or protection against cryptococcosis. In experimental models, Th2 and Th1 responses are linked to susceptibility and protection, respectively, while the roles of other cytokines remain less understood. To evaluate the in vitro effects of IL-4, IFN-γ, and IL-27 (100ng/mL) on human bronchial epithelial cells (BEAS-2B) infected with a strain of Cryptococcus neoformans sensu stricto (multiplicities of infection [MOI] 1-100). Cells were stimulated with each cytokine, followed by C. neoformans infection (MOI 100). After 24h, supernatants were collected to measure CCL2, IL-6, and IL-8 production. STAT1 and STAT6 activation was analyzed by flow cytometry. Phagocytosis and colony-forming unit assays assessed fungal internalization and growth. Cytokine-stimulated, infected cells displayed reduced IL-6 and/or CCL2 production and decreased STAT6 activation (IL-4) or STAT1 activation (IL-27, IFN-γ) compared with cells stimulated with C. neoformans sensu stricto or cytokines alone. IL-27 reduced fungal internalization, while IL-4 and IFN-γ increased it. All cytokines promoted higher fungal growth. The interaction of bronchial epithelial cells stimulated with IL-4, IFN-γ, or IL-27, with yeasts of C. neoformans induced an anti-inflammatory profile in the cells that impaired STAT activation and favored fungal proliferation. These findings suggest that certain cytokine environments within the airway epithelium may create conditions conducive to C. neoformans persistence, potentially influencing the progression of the infection. Show less

Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclear. Here, we aimed to investigate the role of PRMT3 (protein arginine methyltransferase 3) in valvular calcification and calcific aortic valve disease progression. Both aortic valve leaflets and valvular interstitial cells from patients were used to evaluate the expression pattern and investigate the underlying mechanism of PRMT3 in calcific aortic valve disease pathogenesis. High-cholesterol diet-fed Apoe (apolipoprotein E)-deficient ( We found that PRMT3 expression was significantly upregulated during aortic valve calcification. RUNX2 (runt-related transcription factor 2) recruited P300 to promote PRMT3 expression through histone H3 lysine 27 acetylation. Moreover, We identify a previously unrecognized posttranslational mechanism regulating PCSK9 stability in valve interstitial cells during calcific aortic valve disease and establish a link between PRMT3-mediated arginine methylation and valve-specific lipid-osteogenic coupling. Show less

Intramuscular fat (IMF) is a key determinant of meat quality, influencing tenderness, juiciness, and flavor. Previous studies have reported that the deposition of IMF is controlled by various factors. However, there is a shortage of research exploring the variations in IMF deposition across age groups from a microbial perspective. This study evaluated the differences in IMF deposition between yearling (1-year-old) and mature (4-year-old) Longdong Cashmere goats and analyzed its association with gut microbiota. The results revealed that the IMF content in shoulder meat and blood lipid levels increased with age (p < 0.05). Conversely, the contents of lipoprotein lipase (LPL) in the liver and duodenum significantly decreased with age. Microbial diversity differed between the two age groups, with specific microbiota identified from the gut of goats involved in the lipid metabolism pathway. The concentrations of valeric and isovaleric acids in the rumen, as well as acetic, propionic and isovaleric acids in the colon, were higher in yearling goats than in mature goats (p < 0.05). Spearman correlation analysis of IMF deposition indicators with gut microbiota revealed that, within the rumen, the abundances of CAG-791 and Sodaliphilus were positively correlated with IMF content in shoulder meat and TG levels, while exhibiting a negative correlation with the contents of valeric acids. Furthermore, the abundance of Clostridium_R showed a positive association with IMF content in shoulder meat and with the abundances of CAG-791and Sodaliphilus. In contrast, the abundance of Bact₁₁ was negatively correlated with IMF content in shoulder meat, TG levels, and the abundances of CAG-791, Sodaliphilus and Clostridium_R. Within the abomasum, the abundances of UMGS and Hylemonella₅₈₂₃₀₈ were correlated with IMF content in the shoulder meat, as well as serum LDL and VLDL levels. This study provides significant insights into the age-dependent gut microbiota associated with intramuscular fat deposition in goats and identifies several potential gut microbiota for further research on their impacts on IMF deposition. Show less

Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease, and it is particularly associated with premature acute coronary syndrome (ACS). We investigated whether elevated Lp(a) can predict recurrent cardiovascular events in patients who experienced their first ACS less than or equal to 40 years of age. Within the STudy of eArly Myocardial INfArction registry, we recruited 405 consecutive patients who survived their first ACS less than or equal to 40 years of age; of them 378 had complete follow-up data. Clinical endpoint was the development of major adverse cardiovascular events (MACE; i.e. cardiac death, readmission for ACS or malignant ventricular arrhythmias, ischemic stroke, or coronary revascularization due to clinical deterioration). Multi-adjusted Cox regression was used to assess the association between Lp(a) and first recurrent MACE risk. Of the 378 ACS survivors (33.7 ± 4.3 years), 139 (36.8%) experienced a MACE over a median 8-year (5.2-12.5 years) follow-up. Elevated Lp(a) showed a borderline independent association with higher recurrent MACE [hazard ratio per 1 mg/dl: 1.004, 95% confidence interval (CI): 0.999-1.009, P = 0.051]. Moreover, patients with baseline Lp(a) levels greater than or equal to 50 mg/dl had 82.6% higher risk of MACE as compared with those below (hazard ratio 1.826, 95% CI: 1.141-2.925, P = 0.012); similarly, patients with Lp(a) ≥ 70 mg/dl had 118% higher risk as compared with those below (hazard ratio 2.180, 95% CI: 1.330-3.573, P = 0.002). Elevated Lp(a) concentrations demonstrate an independent association with recurrent MACE among very young ACS survivors. Until targeted Lp(a)-lowering treatments become clinically available, an aggressive lipid-lowering approach may be warranted to partially attenuate Lp(a)-related residual cardiovascular risk. Show less

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders. Show less

Spinal TB (STB) is paucibacillary form of disease caused by Mycobacterium Tuberculosis. Late diagnosis of STB can lead to significant disability and morbidity. There is limited data available on diagnostic yield of CT guided biopsy/ultrasonography guided aspiration by various laboratory tests (phenotypic and molecular) used in evaluation STB. Present study was conducted in Department Orthopaedics and Pathology at tertiary care centre in Delhi. Total 68 clinico-radiologically suspected cases undergoing percutaneous aspiration (CT/USG guided) were included in the study. The aspirated tissue/pus was sent for cytology/histopathology/culture/molecular tests. Diagnostic yield of CT/USG guided aspiration for various phenotypic (histopathology/cytology/AFB smear) and molecular tests (CBNAAT/LPA) was calculated alone and in various combination. pvalue <0.05 was considered significant. AFB smear had the lowest diagnostic yield in both USG and CT guided aspirate (28 % and 17.2 % respectively). Histology/cytology combination with molecular method had 100 % diagnostic yield similar to all tests combined. Diagnosis of STB was ascertained in all cases using the combination of molecular methods and phenotypic tests and no single test is effective in ascertaining the diagnosis. The tissue obtained by percutaneous CT guided biopsy/USG guided aspiration technique is adequate to submit tissue to all tests to ascertain diagnosis. Show less

In recent years, young adults have navigated multiple, simultaneous crises - COVID-19, war in Ukraine, economic turbulence, climate change, and rapid AI growth - which pose complex mental-health risks. Drawing on multisystemic resilience models and the dual-factor model of mental health, we examine how individual (emotion-regulation difficulties), relational (attachment, social support), and contextual resources (social engagement, place attachment, socioeconomic status) relate to distinct emotional-response profiles and their change across three waves (July 2023, February 2024, September 2024) in a representative Polish sample ( The online version contains supplementary material available at 10.1186/s12992-026-01199-8. Show less

FGFRs genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in cancers, leading to the initiation and progression of tumors by enhancing FGFR signaling. The substantial problems arising from the lack of decisive clinical evidence have resulted in the cessation of some inhibitor applications, and identifying effective small molecule inhibitors that selectively target FGFRs can advance the therapy of cancers driven by FGFRs abnormalities. The three-dimensional structure of the FGFR1/2/3/4 protein and the amino acid positions within the tyrosine kinase domain were downloaded from the PDB database, and small molecule data were extracted from the ZINC15 database. Then, we used molecular docking and dynamics simulations to assess compounds interacting with FGFR proteins, and screening potential small molecules targeting FGFR. Finally, we evaluated its effects by two CRC cell line HCT116 and NCI-H716. In the study, by docking with 2.8 million small molecules, we identified three promising FGFR small molecule inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of the three compounds, we found that ZINC000101867325 could form the stable binding interactions with FGFR1/2/3. And, ZINC000101867325 inhibited the activity of FGFR signaling, and resulted in cell apoptosis and decrease in cell proliferation and migration in colorectal cancer cell lines. In addition, ZINC000101867325 is also predicted to target FGFR2 mutations in colorectal cancer patients. We predicted three small molecules targeting FGFRs, and ZINC000101867325 shows superior chemical bond types and stability with FGFR1/2/3, and inhibits FGFR signaling in CRC cell lines. This study provides novel FGFRs inhibitors, which enrich treatment strategies for cancers. Show less

The underlying mechanisms for exacerbated brain injury and poor recovery observed in patients with diabetes and ischemic stroke (IS) remain undetermined. We explored the role of microRNA-34a (miR-34a) in diabetic IS (DMIS) and ischemic postconditioning (IPOC)'s neuroprotective effects in tree shrews. We established a tree shrew DMIS model and exposed it to interventions, including miR-34a inhibition (antagomir), IPOC, and miR-34a overexpression (agomir). Infarct size and pathology were assessed via staining. Cellular/molecular changes (astrocytes, neurons, brain-derived neurotrophic factor [BDNF], Sine oculis homeobox 3 [SIX3], proliferation, apoptosis, axon formation) were analyzed using immunofluorescence, polymerase chain reaction (PCR), and Western blotting. In vitro, miR-34a's targeting of BDNF/SIX3 was validated, with rescue experiments testing regulation via these factors. Infarct size and neuronal damage were greater in the DMIS group than in the nondiabetic IS group. miR-34a inhibition or IPOC reduced infarcts, alleviated injury, improved cell survival, upregulated BDNF/SIX3, enhanced proliferation/axon formation, and reduced apoptosis. miR-34a overexpression reversed IPOC's benefits. In vitro, miR-34a directly targeted BDNF/SIX3, suppressing their expression; exogenous BDNF/SIX3 rescued neurotoxicity and restored function. IPOC exerts partial neuroprotection through miR-34a downregulation, highlighting miR-34a as a potential therapeutic target. Show less

To identify distinct latent frailty profiles using latent profile analysis (LPA) in patients undergoing radiotherapy for head and neck cancer (HNC) and to examine the factors associated with profile membership. A cross-sectional study. This research used data acquired from a major tertiary referral hospital in China. This study recruited 391 HNC patients receiving radiotherapy. Validated instruments included a demographic questionnaire, Charlson Comorbidity Index (CCI), Pittsburgh Sleep Quality Index, FRAIL Scale, Hospital Anxiety and Depression Scale and Perceived Social Support Scale. Profile membership associations were assessed using χ The frailty status of patients can be divided into three different categories: (1) robust group (23.0%), (2) prefrail group (49.6%) and (3) frail group (27.4%). Frailty demonstrated independent associations with nine clinical parameters in adjusted regression models: radiotherapy session frequency, social support, age, CCI score, educational attainment, metastasis, nutritional risk, radiation-induced injuries and serum albumin levels (p<0.05). The distinct frailty profiles identified by LPA can inform the future development of targeted care protocols for specific subgroups (eg, the frail group), with a focus on key predictors such as age and nutritional risk. Show less

Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to mediate these effects, and the gene clusters most responsive at each culture stage, remain poorly understood. To address this, we investigated the time-dependent effects of BDNF on the transcriptomes of cultured cortical neurons at different culture durations. We found that the magnitude of the transcriptomic response to a 6-h BDNF treatment, relative to untreated controls, increased with longer culture duration. Furthermore, a BDNF-induced shift towards a more mature-like transcriptional state was observed specifically in neurons cultured for shorter durations, suggesting a response dependent on the length of time in culture. Specifically, matrix metalloproteinase 3 (MMP3) was robustly induced by BDNF. Single-nucleus RNA sequencing (snRNA-seq) revealed that this induction was primarily localized to Lhx6-positive inhibitory neurons. Additionally, BDNF regulated the expression of various ligand and receptor genes through a combination of cell type-specific and non-specific mechanisms. These findings provide a comprehensive view of BDNF-mediated transcriptional regulation over the course of cortical neuron culture. Show less

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for more than two-thirds of cases in older adults. AD is associated with neuropsychiatric symptoms such as depression, anxiety, and sleep disturbances. The coexistence of AD with depression, in particular, poses serious challenges and often results in suboptimal outcomes with conventional therapies. The present study therefore aimed to investigate the therapeutic potential of escitalopram (ESC; SSRI) in combination with galantamine (GAL; AChE inhibitor) on key pathological pathways, including the neurotrophic system, hypothalamic-pituitary-adrenal (HPA) axis, kynurenine pathway, inflammation, and oxidative stress, in an animal model of AD comorbid with depression. Swiss albino mice were subjected to chronic mild stress (CMS) for 21 days and received intrahippocampal administration of amyloid-β peptide to mimic AD-depression comorbidity. Subsequently, ESC (10 mg/kg) combined with GAL (5 mg/kg) was administered orally for 20 days alongside the CMS protocol, followed by behavioral, biochemical, and histopathological assessments. The combined GAL + ESC treatment significantly alleviated depressive symptoms and improved working and spatial memory in CMS and amyloid-β-exposed mice. Furthermore, the therapy normalized hippocampal levels of BDNF, proinflammatory cytokines (IL-6, TNF-α), kynurenine metabolites (3-HK, QUIN), and oxidative stress markers toward those observed in the sham group. Histopathological analysis further confirmed the preservation of hippocampal integrity with combined therapy. Overall, the findings highlight the potential of ESC as an adjunct to GAL in ameliorating depressive symptoms and cognitive deficits, underscoring its promise for further clinical evaluation in the management of AD comorbid with depression. Show less

To explore the association between 24-h movement behaviours and fundamental motor skills in children with intellectual disabilities using compositional data analyses and to investigate the 'dose-effect' characteristics of the reallocation between 24-h movement behaviours and fundamental motor skills. A cross-sectional study was conducted among 306 children with intellectual disabilities aged 6-10 years from 12 special education schools in Beijing and Jinan between 10 September 2023 and 27 March 2024. The ActiGraph GT3X+ accelerometer was used to estimate the amount of time spent in 24-h movement behaviours. The Test of Gross Motor Development-2 was applied to assess fundamental motor skills. The compositional isotemporal substitution was utilized to analyse the relationship between 24-h movement behaviours and fundamental motor skills. (1) After controlling the gender, age and intellectual disability level, MVPA of children with intellectual disabilities was positively associated with their FMS total score, locomotor skills and object control skills (β Special education school administrators, teachers, parents and guardians should consider 24-h movement behaviours as a whole and pay attention to their impact on children with intellectual disabilities. In the process of promoting FMS in children with intellectual disabilities, ensuring adequate sleep and trying to reallocate time from SB to MVPA and LPA may be effective methods. Show less

Ulcerative colitis (UC) is subtype of inflammatory bowel disease that is frequently comorbid with anxiety disorders. However, effective dual-targeting therapies are still lacking. Hyperoside (HYP), a natural flavonoid, exhibits anti-inflammatory and neuroprotective properties, yet its potential therapeutic effects on UC and associated anxiety, as well as the underlying mechanisms, remain largely unexplored. A murine model of DSS-induced colitis was established and treated with HYP. Disease activity was assessed through body weight, colon length, and histopathology. Anxiety-like behaviors were evaluated using open field and elevated plus maze tests. Neuroinflammation was examined through immunohistochemistry of BDNF expression and microglial activation. Gut microbiota composition was profiled by metagenomic sequencing, and metabolomic profiling was conducted using the Q300 Kit. Network pharmacology and molecular docking were employed to predict signaling pathways, which were further validated by Western blotting. Additionally, antibiotic depletion experiments were conducted to determine microbiota dependency. HYP administration significantly ameliorated DSS-induced colitis, as evidenced by attenuated weight loss, restored colon length, and improved histopathology. It suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and restored intestinal barrier integrity by upregulating Mucin-2 and ZO-1. Furthermore, HYP also alleviated anxiety-like behaviors and mitigated neuroinflammation by increasing BDNF levels and suppressing microglial activation. HYP treatment also restored gut microbial homeostasis, enriching beneficial bacteria such as Our findings demonstrate that HYP effectively alleviates DSS-induced colitis and comorbid anxiety-like behaviors. Its efficacy is dependent on the gut microbiota and is associated with the restoration of microbial homeostasis, enhancement of arginine metabolism, and modulation of the MAPK/PI3K-Akt/NF-κB signaling pathways. HYP represents a promising microbiota-targeting therapeutic candidate for UC and its neuropsychiatric comorbidities. Show less

The Gram-negative outer membrane (OM) is an asymmetric bilayer that protects cells from environmental stress and antibiotics. This asymmetry, with lipopolysaccharide (LPS) in the outer leaflet and glycerophospholipids (GPLs) in the inner leaflet, requires coordinated synthesis of both lipid classes. The committed step of LPS biosynthesis is catalyzed by LpxC, a prime antibiotic target. Here, we show that lysophospholipids (LPLs), considered byproducts of membrane turnover, act as signaling molecules restoring OM homeostasis when LPS synthesis is limited. In the presence of the LpxC inhibitor PF-5081090 (PF), loss of the LPL recycling system increased growth, suppressed envelope stress responses, improved OM asymmetry, and lowered GPL levels to maintain GPL-to-LPS balance. This recycling system includes the transporter LplT, which moves LPLs across the inner membrane, and the acyltransferase/acyl-ACP synthetase (Aas), which acylates them to regenerate GPLs. These protective effects required the OM phospholipase PldA that degrades mislocalized GPLs into LPLs and free fatty acids. Although previous work showed that PldA-generated fatty acids stabilize LpxC and promote LPS synthesis, our findings reveal a complementary role for LPLs in signaling reduced GPL synthesis when LPS is limiting. Genetic and chemical manipulation of fatty-acid flux altered PF resistance, confirming that decreased GPLs drives protection. The two PldA-derived signals, fatty acids that promote LPS synthesis and LPLs that suppress GPL synthesis, likely operate under different metabolic conditions to interpret membrane stress and restore OM balance. This lipid-feedback mechanism establishes the first signaling function for bacterial LPLs and reveals a new layer of regulation in envelope homeostasis.IMPORTANCEThe multilayered cell envelope of Gram-negative bacteria provides natural resistance to antibiotics. Understanding cell envelope synthesis and regulation is crucial for the identification of new antimicrobial targets and improved drug design. LpxC inhibitors, a new and promising class of antibiotics, impede function of the committed enzyme in lipopolysaccharide synthesis. Here, we characterize a new mechanism of resistance to the LpxC inhibitor PF-5081090, where the accumulation of lysophospholipids signals a reduction in cellular glycerophospholipid levels to repair outer membrane balance. This work proposes a new pathway to restore outer membrane asymmetry, which is a critical aspect of cell envelope integrity, and describes a role for lysophospholipids in bacterial cell signaling when lipopolysaccharide synthesis is disrupted. Show less