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Juvenile neuronal ceroid lipofuscinosis (JNCL) is a rare neurodegenerative disorder caused by mutations in the CLN3 gene and characterized by early vision loss and a progressive neurological decline. To characterize the progression of retinal pathology, we conducted a 15-month study using the Cln3Δex7/8 mouse model which carries the most common causative mutation of JNCL. Retinal function was assessed every three months from the age of 3-15 months using electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunohistochemistry. OCT and fundus imaging in the Cln3Δex7/8 mice revealed a progressive thinning of the inner nuclear layer (INL) and an accumulation of subretinal drusenoid deposits. We detected a progressive loss of rod bipolar cells (RBCs) with immunofluorescence staining which was accompanied by ubiquitin-positive punctae, indicative of a potential role of the ubiquitin-proteasome system (UPS) in the selective loss of RBCs and the associated inner retinal dysfunction. Furthermore, late-stage immune cell activity was observed in the subretinal space of the Cln3Δex7/8 mice. ERG measurements confirmed previous findings of a predominant inner retinal dysfunction and revealed also a more pronounced photoreceptor impairment, as well as an earlier onset of retinal dysfunction than previously reported. These findings provide new insights into the pathological features of retinal degeneration in Cln3Δex7/8 mice, including subretinal drusenoid deposits, tubular subretinal fluid, and ubiquitin accumulation as well as a better overview of the rate of the degeneration process, thus expanding our understanding of JNCL pathogenesis. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD. Show less

Atrial fibrillation (AF) is a progressive condition characterized by atrial remodeling and dysfunction. This systematic review explores biomarkers that predict new-onset AF, highlighting their potential to improve early diagnosis and risk stratification in high-risk patients, and prevention of stroke and major adverse cardiovascular events. We conducted a literature search of studies published between January 2014-November 2025 in PubMed, Scopus, Web of Science, and Google Scholar, following PRISMA 2020 guidelines. Studies analysing specific populations and patients with prior or postoperative AF were excluded. Quality was assessed using the Newcastle-Ottawa scale. Effect sizes were expressed as HR with 95% CIs. We included 10 cohort studies comprising 472,581patients and 35,271 (7.5%) new-onset AF. Overall, 18 biomarkers were associated with an increased risk of AF, most notably NT-proBNP and sVCAM-1. Conversely, 9 biomarkers were associated with a lower AF incidence, such as ADAMTS13 (HR 0.78, 95%CI 0.70-0.88). A meta-analysis of NT-proBNP demonstrated its association with a higher incidence of AF (HR 1.37, 95%CI 1.19-1.59) with high heterogeneity (I2 = 80%, p<0.01) and Lp(a) was associated with a significant 3% increase in AF incidence per 20 mg/dL increment. Two networks were constructed according to whether biomarkers were associated with a higher or lower incidence of AF, visualising their connection with other biomarkers. Well-known biomarkers, such as NT-proBNP, and others not yet incorporated into clinical practice, such as Lp(a) and sVCAM-1, could play a role in the diagnosis and preventive management of AF. Large-scale prospective studies are needed to validate and optimise their diagnostic utility in predicting new-onset AF. Show less

Auricular vagus nerve stimulation (aVNS) has emerged as a noninvasive neuromodulatory strategy with the potential to modulate central sensitization and inflammatory pathways. However, its role in fibromyalgia (FM) remains insufficiently explored. To investigate whether stimulation laterality (left vs. right auricular branch of the vagus nerve, ABVN) differentially influences clinical and biological outcomes in women with FM. In this randomized, double-blind, sham-controlled trial, 51 women with FM were allocated to sham stimulation, right-sided aVNS (aVNS-R), or left-sided aVNS (aVNS-L). Participants underwent weekly sessions for four weeks and were followed for 12 weeks. Pain intensity was the primary outcome. Secondary outcomes included psychological symptoms, sleep, functional status, quality of life, and circulating biomarkers (pro- and anti-inflammatory cytokines, brain-derived neurotrophic factor [BDNF]). While no significant between-group differences were observed in pain intensity, left-sided stimulation (aVNS-L) was associated with a modest but significant reduction in global symptom severity. Importantly, aVNS-L produced consistent immunomodulatory effects, including decreased IL-1β and TNF-α levels, and increased IL-4, IL-10, and BDNF concentrations. This exploratory trial suggests that stimulation laterality may shape the biological response to aVNS in FM. Although clinical pain relief was not superior to sham, left-sided stimulation promoted an anti-inflammatory profile and enhanced neuroplasticity markers. These findings support further investigation of aVNS laterality as a targeted neuromodulatory approach for FM. Brazilian Clinical Trials Registry RBR-10d3crcf. Show less

Lipoprotein(a) [Lp(a)] is a significant, genetically determined contributor to the risk of atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of mortality worldwide despite successes in the management of LDL cholesterol. Lipoprotein(a) possesses increased atherogenicity, contributing to residual cardiovascular risk. Elevated Lp(a) levels affect a substantial proportion of the population, rendering this a potentially high-impact therapeutic target, but currently available lipid-lowering agents and lifestyle interventions have minimal impact on lowering Lp(a), and lipoprotein apheresis is the sole effective-but impractical-method to significantly reduce Lp(a). Recent advances in Lp(a)-targeted therapies, notably nucleic acid-based approaches (e.g. antisense oligonucleotides and small interfering RNAs) and a small molecule inhibitor of Lp(a) synthesis, demonstrated substantial and often durable Lp(a)-lowering effects in Phase II trials. Phase III trials of these agents are now underway to examine the impact of lowering Lp(a) levels on atherosclerotic cardiovascular disease outcomes, and their results may transform the landscape of cardiovascular risk reduction and management for patients with elevated Lp(a). This review summarizes existing lipid-lowering therapies' limited effects on Lp(a), provides an update on the array of emerging therapeutics and their safety and efficacy, and discusses ongoing Phase III trials as well as other potential benefits of Lp(a)-lowering, such as slowing progression of calcific aortic valve stenosis. Show less

To explore the clinical value of D-lactate (D-LA), apolipoprotein B/A1 ratio (APO B/A1) and systemic immune-inflammatory response index (SIRI) in acute pancreatitis (AP) progression and concurrent infectious pancreatic necrosis. This retrospective study included 116 AP patients (Jun 2021 - Dec 2024, Chongqing University Qianjiang Hospital). Patients were assigned to the model group, categorized into bedside indices for severity in acute pancreatitis (BISAP) of mild (n=57), moderate (n=31), and severe (n=28) subgroups. D-LA, APOB/A1, SIRI, and BISAP were compared. Correlations were analyzed via Pearson. Patients were also divided into an infected group (36 cases) and a non-infected group (80 cases) to compare clinical data as well as the above indices. Multivariate logistic regression identified its influencing factors. An external cohort (54 patients) validated the model via ROC and calibration curves. As the severity of AP worsens, D-LA, APO B/A1, and SIRI all increase, and D-LA, APO B/A1, and SIRI were positively correlated with BISAP scores ( D-LA, APO B/A1, SIRI correlate with AP severity and the combined model enables early assessment and personalized measures. Show less

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and repetitive behaviors, with currently limited therapeutic options. Oxidative stress is suggested as significant in ASD pathophysiology, making antioxidant strategies a promising therapeutic direction. Exercise reduces oxidative stress, alleviates ASD symptoms, and increases tetrahydrobiopterin (BH4) and brain-derived neurotrophic factor (BDNF) levels through AMP-activated protein kinase (AMPK) activation. MOTS-c, a mitochondrial-derived peptide acting through AMPK, mimics the effects of exercise but reportedly does not cross the blood-brain barrier (BBB). Considering the challenges in exercise adherence in ASD, our study hypothesizes that MOTS-c could increase circulating BH4 and BDNF, both of which are BBB-permeable, and alleviate oxidative stress and ASD symptoms. To evaluate this hypothesis, we investigated the effects of MOTS-c in the valproic acid-induced rat model of autism. Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12. Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46. Following behavioral testing, animals were sacrificed, and histological and biochemical analyses were performed. Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage. No significant changes in plasma BH4 or BDNF levels were detected. Through its neuroprotective and antioxidant effects independent of BH4 and BDNF, MOTS-c may alleviate autism-like behaviors, suggesting its potential as a therapeutic candidate for ASD. Show less

Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop Show less

Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited transport across the blood-brain barrier (BBB) and poor penetration to target neurons. Here, we establish an integrated, noninvasive imaging and therapy platform that combines microbubble-enhanced focused ultrasound (MB-FUS) with positron emission tomography/computed tomography (PET/CT) to transiently modulate the BBB, enhance region-specific AAV delivery following systemic dosing, and longitudinally track transduction in vivo. Optimized MB-FUS achieved targeted hippocampal delivery of systemically administered AAV9 in healthy mice, resulting in a 10-fold enhancement of neuronal transduction as compared to non-FUS controls. Importantly, longitudinal PET reporter gene imaging in the 5xFAD AD model demonstrated robust brain AAV transduction that remained stable for at least seven months. Finally, to assess therapeutic impact, we used brain-derived neurotrophic factor (BDNF) as a test cargo. MB-FUS-facilitated delivery elevated BDNF expression in targeted regions and produced short-term improvements in synaptic signaling in 5xFAD mice. Collectively, these results highlight MB-FUS as a next-generation delivery platform to overcome barriers to AAV therapeutic delivery in Alzheimer's disease and position longitudinal PET assessment as a critical, translatable tool for monitoring and optimizing gene therapy. Show less

COG133, a peptide fragment derived from apolipoprotein E (ApoE) corresponding to residues 133-149, has demonstrated significant anti-inflammatory and neuroprotective activity. However, its precise anti-inflammatory mechanisms and its potential to ameliorate depression-like behaviors remain incompletely understood. This study investigated the effects of COG133 in mouse models of depression induced by lipopolysaccharide (LPS), chronic social defeat stress (CSDS), and corticosterone (CORT), as well as in LPS-stimulated BV-2 microglial cells. We found that COG133 treatment significantly alleviated depression-like phenotypes and suppressed hippocampal neuroinflammation by inhibiting microglial overactivation. Using RNA sequencing (RNA-seq) and biochemical validation, we identified the MKK3/6-p38-ATF2 signaling axis as a central mechanism underlying the anti-inflammatory effects of COG133. Pharmacological modulation of p38 MAPK further confirmed that this pathway is essential for COG133-mediated behavioral and cellular recovery. Together, these findings identify COG133 as a promising peptide candidate for the treatment of depression through modulation of the p38 MAPK-mediated neuroinflammation axis. Show less

Thyroid hormones regulate lipoprotein metabolism-primarily by up-regulating the LDL receptor. Whether TSH relates to LDL-C in hypercholesterolemic children, and whether this depends on familial hypercholesterolemia (FH) status or the underlying defective gene, is uncertain. We evaluated TSH-lipid associations in prepubertal children and tested effect modification by FH status and, within FH, by gene with a pathogenic variant (LDLR vs APOB). We performed a cross-sectional study of prepubertal children referred to the Slovenian national tertiary center through the universal FH screening program or cascade screening. Eligibility required concurrent TSH and fasting lipid measurement and completed genetic testing (pathogenic/likely pathogenic variants in LDLR/APOB/PCSK9 vs polygenic hypercholesterolemia). Among 738 children, 182 (24.7%) were FH-positive (LDLR 132; APOB 50). In the pooled cohort, TSH did not correlate with age or lipids (all p ≥ 0.050). After sex stratification, TSH correlated with triglycerides only in males (ρ = 0.156; p = 0.012). In FH-positive children, TSH correlated with total cholesterol, LDL-cholesterol, and ApoB (ρ ~ 0.184-0.207; all p < 0.050), with no associations in FH-negative children. Interaction testing confirmed effect modification by FH (TSH × FH β = 0.141 mmol/L per mIU/L, p = 0.023). Within FH-positive children, a positive TSH-LDL-C slope was seen in LDLR carriers (β = 0.237, p = 0.004) but not in APOB carriers (β = -0.065, p = 0.655). TSH was positively associated with LDL-C only in FH due to LDLR variants, not in APOB carriers. These findings suggest that genetic background may shape hormonal sensitivity, and that attention to thyroid status could be particularly relevant in LDLR-FH. Show less

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder characterized by hyperandrogenism, has been increasingly associated with a high risk of autism spectrum disorder (ASD) in offspring. The emerging interaction between reproductive endocrinology and neurodevelopmental biology suggests that excessive androgen exposure during gestation may perturb neurotrophic signaling and impair neural circuit formation. Brain-derived neurotrophic factor (BDNF) acts through tropomyosin receptor kinase B receptor to activate downstream phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways, both of which are fundamental to neuronal survival and synaptogenesis. Disruption of these signaling cascades under hyperandrogenic conditions may lead to altered neuroarchitecture, impaired synaptic connectivity, and ASD-like behavioral phenotypes. Clinical and experimental studies also implicate aberrant BDNF expression in ovarian dysfunction, oocyte maturation deficits, and placental steroidogenic imbalance, highlighting a shared endocrine-neurodevelopmental axis in PCOS. Moreover, androgen excess may induce epigenetic modifications and post translational alterations of BDNF or tropomyosin receptor kinases B receptors, further compromising downstream signaling. These molecular events can dysregulate the transcriptional control of multiple synaptic and neurodevelopmental genes, thereby promoting atypical neuronal circuit formation. Understanding the interaction between BDNF signaling and androgen excess provides a mechanistic framework to explain how maternal endocrine imbalance influences neurodevelopment of offspring. This review integrates multidisciplinary findings spanning clinical cohorts, animal models, and molecular studies to delineate how androgen-BDNF interactions amplified by epigenetic, transcriptional, and post translational dysregulation underpin key neurodevelopmental disruptions observed in ASD. Furthermore, it emphasizes the translational potential of targeting BDNF-related pathways as early biomarkers or therapeutic entry points to mitigate the intergenerational neurodevelopmental consequences of PCOS. Show less

The pituitary gland plays a pivotal role in regulating puberty and reproductive physiology; however, the precise cellular and molecular mechanisms driving the pubertal transition in large animal, such as ewes, remain poorly understood. Here, we generated a comprehensive single-cell transcriptomic atlas of the ovine anterior pituitary, specifically comparing the pre-pubertal (3 month) and post-pubertal (6 month) stages. We identified 30 335 cells classified into ten distinct clusters. Comparative analysis revealed a global transcriptional reprogramming during puberty, characterized by a marked upregulation of genes associated with ribosome biogenesis, unfolded protein response, and hormone secretion across endocrine cells, reflecting an expanded biosynthetic capacity. Specifically, we identified SCG2 as a critical regulator of gonadotroph maturation. Functional validation demonstrated that SCG2 facilitates the biogenesis of secretory granules, thereby promoting FSH synthesis and secretion. Furthermore, intercellular communication analysis uncovered a distinct shift in the pituitary microenvironment: the 6 month pituitary exhibited enhanced regulatory networks, including IGF signaling mediated by non-endocrine cells and NT signaling (e.g., BDNF-NTRK2) driven by multiple cell types. These findings suggest that the onset of puberty relies on a coordinated "endocrine-to-endocrine" and "non-endocrine-to-endocrine" crosstalk. This study provides a high-resolution molecular blueprint of the pubertal transition, highlighting the key roles of biosynthetic machinery upgrades and microenvironmental remodeling in establishing the high reproductive performance of Hu sheep. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that drives a significant residual risk through proatherogenic, proinflammatory, and prothrombotic pathways. However, current mainstay lipid-lowering therapies such as statins have limited efficacy in reducing Lp(a) levels, highlighting a critical therapeutic gap. This review aims to synthesize evidence on the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors in targeting Lp(a). We systematically searched PubMed and Embase for clinical trials and mechanistic studies (2010-2025), using the PRISMA and AMSTAR-2 frameworks to ensure methodological rigor and demonstrated that PCSK9 inhibitors (eg, alirocumab, evolocumab, and tafolecimab) not only reduced low-density lipoprotein (LDL-C) by 55%-60% but also lowered Lp(a) by 20%-30%. The efficacy of these agents varies ethnically, with tafolecimab showing superior performance in East Asian populations, which is partly attributable to the higher prevalence of the PCSK9 R46L loss-of-function allele. Mechanistically, PCSK9 inhibitors lowered Lp(a) levels through 2 pathways: suppression of hepatic synthesis and enhanced plasma clearance. This evidence supports the 2023 ESC guidelines, which issued a Class IIa recommendation for PCSK9 inhibitor use in patients with ASCVD and elevated Lp(a) levels. Given the evolving landscape, further research is warranted to confirm the role of these therapies in precision medicine paradigms for managing Lp(a)-associated risks. Show less

Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We examined whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome for these patients. Ectopic expression of FGFR1N546K induced constitutive downstream signaling and IL-3-independent growth in Ba/F3 cells, indicating oncogene-addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life, with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1-mutant, high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K-mutant neuroblastoma cells and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant, patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K-mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma associated with failure of current standard chemotherapy and suggest potential clinical benefit of FGFR-directed therapies in patients with high-risk mutant FGFR1. Show less

Luminal breast cancer (LBC) is the most common subtype of breast cancer affecting women worldwide. Although luminal breast cancer typically has a better prognosis, it mostly responds poorly to neoadjuvant chemotherapy. Non-coding RNAs, especially long non-coding RNAs and microRNAs are crucial in regulating biological processes that contribute to breast cancer development. MALAT1, a long non-coding RNA, is pivotal in the progression of breast cancer. Epithelial-mesenchymal transition (EMT) is critical for cell movement during embryonic development. Clarifying this role could pave various avenues for developing innovative strategies for combating this subtype of malignancy. The present study aimed to investigate the expression profiles and clinical relevance of MALAT1 level and EMT-related miRNAs (miR-17-5p, miR-20a-5p, miR-93-5p, miR-135b-5p, and miR-146a-5p) alongside EMT markers (E-cadherin, N-cadherin, vimentin, fibronectin, twist, SNAI1, Slug, ZEB1, and ZEB2) in LBC patients. Fresh tissues were collected from fifty patients and twenty noncancerous controls. Differential expression of the markers was evaluated using qRT-PCR assay. Spearman Rho test assessed the relationship between the expression levels. Linear regression test evaluated the correlation between the parameters and various clinico-pathological features. Our results revealed an overall upregulation of MALAT1 in breast cancer tissues although this increase did not reach statistical significance. Overexpression of miR-20a-5p, miR-135b, and ZEB2 was reported, whereas miR146a-5p, ZEB1 and Vimentin levels were suppressed. Correlation analysis demonstrated that miR-20a-5p was positively correlated with SNAI1, E-cadherin, N-cadherin and Slug also it was significantly associated with family history and tumor laterality. Our findings suggest that miR-20a-5p plays an oncogenic role in luminal breast cancer by promoting EMT, while MALAT1 may contribute to disease progression through indirect regulatory mechanisms. Finally, MALAT1 and miR-20a-5p might serve as potential therapeutic and prognostic targets in LBC. Show less

Respiratory tract infections (RTIs) remain a major global cause of morbidity, yet the causal role of circulating plasma proteins in RTI susceptibility is unclear. We aimed to systematically identify plasma proteins that causally influence the risk of upper and lower respiratory tract infections (URTIs, LRTIs) using a proteome-wide Mendelian randomization (MR) framework. We performed two-sample MR analyses using genetic instruments for 2923 plasma proteins from 54,219 UK Biobank participants and outcome data from the FinnGen consortium (97,696 URTI and 28,542 LRTI cases). Colocalization analyses were conducted to confirm shared genetic architecture. Functional enrichment and protein-protein interaction (PPI) analyses were used to elucidate potential biological pathways. We identified 11 plasma proteins with significant causal associations with RTI risk. Four proteins (FKBP1B, GFRA1, UBE2L6, and CSF3) showed consistent effects for both URTI and LRTI, with moderate-to-strong colocalization evidence for UBE2L6 and GFRA1. The remaining seven proteins demonstrated infection-specific associations: YAP1 and MST1 (URTIs), and APOE, IL1RL1, and FKBPL (LRTIs). PPI and Gene Ontology (GO) enrichment analyses highlighted tumor necrosis factor (TNF) as a central hub, with cytokine-cytokine receptor interaction and leukocyte-mediated immunity as dominant pathways. This proteome-wide MR and colocalization study identifies novel plasma proteins and immune pathways implicated in RTI susceptibility, providing insights into potential biomarkers and therapeutic targets for infection prevention and management. Further validation in diverse populations and tissue-specific proteomic studies is warranted. Show less

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Show less

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) may contribute to Alzheimer's disease (AD) pathogenesis by promoting amyloid-β (Aβ) aggregation. ASC protein is mainly composed of the N-terminal pyrin domain (PYD) and the C-terminal caspase recruitment domain (CARD). This study aims to explore the different roles of the two domains of ASC in AD. The SH-SY5Y-APP695 cells were treated with ASC neutralizing antibodies against the N-terminal domain (anti-ASC N-terminal antibodies) or C-terminal domain(anti-ASC C-terminal antibodies). The cell apoptosis and Aβ production were detected. The eight-month-old APP/PS1 mice received lateral ventricle injections of anti-ASC N-terminal antibodies or anti-ASC C-terminal antibodies. The cognitive function and AD-like pathology of APP/PS1 mice were assessed. The anti-ASC N-terminal and C-terminal antibodies attenuated apoptosis and mitochondrial damage, and reduced Aβ production by inhibiting BACE1 in vitro. Furthermore, intracerebroventricular administration of anti-ASC N-terminal and C-terminal antibodies improved cognitive impairment and reduced Aβ deposition, tau hyperphosphorylation, and neuroinflammation in the APP/PS1 mice. The anti-ASC N-terminal and C-terminal antibodies may have neuroprotective effects, which are manifested as reducing cell apoptosis, improving cognitive function, and alleviating AD-like pathology in AD mice. Immunotherapies targeting ASC are promising for treating AD. Show less

Keratoconus (KC) is a progressive disorder of corneal thinning characterized by responses in the extracellular matrix and cellular interactions. This study used bioinformatics methods to identify key genes involved in KC development and in anoikis and endoplasmic reticulum (ER) stress. KC and control datasets from the GEO database were analyzed to identify differentially expressed genes (DEGs). These were cross-referenced with anoikis and ER stress-related genes from Genecards. Functional enrichment, immune infiltration analysis, and machine learning techniques (LASSO, Random Forest) were used to identify candidate molecular signatures, which were then validated in an animal model. We identified 46 DEGs associated with anoikis and 41 DEGs related to ER stress. Functional analysis linked them to apoptosis and IL-17 signaling. Five key molecular signatures were identified: CDKN1A, MCL1, PTGS2, PTHLH, and ANGPTL4. The expression of ANGPTL4, CDKN1A, and MCL1 was consistent in the animal model. These genes are associated with inflammatory and oxidative stress responses. Twelve potential therapeutic drugs were predicted. This study identifies five candidate molecular signatures for KC related to anoikis and ER stress, offering insights into KC pathogenesis and potential targeted therapies. Show less

Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy. Show less

Brain aging is a multifactorial process associated with oxidative stress, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to cognitive decline and increased susceptibility to neurodegenerative disorders. Epigallocatechin gallate (EGCG) is a potent antioxidant and anti-inflammatory agent, but its therapeutic potential is limited by poor stability and bioavailability. In this study, a dual nano delivery system was developed by loading chitosan-EGCG nanoparticles into mesenchymal stem cell-derived exosomes (Ex-Chit-EGCG NPs) and evaluated for neuroprotective efficacy in a D-galactose-induced brain aging model. Intranasal administration of Ex-Chit-EGCG NPs significantly improved cognitive and locomotor performance compared with exosomes alone, as evidenced by enhanced outcomes in Y-maze and open field tests. Biochemical analyses revealed that Ex-Chit-EGCG NPs effectively reduced lipid peroxidation, restored glutathione levels, and reactivated the LKB1/AMPK/SIRT1 signaling pathway. Molecular investigations demonstrated upregulation of Nrf2, BDNF, and SIRT1 together with suppression of NF-κB and Iba-1 expression, indicating attenuation of oxidative and inflammatory responses. Histopathological and immunohistochemical evaluations confirmed these findings, showing preservation of cortical and brain stem architecture with marked reductions in neuronal necrosis, gliosis, BAX, GFAP, and NLRP3 expression. Collectively, the results demonstrate that Ex-Chit-EGCG NPs exert superior neuroprotective effects compared with exosomes alone, highlighting the therapeutic advantage of combining EGCG with chitosan nanocarriers and exosomal delivery. This dual nanotherapeutic strategy offers a promising and non-invasive approach for mitigating brain aging and holds potential for translation into therapies targeting age-related neurodegenerative disorders. Show less

Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are neurodegenerative conditions that afflict millions of elderly people around the world. AMD is a progressive retinal disorder that leads to central vision loss whereas AD primarily causes cognitive decline and behavioral changes. While each disease has distinct clinical manifestations, the accumulation of extracellular amyloid-β is a common histopathologic finding. Similarly, cerebral amyloid angiopathy (CAA), a vascular condition that can exist independent or with AD, is characterized by the accumulation of amyloid-β in cerebral blood vessels. While significant investigation of the pathophysiologic links between AMD and AD has been conducted, the underlying similarities and differences in the pathobiology of AMD and CAA has not been considered. In this review, we discuss the common pathological features of these two conditions. We then discuss the similar pathobiology that involves cholesterol metabolism, apolipoprotein E, amyloid-β, and complement mediated inflammation. At the same time, we discuss key differences in their pathobiology. This discussion sheds new perspective and insights of their pathobiology. Show less

Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less

Cereal vinegar sediment (CVS), a byproduct of traditional vinegar fermentation, has been regarded as a health-promoting product. However, its role in genetically induced hyperlipidemia remains unclear. This study systematically evaluated the effects of Dade-CVS (DD-CVS) and Hengshun-CVS (HS-CVS) on apolipoprotein-E-deficient ( Show less

Genetic factors are thought to play an important role in antipsychotic-induced weight gain (AIWG). This study conducted a meta-analysis of current research of the pharmacogenetic associations of adult AIWG. The analysis included papers providing comparisons of weight gain across at least two allele combinations for at least one single nucleotide polymorphism (SNP). Inclusion criteria were, patients 18 years of age or older and had received a diagnosis of severe mental illness, for which antipsychotic medication was prescribed. The association with AIWG needed to be replicated across at least two papers reporting separate sample sets. Two hundred twenty-three papers were assessed for eligibility. Of the 223 papers, 148 were excluded, leaving 75 studies to be included. Six SNPs in six different genes were identified as having significant associations ( The study identified six SNPs that predispose adult individuals to AIWG, with Show less

Flavonoids are a diverse group of natural polyphenolic compounds, recognized for their ability to modulate cellular pathways and mitigate the pathological processes of many neurodegenerative diseases. This study investigates the neurotrophic potential of a polyphenolic-rich lemon peel extract (Lpe) in a Zebrafish larvae spinal cord injury (SCI) model. To evaluate its potential effects, embryos were divided into six experimental groups: a baseline control group in which larvae were neither subjected to spinal cord injury nor treated (Ctrl Group); a group with larvae subjected to spinal cord injury at 3 dpf without treatment (SCI Group); a group treated continuously with Lpe (25 µg/mL) from 0 to 5 dpf without injury (Continuous Group); a group treated continuously with Lpe and injured at 3 dpf (Continuous SCI Group); a group treated with Lpe starting at 3 dpf without injury (Curative Group); and finally, a group injured at 3 dpf and treated simultaneously with Lpe (Curative SCI Group). Lpe treatment significantly downregulated proinflammatory cytokines ( Show less

Vitiligo is an autoimmune disorder characterized by the destruction of melanocytes. We performed a rank-based meta-analysis of six independent transcriptomic studies (115 samples) spanning microarray, bulk, and single-cell RNA-seq platforms to identify consensus signatures of lesional skin. Robust rank aggregation identified 108 downregulated and 6 upregulated genes. Pathway analysis revealed consistent suppression of melanin synthesis and neural development pathways in vitiligo, whereas immune response activation was heterogeneous across studies. Re-analysis of single-cell data from three studies confirmed melanocyte depletion. The 108 downregulated genes were expressed exclusively in melanocytes. These include neural development genes (PLP1, GPM6B, NRXN3), consistent with melanocytes' neural crest origin. We also identified candidate melanocyte markers, such as CYB561A3 and QPCT, with high melanocyte specificity and consistent downregulation in vitiligo. These findings reveal a robust melanocyte-loss signature in vitiligo, detectable across different studies. Study-dependent immune activation, possibly influenced by sampling method and disease characteristics, warrants further study. Show less

Adverse childhood experiences (ACEs) increase susceptibility to depression and anxiety disorders in adulthood. This study investigated the potential mechanisms through which ACEs enhance vulnerability to depression and anxiety in adulthood, using a novel "two-hit" mouse model by combining maternal separation (MS) with 14 or 21 days of restraint stress (RS). Behavioral assessments (sucrose preference test, tail suspension test, open field test, elevated zero maze) confirmed depressive- and anxiety-like behaviors in the MS + RS 21d group mice. Neurobiological analyses revealed hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (elevated serum corticosterone [CORT] and adrenocorticotropic hormone [ACTH]) and dysregulation, characterized by reduced levels of monoamine neurotransmitters (5-hydroxytryptamine [5-HT], 5-hydroxyindoleacetic acid, dopamine, norepinephrine), altered mRNA expression of key genes (e.g., increased ACTH, CRH, SERT; decreased GR, brain-derived neurotrophic factor [BDNF]), and corresponding protein-level changes (e.g., increased 5-HT1AR, CRHRs; decreased BDNF, TrkB). Our findings indicate that the two-hit mouse model, combining MS with a 21-day RS, stably induces depressive- and anxiety-like behaviors in mice. The underlying mechanism may be associated with HPA axis dysfunction, serotonergic system dysregulation, and aberrant BDNF signaling within the prefrontal cortex-amygdala-hypothalamus circuit. Show less