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Breast cancer remains among the most prevalent cancers in women worldwide. During tumor development, the extracellular matrix is altered to support tumor progression and therapy resistance. Therefore, there is a need to develop breast cancer models that replicate the complex tumor extracellular matrix to accurately mimic the mechanisms by which it influences drug resistance and cancer cell malignancy. In this study, we fabricated an innovative breast cancer 3D in vitro model consisting of core-shell hydrogel beads from alginate, gelatin, and collagen I by extrusion through a coaxial needle. Breast cancer cells proliferated in the core of all prototypes designed, forming spheroids and cell aggregates with a high resistance to doxorubicin. The addition of Collagen I to the developed model enabled the upregulation of malignancy markers (Col1A1, Ki67, FOXC2, SNAI1, NFKB1, WWTR1), invasion markers (WASL, ACTA1, MYO1E, TPM4, PODXL, ITGA2, ITGA5, MENA, EGFR, CDC42), and drug resistance markers (ABCG2, CYP1A1, BAX, HSP90AA1) occurring in vivo. The developed 3D in vitro model can clarify the contribution of the extracellular matrix to the tumor outcome and drug efficacy by replicating some key characteristics of breast tumors, establishing a novel tool for chemotherapeutic agents and drug screening. Show less

Targeting the glucose dependent insulinotropic polypeptide receptor (GIPR) is of growing interest for treating type 2 diabetes and obesity, though the optimal approach remains unclear. Both GIPR agonism and antagonism, respectively, incorporated into drugs like tirzepatide and maridebart cafraglutide, have paradoxically both shown significant weight loss effects in humans. In this study, the metabolic impacts of a GIPR agonist (GIP108) and antagonist (NN-GIPR-Ant) were evaluated in lean and high-fat diet (HFD)-induced obese male mice. We assessed the impacts on food intake, body weight, glucose and insulin tolerance, liver triglyceride levels, bone markers and adipose tissue lipolytic gene expression. In lean mice, neither peptide affected food intake or body weight, but GIP108 improved glucose tolerance. In obese mice, both agents reduced food intake and body weight, with NN-GIPR-Ant producing more sustained appetite suppression. Energy expenditure remained unchanged, as weight loss matched that of pair-fed controls. GIP108 improved glucose tolerance independently of weight loss, whereas NN-GIPR-Ant reduced insulin sensitivity compared to pair-fed controls. Both treatments slightly increased liver triglyceride content compared to their pair-fed controls, and no treatment significantly affected plasma bone marker levels. Finally, NN-GIPR-Ant reduced the expression of adipose tissue lipolytic genes. Our data highlights the distinct metabolic effects of GIPR agonism and antagonism, offering insights for their future application in personalised metabolic disease treatments. Further human studies are needed to understand the long-term metabolic impacts of these therapies. Show less

Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes. 3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels. 3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy- 3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer. Show less

Integration of the hepatitis B virus (HBV) genome into the host chromosome of infected patients poses a threat to those with HBV-associated hepatocellular carcinoma (HBV-HCC) due to challenges in early diagnosis and poor prognosis. CircRNAs are known for their oncogenic and biomarker potential in various cancers, including HBV-HCC, by sequestering tumor suppressive miRNAs, which, when free, can silence the expression of oncogenic mRNAs. Therefore, we aimed to develop a bioinformatic model to identify the circRNA-miRNA-mRNA axis in HBV-integrated HCC cell lines and to identify prognostic biomarkers specific to HBV-HCC patients. We identified dysregulated host circRNAs and mRNAs in HBV-negative and HBV-integrated cells using RNA-seq, followed by differential gene expression analysis with DESeq, and performed pathway analysis using Gene Set Enrichment Analysis (GSEA). Junctional sequences of the circRNAs were validated by Sanger sequencing of the amplified products. RT-qPCR further confirmed the dysregulation of 9 randomly selected circRNAs chosen from those with the highest fold-change and adjusted p-values. The miRNA partners for each circRNA were identified using mirDB. miRNA expression validation was performed using the publicly available Gene Expression Omnibus (GEO) database of the same cells, and Empirical Cumulative Distribution Function (ECDF) plots were generated to assess the fold change of mRNAs in potential binding miRNA partners. The mRNA targets for 10 miRNA ECDF plots were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and hub genes were identified using Search Tool for the Retrieval of Interacting Genes (STRING) Cytohubba protein-protein interaction (PPI) analysis. Survival analysis of hub genes was plotted, and a competitive endogenous RNA (ceRNA) network was constructed using Cytoscape. We identified 494 dysregulated circRNAs, 346 dysregulated miRNAs, and 10,419 dysregulated mRNA in HBV-integrated cells through a comprehensive bioinformatic model. circADGRL2 (~ 25-fold) showed the highest upregulation and miR-361-5p acted as a central node of multiple circRNAs: circADGRL2, circPROX1 and circPALS2. BDNF, a target mRNA of miR-361-5p, was identified as the highest risk ratio in HBV-HCC patients, suggesting a possible circADGRL2-miR-361-5p-BDNF axis involved in HBV-HCC. The target mRNAs of miRNAs were predicted to be associated with several cancer pathways, such as MAPK and RAS. Our data suggest a potential dysregulated circRNA-miRNA-mRNA axis in HBV-integrated hepatocytes, which may indicate a poor prognosis for HBV-HCC patients. Show less

The dysregulated immune system, which drives chronic vascular inflammation and remodeling, plays a critical role in the pathogenesis of abdominal aortic aneurysm (AAA). CCR4 (C-C chemokine receptor 4), which is predominantly expressed on T cells and mediates their responses, has been shown to protect against inflammatory diseases including atherosclerosis. However, its role in AAA remains unknown. By analyzing hypercholesterolemic CCR4-deficient ( Genetic deletion of CCR4 on an CCR4 may serve as a potential therapeutic target for AAA. Show less

Vascular smooth muscle cells (VSMCs) contribute to atherosclerotic foam cell formation, but mechanisms regulating their phenotypic switching and programmed cell death remain unclear. O-GlcNAcylation, a nutrient-sensitive post-translational modification implicated in vascular calcification, lacks defined roles in VSMC foam cell biology. Inducible smooth muscle-specific Ogt knockout mice on an Apoe OGT expression and global O-GlcNAcylation were reduced in VSMCs during atherogenic progression. Ogt deletion in VSMCs promoted foam cell formation with enhanced lipid accumulation but paradoxically reduced atherosclerotic lesion area concurrent with increased intraplaque cell death. Both genetic and pharmacological OGT inhibition recapitulated this duality in vitro, simultaneously accelerating lipid accumulation while triggering PANoptosis, as evidenced by concurrent activation of cleaved caspase-3, phosphorylated MLKL, and cleaved GSDMD. Individual inhibition of apoptosis, necroptosis, or pyroptosis provided only partial rescue. OGT acts as a dual regulator of VSMC fate, attenuating plaque burden through PANoptosis induction while promoting foam cell formation, revealing its complex role in atherosclerosis pathogenesis and suggesting context-dependent therapeutic implications. Show less

The maternal environment during gestation influences fetal development, with long-lasting effects on postnatal health and productivity. This study evaluated the effect of prenatal heat stress (PNHS) on blood DNA methylation of dairy calves immediately after birth and whether such modifications persist into early life. Holstein calves were born to dams exposed to either PNHS (n = 36, temperature-humidity index >68, access to shade of a freestall barn) or prenatal cooling (PNTN; n = 37, access to shade and evaporative cooling) during the last 54 ± 5 d of gestation. Whole-genome enzymatic DNA methyl sequencing was performed on blood samples collected at birth (d 0; n = 3 PNHS, n = 5 PNTN) and 1 wk post-weaning (d 63 of age; n = 8 PNHS, n = 8 PNTN). From birth onward, all calves were actively cooled and managed under the same conditions. At birth, 682,898 differentially methylated cytosines (DMC) were identified genome-wide. Principal component analysis using 55,304 DMC located in genes expressed in blood cells revealed a clear clustering by prenatal treatment. However, at weaning, clear clustering by treatment was no longer observed using 23,977 treatment-associated DMC in blood-expressed genes, despite 97,289 DMC persisting genome-wide from birth to weaning. Immune cell deconvolution showed only minor differences in granulocytes (d 0) and CD4/CD8 Show less

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E-deficient (ApoE Show less

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) have strong triglyceride-lowering and anti-inflammatory properties, and high levels of these fatty acids have been associated with reduced risk of cardiovascular disease. The synthesis of n3-LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and n6-LCPUFA, arachidonic acid, share a common pathway mediated by fatty acid desaturase genes, FADS1 and FADS2. LCPUFA synthesis is regulated by both modifiable and non-modifiable factors. Of particular interest is the role of genetic variants in the FADS gene cluster, which are associated with altered FADS1 and FADS2 expression, as well as LCPUFA levels. However, the specific functional variants and the precise molecular mechanisms by which these variants regulate FADS gene expression remain to be elucidated. Variation in the FADS gene cluster is thought to have arisen through natural selection and changing dietary patterns. Available evidence suggests these variants, either individually or as a haplotype, may alter FADS gene expression by modifying DNA methylation in regulatory regions, as well as microRNA and transcription factor binding sites. This review explores the current state of knowledge regarding the functional roles of these variants on LCPUFA synthesis and how these new insights will help support precision nutrition strategies aimed at improving an individual's n3-LCPUFA status and health. Identifying specific functional variants in or near the FADS gene cluster and elucidating the mechanisms by which these variants impact LCPUFA synthesis requires further investigation. However, hypothesis generating in vitro studies have revealed roles for epigenetics, non-coding RNAs, and modification of transcription factor binding sites. This knowledge will generate new insights that will help improve our understanding of the genetic basis underlying LCPUFA synthesis and how this may differ across populations. Show less

Health-related fitness (HRF) is essential for wellbeing and daily functioning. While objective fitness assessments are preferred, self-report measures are practical for large-scale or geographically diverse studies. Existing self-report HRF measures may lack sensitivity for younger or healthy adults. Additionally, many include items with no or poorly defined reference populations, potentially limiting their validity and comparability. This study examined the reliability and validity of single-item self-reported HRF measures of aerobic fitness, muscular strength and endurance, flexibility, coordination, agility, and body composition. Between April and July 2023, University of Calgary students and staff (N.=129; mean age 28±9 years) completed the first questionnaire, with subsets completing a second questionnaire and validated fitness assessment. Nine items captured participants' self-rated HRF relative to those of the same age and gender. The nine self-reported HRF items were aggregated to obtain an estimate of overall HRF (Multidimensional Health-Related Fitness Scale, MHFS). We used intraclass correlations (ICC) to estimate test-retest reliability of the individual self-reported HRF items and MHFS. We assessed convergent validity with self-reported leisure physical activity (LPA) and concurrent validity with objective fitness measures using age- and sex-adjusted partial correlations. The single-item self-reported HRF measures (ICC=0.60-0.85) and MHFS (ICC=0.87) had acceptable test-retest reliability. The MHFS also had high internal consistency (Cronbach's α=0.87). Evidence of validity was observed with partial correlations ≥0.30 between self-reported HRF and LPA, and objective fitness measures. The MHFS provides a reliable and valid HRF indicator among younger adult populations. Show less

Wilson disease (WD) and familial hypertriglyceridemia (FHTG) are both genetic metabolic diseases, and their comorbidity is extremely rare. This article reports a case of WD with FHTG in a 12-year-old Chinese boy. The patient was diagnosed due to elevated transaminase levels, combined with clinical manifestations, copper metabolism indexes, lipid profile analysis, and genetic testing results (pathogenic mutations of Show less

Resveratrol (RSV), a dietary polyphenol widely present in traditional medicinal plants and foods, exhibits antioxidant and anti-inflammatory properties that are relevant to ethnopharmacological strategies for protecting against environmental neurotoxicants. Given increasing real-world co-exposure to lead (Pb) and cadmium (Cd), elucidating RSV's capacity to preserve gut-brain axis (GBA) homeostasis has direct translational relevance for populations relying on phytochemical interventions. Sprague-Dawley rats were randomized into control, Pb-Cd model, and RSV treatment groups (10, 20, or 40 mg/kg). For 4 weeks, rats received Pb (300 mg/L) and Cd (50 mg/L) in drinking water with daily RSV. Cognitive function was assessed by Morris water maze; barrier integrity by Evans blue assay, histology, and Western blot for ZO-1/Occludin; synaptic ultrastructure by TEM; microbiota composition by 16S rRNA sequencing; and short-chain fatty acids (SCFAs) by GC-MS. Neurotransmitters (5-HT, GABA, SP, VIP) and cytokines (IL-6, IL-1β, TNF-α) were measured by ELISA. RSV improved spatial learning, reduced EB extravasation, preserved synaptic ultrastructure and proteins (BDNF, SYN, PSD-95), and restored intestinal architecture with increased ZO-1/Occludin. RSV attenuated cytokine release, normalized goblet cells, reversed dysbiosis by restoring Lactobacillaceae/Prevotellaceae, and increased acetate, propionate, and butyrate. It reinstated 5-HT and GABA while reducing SP and restoring VIP across serum, colon, and hippocampus. RSV attenuated Pb-Cd-associated neurotoxicity and was accompanied by improved intestinal and BBB-related readouts, partial normalization of gut microbiota features and SCFA levels, and preservation of synaptic and neurotransmitter-related markers, consistent with a link to gut-brain axis function. This study is among the first to test RSV in a Pb-Cd co-exposure model using a multi-dose regimen with integrated behavioral, barrier, microbial, and neurochemical endpoints. Show less

Molecular genetic testing was performed on a fetus with ectrodactyly of the right foot to clarify the pathogenic cause and provide evidence for prenatal counseling. Trio whole-exome sequencing (trio-WES) was performed on the fetus and his parents to identify the underlying genetic cause. Candidate variants were validated by Sanger sequencing, and their molecular effects were analyzed through minigene assays. Trio-WES identified a novel heterozygous variant (c.1977+1G>C) in FGFR1, which is consistent with FGFR1-related Hartsfield syndrome (HS; OMIM#615465). Sanger sequencing confirmed that this variant was de novo. The minigene assay revealed that all variants (c.1977+1G>C, c.1977+1G>A, and c.1977+1G>T) at the splice site generated two aberrant splicing events: (1) complete retention of intron 14, leading to a frameshift and premature termination codon; and (2) skipping of exon 14, causing an in-frame deletion of 41 amino acids. These events collectively impaired the function of the FGFR1 protein's tyrosine kinase domain. To our knowledge, prenatal reports of FGFR1-related HS remain extremely limited, and this is the first molecularly confirmed prenatal diagnosis of HS in China. The findings not only expand the mutational spectrum of HS but also provide genetic counseling and reproductive guidance for this family. Show less

The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF. Show less

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and psychiatric impairments, with depression as a major comorbidity. Existing treatments for Huntington-related depression are inadequate, highlighting the need for strategies that target molecular mechanisms underlying mood dysregulation. This review examines the mechanistic interplay between environmental enrichment (EE), a paradigm enhancing sensory, cognitive, and social stimulation and Neuropeptide S (NPS), a neuropeptide involved in stress modulation and emotional regulation. It focuses on their potential synergistic effects in modulating depression-associated molecular pathways in HD. EE activates signalling cascades that promote synaptic plasticity and neurogenesis, including the upregulation of brain-derived neurotrophic factor (BDNF), enhanced activation of cAMP response element-binding protein (CREB), and remodelling of glutamatergic and GABAergic transmission. NPS exerts antidepressant-like effects by attenuating hyperactivity of the hypothalamicpituitary- adrenal (HPA) axis, modulating corticotropin-releasing factor (CRF) signalling, and influencing monoaminergic systems. Evidence indicates that EE may enhance NPS receptor (NPSR1) expression and downstream intracellular calcium signalling, reinforcing adaptive plasticity in the striatum and prefrontal cortex regions vulnerable in HD. Integrating EE with NPS-targeted therapy could provide a multimodal approach to restore molecular homeostasis and alleviate depressive phenotypes in HD. Further research should elucidate optimal intervention timing, dose-response relationships, and potential cross-talk between EE-induced BDNF pathways and NPS-mediated stress resilience for translational application in neurodegenerative depression. Show less

In the core of a stroke, cell death occurs within minutes. In the penumbra, activity quickly drops, but cells typically remain viable for several hours. Improving neuronal survival in the penumbra is crucial for enhancing recovery in patients with stroke. Earlier work showed that mild activation may improve recovery, but the mechanisms are unclear. Brain-derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions via activation of tyrosine receptor kinase B (TrkB) receptors, and its release is activity-dependent. This study explored the role of BDNF/TrkB signaling in neuronal survival under hypoxic conditions, using cultures of dissociated cortical rat neurons. When exposed to hypoxia, activity quickly drops and cells become apoptotic after ∼12 h, similar to observations in the ischemic penumbra. Inhibition of the TrkB receptor in healthy, normoxic cultures led to a fivefold increase in apoptosis, confirming the importance of BDNF/TrkB signaling for cell viability in these preparations. The addition of BDNF to hypoxic cultures significantly improved neuronal survival, comparable with the effects of mild activation. These findings suggest that the beneficial effect of mild stimulation to prevent apoptosis in hypoxic cultures is mediated by BDNF/TrkB signaling, offering insights for potential therapeutic strategies aimed at promoting neuronal recovery after a stroke. Show less

The regulatory mechanisms of epithelial-mesenchymal transition (EMT) involved in periodontitis pathogenesis are poorly understood. Consequently, this study aimed to investigate the association of the long noncoding (lnc) RNAs, NEAT1 and MALAT1, with EMT in periodontitis. Gingival tissue samples (n = 57) were obtained from periodontitis patients indicated for surgical treatment and healthy control individuals. Full mouth periodontal charting was recorded for all patients together with collection of subgingival biofilm samples to determine bacterial load for key-periodontal pathogens. Histopathological analysis was used to assess inflammatory cell infiltration, and RT-qPCR analysis was performed to quantify the expression of the key EMT biomarkers of E-cadherin, β-catenin, Snail1 and vimentin, and the lncRNAs of Neat1 and Malat1. The clinical parameters and percentage of inflammatory cell infiltration were significantly higher in the periodontitis group compared with healthy controls. In periodontitis, expressions of Malat1 and E-cadherin were significantly downregulated, whereas Neat1, Snail1 and vimentin were significantly upregulated in comparison to controls. Receiver-operating characteristic (ROC) analyses demonstrated moderate-to-good diagnostic accuracy of Neat1, Malat1, Snail1, E-cadherin and vimentin (area under the curve [AUC]: 70.3%, 67.5%, 78.7%, 89.9% and 74.3%, respectively) to discriminate periodontal health from disease. Probing pocket depth, bleeding scores, expression of Neat1, red complex bacteria (Porphyromonas gingivalis and Treponema denticola) and downregulation of Malat1 and E-cadherin were strongly associated with EMT. Data also highlighted an association between Neat1 and Malat1 with the induction of the EMT phenotype in periodontitis, and these lncRNAs may therefore provide novel diagnostic biomarkers. Show less

Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Aberrant canonical Wnt signaling is a hallmark of this cancer type. It has been reported that LPA is a bioactive lipid that plays different roles in colon cancer by activating its G-protein-coupled receptors, promoting cell proliferation, migration, survival, and angiogenesis. Although it has been reported that LPA activates canonical Wnt signaling, the mechanisms underlying their interaction remain unclear; this study aims to investigate them. As previously reported, LPA receptor expression changes under malignant conditions: while LPA Show less

Maternal physical activity during pregnancy has been shown to confer benefits on the brain functions of offspring. This study investigated the positive effects of maternal exercise during pregnancy on enhancing hippocampal synaptic plasticity and resilience to stress-induced depressive behavior in adult murine offspring. Using a mouse model with mother mice engaged in voluntary wheel running during pregnancy, we assessed changes in long-term potentiation (LTP) in the hippocampal dentate gyrus, synaptic protein expression, and behavioral responses to chronic stress in adult male and female offspring from exercised dams compared with those from sedentary dams. We found that maternal exercise enhanced LTP in offspring of both sexes. Western blot analysis of hippocampal synaptoneurosome extractions revealed significant main effects of maternal exercise on increasing the expression of brain-derived neurotrophic factor (BDNF), PSD-95, synaptophysin, and phosphorylation of N-methyl-D-aspartate receptor subunit GluN2A and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA1. Maternal exercise significantly increased synaptophysin levels in both male and female offspring, with sex-specific effects on increasing PSD-95 levels in male offspring and increased p-GluN2A levels in female offspring from exercised dams. Golgi staining revealed a significant increase in hippocampal dendritic spine density in female offspring only. Maternal exercise-induced improvements in hippocampal synaptic plasticity were associated with reduced depression-like behaviors in both male and female offspring exposed to chronic unpredictable stress. Additionally, male offspring displayed reduced anxiety-like behavior, while female offspring showed no significant anxiolytic changes. These findings elucidate the sex-specific effects of maternal exercise on enhancing hippocampal synaptic plasticity, which may contribute to increased resilience against stress-induced depressive behaviors in adult offspring. Show less

To elucidate the molecular mechanism by which ginsenoside Rg3 (G-Rg3) protects human bronchial epithelial (HBE) cells against lipopolysaccharide (LPS)-induced injury, focusing on its regulation of autophagic flux and the TLR4/NF-κB-mediated inflammatory pathway. HBE cells were treated with LPS (1-100 ng/mL) to induce autophagy dysregulation and inflammation. G-Rg3 (2-16 μM) was administered to evaluate its protective effects. Western blotting was used to detect autophagy-related proteins (ATG4B, ATG7, PIK3C3, LC3B, p62) and TLR4/NF-κB signaling molecules; ELISA quantified proinflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6, IL-8); PI staining and flow cytometry analyzed cell death and apoptosis. LPS dose-dependently upregulated the expression of autophagy-related proteins (ATG4B, ATG7, PIK3C3, p62, LC3B-II), with accumulated p62 and LC3B-II indicating impaired clearance of autophagic substrates. Additionally, G-Rg3 inhibited LPS-induced TLR4/NF-κB activation, suppressed proinflammatory cytokine secretion, and attenuated HBE cell apoptosis/necrosis. G-Rg3 mitigates LPS-induced HBE cell injury by dual mechanisms: restoring impaired autophagic flux and inhibiting the TLR4/NF-κB inflammatory cascade. These findings identify G-Rg3 as a promising therapeutic agent targeting the crosstalk between autophagy and inflammation in respiratory diseases such as COPD and acute lung injury. Show less

Intracerebral hemorrhage (ICH) has a high rate of death and disability. LncRNA-TUG1 is essential for the pathological changes secondary to ICH. The purpose of this work was to investigate the possible mechanism by which TUG1 inhibits neural repair subsequent to ICH through adjusting miR-381-3p/brain-derived neurotrophic factor (BDNF). After the ICH model was created, miR-381-3p agomir and pcDNA-TUG1 were injected. The neural function of rats was estimated using the modified neurological severity score. To quantify the expression of genes and proteins, western blotting, immunohistochemistry, and qRT-PCR were used. To confirm the interaction between TUG1 and miR-381-3p and between miR-381-3p and BDNF mRNA, a luciferase reporter assay was employed. In rats treated with miR-381-3p agomir, a trend of improvement in neurological dysfunction was observed, while the pcDNA-TUG1-treated ones showed deterioration. Furthermore, miR-381-3p agomir increased, while pcDNA-TUG1 reduced the expression level of BDNF in ICH rats. TUG1 and BDNF mRNA were validated to attach directly to miR-381-3p. Overexpressing TUG1 inhibited the level of BDNF by sponging miR-381-3p and antagonized its protective effect on neural repair in ICH rats. Our study suggests that TUG1 can sponge miR-381-3p to downregulate BDNF expression and inhibit neural repair following ICH, demonstrating a potential signaling pathway that is conducive to a better understanding of the pathological mechanisms of ICH. Show less

This narrative review aims to synthesize and critically evaluate the complex molecular mechanisms by which amyloid-β (Aβ) accumulation disrupts hippocampal synaptic plasticity, the cellular cornerstone of learning and memory in Alzheimer's disease (AD). AD is characterized by progressive hippocampus-dependent cognitive decline, strongly linked to impaired synaptic plasticity, the cellular basis of learning and memory. This review deciphers how Aβ accumulation orchestrates synaptic sabotage in the hippocampus. We detail the core molecular machinery of hippocampal synaptic plasticity, emphasizing glutamate receptor trafficking (NMDAR/AMPAR), Ca Show less

Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD - anti-Aβ antibodies - work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y Show less

In vitro maturation (IVM) is highly susceptible to influences of the culture environment, which can lead to increased intracellular reactive oxygen species (ROS) levels and thereby induce a stress response in oocytes, ultimately reducing the developmental potential of early embryos. Brain-derived neurotrophic factor (BDNF) is an ovarian endocrine factor that can enhance the function of follicular granulosa cells and promote oocyte maturation, but the specific pathways remain unclear. We supplemented IVM cultures of sheep oocytes with BDNF and examined aspects of oocyte nuclear and cytoplasmic maturation. The addition of 50 ng/mL BDNF promoted the expansion of cumulus cells and increased the rates of first polar body extrusion, cleavage, and blastocyst formation. Compared with untreated controls, BDNF-treated oocytes had improved Ca Show less

Primary Sjögren's disease (SjD) is a systemic autoimmune disorder where diagnosis relies on the presence of Ro/SS-A and La/SS-B autoantibodies. However, approximately one-third of SjD patients are seronegative, often requiring an invasive minor salivary gland biopsy, which can lead to significant diagnostic delays. This review comprehensively evaluates a wide array of novel autoantibodies to determine their potential as diagnostic biomarkers for Ro/SS-A-negative SjD patients. While many newly identified autoantibodies, such as those targeting ASCA, TRIM38, and PUF60, were found to be strongly associated with Ro/SS-A positivity and thus offer limited utility for seronegative diagnosis, several others show significant promise. Notably, autoantibodies targeting functional proteins like the muscarinic M3 receptor (anti-M3R) have demonstrated high diagnostic sensitivity and specificity. Furthermore, systematic screenings have uncovered highly specific markers. One panel of 12 autoantigens (including GMNN, GRAMD1A, and NUP50) identified by human proteome arrays exhibited 54% sensitivity with 100% specificity for Ro/SS-A-negative SjD. Another validated panel combining immunoglobulin G autoantibodies against FNBP4, SNRPC, CCL4, M3R, and KDM6B achieved 46% sensitivity with 95% specificity. Other individual markers, such as anti-NA14 and anti-calponin-3, also show potential for identifying seronegative SjD subsets. In conclusion, a growing body of evidence supports the clinical utility of several novel autoantibodies in diagnosing Ro/SS-A-negative SjD. The integration of these biomarkers into clinical practice could significantly improve early and accurate diagnosis, reduce the reliance on invasive procedures, and potentially aid in patient stratification for targeted therapies. Further validation of these markers in large cohorts is warranted. Show less

Current therapeutic approaches for Alzheimer's disease (AD) demonstrate limited efficacy and fail to address disease progression. In the present study, we present HSN-G1, a novel ginsenoside-enriched pharmaceutical formulation that employs a dual-target mechanism through the modulation of amyloid clearance pathways and cholinergic neurotransmission. HSN-G1 demonstrates a reproducible ginsenoside profile enriched with Re (33.27 mg/g), Rd (25.00 mg/g), and Rg3 stereoisomers (12.18 mg/g), ensuring pharmaceutical-grade reproducibility. HSN-G1 enhanced amyloid-beta (Aβ) clearance in microglial cells, with significantly greater effects observed in SRA-overexpressing cells, suggesting SRA-dependent clearance mechanisms. In APP/PS1 transgenic mice, six-week oral administration of HSN-G1 (100-400 mg/kg) elicited significant dose-dependent improvements in cognitive performance. Male mice exhibited more stable and consistent enhancements in both passive avoidance and spatial memory tests compared to vehicle controls (p < 0.001), while both sexes demonstrated comparable reductions in brain Aβ levels (approximately 45%) and differential increases in acetylcholine (73% in males; 55% in females, p < 0.01). HSN-G1 administration enhanced the expression of neurotrophic factors, with NGF upregulation predominantly observed in males, whereas BDNF, CNTF, and GDNF were consistently elevated across both sexes. These findings establish HSN-G1 as a promising disease-modifying agent with standardized composition and therapeutic efficacy, surpassing the limitations of conventional single-target approaches. The superior efficacy of HSN-G1 compared to existing treatments validates its potential for clinical development, highlighting the significance of sex-specific therapeutic responses in future AD therapeutics. Show less

Apolipoprotein E (ApoE) plays an important role in cerebral lipid transport. Beyond lipid transport, ApoE also contributes to the maintenance of neuronal integrity. Although DNA damage and dysfunction in the DNA damage response are recognized as early contributors to neuropathology, the connection between ApoE and DNA damage remains poorly understood. In this study, we investigated cells expressing endogenous mouse ApoE (mApoE) in the brain under both normal condition and etoposide-induced DNA damage. Immunohistochemical analysis revealed that mApoE was predominantly expressed in astrocytes and a subset of neurons across various brain regions, with minimal expression in microglia and no detectable expression in oligodendrocytes. Induction of DNA damage through etoposide treatment did not alter the expression level or distribution pattern of mApoE in brain. However, a correlation between neuronal mApoE expression and DNA damage was observed: mApoE-positive neurons were more affected and exhibited a higher number of γH2A.X foci upon etoposide treatment. This observation warrants further investigation to determine whether the increased sensitivity of mApoE-positive neurons to DNA damage is neuroprotective or contributes to neurodegeneration. Our study provides a foundation for understanding the physiological role of mApoE in response to DNA damage and suggests a potential involvement of neuronal mApoE in neurodegeneration. Show less

The development and function of B lymphocytes require the precise integration of signaling, transcriptional networks, and metabolic programs. While interferon (IFN)-inducible proteins can bridge innate and adaptive immunity, their roles in B cells remain poorly defined. Here, we identified RNF213, a giant IFN-inducible RING finger E3 ligase, as a key orchestrator of B-cell biology. Mice lacking Rnf213 exhibited defective splenic B-cell development, impaired B-cell receptor (BCR) signaling, and compromised metabolic activity. Mechanistically, RNF213 targeted the transcription factor SPIB for proteasomal degradation via K11-linked ubiquitylation. In Rnf213‑deficient B cells, stabilized SPIB transcriptionally upregulated Pik3c3, thereby increasing phosphatidylinositol 3-phosphate (PI3P) production. Excess PI3P recruited PTEN to early endosomes, where PTEN hydrolyzed phosphatidylinositol-3,4,5-trisphosphate (PIP3) and attenuated AKT-mTOR signaling. Strikingly, both genetic deletion of Spib and pharmacological inhibition of PIK3C3 restored AKT-mTOR activation, metabolic fitness, and B-cell development in Rnf213-null mice. Furthermore, Rnf213 deficiency impaired both T-independent and T-dependent antibody responses, highlighting its critical role in humoral immunity. Overall, our work reveals a novel ubiquitin-dependent circuit that links interferon signaling to the transcriptional and metabolic control of B-cell homeostasis. This study also establishes RNF213 as a crucial bridge between innate immune sensing and the dynamic regulation of lymphocyte development. Show less

Left pulmonary artery (LPA) sling is a rare congenital anomaly in which the LPA abnormally originates from the right pulmonary artery (RPA) and courses between the trachea and esophagus to reach the left pulmonary hilum. This anomaly is frequently associated with tracheobronchial and other cardiovascular anomalies and patients may manifest with varying airway and cardiovascular symptoms. Surgical repair is often required for symptomatic patients. Clinical outcomes largely depend on the extent and severity of coexisting anomalies, particularly tracheobronchial abnormalities. We report 2 autopsy cases of LPA sling, 1 pre- and 1 post-surgical repair. Comprehensive autopsy examination was crucial for confirmation of the clinical diagnoses and identification of a rare surgical complication. Show less

Monocytes and regulatory noncoding RNAs play a crucial role in the development of atherosclerosis (ATH). We have previously shown that miR-125b-5p was upregulated in aortic macrophages, and the aim of this paper was to further study the "in vivo" impact of miR-125b-5p in ATH progression. Eight-weeks-old Show less