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Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regulates hepatic DNL remains unclear. In this study, we investigated whether low-dose galactose supplementation attenuates glucose- or fructose-induced DNL activation and protects against fatty liver diseases driven by DNL overactivation, such as alcohol-associated liver disease (ALD). In this study, we used integrated hepatocyte and mouse models to assess hepatic DNL and related signaling under high-glucose or high-fructose conditions, with or without low-dose galactose. Pharmacological and genetic interventions targeting the Leloir and hexosamine biosynthetic pathways (HBP) defined underlying mechanisms. For in vivo validation, male C57BL/6 mice were fed an isocaloric control or ethanol-containing diet for 4 wk. We found that glucose engages the HBP-mTORC1-SREBP-1c axis to stimulate hepatic DNL, whereas fructose acts predominantly through carbohydrate-responsive element-binding protein (ChREBP). Low-dose galactose selectively suppressed glucose-induced hepatic fat accumulation, concomitant with the inhibition of the HBP-mTORC1-SERBP-1c pathway. These effects required an intact Leloir pathway for galactose metabolism and were not observed with fructose. In alcohol-fed mice, hepatic HBP-mTORC1-SREBP-1c signaling was markedly upregulated, contributing to steatosis and liver injury. Replacing even a small fraction of dietary glucose with galactose normalized these alterations, attenuating hepatic lipid accumulation and injury without altering systemic glucose levels. In conclusion, glucose-induced hepatic lipogenesis involves the HBP-mTORC1-SREBP-1c pathway, which is also activated during chronic alcohol exposure. Low-dose galactose, obtainable from dairy sources, attenuates this pathway, thereby limiting excessive lipogenesis and protecting against early-stage ALD. Show less

Unhealthy diets characterized by high salt, fat, and fructose content are established risk factors for metabolic and cardiovascular disorders and may have indirect effects on cognitive function. However, the combined impact of a high-salt, high-fat, and high-fructose diet (HSHFHFD) on systemic physiology and brain health remains to be fully elucidated. Sprague-Dawley (SD) rats received a customized high-salt, high-fat diet supplemented with 30% fructose water for 18 weeks. Physiological and brain parameters were assessed, in combination with multi-omics analyses including brain proteomics and metabolomics, serum metabolomics, and gut microbiota profiling. HSHFHFD significantly elevated blood glucose, blood pressure, and serum levels of TG, TC, and LDL in rats. Serum metabolomic profiling identified over 100 differentially abundant metabolites in the Model group. Proteomics, metabolomics, and gut microbiome integration revealed pronounced alterations in both brain proteomic and metabolomic profiles, with 155 differentially expressed proteins associated with glial cell proliferation and 65 differential metabolites linked to fatty acid and amino acid metabolism, among others. Experimental validation confirmed marked upregulation of GFAP and Bax protein, concomitant with downregulation of ZO-1 and occludin. Furthermore, HSHFHFD perturbed the CREB signaling pathway, leading to diminished BDNF expression. The levels of inflammatory factors, including IL-6, IL-10, IL-1β and TNFα, were significantly elevated in the brain. Oxidative stress was evident, as indicated by elevated malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) activity, and altered NAD HSHFHFD-induced depletion of gut Show less

Brain-derived neurotrophic factor (BDNF) is crucial for brain development, neuronal function, and metabolism. This systematic review aims to comprehensively examine the impact of various diets on BDNF levels, addressing gaps in understanding diet's influence on BDNF's role in neuroprotection and metabolism. This systematic review was conducted in accordance with PRISMA 2020 guidelines. An extensive search was conducted in PubMed, Web of Science, and Scopus up to April 2024, using terms related to diet and BDNF. Relevant clinical trials involving adults were included. Data extraction covered study design, participant details, and outcomes, with quality assessed using the Cochrane method. Clarifications from authors were sought as needed to ensure comprehensive analysis. This review examined 7633 articles to assess the impact of various diets on BDNF levels, narrowing down to 13 studies. The study found varying effects: intermittent fasting and ketogenic diets generally increased BDNF, while other diets showed minimal or no impact. The review highlights diverse outcomes and the need for further research on dietary effects on BDNF. The review found that fasting and calorie restriction diets generally increase BDNF levels, while other dietary interventions showed inconsistent effects. Further research is needed to better understand these dietary impacts on BDNF and to develop optimized strategies for enhancing cognitive health and managing obesity. Show less

Primary cilia orchestrate several signaling pathways, and their disruption results in pleiotropic disorders called ciliopathies. Bardet-Beidl syndrome (BBS), one ciliopathy, provides insights into cilia function in many tissues. Using a mouse model of BBS, Bbs4 knockout (Bbs4 Show less

Gynostemma pentaphyllum (GP) is known as the "elixir of life" in Guizhou Province, China, as it has been widely consumed by the elderly. Numerous studies have shown that gypenosides (GPS) extracted from GP are involved in lipid metabolism. Apolipoprotein E (ApoE) is a polymorphic protein with multiple biological functions, such as regulating lipid transport and iron metabolism. The deficiency of ApoE can lead to disorders in both lipid and iron metabolism. Therefore, ApoE knockout (ApoE We randomly divided C57BL/6 mice were randomly divided into blank group (WT), apolipoprotein E knockout group (ApoE KO/ApoE The results demonstrate that gypenosides reduce ApoE deficiency-induced iron accumulation by downregulating TfR1 (a cellular iron import protein) and upregulating Fpn1 (an iron export protein). In the spleen of ApoE Gypenosides can reduce tissue iron accumulation in the liver and spleen of ApoE-deficient mice, suggesting that, based on its function in regulating lipid metabolism, gypenosides also possess the potential ability to regulate iron metabolism. Show less

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with systemic manifestations, including cognitive impairment linked to gut‒brain axis dysregulation. While probiotic therapies show promise, their mechanisms in mitigating neuropsychiatric comorbidities remain unclear. Here, we investigated the therapeutic potential of Show less

Huntington's Disease (HD) is characterized by prominent degeneration of the principal neurons of the striatum and by progressive motor and cognitive deterioration. Striatal neurons degenerate in HD due to multiple cell-autonomous and non-autonomous factors. Impaired neurotrophin signaling by brain-derived neurotrophic factor (BDNF) and its cognate receptor Tropomyosin receptor kinase B (TrkB) is an important mechanism underlying neuronal loss in HD. Fingolimod, a clinically approved oral drug for Multiple Sclerosis, was originally developed based on its anti-inflammatory properties. Recent work suggests that fingolimod can also promote BDNF expression and enhance neurotrophic support in the brain. We hypothesized that fingolimod treatment initiated during the presymptomatic phase would increase striatal BDNF levels and protect against motor dysfunction in HD. In wild-type mice, fingolimod treatment increases striatal BDNF levels and enhances BDNF-TrkB signaling. However, chronic fingolimod therapy (0.1 mg/kg, i.p., twice per week, over 7 weeks) initiated at age 4 weeks in the R6/2 mouse model of HD failed to improve behavioral locomotor deficits and exacerbated limb clasping. Furthermore, fingolimod treatment in these presymptomatic R6/2 mice acutely decreased BDNF-TrkB signaling in the striatum in a dose-dependent manner. In contrast, acute administration of fingolimod in symptomatic 7-week-old R6/2 mice increased striatal BDNF-TrkB signaling in a dose-dependent manner, consistent with previous work suggesting that chronic fingolimod can improve motor behavior when given during the symptomatic phase. Thus, the effects of fingolimod striatal BDNF-TrkB signaling and motor behavior in HD are complex and vary with disease stage. Addressing this variability is critical for the design of neuroprotective drug trials in HD, including those utilizing sphingosine-1-phosphate receptor (S1P) modulators. Show less

The trend of global population aging is closely associated with a rising incidence of neurodegenerative diseases (NDs), including stroke, Alzheimer disease, Parkinson disease, and depression. These conditions, characterized by progressive neuronal loss, currently pose a significant challenge due to the lack of curative therapies. Brain-derived neurotrophic factor (BDNF) serves as a critical regulator of synaptic plasticity, a fundamental mechanism believed to underpin essential cognitive and motor functions such as learning, memory formation, and recovery. Decreased BDNF and deficits in BDNF signaling leads to the pathogenesis of NDs. Numerous studies support the therapeutic potential of acupuncture in managing NDs. Its beneficial effects are largely attributed to the ability to elevate BDNF expression and potentiate associated neurotrophic signaling. Beyond direct BDNF modulation, acupuncture exerts regulatory effects on specific micro-RNAs (miRNAs). This includes miRNAs that directly target BDNF transcripts for posttranscriptional control, as well as others that independently influence molecules critical for maintaining synaptic plasticity. The binding of acupuncture-elevated BDNF to its high-affinity receptor, Tropomyosin-related kinase B (Trk-B), initiates the activation of key downstream signaling cascades, including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) and phospholipase C-γ (PLCγ) pathways which are involved in synaptic plasticity, survival, proliferation and differentiation of neurons. In this review, we present the effects of acupuncture on BDNF, miRNAs and the downstream signal transduction pathways of BDNF in NDs and the review may partly elucidate the biological molecular mechanisms of acupuncture in the therapy of NDs. Show less

This study investigated the effects of "Luem Pua" black glutinous rice extract on behavior and neuronal integrity by assessing memory impairment, anxiety-like behavior, histology, as well as expression of brain-derived neurotrophic factor ( Show less

Depression is a widespread neuropsychiatric disorder that significantly impacts emotional and cognitive function. Antidepressant medications are frequently accompanied by various adverse effects. C-phycocyanin has been previously shown to exert potent anti-inflammatory, and neuroprotective properties. Therefore, this study evaluated the therapeutic effects of C-phycocyanin against anxiety and depressive-like behaviors, and memory dysfunction in an animal model of chronic unpredictable mild stress (CUMS)-induced depression and explored the underlying mechanisms. Rats were daily exposed for six weeks to CUMS, during which phycocyanin (100 mg/kg, orally) was administered in the final three weeks of the study. Following the assessment of anxiety/ depressive-like behaviors, and memory dysfunction by the open field test (OFT), tail suspension test (TST), elevated plus maze (EPM), and passive avoidance test (PAT), rats were euthanized by decapitation. Then, hippocampal TNF-α and IL-1β concentrations, and hippocampal protein expressions (Iba-1, CD86, NF-κβ, CREB, and BDNF) were determined by an ELISA assay, and western blots, respectively. C-phycocyanin significantly decreased immobility time in OFT and TST, increased open arm time in EPM, and step-through latency time in PAT. Furthermore, C-phycocyanin suppressed CUMS-induced the M1 microglia polarization and neuroinflammation by reducing hippocampal TNF-α and IL-1β concentrations, and the protein expression of Iba-1, CD86, and NF-κβ in the hippocampus of CUMS-exposed rats. It also increased the hippocampal protein expression of CREB and BDNF. C-phycocyanin improved CUMS-induced anxiety and depressive-like behaviors, and memory dysfunction, which could be explained, at least in part, by inhibition of M1 microglial polarization and neuroinflammation, and enhancement of CREB/BDNF signaling. Show less

Psoriasis and atopic dermatitis (AD) are two prevalent inflammatory skin disorders, each characterized by distinct adaptive immune responses. However, recent evidence suggests that these diseases may share overlapping immune mechanisms, especially concerning keratinocyte function. The specific cytokines that coordinate these inflammatory pathways remain largely undefined. The expression of IL-27 and its receptor was analyzed using data derived from GEO datasets. Imiquimod-induced psoriasis-like and MC903-induced AD-like skin inflammation models were established in wild-type and Il27ra knockout littermates. Skin inflammation was evaluated using clinical scoring, histology, and immunostaining. Flow cytometry was employed to characterize immune cell populations in skin. Expression of relevant cytokines and signaling molecules was assessed using quantitative PCR, bulk RNA sequencing, and Western blotting. We found significantly elevated expression of the IL-27 receptor in the lesional skin of patients with psoriasis or AD. IL-27 receptor-deficient mice exhibited markedly reduced skin inflammation in both psoriasis-like and AD-like murine models. Mechanistic investigations revealed that IL-27 induces tumor necrosis factor-α production via signal transducer and activator of transcription 1 activation in keratinocytes, thereby potentiating inflammatory responses. Our findings identify IL-27 signaling in keratinocytes as a pivotal regulator of skin inflammation in both psoriasis and AD. This highlights IL-27 as a promising therapeutic target for inflammatory skin diseases. Show less

TrkB, a receptor tyrosine kinase encoded by gene NTRK2, is essential for diverse biological processes in both the developing and mature mammalian nervous systems. Whole exome sequencing of children with developmental epileptic encephalopathy revealed an intriguing syndrome caused by a rare de novo recurrent variant of TrkB, namely Y434C. Investigating the biochemical properties of the Y434C mutant protein is an important initial step toward understanding how this mutation causes this devastating disease. This led us to establish and characterize multiple cell lines stably expressing mouse WT or Y434C TrkB. In comparison to WT, Y434C mutant cell lines expressed low to undetectable levels of mature form (145 kDa) of TrkB protein and varying levels of mutant forms migrating at sizes ranging from 40 to 110 kDa. Y434C mutant cell lines exhibited striking impairments of brain-derived neurotrophic factor-mediated activation of TrkB signaling. Reducing agents reduced high molecular weight forms of Y434C protein multimers detected in protein gel electrophoresis, consistent with disulfide bond formation between the Y434C mutant proteins. We propose that conversion of tyrosine to cysteine at amino acid 434 results in a novel intermolecular disulfide bond between Y434C mutant proteins, thereby modifying their structure and enhancing their proteolytic digestion. The ensuing reductions of the mature form of TrkB likely underlie impaired TrkB signaling. The proteolytic fragments of TrkB may themselves have deleterious consequences, which contribute to the phenotypic manifestations of the Y434C TrkB mutation. Show less

This review article summarizes the available data about the potential link between war-related trauma and post-traumatic stress disorder (PTSD) and epigenetic alterations that could manifest in future generations. DNA methylation variations in stress-related genes such FKBP5, NR3C1, NR3C2, BDNF, and SLC6A4 have been seen in parents and/or their offspring in populations exposed to genocide, conflict, or combat. Certain results point to timing-dependent or parent-specific patterns, especially when maternal stress occurs during pregnancy. Results, however, are not consistent; some studies have found no significant differences in methylation, and the effects that are seen vary depending on the tissues, methods, and populations. Conclusions about causality or genuine inheritance are limited by the majority of existing studies' small sample sizes, cross-sectional designs, and inadequate control of environmental and psychosocial variables. Overall, existing research suggests potential links between epigenetic variation and war-related trauma, but clear evidence for transgenerational inheritance is still unconclusive, underscoring the need for more thorough and longitudinal studies. Show less

Perinatal psychological stress significantly impacts maternal and fetal health through complex molecular pathways, yet the biological basis of digital health interventions for pregnant and postpartum women remains poorly understood. This study investigated molecular effects underlying digital psychological intervention effectiveness through cell culture experiments, animal models, and computational biomarker analysis relevant to obstetric populations. Cell culture studies using stress-responsive cellular models revealed that glucocorticoid exposure induced NR3C1 upregulation (2.3-fold, p = 0.003), FKBP5 elevation (3.1-fold, p < 0.001), and IL6 increase (2.7-fold, p = 0.002), while BDNF decreased by 39% (p = 0.012) and SLC6A4 decreased by 48% (p = 0.009). Intervention-simulating treatment partially restored BDNF expression to 0.85-fold of control levels (p = 0.023) and reduced IL6 to 1.4-fold above control (p = 0.007). Animal model validation confirmed that hippocampal BDNF showed 45% reduction under chronic stress (p < 0.001) with recovery to 82% following intervention (p = 0.009), while serum corticosterone decreased from 243.7 ± 42.1 ng/mL to 132.6 ± 28.4 ng/mL after intervention (p < 0.001). Machine learning ensemble methods achieved the highest predictive accuracy for intervention responsiveness with AUC of 0.91 (95% CI: 0.88-0.94). Regional biomarker screening across 2,847 individuals identified 23 biomarkers with significant predictive contributions (Bonferroni-corrected p < 0.01). These findings provide molecular frameworks for understanding digital psychological intervention effectiveness in perinatal care and support evidence-based personalized intervention strategies for pregnant and postpartum women. Show less

Individuals with atrial fibrillation (AF) are at increased risk of stroke, cognitive impairment and dementia. Observational studies suggest that anticoagulation may reduce the risk of cognitive decline in patients with AF and elevated thromboembolic risk, implicating subclinical cerebral emboli as a potential mechanistic link. Whether anticoagulation prevents cognitive deterioration in patients with AF at low risk of stroke remains uncertain. Here we conducted a multicenter, double-blind, placebo-controlled trial in which participants with AF and low thromboembolic risk (CHA Show less

Mounting evidence implicates inflammation as a key factor in Alzheimer’s disease (AD) development. We previously identified pro-inflammatory soluble epoxide hydrolase (sEH) metabolites to be elevated in plasma and CSF of AD participants and to be associated with lower cognition in non-AD subjects. Soluble epoxide hydrolase is a key enzyme converting anti-inflammatory epoxy fatty acids to pro-inflammatory diols, reported to be elevated in multiple cardiometabolic disorders. Here we analyzed over 700 fasting plasma samples from the baseline of Alzheimer’s Disease Neuroimaging Initiative (ADNI) 2/GO study. We applied targeted mass spectrometry method to provide absolute quantifications of over 150 metabolites from oxylipin and endocannabinoids pathway, interrogating the role for inflammation/immune dysregulation and the key enzyme soluble epoxide hydrolase in AD. We provide further insights into the regulation of this pathway in different disease stages, APOE genotypes and between sexes. Additionally, we investigated in mild cognitive impaired (MCI) participants, metabolic signatures that inform about resilience to progression and conversion to AD. Key findings include I) confirmed disruption in this key central pathway of inflammation and pointed to dysregulation of sEH in AD with sex and disease stage differences; II) identified markers of disease progression and cognitive resilience using sex and ApoE genotype stratified analysis highlighting an important role for bile acids, lipid peroxidation and stress response hormone cortisol. In conclusion, we provide molecular insights into a central pathway of inflammation and links to cognitive dysfunction, suggesting novel therapeutic approaches that are based on targeting inflammation tailored for subgroups of individuals based on their sex, APOE genotype and their metabolic profile. The online version contains supplementary material available at 10.1186/s13195-025-01939-9. Show less

This study investigated effects of prenatal exposure to diazepam on maternal and caregiving behaviors in rats postpartum.Twenty-four female rats were randomly divided into two groups: diazepam group and control group. Diazepam was administered during, and maternal behaviors were observed and recorded after delivery. Serum corticosterone levels during pregnancy, GABAARα1 expression, and serotonin and BDNF concentrations were measured in hippocampus and prefrontal cortex of the dams. The results showed that mothers exposed to diazepam exhibited a significant reduction in self-grooming (p = 0.0016), nursing (p < 0.0001), and nest-building behaviors (p < 0.0001) compared to the control group. Additionally, diazepam group showed fewer instances of pup retrieval (p = 0.0032) and licking (p = 0.0019). A significant increase in the latency to retrieve pups was observed in the diazepam group (p < 0.0001). The findings demonstrate a significant decrease in GABAARα1 mRNA expression within the prefrontal cortex (P = 0.0023) and hippocampus (P = 0.0138) of diazepam-treated group compared to the control group. Dams in the diazepam group exhibited significantly lower serum corticosterone levels at gestational day 20 (p = 0.0288) and postnatal day 1 (p = 0.0009) compared to the control group. Additionally, serotonin concentration in the prefrontal cortex (p = 0.0036) was significantly reduced in the diazepam group relative to controls.The present study demonstrated that prenatal diazepam exposure significantly impaired maternal caregiving behaviors in rats. These behavioral deficits were associated with disrupted serum corticosterone levels, diminished prefrontal serotonin concentrations, and reduced GABAARα1 mRNA expression in the prefrontal cortex and hippocampus. The findings suggest that diazepam interferes with neurochemical pathways critical for maternal motivation, potentially weakening maternal-infant bonding. Show less

The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we retrospectively characterized the genomic landscape of 105 pediatric patients with AML of East Asian ancestry using transcriptome and whole-exome sequencing (WES). In addition to the common recurrent fusions such as RUNX1::RUNX1T1 and CBFB::MYH11, we identified rearrangements involving KMT2A, NUP98, GLIS, as well as FLT3 and UBTF tandem duplications. The median somatic mutation rate in AML was 0.97 per megabase, as estimated by WES. Frequently mutated pathways included signaling: 68.6% (72/105), transcription: 37.1% (39/105), epigenetic regulation: 26.7% (28/105), cohesin: 7.6% (8/105), RNA binding: 3.8% (4/105), and protein modification: 5.7% (6/105). When analyzed together, high-risk genetic subtypes including GLISr, UBTF tandem duplications, PICALM::MLLT10, and HOXr were significantly associated with poorer 5 year overall survival (OS) in multivariable analysis (p-value = 0.037). Although FLT3 internal tandem duplications were significantly associated with inferior 5 year OS in univariable analysis, this effect was not significant in multivariable analysis (p-value = 0.382). Patients with RUNX1 mutations had inferior 5 year OS in multivariable analysis (p-value = 0.009). These findings suggest specific genomic alterations that may refine risk stratification and guide future therapeutic protocols in Taiwanese pediatric patients with AML. Show less

ObjectiveColorectal cancer (CRC) patients with high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) had heterogeneous pathology and distinct prognoses. This study aimed to examine the difference in the gene expression profile of dMMR/MSI-H CRC patients with different disease stages and explore the different molecular mechanisms of disease progression.MethodsA total of 47 patients with dMMR/MSI-H CRC were enrolled and retrospectively studied, including 27 stage II and 20 stage IV patients. Each patient had paired tumor tissue and white blood cell samples, which were analyzed by next-generation sequencing (NGS) of 416 cancer-relevant genes. Pathway enrichment analysis was then performed to analyze the disease stage-specific signaling pathways.ResultsA total of 2878 mutation sites, spanning 378 mutated genes, were detected from the 47 dMMR/MSI-H CRC patients. The mutation frequencies of SMARCA4, EPHA3, MTHFR, RAD50, and PDGFRB were significantly higher in stage II patients than in stage IV patients ( Show less

During a normal pregnancy, the body undergoes several physiological adaptations, and a woman's body weight and size change rapidly over a short period of time. Pregnancy may be associated with increased susceptibility to developing body image dissatisfaction, which can have negative consequences for the mother (e.g., depression, eating disorders) and the child (e.g., childhood obesity). Women who were already overweight/obese prepregnancy appear to be particularly at risk, as they are often dissatisfied with their body image already before pregnancy. This study aims to investigate the relationship between prepregnancy overweight/obesity, gestational weight gain (GWG), and body image as assessed immediately after birth. This is a cross-sectional observational study. Body image was assessed in healthy pregnant women (N = 197) using the German version of the Body Image in Pregnancy Scale (BIPS-G). Univariate analyses of variance and hierarchical linear regression analyses were conducted to examine the association between prepregnancy weight, GWG, and the subscales of the BIPS-G. Additionally, a latent profile analysis (LPA) was conducted. Overall, women with prepregnancy obesity and GWG above recommendations were more dissatisfied with certain aspects of their body image during pregnancy. The strongest association was found between prepregnancy obesity and the subscale preoccupation with appearance. The LPA revealed three distinct profiles. Women with obesity and overweight and with GWG above recommendations were more likely to have a profile characterized by increased body image concerns during pregnancy. It is important to implement psychological, behavioral, and weight-related interventions in women who are already overweight and obese prior to pregnancy. Show less

Endometriosis-associated ovarian cancer (EAOC), encompassing subtypes like ovarian clear cell (OCCC) and endometrioid (OEC) carcinoma, represents a distinct Type I malignancy arising from endometriotic lesions. These tumors are characterized by a specific molecular landscape, including high-frequency driver mutations in genes such as ARID1A, PIK3CA, and PTEN. Within this setting, the role of estrogen receptor β (ERβ), whose expression is progressively upregulated during malignant transformation, requires a nuanced re-evaluation. This review repositions ERβ not as a primary oncogenic driver, but as a critical, spatiotemporal modulator. Its principal function appears to be potentiating pro-survival signaling, such as the PI3K/AKT pathway, within a cellular environment already primed by constitutive genetic alterations. Furthermore, ERβ appears to couple apoptosis resistance with microenvironmental remodeling and metastatic programming. We further dissect the role of the downstream ERβ–brain-derived neurotrophic factor (BDNF)/Tropomyosin receptor kinase B (TrkB) signaling axis, proposing it as a key cooperative network that provides parallel and compensatory survival signals. The central thesis is that the significance of this axis is profoundly context-dependent, and its roles should be interpreted alongside the tumor’s underlying genomic status. Finally, we outline translational prospects, arguing that targeting this pathway will require precision medicine strategies, including composite biomarkers and rational combination therapies. These strategies should be tailored to the specific molecular subtype of each patient’s tumor. Show less

The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventional computational prediction tools often overlook disease-specific pathophysiological contexts and lack pertinence and interpretability. Therefore, the present study aimed to develop a novel, interpretable framework for predicting the pathogenicity of AD missense variants by integrating transcriptomic and proteomic data enrichment patterns with machine learning methods. A cross-sectional variant-level analysis was performed using publicly available databases. Missense variants in APOE, APP, PSEN1, PSEN2, SORL1, and TREM2 reported in AD patients were retrieved from Alzforum and compared with missense variants from individuals without neurological diseases, as cataloged in the gnomAD v2.1.1 non-neuro subset. Variants were annotated with tissue-specific expression, secondary structure, relative solvent accessibility, and other functional features using tools like AlphaFold. Enrichment of specific features was assessed with Fisher's exact tests with Bonferroni correction for multiple comparisons. Given that PSEN1 showed the strongest enrichment signals, six machine-learning algorithms were trained on PSEN1 variants to distinguish AD-associated variants from gnomAD variants, using a 10 × 5 nested cross-validation scheme. External validation was conducted using PSEN1 missense variants from ClinVar annotated as pathogenic/likely pathogenic or benign/likely benign. Model performance was compared with SIFT and PolyPhen-2, and interpretability was evaluated by feature ablation and SHapley Additive exPlanations analyses. AD-associated variants exhibited statistically significant enrichment within some transcriptomic or proteomic features, with PSEN1 contributing significantly to the enrichment observed across these features. Random forest and gradient boosting models achieved high performance in the internal training dataset and maintained high recall in the external validation dataset, outperforming SIFT and approaching the performance of PolyPhen-2. Relative solvent accessibility was the most discriminative individual feature, while regional and topological features provided complementary discriminative power. This integrative, multi-omics framework links disease-specific enrichment patterns with interpretable gene-level machine learning for AD missense variants. The results highlight the importance of expression level, structural context, etc. for PSEN1 variant pathogenicity and may help prioritize variants for functional studies. Further validation in additional genes and independent cohorts is warranted prior to any clinical application. Show less

Chronic myocardial ischemia (CMI) is a key pathological condition in coronary artery disease (CAD), yet small animal models for CMI are limited. This study developed and characterized a CMI mouse model using ApoE-/- mice fed a high-fat diet for 3 months. Cardiac function was assessed through electrocardiography (ECG), myocardial action potential, and perfusion echocardiography. The model group exhibited elevated cholesterol, aortic lipid plaques, and T-wave flattening, correlated with atherosclerosis severity. Impaired myocardial perfusion, reduced ATP content, and accelerated inner cardiomyocyte repolarization were also observed. PET/CT scans revealed filling defects, while myocardial contractile function showed reactive suppression under CMI conditions. This model replicates CMI's pathological features, providing a valuable tool for studying CAD progression and treatment. Show less

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single exposure to the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, 7 days of repeated intranasal administration of gangliosides GM1 or GD3 24 h after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 may offer a preventative strategy against organophosphate-related alterations in these brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological and psychiatric deficits associated with a class of poisons that endangers millions of people worldwide. Show less

The potential role of artificial sweeteners in eosinophilic esophagitis (EoE) remains poorly understood. This study aimed to investigate the molecular mechanism by which saccharin might exacerbate EoE. We integrated network toxicology with machine learning approaches to identify core pathogenic genes of EoE. The interactions between saccharin and the predicted targets were validated via molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR). Our analysis identified MAPK3, CPS1, and HS3ST1 as potential EoE-related targets of saccharin. Molecular docking demonstrated strong binding affinities between saccharin and these proteins, which was confirmed by stable binding via molecular dynamics simulations. Further SPR analysis revealed that saccharin binds directly to MAPK3. This study demonstrated that saccharin potentially aggravates EoE by directly targeting MAPK3 to activate pro-inflammatory pathways, highlighting a novel dietary risk factor and underscoring the need for a safe reevaluation for susceptible populations. Show less

This study explores the therapeutic potential of hydrogel-encapsulated neurospheres derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) in mitigating traumatic brain injury (TBI) and enhancing functional recovery in a rodent model. Trans-septal (intranasal) transplantation of these neurospheres demonstrated significant neurological improvement, reduced neuronal damage, and preserved neuronal structures and functions. The hUC-MSCs cultured in a customized bioreactor retained essential MSC characteristics, including marker expression and multi-lineage differentiation potential, ensuring their therapeutic efficacy. Following neural induction, hUC-MSCs formed neurospheres that promoted cell aggregation, differentiation, and neuroprotective effects. Encapsulation within a hydrogel provided a stable environment, significantly reducing TBI-induced cell death in co-cultured HT22 cells and improving Show less

Lp(a) is a genetically determined lipoprotein targeted by emerging therapies. In a UK Biobank analysis (1,026 abdominal aortic aneurysm [AAA] cases, 469,989 controls), elevated Lp(a) was associated with increased risk of AAA, including at clinically relevant thresholds while controlling for traditional risk factors, including ApoB. Multivariable Mendelian randomization confirmed a causal relationship between lipoprotein(a) [Lp(a)] and AAA independent of apolipoprotein B. These findings support Lp(a) as a modifiable risk factor and potential therapeutic target for AAA, a condition with limited medical treatment options. AAA should be considered as an outcome in future clinical trials of Lp(a)-lowering therapies. Show less

Excessive stress leads to injury and dysfunction, but the underlying mechanism remains unclear. As a human longevity gene, forkhead box O3a (FoxO3a) is a transcription factor that regulates various cellular processes, including the response to oxidative stress, apoptosis, and autophagy. This study aims to explore whether FoxO3a in the dentate gyrus (DG) of the hippocampus is involved in the formation of anxiety- and depressive-like behavior and cognitive impairment in stressed rats and to investigate the detailed mechanism. This study was conducted using the 6-week chronic unpredictable stress (CUS) model. Before the stress treatment, we injected an adeno-associated virus (AAV) vector to overexpress FoxO3a specifically in the DG. Following the 6-week CUS treatment, a series of behavioral tests was conducted. Depression-like behavior was assessed using the sucrose preference test (SPT) and the open field test (OFT). The state of desperation was assessed with the forced swim test (FST) and tail suspension test (TST). Anxiety-like behavior was measured in the elevated plus maze (EPM) and OFT. Cognitive function was examined using the Y-maze test (Y-maze), novel object recognition test (NORT), and Morris water maze test (MWM). The level of reactive oxygen species (ROS) and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured. The levels of inflammatory factors were detected by ELISA. Pathological injury in DG was observed using thionine staining. The expression levels of FoxO3a, brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), synaptophysin (SYN), and proliferation marker Ki67 (Ki67) were determined using western blot. CUS leads to various abnormal changes, including anxiety- and depressive-like behavior, cognitive impairment, oxidative stress, neuroinflammation, neuropathological alterations in the DG, and decreased expression of FoxO3a, BDNF, PSD95, SYN, and Ki67. All these abnormal changes were significantly alleviated by targeted AAV-FoxO3a injection in the DG. In conclusion, our study demonstrates that the downregulation of FoxO3a induced by CUS in the DG triggers oxidative stress and inflammatory response, inhibits cell proliferation, and induces abnormal synaptic plasticity, ultimately leading to anxiety- and depressive-like behaviors and cognitive impairment. Show less

Repetitive traumatic brain injury (RTBI) refers to brain injuries resulting from an external mechanical force causing cumulative and frequently severe neurological consequences. This study aimed to explore the neuroprotective effect of alogliptin (ALO) on RTBI-provoked endoplasmic reticulum (ER) stress and investigate the potential underlying mechanisms. For RTBI induction, rats were exposed to a sharp-edged weight at the right interior frontal area of the right cortex, one drop per day for five successive days. ALO (20 mg/kg/day, p.o.) was administered for one week. Results depicted that ALO recovered motor abnormalities and enhanced motor coordination in the open field test, decreased immobility and increased climbing time in the forced swimming test, and corrected histological aberrations. Moreover, ALO counteracted RTBI-triggered ER stress via suppression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), aggregation of β-amyloid and Tau proteins, as well as elevation of the cortical content of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrKB). ALO also exhibited an antioxidant and anti-inflammatory potential in addition to its effect on the gene expression of miRNAs (miRNA-322 and miRNA-125b). In conclusion, ALO exhibited a neuroprotective effect by mitigating ER stress induced in an RTBI rat model. Show less