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After feeding carnivorous mandarin fish ( Compared to the easy-acclimation group (EA), the difficult-acclimation group (DA) exhibited significantly lower body weight and length ( The results of this study indicate that the observed differences in growth performance post-acclimation are associated with the synergistic regulation of brain gene expression, host metabolites, and intestinal microbiota. These results elucidate key molecular mechanisms in the acclimation process of mandarin fish. The online version contains supplementary material available at 10.1186/s12864-025-12446-4. Show less

This study aims to evaluate 5-(but-1-en-1-yl)-1,2,3-trimethoxybenzene (BETMB) as a novel dual-target anti-seizure agent for refractory epilepsy and elucidate the synergistic neuroelectrophysiological mechanism between Na Whole-cell patch-clamp recordings characterized BETMB's dual-target activity. Antiseizure efficacy was assessed in maximal electroshock (MES), pentylenetetrazole (PTZ), and kainic acid (KA) models. Cognitive function in chronic KA mice was evaluated using the Morris water maze (MWM). Histopathological, immunohistochemical, and Western blot analyses explored neuroprotection. Synergy between Na BETMB acted as a GABA BETMB is a promising dual-target therapy for refractory epilepsy, supported by the first electrophysiological evidence that dual modulation of GABA Show less

Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to cancer progression remain poorly understood. Here, we identified a lung cancer-specific chimeric RNA KANSL1-ARL17A (chKANSARL) and its circular variant fusion circular RNA KANSL1-ARL17 A (F-circKA), both derived from the fusion gene KANSARL. Functional assays revealed that overexpression of either chKANSARL or F-circKA significantly enhanced lung cancer cell proliferation, migration, and invasion, while their knockdown suppressed these malignant phenotypes. In vivo experiments demonstrated that chKANSARL overexpression accelerated tumor growth in immunodeficient mice. Notably, coexpression experiments uncovered a synergistic regulatory interaction between F-circKA and chKANSARL, amplifying oncogenic effects. Mechanistically, miRNA sequencing and dual-luciferase assays revealed that F-circKA acts as a molecular sponge for miR-6860, thereby derepressing chKANSARL expression. Rescue experiments further validated this regulatory axis, wherein miR-6860 inhibition reversed the tumor-suppressive effects of F-circKA knockdown. Collectively, our study identifies and characterizes a novel F-circKA/miR-6860/chKANSARL regulatory axis, revealing how dual transcriptional outputs from the KANSARL fusion gene can synergistically drive lung cancer progression. These findings highlight a previously unrecognized layer of cooperative regulation between linear and circular fusion RNAs in oncogenesis and provide a new framework for understanding fusion gene-mediated tumorigenesis. Show less

Limited data support the beneficial effects of fecal microbiota transplantation (FMT) against intracranial ischemic injury under chronic cerebral hypoperfusion (CCH). However, a comprehensive understanding is lacking, hindering its clinical translation. In the present study, we evaluated microbial, metabolic, cellular, and behavioral alterations to explore the roles and mechanisms of FMT in hippocampal neurogenesis under CCH. Rats underwent bilateral common carotid artery occlusion to induce CCH. Intestinal microbiota (IM) and fecal/hippocampal metabolites were assessed by 16S ribosomal RNA sequencing and untargeted liquid chromatography-mass spectrometry, respectively. Potential molecular pathways and differentially expressed genes in the hippocampus were identified by RNA sequencing and verified by western blot, immunofluorescence, and dual-luciferase reporter assays. Neurogenesis was quantified by BrdU/DCX, BrdU/nestin, BrdU/GFAP, and BrdU/NeuN labeling. Cognitive function was evaluated with the Morris water maze. FMT altered IM composition by enriching Verrucomicrobiae, Ruminococcaceae, Akkermansiaceae, Turicibacter, Akkermansia, Verrucomicrobiales, Oscillospirales, Verrucomicrobiota, and Akkermansia_muciniphila. These shifts were associated with significantly elevated metabolites in tryptophan- and arginine-related pathways, including fecal L-tryptophan and hippocampal L-arginine, L-glutamine, indolepyruvate, indoleacetaldehyde, and kynurenic acid. Furthermore, FMT potentiated the Wnt3a/β-catenin/Neurog2/BDNF pathway, promoting hippocampal neurogenesis. FMT-induced activation of Wnt3a/β-catenin/Neurog2 signaling also up-regulated hippocampal C3 expression, contributing to neurogenesis and cognitive recovery under CCH. These findings provide evidence that FMT exerts protective effects against CCH insult through Wnt3a-mediated neurogenesis. Show less

Studies suggest that obesity is linked to both autonomic nervous system dysfunction and cognitive impairment, but the specific quantitative associations are not well explored. This study was proposed to explore the quantification of different neurocognitive signatures and heart rate variability (HRV) parameters with increasing body weight among metabolically healthy obese participants for better analytical predictors. The present research is a cross-sectional study, including a total of 101 ( Significant changes were observed for neurocognitive performances and HRV indices for the metabolically healthy obese group compared with the control group. With the association heatmaps, BMI was found to be significantly negatively associated with the BDNF and high-frequency band (HF band, ms The findings of the present study support that HRV could be a valuable early non-invasive tool for future cognitive decline in a population with metabolically healthy obesity. The study was registered at Clinical Trial Registry of India (CTRI/2022/10/046935). Show less

Depression induce by chronic neuroinflammation disrupts daily life and work, underscoring the importance of its treatment. It this study, depressive- and anxiety-like behaviors were induced in mice by injecting bacillus Calmette-Guérin (BCG), resulting from chronic neuroinflammation. Daily stimulation with specific acupuncture points (Baihui and Yintang, GV20 and GV29) with electroacupuncture (EA) for 14 days significantly alleviated depressive- and anxiety-like behaviors. Additionally, it also markedly reduced the levels of pro-inflammatory cytokines, including interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, as well as inflammatory markers such as cyclooxygenase-2, in both the plasma and hippocampus. EA Stimulation significantly increased brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. Our results demonstrated that EA stimulation improved depression- and anxiety-like behaviors induced by chronic inflammation, an effect associated with the decreased expression of BDNF via regulation of NF-κB pathway. Show less

BackgroundSedentary behavior is common in older adulthood and is associated with poor health outcomes. Less is known about how sedentary behavior relates to cognition in older adulthood and how it relates to increased risk for cognitive decline associated with Alzheimer's disease (AD).ObjectiveWe sought to examine these associations in a large, population-based cohort of community-dwelling older adults residing in a Rust Belt region of the United States.MethodsA subset of the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) participants (n = 193) completed 7 days of wrist-accelerometry following comprehensive neuropsychological assessment. Cross-sectional linear regression models related sedentary time to domains of cognition. Models were adjusted by age, sex, education, and Show less

Major depressive disorder (MDD) remains a leading cause of disability worldwide, and innovative adjunctive strategies are needed to enhance treatment outcomes. This critical appraisal examines a recent pilot study by Decker et al., which evaluated a 10-12 week well-formulated ketogenic diet (WFKD) as an adjunct therapy for college students with MDD. In this uncontrolled cohort (n = 16 completers), mean PHQ-9 and HRSD scores decreased by approximately 69-71% (p < 0.001), accompanied by notable improvements in self-reported wellbeing, cognitive performance, body composition, and metabolic biomarkers (e.g., leptin reduction, BDNF increase). These findings suggest that metabolic interventions may exert clinically meaningful antidepressant effects comparable to conventional therapies. However, as a single-arm study with a small, self-selected sample, causality cannot be established, and placebo effects or concurrent counseling may have contributed to outcomes. The authors appropriately call for larger, randomized controlled trials with longer follow-up and diverse populations to confirm efficacy, explore underlying mechanisms (e.g., neuroinflammation, gut-brain axis modulation), and optimize implementation. If validated, integrating dietary strategies into psychiatric and college counseling programs could offer a low-risk, holistic approach to improving mental health outcomes. Show less

Growing evidence suggests that women with endometriosis may be particularly vulnerable to disordered eating behaviors (DEBs) and clinically defined eating disorders (EDs). This narrative review aims at integrating and critically analyzing the current evidence regarding the relationship between endometriosis and EDs, as well as highlighting the psychosocial and neurobiological vulnerabilities of women with endometriosis to DEBs. A large-scale genetic study showed a nearly threefold increase in the odds of EDs in women with endometriosis, and a significant genetic correlation. Although the prevalence of formal ED diagnoses appears low in small clinical samples, DEBs such as emotional eating, binge tendencies, and maladaptive dietary restriction, are common and strongly associated with pain intensity, and borderline BMI. Psychological factors, including body image disturbance, heightened self-criticism, emotional dysregulation, and the need for control further contribute to the vulnerability to EDs. At the biological level, the dysregulation of leptin, endocannabinoids, dopamine, brain-derived neurotrophic factor, and inflammatory cytokines, molecules involved in both appetite regulation and some aspects of the pathophysiology of endometriosis, suggests overlapping neuroimmune pathways that may link endometriosis to DEBs and EDs. Clinical management must, therefore, integrate screening for DEBs, supervised and personalized dietary counseling, balanced exercise prescription, and psychological interventions targeting pain coping, emotion regulation, and body image. A multidimensional, biopsychosocial framework is essential to prevent the onset or exacerbation of EDs in women with endometriosis. Show less

Parenting behaviors, including autonomy support and psychological control, have been shown to significantly influence adolescent non-suicidal self-injury (NSSI). However, the underlying mechanisms linking heterogeneous parenting behavior profiles to adolescent NSSI remain unclear. This two-wave longitudinal study (with a one-year interval) of 742 Chinese adolescents (52.7% girls; Mage at Time 1 = 13.40 years) identified four distinct parenting profiles using latent profile analysis (LPA): Supportive (43.6% of the sample), Controlling (17.4%), Moderate Mixed Parenting (33.1%) and High Mixed Parenting (5.9%). Multicategorical serial mediation analysis revealed that adolescent emotion regulation difficulties and depressive symptoms serially mediated the relationship between parenting profiles and NSSI for adolescents in the Controlling, Moderate Mixed Parenting and High Mixed Parenting Profiles. Notably, these mediating effects were significant only for girls. These findings underscore the importance of adopting person-centered and sex-sensitive intervention strategies to mitigate the adverse effects of detrimental parenting behaviors on adolescent NSSI. Show less

Coronary artery disease (CAD) has been associated with elevated Lp(a) levels, yet the mechanism driving the pro-atherogenic and inflammatory effects remains unclear. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of lipid metabolism with emerging roles in vascular inflammation. This study explored the relationship between Lp (a) and PCSK9 in an Asian cohort with angiogram-proven premature CAD (AP-pCAD), with and without familial hypercholesterolemia (FH). Patients were recruited from Cardiology and Specialist Lipid Clinics; grouped into pCAD with FH ( Show less

Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood. Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E ( We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E ( Show less

Mild traumatic brain injury can disrupt brain function and is associated with high morbidity and healthcare utilization. While many individuals recover from mild traumatic brain injury, a significant proportion experience long-term sequelae, collectively known as post-concussion syndrome. Symptoms of post-concussion syndrome include headache, dizziness, insomnia, cognitive processing difficulties and mental health disturbances. The disease burden is augmented by the current lack of objective measures to accurately predict long-term symptoms and deficits, providing an opportunity to utilize biomarkers in biofluids. A large proportion of available diagnostic clinical tools are subjective symptom scores. This review aims to explore current fluid biomarkers, grouped by clinical symptoms. With the available literature, we have discovered a wide range of fluid biomarkers that have been investigated for predicting post-traumatic headache, including neuropeptides; sleep disturbances, such as cortisol and melatonin; vestibular disturbances, including interleukin-6 and neurone-specific enolase; and vomiting, such as S100B. Along with physical symptoms, biomarkers investigated for predicting cognitive disturbances include inflammatory markers, S100B, neurofilament light chain, tau, microRNA and hormones. Biomarkers to predict mental health disturbances may include brain-derived neurotrophic factor, tau and cortisol. By utilizing such biomarkers, there is capacity to adopt a personalized medicine approach to facilitate early interventions for those most in need while also identifying individuals with a favourable prognosis who can safely return to their normal activities. Show less

COG133, an apolipoprotein E-derived mimetic peptide, has been proposed as a therapeutic candidate due to its immunomodulatory properties. Its potential role in diabetic wound healing, where impaired fibroblast function and chronic inflammation are major obstacles, remains largely unexplored. In this study, human diabetic dermal fibroblasts were treated with COG133 to evaluate its effects on cell viability, migration, and gene expression of ApoE, miR-146a, NF-κB, TRAF-6, and IL-6. In addition, the antibacterial and antibiofilm activities of COG133 were assessed against Gram-positive and Gram-negative bacteria. COG133 enhanced fibroblast migration without affecting viability, upregulated miR-146a, and reduced IL-6 and ApoE expression, while NF-κB and TRAF-6 remained unchanged. Antibacterial assays revealed inhibitory effects, with the lowest MIC against Show less

Lifelong APOB gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in APOB variant carriers has never been evaluated. Using UK Biobank data, we analysed 241 APOB loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the PNPLA3-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages. APOB carriers had ~35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all p < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (P Long-term exposure to low LDL-C levels due to APOB LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies. Show less

DNA double-strand break repair has emerged as a vital pathway to repair DNA damage seriously related to the risk of colorectal cancer (CRC). To explore valid susceptible biomarkers of CRC via investigating the association of single nucleotide polymorphisms in DSBR genes with CRC risk, seven polymorphisms located in 3'-untranslated regions of DSBR genes including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440 were detected and analyzed in a CRC case-control study (cases (202) and also controls (202)). The PolymiRTs and miRSNP database were used to predict the microRNAs that can bind to 3'UTR SNPs. Since long non-coding RNA as a miRNA "sponge" played the role of competing endogenous RNA, DAVID database was used to find the lncRNAs that can bind to the candidate miRNA seed sequences. BRCA1 rs12516 minor A allele was found to be linked with a higher risk of CRC than its major G allele (OR = 2.716, 95%CI: 1.394-5.292, P = 0.003). The stratified analyses demonstrated rs12516 AA genotype with a more elevated risk of CRC in male (OR = 3.089, 95% CI:1.315 ~ 7.255) or age > 50 population (OR = 3.318, 95%CI:1.571 ~ 7.006) than its GG genotype. BRCA1 rs12516 A allele created a novel miR-4704-5p binding target, and there was a negative correlation between miR-4704-5p and BRCA1 expression (r =-0.7199, P = 0.0440). Based on the theory of ceRNA network, it was predicted that lncRNA BDNF-AS can competitively bind to miR-4704-5p, whose expression was exhibited to be negatively correlated with BDNF-AS (r=-0.3481, P = 0.0375). On the contrary, BDNF-AS expression showed a positive correlation with BRCA1 mRNA level in colorectal tissue carrying rs12516 of A allele (adjacent tissue: r = 0.7269, P = 0.0411; cancer tissue: r = 0.7134, P = 0.0469). ROC curve showed both BDNF-AS (AUC = 0.651, P = 0.0277) and miR-4704-5p (AUC = 0.7215, P = 0.0012) can distinguish CRC tissues from their adjacent tissues. BRCA1 rs12516 is characterized as a potential biomarker associated with CRC risk, via a possible functional ceRNA network of BDNF-AS, miR-4704-5p and BRCA1. The interaction of a lower expression of BDNF-AS, a higher expression of miR-4704-5p and rs12516 A allele could together increase the risk of colorectal cancer. Show less

Systemic inflammation has been identified as a key factor in neurodegeneration but the value of circulating inflammatory proteins in dementia risk prediction and their causal role has not been elucidated. We leveraged proteomic data from 43,685 UK Biobank participants to investigate associations between 728 Olink inflammatory proteins and incident dementia using Cox proportional-hazards (Cox-PH) models. We used Cox-PH with LASSO regularisation to calculate a sparse signature of inflammatory proteins (ProSig) predicting incident dementia. Linear regressions assessed the association between ProSig and individual proteins with brain image-derived phenotypes and Brain Age in participants with available neuroimaging data (n = 4,106). Formal mediation analyses investigated whether inflammatory proteins mediated associations between genetic and modifiable risk factors and dementia outcomes. Mendelian randomisation (MR) tested the causal relationship between inflammatory proteins and dementia outcomes. 218 inflammatory proteins were individually associated with incident dementia in Cox-PH models (p By triangulating evidence, this study shows that inflammatory proteins improve dementia risk prediction and play heterogeneous roles in dementia pathophysiology. Show less

Postinfectious olfactory dysfunction (PIOD) is common in COVID-19 patients. This 2-arm double-blinded randomized controlled trial (RCT) aimed to establish proof-of-concept for vitamin A versus placebo as a treatment modality for patients with PIOD. This study compared 9,000 IU daily self-administered vitamin A intranasal drops versus peanut oil drops over 12 wk in COVID-19 patients with PIOD. Outcome measures included: olfactory bulb volume (OBV), olfactory sulcus depth, cerebral functional MRI blood oxygen level dependent (BOLD) signal, Sniffin' Sticks TDI score, SSParoT, olfactory disorder questionnaire (ODQ) score, and brain-derived neurotropic factor (BDNF) levels were collected from participants at baseline and after trial intervention at 12 wk. Fifty-seven PIOD were recruited in the trial and allocated to vitamin A or placebo arm at a 2:1 ratio. After withdrawals and exclusions, 30 participants in the vitamin A arm and 15 in the placebo arm were analyzed. There was no significant difference in the change in OBV between both groups. Aside from an improvement in the quality-of-life component of ODQ questionnaire scores (P = 0.01), there were no significant differences in any of the other secondary outcome measures. This proof-of-concept trial has demonstrated no significant effect of intranasal vitamin A on olfactory function in COVID-19 PIOD patients. Further work is required to identify other therapeutic agents in the management of PIOD or evaluate a different PIOD cohort with non-COVID etiology. Show less

Brain-derived neurotrophic factor (BDNF) has been suggested to support dopaminergic neuron's endurance and dopamine release. Its Val66Met polymorphism might modify Parkinson's disease (PD) evolution, although evidence in Asian populations remains limited. This study aimed to explore how the BDNF rs6265 genotypes are associated with the clinical characteristics and longitudinal progression patterns of PD patients in a Korean population. A total of 247 patients were enrolled and followed for a mean duration of 50.9 ± 23.9 months. Baseline and/or periodic assessments captured motor severity, non-motor burden, cognition, orthostatic stress, cardiac denervation, and presynaptic dopamine transporter availability. The repeated measures were manipulated to infer any genotypic differences in the trajectories of each clinical domain. Genotype frequencies were 31.2% (77/247) for Val/Val and 68.8% (170/247) for Met-allele carriers. Baseline clinical characteristics and presynaptic dopamine transporter availability were comparable between genotypes; however, Val homozygotes showed more preserved myocardial innervation and poorer non-frontal cognitive performance. Longitudinal analyses demonstrated genotype-specific increases in motor and cognitive severity. Compared to Met-allele carriers, the homozygous Val group exhibited accelerated motor progression and more rapid decline in frontal domain after three years of follow-up. The differences in myocardial denervation at diagnosis, cognitive profiles, and motor progression might suggest a potential modulatory role of BDNF polymorphism in PD progression in the Korean population. Show less

Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), yet its underlying mechanisms remain poorly understood. Apolipoprotein E4 (APOE4), a genetic risk factor of Alzheimer's Disease, has been associated with PD-related cognitive impairment. However, findings are inconsistent, highlighting the need for further investigation. Neuroimaging studies have found gray matter abnormalities, mainly reductions in gray matter volume (GMV) and cortical thickness (CTh), in both cognitively impaired PD patients and APOE4 carriers. Yet, APOE4's role in these structural changes and their cognitive impact in PD is underexplored. This study aimed to determine whether APOE4 influences early structural brain differences in terms of GMV and CTh in PD prior to the emergence of cognitive dysfunction. A total of 51 PD APOE4 carriers and 120 non-carriers who were cognitively unimpaired from the Parkinson's Progression Markers Initiative (PPMI) database were included. T1-weighted MRI scans were used to calculate GMV and CTh in regions previously associated with PD-related cognitive impairment, including hippocampal subregions. Cognitive scores assessing global cognition and specific cognitive domains were used to examine associations between regions showing significant GMV or CTh group differences and cognitive performance. PD APOE4 carriers showed increased GMV in the left angular gyrus (AnG) and decreased GMV in the left nucleus accumbens (NAcc) compared to non-carriers, though neither survived multiple comparison correction. Left AnG GMV correlated with visuospatial function in both groups but did not remain significant after co-variate adjustment. Left NAcc GMV correlated with visuospatial function and working memory, but only in non-carriers even after co-variate adjustment. No group differences were observed in CTh measures and hippocampal subregion GMVs. This study suggests that APOE4 may not influence cognitive function in PD by affecting GMV and CTh. However, longitudinal analyses must confirm these observations. Show less

Lipoprotein(a) [Lp(a)] is a potent, independent causal risk factor for coronary artery disease (CAD). This study aimed to assess the association between Lp(a) and the diagnosis, clinical presentation, and angiographic characteristics of obstructive CAD and occurrence of myocardial infarction (MI). We included 446 individuals with very high Lp(a) (>230 nmol/L) who underwent routine lipid profiling, matched 2:1 by age and sex using nearest-neighbor propensity matching to 223 controls with low Lp(a) (≤7 nmol/L). Kaplan-Meier analysis was used to assess CAD- and MI-free survival. Multivariable ORs were calculated for multivessel disease and the SYNergy Between percutaneous coronary intervention with TAXus and Cardiac Surgery-1 score. Median follow-up time, defined by age at last follow-up, was 60 years (Q1-Q3: 50-71). Individuals with very high Lp(a) had significantly lower event-free survival time for the diagnosis of obstructive CAD and occurrence of MI (P = 0.006 and P = 0.012, respectively). In multivariable analysis, Lp(a) was associated with multivessel CAD (adjusted OR: 1.43 [per 100 nmol/L]; 95% CI: 1.04-1.96; P = 0.028), but not with an intermediate or high SYNergy Between percutaneous coronary intervention with TAXus and Cardiac Surgery-1 score (adjusted OR: 1.28 [per 100 nmol/L]; 95% CI: 0.82-1.99, P = 0.279). Individuals with very high Lp(a) levels had a 2.4-fold higher risk of ST-segment elevation MI and a 15.9-fold higher risk of recurrent MI compared to those with low Lp(a). Very high Lp(a) is associated with earlier diagnosis of obstructive CAD and MI, predominantly ST-segment elevation MI. In addition, individuals with very high Lp(a) levels seem at a particular high risk of recurrent MI. Show less

Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders. Show less

Cerebral deposition of fibrillar amyloid-β (Aβ) is a pathological hallmark of Alzheimer's disease. Although Aβ is present in human placentas and accumulates in preeclamptic placentas characterized by poor placentation, the production and role of Aβ in the human placenta remain unclear. Because hypoxia in mid-to-late pregnancy is a risk for preeclampsia, we found that levels of hypoxia-inducible factor 1-α and β-secretase (BACE-1) increased concurrently with placental Aβ deposition in late-stage preeclamptic placentas. We also found that a human cytotrophoblast (CTB) model, BeWo cells, actually produced Aβ species and that hypoxia increased Aβ production and BACE-1 protein levels. Aβ42 fibrils inhibited CTB syncytialization, a critical step in maintaining pregnancy, by inducing loss of membrane localization of cell-cell adhesion molecules. Primary human CTBs confirmed these observations. Taken together, our results suggest that increased Aβ production in CTBs by hypoxia may lead to the formation of Aβ fibrils, which inhibit syncytiotrophoblast formation and are detrimental to pregnancy. Thus, our results reveal the novel role of Aβ fibrils in the pathogenesis of preeclampsia. Show less

Transferrin receptor 1 (TfR1), an intracellular iron receptor, has multiple biological functions. We have previously reported that aortic TfR1 expression increases in human and murine abdominal aortic aneurysm, but its role in the development of atherosclerosis remains unclear. In the present study, we generated apolipoprotein-E (ApoE) and TfR1 deficient mice and examined the impact of its deletion on the development of atherosclerosis. Homozygous ApoE deficient ( These results indicate that TfR1 deletion attenuates the development of atherosclerotic lesion formation in Show less

Problematic social media use (PSMU) has emerged as a societal and behavioral concern, especially among young adults. However, individual differences in symptom manifestation remain understudied. The present study adopted a person-centered approach to identify distinct profiles of PSMU and to examine the predictive roles of fear of missing out (FoMO), problematic smartphone use (PSU), age, and sex among a sample of 625 Italian university students aged 18 to 40 years ( Show less

The gastrointestinal system is of particular importance in radiation biodosimetry because of its constant cell renewal and sensitivity to radiation-induced injury. It has been reported that total abdominal irradiation causes distant cognitive defects in a mouse model. In this study, we demonstrated that metformin alleviated the cognitive dysfunction caused by total abdominal irradiation. No neuropathological changes were observed in hippocampal tissues in control, irradiated, and irradiated plus metformin-treated groups. However, we found that metformin treatment improved the expression of brain-derived neurotrophic factor and the phosphorylation level of cAMP response element-binding in the hippocampus from irradiated mice. Furthermore, our results revealed that metformin treatment reduced the expression of miR-34a-5p, which targets the brain-derived neurotrophic factor mRNA, in the small intestine, peripheral blood, and hippocampus. More importantly, injection of miR-34a-5p agomir inhibited the enhancement effects of metformin on the cognitive defects induced by total abdominal irradiation, as well as the enhanced expression of BNDF and the phosphorylation level of cAMP response element-binding in the hippocampus. Thus, our results provide alternative strategies for the treatment of total abdominal irradiation-induced distant cognitive impairment using metformin and further confirmed that miR-34a-5p is a potential drug target to reduce the cognitive defects caused by total abdominal irradiation. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with plasma levels largely unaffected by lifestyle modification or conventional lipid-lowering therapy. Although international guidelines increasingly recognize Lp(a) as a risk-enhancing factor, in many Asian populations thresholds for high Lp(a) and treatment strategies remain undefined. This Korean position paper, developed by the Lp(a) Task Force of the Korean Society of Lipid and Atherosclerosis, presents an evidence-based summary of the pathophysiology, clinical relevance, and therapeutic landscape surrounding Lp(a), with a focus on Korean-specific data. It reviews the genetic architecture of Lp(a), ethnic variability in concentrations, and its mechanistic roles in inflammation, thrombosis, and calcification. Based on large Korean cohorts, a 3-tiered classification is proposed of normal (<30 mg/dL), borderline high (30-49 mg/dL), and high (≥50 mg/dL), harmonizing global thresholds with local data. The document also highlights the limitations of current Lp(a) assays in Korea, and calls for standardized, isoform-insensitive testing. Novel therapeutics, including antisense oligonucleotides, small interfering RNAs, and small molecular inhibitors, have shown promising Lp(a)-lowering effects, with multiple phase 3 trials currently ongoing, or in planning. Given the unmet clinical need, the paper recommends incorporating Lp(a) into cardiovascular risk assessment, and calls for Korean-specific longitudinal studies, national screening strategies, and participation in clinical trials. These efforts will help clarify Lp(a)-associated risk in Korean patients and guide the adoption of future targeted therapies. Show less

The comparative efficacy and safety profiles of PCSK9 inhibitors in familial hypercholesterolemia (FH), including genotype-dependent treatment responses, remain unclear. This systematic review was conducted in accordance with the Preferred Reporting Items for Meta-Analyses guidelines. A network meta-analysis of randomized clinical trials evaluating the use of PCSK9 inhibitors for the treatment of FH patients, including subgroup analyses of efficacy, was performed. Fifteen randomized clinical trials (n = 2954 patients) were included. All PCSK9 inhibitors significantly improved lipid parameters compared to control. In heterozygous FH (HeFH) populations, ongericimab showed the greatest reductions in LDL-C (mean difference [MD]: -74.98 %), ApoB (MD: -64.64 %), and Lp(a) (MD: -59.66 %), with SUCRA rankings of 68.7 %, 63.6 %, and 95.0 %, respectively. However, these results are based on a single trial and require further validation. No significant lipid-lowering effects were observed in HoFH patients. In terms of safety, lerodalcibep showed the most favorable profile for injection-site reactions and ALT >3 × ULN, with SUCRA values of 98.5 % and 96.7 %, respectively. Inclisiran was associated with a significantly higher risk of injection-site reactions. PCSK9 inhibitors generally show favorable efficacy and safety in FH patients. However, comparative rankings and point estimates should be interpreted with caution due to funnel plot asymmetry for LDL-C and imbalances in trial data. Ongericimab demonstrated promising results in HeFH, but further validation is required. Inclisiran's efficacy may be underestimated due to short-term follow-up. Monotherapy with PCSK9 inhibitors has limited efficacy in HoFH patients, highlighting the need for combination therapies. Show less

To elucidate the molecular basis of intramuscular fat (IMF) variation in yellow-feathered broilers, we selected 10 high-IMF (HF) and 10 low-IMF (LF) breast muscle samples from a total of 214 samples, after z-score filtering for LC-MS lipidomics and RNA-seq analyses. Lipidomics identified 94 differentially expressed lipids (DELs; 83 upregulated, 11 downregulated in HF), predominantly triglycerides (TGs, 20.2%), phosphatidylethanolamines (PEs, 15.3%), phosphatidylcholines (PCs, 12.1%), and sphingomyelins (SMs, 8.4%). LION/web enrichment indicated an unsaturated lipid-rich phenotype, characterized by fatty acids containing ≥ 2 double bonds and membrane structural components. RNA-seq revealed 423 differentially expressed genes (DEGs; 312 upregulated, 111 downregulated in HF), enriched in plasma membrane, cell periphery, retinol metabolism, and steroid hormone biosynthesis pathways. RT-qPCR validation of nine lipid metabolism-related DEGs confirmed the RNA-seq trends. Cross-omics Pearson correlation between these DEGs and the top 20 DELs identified PLIN1, SCD, and APOB as central regulatory hubs strongly associated with multiple polyunsaturated TGs and PCs. Functional overlap across omics layers suggests coordinated membrane remodeling and unsaturated lipid deposition in HF breast muscle, providing a data-driven framework for future mechanistic validation and breeding strategies. Show less