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Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition and neurofibrillary tangles, which collectively drive neuroinflammation, synaptic dysfunction, and cognitive decline. Here, we investigated whether a peptide epitope vaccine targeting the Aβ1-10 sequence could mitigate Aβ-induced pathology in AD mouse model. Three Aβ1-10 peptides, i.e. Aβ1-10-N, Aβ1-10-D1H, and Aβ1-10-S8R were synthesized, and Aβ1-10-S8R was further conjugated to ovalbumin (OVA) or keyhole limpet hemocyanin (KLH) to enhance immunogenicity. Among seven treatment groups, Aβ1-10-D1H and Aβ1-10-S8R, particularly when conjugated to OVA or KLH, effectively suppressed Aβ, amyloid-beta precursor protein (APP), and beta-secretase 1 (BACE-1) expression, decreased inflammatory cytokine production by astrocytes and microglia, and increased the levels of key synaptic markers (synaptophysin, synaptosomal-associated protein 23 [SNAP-23], postsynaptic density protein 95 [PSD-95]). Carrier protein conjugation also elevated immunoglobulin G (IgG) levels in the spleen, indicative of a robust humoral response. Taken together, these findings demonstrate that Aβ1-10-based immunization, especially with OVA or KLH conjugation, reduces Aβ-driven neuroinflammation, synaptic dysfunction, and memory deficits, suggesting a promising immunotherapeutic strategy for AD. Show less

Lacticaseibacillus paracasei cell wall presents two capsular polysaccharides, CPS-1 and CPS-2, and a teichoic acid. CPS-1 is novel and it presents a branched heptasaccharide repeating unit, with the sequence →6)-α-d-Gal-(1→3)-β-l-Rha-(1→4)-β-d-Glc-(1→3)-α-d-GlcNAc-(1→2)-β-d-Glc-(1→6)-β-d-Glc-(1→ in the linear part to which a β-l-Rha is attached to O-4 of GlcNAc. Regarding CPS-2, its structure was previously reported for L.casei, and it presents the tetrasaccharide repeat 2)-α-l-Rha-(1→2)-α-l-Rha-(1→3)-α-l-Rha-(1→3)-α-d-GalNAc-(1→ as backbone, where the first Rha is substituted with a trisaccharide made of Rha, GlcNAc and Glc, and the third Rha has a Glc as a non-stoichiometric substituent. Preliminary in-vitro immunological analyses disclosed that the two glycans exert different activities. CPS-1 is superior to CPS-2 for the elicitation of IL-33, an interleukin that alerts the immune system to tissue damage or danger. CPS-2 instead is more efficient than CPS-1 in the elicitation of the antimicrobial peptides LL-37 and HBD-2, and it is a strong elicitor of occludin, a protein of the tight junctions relevant for the epithelium integrity. These findings suggest that L.paracasei CPSs play a synergistic and beneficial role in the gut, thus paving the way to studies aimed to examine their mode of action or their exploitation in the prevention and treatment of human gastrointestinal diseases. Show less

Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration. Show less

Decreased serum high-density-lipoprotein-cholesterol (HDL-C), HDL particles, and cell-cholesterol-efflux-capacity have all been associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. Our goals are to summarize recent findings with regard to these topics. Apolipoprotein (apo) A1 containing HDL particles have been characterized by two-dimensional gel electrophoresis and apoA1 immunoblotting and range from very small preβ-1 HDL, small α-4 HDL, medium α-3 HDL to large and very large α-2 and α-1 HDL. Preβ-1 HDL are most efficient in serving as acceptors of free cholesterol and phospholipid from cells via ATP binding cassette transporter A1, while α-2 and α-1 HDL are most efficient in delivering cholesteryl-ester to the liver via scavenger receptor-B1 or to triglyceride-rich lipoproteins (TRL) in exchange for triglycerides via cholesteryl ester transfer protein (CETP). Recent research on the relationships of the lipid and protein composition, function, metabolism and levels of HDL particles to ASCVD risk will be reviewed, as will advances in potential therapeutic options. HDL particles are by far the most abundant lipoproteins in plasma and contain 110 proteins involved in lipid metabolism and immune function. ApoA1, apoA2, and all lipid classes are found in all HDL particles. Low levels of large and very large α-HDL and increased levels of very small preβ-1 HDL have been associated with increased ASCVD risk. The best therapeutic options for ASCVD risk reduction in patients with low HDL-C is optimizing other risk factors including low-density-lipoprotein (LDL)-C, small-dense LDL-C, plasma-glucose, body-mass-index, blood pressure, and the promotion of smoking cessation. Show less

Alzheimer's disease (AD) is a degenerative neurological disease characterized by a loss of memory and cognitive ability. One of the main factors influencing the development of AD is the accumulation of amyloid β (Aβ) plaque in the brain. The sequential production of Aβ is mediated by two enzymes: gamma-secretase and β-secretase (BACE1). The goal of beta-secretase inhibitors is to prevent the initial cleavage of amyloid precursor protein (APP), which reduces the production of (Aβ) peptides by limiting the substrate available for gamma-secretase. Simultaneously, gamma-secretase modulators are engineered to specifically modify enzyme performance, reducing the synthesis of the harmful Aβ42 isoform while maintaining vital physiological processes. Targeting both secretases reduces amyloidogenic processing synergistically. Selective inhibitors, which have been recently developed, have also shown good clinical development. They can reduce Aβ levels effectively with minimal side effects. The therapeutic strategy also underlines the importance of early therapy intervention in the preclinical AD phase for an optimum effect. Although there are some problems in the optimization of drug delivery and the alleviation of side effects, targeting beta and gamma secretases remains a promising direction. However, all these strategies still need more research and clinical testing to improve existing treatments and develop new, efficient Alzheimer's disease therapies. This review seeks to examine the therapeutic promise of β- and γ-secretase inhibition in Alzheimer's disease and review recent progress, challenges, and new dual-inhibition approaches. Show less

Transforming growth factor-β (TGF-β) plays well-established roles in cancer cell invasion and epithelial-mesenchymal transition (EMT); however, its role in thyroid carcinoma (TC) remains unclear. This study aimed to evaluate the effects of TGF-β on EMT in TC and determine its underlying mechanisms. Treatment of TC cell lines with TGF-β the morphology of thyroid cancer cells changed, Immunofluorescence staining revealed that the localization of E-cadherin shifted from the cell membrane to the cytoplasm, and the fluorescence intensity decreases. Wound-healing assay in BCPAP and TPC-1 revealed that migration ability was significantly higher in the TGF-β (5 ng/mL) treatment group than in the control group (P < 0.01). Transwell assays showed that the invasive abilities of TGF-β-treated BCPAP, TPC-1, and K1 cells were 7-, 10-, and 6-fold higher than those of the control group, respectively (P < 0.05). After TGF-β treatment, mRNA levels of SNAI1 significantly increased in TPC-1 and BCPAP cell lines. Treatment of TC cell lines with TGF-β downregulated the epithelial marker E-cadherin and upregulated the mesenchymal markers N-cadherin and vimentin, at the mRNA level. Western blotting indicated similar results at the protein level, TSH could enhance this process. TGF-β promotes EMT-like phenotypic changes in thyroid cancer cells, accompanied by upregulation of SNAI1 and EMT-related markers, which is enhanced by TSH. Overall, this study provides a basis for the development of therapeutic strategies for TC targeting the EMT. Show less

Recent studies suggest that dyslipidaemia may play a critical role in the progression of cardiovascular disease in Takayasu arteritis (TA), although the exact relationship between dyslipidaemia and TA disease activity remains unclear, which is the focus of this study. We evaluated dyslipidaemia and atherosclerosis in a cohort of untreated female patients. Fifty untreated female patients with TA (median age 30 years) and 98 healthy controls matched for age and body mass index (median age 30 years) were assessed for lipid profiles [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), ApoB, ApoE, lipoprotein(a)], inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)], and atherosclerotic plaque frequency. TA patients exhibited significantly higher levels of TG and the non-HDL-C/HDL-C ratio than the control group, whereas TC, HDL-C, LDL-C, and ApoA1 levels were significantly lower. Pearson's correlation analysis indicated a positive correlation between CRP and ApoB, as well as the non-HDL-C/HDL-C ratio, and negative correlations with TG, HDL-C, and ApoA1. Atherosclerotic plaques were detected in 14.3% of the TA patients. Multivariate regression analysis revealed that the presence of atherosclerotic plaques was associated only with age, independent of inflammatory markers and lipoprotein levels. The results of this study indicate that untreated female TA patients exhibit a markedly dysregulated serum lipid profile. Atherosclerosis in early TA was not related to lipids or markers of inflammation. Show less

NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays a pivotal role in the progression of cerebral ischemia/reperfusion injury (CI/RI). We aimed to investigate the implication of WW domain-containing protein 2 (WWP2), an E3 ubiquitin ligase, in CI/RI and its mechanism. Microglia were subjected to oxygen-glucose deprivation/reoxygenation, and mice were subjected to middle cerebral artery occlusion (MCAO) for modeling. WWP2 was reduced in the brain tissues of mice with MCAO/R. WWP2 overexpression in microglia inhibited the NLRP3 inflammasome activation to alleviate MCAO/R-induced injury and microglia-induced neurotoxicity. WWP2 inhibited the mitochondrial translocation of NLRP3 by degrading mitochondrial antiviral-signaling protein (MAVS) to block its interaction with NLRP3, and MAVS overexpression in microglia promoted the NLRP3 activation to exacerbate MCAO/R and neurotoxicity. The nuclear export of TAR DNA-binding protein 43 (TDP-43) in MCAO/R promoted the WWP2 degradation via the (UG)n element of the 3'UTR of WWP2. TDP-43 overexpression also impaired the blockade of NLRP3 activation and exacerbated neurotoxicity in the presence of WWP2. Overall, our investigations demonstrate that nuclear export of TDP-43 in microglia activates NLRP3 inflammasome and exacerbates CI/RI by blocking MAVS degradation through (UG)n element-mediated instability of WWP2. Show less

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. While prostate-specific antigen is a widely used biomarker, its specificity is limited. This study investigated the prognostic significance of gene subsets associated with the ubiquitin-proteasome pathway in PCa. We analyzed transcriptomic and clinical data of 94 early-onset (age <55) patients with prostate cancer using public dataset. Differentially expressed genes linked to the ubiquitin-proteasome system were identified across cancer progression stages. Kaplan-Meier survival analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) modeling were applied to assess their prognostic potential. Differential expression of The identified gene subset provides novel prognostic insights into PCa progression and survival. These findings highlight potential biomarkers and therapeutic targets within the ubiquitin-proteasome pathway, offering new avenues for personalized treatment strategies. Show less

Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160. Show less

Background Long-term/low grade epilepsy-associated tumors (LEATs) compose a complex group of low-grade brain neoplasms associated with drug-resistant focal epilepsy, primarily affecting pediatric and adolescent populations. LEATs exhibit significant epileptogenic potential, profoundly impacting patients' neurological and psychosocial outcomes. Advances in molecular pathology, particularly the identification of BRAF V600E and FGFR1 mutations, have enhanced the classification and understanding of these tumors, opening potential avenues for targeted therapies. Summary This review synthesizes current knowledge on LEAT biology, epileptogenesis, and clinical manifestations, highlighting the tumor microenvironment's role in seizure generation through disrupted neurotransmitter signaling, inflammatory processes, and network hyperexcitability. The integration of advanced neuroimaging, electrophysiology, and molecular diagnostics has refined LEAT detection and classification, improving surgical decision-making. Surgical resection remains the mainstay of treatment, with seizure freedom rates exceeding 80% when combined with tailored epilepsy surgery. However, variability in surgical outcomes underscores the need for individualized approaches, incorporating emerging minimally invasive techniques, such as laser interstitial thermal therapy (LITT), and neuromodulation strategies. Key Messages Despite advancements in the diagnosis and treatment of LEATs, key challenges remain, including refractory epilepsy, malignant progression, and the long-term impact of LEATs on cognitive function. Future research aims to refine the molecular and histopathological classification of LEATs, develop predictive biomarkers for seizure outcomes, and explore precision therapies targeting tumor-associated epileptogenesis. As the field evolves, a multidisciplinary approach integrating surgery, molecular therapeutics, and neurorehabilitation will be essential in optimizing patient outcomes. Show less

Rheumatoid arthritis (RA) frequently leads to osteoporosis (OP) and increased fracture risk. The protein Klotho plays a recognized role in bone metabolism, yet its specific function in RA-associated osteoporosis (RA-OP) remains incompletely understood. This study investigated the molecular mechanisms by which Klotho maintains bone homeostasis in RA-OP patients. We quantified Klotho levels in RA-OP patients and healthy controls and then conducted in vitro experiments using mouse embryonic osteoblast precursor cell line (MC3T3-E1) preosteoblastic cells to examine Klotho's effects on osteogenic differentiation and ferroptosis. We assessed osteogenic differentiation through runt-related transcription factor 2 (Runx2), collagen type i alpha 1 chain (Col1a1), and osteocalcin (Ocn) expression, while ferroptosis regulation was evaluated via glutathione peroxidase 4 (Gpx4) and Acyl-CoA synthetase long-chain family member 4 (Acsl4) expression. The interaction between fibroblast growth factor 23 (Fgf23) and fibroblast growth factor receptor 1 (Fgfr1) was analyzed using coimmunoprecipitation assays, with Fgf23's role examined through knockdown and overexpression experiments. Results showed RA-OP patients had significantly reduced Klotho levels compared to controls. Klotho overexpression in MC3T3-E1 cells enhanced osteogenic differentiation and protected against ferroptosis by upregulating Gpx4. Mechanistically, Klotho facilitated Fgf23-Fgfr1 interaction and repressed nuclear factor κ (NF-κB) signaling. Our findings demonstrate that Klotho mediates osteogenic action through the Fgf23/Fgfr1-NF-κB pathway while simultaneously protecting osteoblasts from ferroptosis, advancing our understanding of RA-OP pathophysiology and identifying Klotho as a promising therapeutic target for preventing RA-related bone loss. Show less

β-secretase 1 (BACE1), known for its role in amyloid-β production associated with Alzheimer's disease (AD), has also been suggested to be elevated in patients with Type 2 diabetes mellitus (T2DM). Notably, BACE1 could cleave the insulin receptor (InsR), leading to reduced InsR levels, which may impair insulin signaling and contribute to insulin resistance. Presently, we observed decreased InsR levels and impaired glucose disposal in the livers of mice with systemic overexpression of BACE1 (HUBC mice). This suggests that elevated BACE1 could contribute to insulin resistance by shedding membrane InsR. Additionally, mice fed a high-fat diet (HFD), a well-established model of T2DM, displayed increased BACE1 levels and decreased InsR. To further investigate whether inhibiting BACE1 could enhance insulin sensitivity and alleviate symptoms of diabetes, we treated HFD mice with the BACE1 inhibitor Elenbecestat. Remarkably, the administration of Elenbecestat restored InsR levels and improved their downstream signaling pathways, leading to increased insulin sensitivity and enhanced glucose tolerance. In summary, our findings suggest that inhibiting BACE1 can restore InsR expression and improve insulin-signaling sensitivity, ultimately resulting in enhanced diabetic phenotypes. Show less

Osteoporosis diagnoses are increasing in the ageing population, and although some treatments exist, these have several disadvantages, highlighting the need to identify new drug targets. G protein-coupled receptors (GPCRs) are transmembrane proteins whose surface expression and extracellular activation make them desirable drug targets. Our previous studies have identified 144 GPCR genes to be expressed in primary human osteoclasts, which could provide novel drug targets. The development of high-throughput assays to assess osteoclast activity would improve the efficiency at which we could assess the effect of GPCR activation on human bone cells and could be utilised for future compound screening. Here, we assessed the utility of a high-content imaging (HCI) assay that measured cytoplasmic-to-nuclear translocation of the nuclear factor of activated T cells-1 (NFATc1), a transcription factor that is essential for osteoclast differentiation, and resorptive activity. We first demonstrated that the HCI assay detected changes in NFATc1 nuclear translocation in human primary osteoclasts using GIPR as a positive control, and then developed an automated analysis platform to assess NFATc1 in nuclei in an efficient and unbiased manner. We assessed six GPCRs simultaneously and identified four receptors (FFAR2, FFAR4, FPR1 and GPR35) that reduced osteoclast activity. Bone resorption assays and measurements of TRAP activity verified that activation of these GPCRs reduced osteoclast activity, and that receptor-specific antagonists prevented these effects. These studies demonstrate that HCI of NFATc1 can accurately assess osteoclast activity in human cells, reducing observer bias and increasing efficiency of target detection for future osteoclast-targeted osteoporosis therapies. Show less

Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the blood-brain barrier and enter the brain to exert their effects. Moreover, some existing studies have pointed out that CS exposure is closely related to the accelerated pathology of Alzheimer's disease (AD). Transgenic mice with the five familial AD mutations (5xFAD), which are 1-month-old, were used for chronic CS exposure for 100 days. Subsequently, cognitive function and behavioral changes were evaluated through morris water maze and new object recognition tests. The acceleration of pathological changes due to CS exposure was assessed by HE, Tunel and Aβ immunohistochemical staining. Differential expression proteins and metabolites were screened through hippocampal proteomics and metabolomics analyses. Finally, the expression levels of key proteins were verified by Western blot. Compared with unexposed 5xFAD mice, the behavioral results of mice showed that FAD mice after CS exposure exhibited poorer cognitive abilities, with longer latencies in the Morris water maze, and decreased time spent and entries in the target quadrant. The results of pathological sections indicated that the total nuclei density in the DG and CA3 regions of the hippocampus of 5xFAD mice decreased significantly after chronic CS exposure, the number of TUNEL-positive cells increased, and the expression of Aβ42 increased. Multi - omics analysis revealed that CS exposure up - regulated the expression of 46 proteins and down - regulated the expression of 80 proteins in the hippocampus of 5xFAD mice, and caused changes in 92 metabolites. Analysis of the correlation between differential proteins and differential metabolites revealed six key cross-node proteins: Kng1, Hbb-b1, Fabp3, Apoa1, Ilk, and Apoa4. CS exposure may accelerate pathological changes and cognitive impairment in 5xFAD mice by affecting energy metabolism through the PPAR signaling pathway. Show less

Hypothalamic obesity (HO) is a severe, treatment-refractory metabolic disorder resulting from hypothalamic injury secondary to craniopharyngioma directly or from its surgical resection. Characterised by dysregulated energy balance from disruption of complex hypothalamic neuroregulatory circuits, hyperphagia, and reduced sympathetic tone, HO arises due to impaired leptin-melanocortin signalling and autonomic dysfunction. Conventional lifestyle modifications remain largely ineffective, necessitating pharmacotherapeutic approaches targeting neuroendocrine and metabolic pathways. Amelioration of sleep disturbances and pituitary dysfunction serve as an important foundation for management of HO. The use of dextroamphetamine in some HO patients has proved effective. Emerging therapies include melanocortin-4 receptor (MC4R) agonists such as setmelanotide, which restore anorexigenic signalling, glucagon-like peptide-1 (GLP-1) receptor agonists that enhance satiety and energy expenditure, and combination strategies integrating adrenergic modulation (Tesomet). Despite promising preliminary data, long-term efficacy and safety profiles require further validation. Optimizing precision medicine approaches incorporating polypharmacotherapy and neuroendocrine modulation may redefine therapeutic paradigms for HO management. Show less

Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer's disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and known to cause hyperactivity of the early endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule has been shown in vitro to interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo, we generated a transgenic mouse model overexpressing human APPL1 within neurons (Thy1-APPL1). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice (both sexes) develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target. Show less

Anoikis is a new mode of cell death that has been shown to correlate significantly with tumors. However, the clinical prognostic significance of anoikis in lung squamous cell carcinoma (LUSC) remains poorly studied. The differentially expressed ARGs and candidate genes were selected by the differential analysis to construct a predictive model. Independent prognostic gene was determined by Cox and LASSO analysis and we used the HCC95 and NCI H520 cell line to verify the gene function. We used the data from TCGA, GEO, GeneCards, and Harmonizome databases to analyze the immune microenvironment, functional enrichment, and drug sensitivity analysis. We identified 717 differentially expressed and selected 3 ARGs (FADD, SNAI1, and BAG4) to construct a predictive model. We found that SNAI1 is an independent prognostic gene and confirmed that knocking out the SNAI1 inhibited the HCC95 We used ARGs to construct a prognosis model for LUSC that can accurately predict the prognosis of LUSC patients. ARGs, especially SNAI1, play an essential role in developing LUSC. These findings could provide individualized treatment plans and new research ideas for LUSC patients. Show less

To clarify the anatomical characteristics of the lateral plantar ligament (LPL) of the transverse metatarsal arch (TMA) in the population of southwest Shandong Province, so as to complement the anatomical structures of the midfoot and Lisfranc joint complexes. A total of 100 adult lower limbs were dissected and the types of LPL were divided according to their insertions, among them, 63 were (63%) and 37 were female (37%); 50 were on the left side (50%) and 50 were on the right side (50%). The fiber bundle length, origin width, insertion width, and thickness of the LPL were measured. (1) According to the insertions of the LPL, they were divided into: ① Type I, the LPL was inserted at the base of the second metatarsal (M2) in 47 cases; ② Type II, the LPL was inserted at the base of M2 and fused with tibialis posterior tendon (TPT) in 16 cases; ③ Type III, the LPL was absent in 16 cases; ④ Type IV, the LPL was inserted at TPT in 6 cases; ⑤ Type V, the LPL was inserted at the intermediate cuneiform (IC) in 1 case; ⑥ Type VI, bifid LPL with one bundle inserted at the base of M2, and the other bundle inserted at the medial cuneiform (MC) in 4 cases; ⑦ Type VII, two bundles of LPL inserted at the base of M2 in 8 cases; ⑧ Type VIII, the LPL consisted of 3 bundles; the distal, middle and proximal bundles was inserted at the base of M2, the TPT and the lateral side of navicular bone in 2 cases, respectively. (2) There was a statistical significance in the length of LPL between male (31.62 ± 3.83) mm and female (28.07 ± 3.46) mm (t=-3.050, P = 0.003). There was no statistical significance in the types of LPL between male and female (Z=-1.721, P > 0.05), and no statistical significance in the types between left and right sides (Z=-0.026, P > 0.05). According to our research, LPL originates from M5 and is divided into 8 types according to its insertion location, of which insertion at the base of M2 is the most common. In addition, we found that LPL has fibrous fusion with the long plantar ligament and the TPT, which may be involved in maintaining arch stability. The classification of LPL in this study is a supplement to the anatomical structure of the middle foot and Lisfranc joint complex, providing a new direction for the diagnosis and treatment of middle foot and arch injury in the future. Show less

Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in the progression of various cancers through its involvement in cell proliferation, survival, and differentiation. More recently, FGFR1 has been implicated in the mechanisms of immune evasion, particularly its role in resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Targeting FGFR1 with monoclonal antibodies and tyrosine kinase inhibitors has emerged as a promising therapeutic strategy to enhance ICI efficacy by altering the tumor microenvironment and countering immune suppression. Preclinical studies demonstrate that combining FGFR1 inhibitors, such as the novel monoclonal antibody OM-RCA-01, with ICIs significantly improves antitumor activity, enhancing T cell responses and cytokine production. This article explores the role of FGFR1 in cancer biology, its contribution to immunotherapy resistance, and the therapeutic potential of targeting FGFR1 to enhance the efficacy of ICIs. Show less

Excessive aluminum exposure is a contributing factor in several neurodegenerative diseases. Natural plant compounds such as Licochalcone A have been shown to have significant neuroprotective effects in vivo and in vitro. In this study, we aim to elucidate the neuroprotective effect of Licochalcone A against aluminum chloride-induced neurotoxicity and its possible mechanism. Adult zebrafish and PC12 cells were used as animal and cell models. Zebrafish and PC12 cells were treated with excessive aluminum trichloride (100 μg/L aluminum chloride hexahydrate solutions for zebrafish or 500 μM Al-malt solution for PC12 cells) to cause neuronal damage. The neuroprotective effect of Licochalcone A was evaluated by measuring ROS production, Aβ Show less

Apolipoprotein B is an essential causal marker of cardiovascular disease. Studies have attempted to understand the impact of fatty acids on cardiovascular disease risk by measuring changes in apolipoprotein B. Linoleic acid is an omega-6 polyunsaturated fatty acid that has demonstrated effects on cardiovascular disease outcomes. This study attempts to investigate the causal association of plasma concentrations of linoleic acid with apolipoprotein B via Mendelian Randomization, in addition to confounders of this relationship. The UK Biobank was used to obtain participant data for omega-6 polygenic risk scores, linoleic acid, and apolipoprotein B concentrations, in addition to confounding variable data. This study excluded individuals with a cardiovascular disease diagnosis or taking cholesterol-lowering medications. Multivariable regression was utilized to identify statistically significant impacts on apolipoprotein B, followed by Mendelian Randomization via two-stage least-squares analysis. Multivariable regression identified a statistically significant association of apolipoprotein B with linoleic acid, monounsaturated fatty acids, saturated fatty acids, age, sex, fasting, BMI, alcohol intake frequency, vigorous exercise, and smoking status. Two-stage least-squares analysis found a statistically significant causal association of genetically predicted linoleic acid on apolipoprotein B concentration (b = 0.23; 95 % CI: 0.207-0.243; p < 0.001), with the first stage of the analysis yielding an eigenvalue of 755.79 and F-statistic of 2796.93 and the second stage of the analysis yielding a statistically significant Wald χ This study demonstrates a causal association of linoleic acid with apolipoprotein B concentrations. Future studies should evaluate this association and the confounders of this relationship. Show less

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. This study examined the polygenic variants associated with high serum triglyceride concentration (high-TG) and their interactions with lifestyle factors using data from the UK Biobank (n = 479,300) and the Korean Genome and Epidemiology Study (KoGES; n = 57,939). High-TG group was categorized based on over 200 mg/dL fasting serum TG concentrations (Caucasians, UK Biobank, n = 100,543; Koreans, KoGES, n = 7211). Polygenic risk scores (PRS) were calculated using risk alleles from genetic variants identified through a genome-wide association study (GWAS) and generalized multifactor dimensionality reduction (GMDR) analyses. Koreans showed higher frequencies of risk alleles in GCKR, APOA5, SIK3, and APOE genes compared to Caucasians. After adjusting for covariates, a PRS including lipoprotein lipase (LPL)_rs328, apolipoprotein A5 (APOA5)_rs2072560, and glucokinase regulator (GCKR)_rs780093 showed a 2.2-fold (UK Biobank) and 2.6-fold (KoGES) increased risk of high-TG among Caucasians and Koreans, respectively. In both cohorts, the PRS was positively associated with metabolic syndrome, serum low high-density lipoprotein (HDL)-cholesterol, and high low-density lipoprotein (LDL)-cholesterol concentrations, but inversely associated with high-TG. These variants were linked to the chylomicron and very low-density lipoprotein (VLDL) remodeling pathways in Multimarker Analysis of GenoMic Annotation (MAGMA) gene analysis. Significant interactions were observed between the PRS and lifestyle factors, namely plant-based diet (P = .0008), alcohol consumption (P = .0022), and smoking status (P < .001) in both cohorts. Additionally, in the KoGES cohort, vitamin D intake (P = .027) and the glycemic index (P = .045) interacted with the PRS to influence high-TG risk. Similar genetic variants affected high-TG risk across populations despite ethnic differences in risk allele frequencies. The identified PRS significantly interacted with plant-based diet, alcohol consumption, and smoking status in both cohorts, with additional interactions observed with vitamin D intake and glycemic index in the Korean cohort. Show less

The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought. Here, we describe the synthesis and properties of a molecule which binds to both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R and GIPR) to enhance insulin secretion. HISHS-2001 shows increased affinity at the GLP-1R, as well as a tendency towards reduced internalization and recycling at this receptor Show less

Acute cold stress can disrupt physiological homeostasis in marine fish and may induce pronounced metabolic and immune responses in pelagic species such as yellowfin tuna (Thunnus albacares), which possess regional endothermic capabilities. As a key tissue interfacing with the environment, the gill plays essential roles in gas exchange, ion regulation, immune defense, and energy metabolism, making it highly susceptible to thermal fluctuations. This study investigated the physiological responses of gill tissue in juvenile yellowfin tuna under acute cold stress, using two treatment groups-LT (24 °C) and ULT (18 °C)-with a control group (CG, 30 °C). Sampling was conducted at 0, 12, 24, and 36 h to assess antioxidant and metabolic enzyme activities, histopathological alterations, and the expression of immune- and metabolism-related genes. Results showed time-dependent changes in antioxidant enzymes (SOD, CAT, POD, GSH-Px), with significantly elevated MDA and LPO levels at 12 h and 24 h (p < 0.05), especially under 18 °C, indicating intensified oxidative stress. Significant alterations in AST, LDH, ACP, and AKP suggested metabolic reprogramming and membrane function changes. Variations in Na Show less

Neovascular age-related macular degeneration (nAMD) is an advanced stage of AMD and is associated with an increased risk of visual impairment. Disturbances in lipid metabolism have been proposed as a major contributing factor to the pathogenesis of AMD. This study aims to investigate whether lipid profiles in the serum and components of dyslipidemia can be used as indicators for predicting progression to nAMD. A retrospective analysis was conducted involving 125 participants with nAMD. 125 non-AMD controls, matched by age, sex, and BMI, were incorporated into the study. The comparative analysis between the groups involved six lipid biomarkers in the serum: HDL-C, LDL-C TG, TC, ApoA1, and ApoB. Moreover, the existence of dyslipidemia and its constituents was assessed through t-tests, as well as univariate and multivariable logistic regression models. Individuals with nAMD exhibited significantly higher serum HDL-C (P = 0.02) compared to the controls without AMD. Furthermore, the concentrations of ApoB were significantly less in the nAMD cohort (P < 0.01) when compared to the control group. During the investigation of the correlation between levels of serum HDL-C (P < 0.01) and serum ApoB (P < 0.01) with nAMD through logistic regression analysis, notable findings indicated a significant association between both variables and nAMD. However, by multivariate logistic regression analysis, neither serum HDL-C nor serum ApoB was an independent risk factor for nAMD. While individuals with nAMD demonstrated elevated serum HDL-C and reduced serum ApoB levels, these lipid markers may not be suitable as biomarkers for monitoring or preventing nAMD. Show less