Search Results (75)

Ricin is a highly potent toxin that causes severe lung injury upon inhalation by initiating a complex cascade of cellular responses that ultimately leads to cell death. The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in various physiological processes, including ricin-mediated toxicity. This study explores the role of LRP1 shedding in the development of ricin-induced lung injury. Analysis of bronchoalveolar lavage fluid (BALF) from ricin-intoxicated mice and swine showed a significant increase in soluble LRP1 (sLRP1) levels, whereas serum LRP1 levels remained largely unchanged, suggesting the lungs are the primary source of sLRP1 release. In vitro assays demonstrated the formation of ricin-sLRP1 complexes, indicating that sLRP1 in BALF retained ricin-binding capability. Flow cytometric analysis of lung cells revealed a reduction in both the percentage and total number of LRP1-expressing cells following ricin exposure. Further investigation of specific lung cell populations showed that alveolar epithelial type II (AT-II) cells, despite experiencing significant injury, exhibited minimal LRP1 shedding. No shedding of LRP1 occurred in neutrophils. In contrast, fibroblasts, which were resistant to ricin-induced cell death, exhibited increased shedding of LRP1 and a corresponding decrease in membrane-bound LRP1 expression. This shedding of the LRP1 ectodomain was mediated by metalloproteinases. Immunohistochemical staining further confirmed decreased LRP1 expression in fibroblasts from ricin-exposed mice. Macrophages also showed substantial LRP1 shedding, despite undergoing significant depletion. These findings highlight the complex cell-specific nature of LRP1 shedding in response to ricin intoxication and suggests the potential role of LRP1 in modulation of cellular susceptibility and resistance to ricin-induced lung injury. Full article

Wound healing is a complex, multiphase process crucial for restoring tissue integrity and functionality after injury. Among the emerging therapeutic approaches, antimicrobial peptides (AMPs) have shown substantial promise because of their dual role in microbial defense and cellular modulation. AMP-IBP5, a novel AMP derived from insulin-like growth factor-binding protein 5, exhibits both antimicrobial and wound-healing properties, making it a promising therapeutic candidate. This peptide exhibits robust antimicrobial activity, augments keratinocyte proliferation, increases fibroblast migration, induces angiogenesis, and modulates the immune response. Mechanistically, AMP-IBP5 activates Mas-related G protein-coupled receptors and low-density lipoprotein receptor-related protein 1 (LRP1) in keratinocytes, stimulating IL-8 production and vascular endothelial growth factor expression to accelerate wound healing. This molecule also interacts with LRP1 in fibroblasts to increase cell migration and promote angiogenesis while mitigating inflammatory responses through targeted cytokine modulation. Preclinical studies have demonstrated its remarkable efficacy in promoting tissue repair in diabetic wounds and inflammatory skin conditions, including atopic dermatitis and psoriasis. This review delves into the broad therapeutic potential of AMP-IBP5 across dermatological applications, focusing on its intricate mechanisms of action, comparative advantages, and its path toward clinical and commercial application. Full article

In this review paper, we will evaluate LRP4, a low-density lipoprotein receptor-related protein, and its many roles involving myasthenia gravis (MG), Wnt signaling, bone formation and craniofacial development. In MG, LRP4 is critical to the formation of the neuromuscular junction (NMJ) and the key function is to allow for controlled muscle contraction. LRP4 works in combination with agrin and MuSK to form the functional complex. In Wnt signaling, LRP4 was recently identified as a critical player in the pathway for both bone and tooth development and function. Its ability to act as an inhibitor sheds new light on bone formation and resorption. LRP4 binds sclerostin to LRP5 and LRP6, facilitating inhibitory effects important for bone homeostasis and remodeling. In this review paper, we will summarize the known roles of LRP4 as well as explore future directions for research surrounding LRP4 functionality. Full article

We investigated the roles of low-density lipoprotein receptor-related protein (LRP) 4 and its ligand Agrin in the pathophysiology of cartilage degeneration. Immunohistochemical analysis of human normal articular cartilage and cartilage tissues from patients with osteoarthritis (OA) obtained during surgery of the knee joint showed marked LRP4 expression in the early stages of OA, which then decreased with cartilage degeneration, whereas Agrin was consistently increased with cartilage degeneration. In normal human articular chondrocytes (NHACs), mild cyclic tensile strain (CTS) (0.5 Hz, 5% elongation, 2 h) increased the expression of LRP4 and aggrecan (ACAN), while intense CTS (0.5 Hz, 10% elongation, 6 h) increased the expression of Agrin without affecting LRP4 expression. Treatment with recombinant human (rh) Agrin downregulated the mRNA expression of LRP4 and ACAN, but upregulated the expression of LRP5/6, SRY-box transcription factor 9 (SOX9), Runt-related transcription factor 2 (RUNX2), and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4). Immunocytochemistry and Western blot analysis showed that rhAgrin treatment upregulated the expression of β-catenin and SOX9. Agrin knockdown by siAGRN transfection partially reduced the nuclear protein expression of β-catenin, which was increased with intense CTS. LRP4 knockdown by siLRP4 transfection increased the expression of LRP5/6, SOX9, RUNX2, ADAMTS-4, and Agrin. These results suggested that intense CTS increases the expression of Agrin, which might interfere with the role of LRP4 in the inhibition of LRP5/6 and their downstream β-catenin signaling, leading to cartilage degeneration. Full article

Background: PCSK9 inhibitors (PCSK9i) represent a newer form of atherosclerosis treatment. Inflammation and haemostasis are key processes in the development of atherosclerosis. In this study, we investigated the influence of therapy with PCSK9i in patients with coronary artery disease (CAD) on regulators for lipoprotein homeostasis, inflammation and coagulation. Methods: Using quantitative polymerase chain reaction (qPCR), we measured the expression of the genes involved in lipoprotein homeostasis, namely for sterol regulatory element-binding protein 1 (SREBP1), SREBP2, low-density lipoprotein receptor (LDLR), hepatic lipase type C (LIPC), LDLR-related protein 8 (LRP8), and the genes associated with inflammation and coagulation, such as cluster of differentiation (CD) 36 (CD36), CD63, and CD14 in 96 patients with CAD and 25 healthy subjects. Results: Significant differences in the expression of the investigated genes between patients and healthy controls were found. Treatment with PCSK9i also resulted in significant changes in the expression of all studied genes. Conclusions: We established that PCSK9i may have a significant effect on the gene expression of lipid regulators, inflammatory markers, and coagulation parameters, independent of their lipolytic effect. Full article

Introduction: Neuroendocrine tumors are a diverse group of tumors predominantly found in the gastrointestinal tract or respiratory system. Methods: This retrospective study aimed to measure the serum concentrations of LRP6 (low-density lipoprotein receptor-related protein 6), SFRP3 (secreted frizzled-related protein 3), and DVL1 (segment polarity protein dishevelled homolog) using the ELISA method in patients with NETs (N = 80) and a control group (N = 62). We evaluated the results against various demographic, clinicopathological, and biochemical characteristics. Results: Our analyses revealed that the concentration of SFRP3 in patients with neuroendocrine tumors was significantly elevated (p < 0.001) compared to the control group. Additionally, DVL1 concentrations were significantly higher (p < 0.01) in patients with BP-NETs compared to GEP-NETs. Furthermore, DVL1 analysis showed a moderate negative correlation with chromogranin A (p < 0.001) and weak negative correlations with serotonin (p < 0.05) and 5-HIAA (p < 0.05). Significant negative correlations were also observed between DVL1 and age in the control group (p < 0.01), and between LRP6 and Ki-67 in the study group. Conclusions: These results suggest that changes in the SFRP3 and DVL1 pathways play a key role in NET development. Elevated levels of these proteins highlight their importance in tumor biology, with SFRP3 and DVL1 potentially being crucial in NET molecular mechanisms. Further research is needed to explore their roles and potential in diagnosis and treatment. Full article

Dengue virus (DENV) causes the most prevalent and rapidly spreading arboviral disease of humans. It enters human cells by receptor-mediated endocytosis. Numerous cell-surface proteins were proposed as DENV entry factors. Among these, the phosphatidylserine receptor TIM-1 is the only one known to mediate virus internalization. However, several cellular models lacking TIM-1 are permissive to DENV infection, suggesting that other receptors exist. Here, we show that the low-density lipoprotein receptor-related protein-1 (LRP1) binds DENV virions by interacting with the DIII of the viral envelope glycoprotein. DENV infection is effectively inhibited by the purified receptor at 5 × 10⁻⁸ mol/L, and the interaction of the envelope protein with LRP1 is also blocked by a natural ligand of LRP1. The depletion of LRP1 causes 100-fold lower production of infectious virus than controls. Our results indicate that LRP1 is another DENV receptor, thus becoming an attractive target to evaluate for the development of effective antiviral drugs against DENV. Full article

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer’s disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ₄₂ anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ₄₂ complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ₄₂ production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ₄₂. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between the production and Aβ clearance in the brain and across the blood–brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aβ production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research. Full article

Low-density lipoprotein receptor-related protein 5 (LRP5) is a constitutively expressed receptor with observed roles in bone homeostasis, retinal development, and cardiac metabolism. However, the function of LRP5 in the brain remains unexplored. This study investigates LRP5’s role in the central nervous system by conducting an extensive analysis using RNA-seq tools and in silico assessments. Two protein-coding Lrp5 transcripts are expressed in mice: full-length Lrp5-201 and a truncated form encoded by Lrp5-202. Wt mice express Lrp5-201 in the liver and brain and do not express the truncated form. Lrp5^−/− mice express Lrp5-202 in the liver and brain and do not express Lrp5-201 in the liver. Interestingly, Lrp5^−/− mouse brains show full-length Lrp5-201 expression, suggesting that LRP5 has a role in preserving brain function during development. Functional gene enrichment analysis on RNA-seq unveils dysregulated expression of genes associated with neuronal differentiation and synapse formation in the brains of Lrp5^−/− mice compared to Wt mice. Furthermore, Gene Set Enrichment Analysis highlights downregulated expression of genes involved in retinol and linoleic acid metabolism in Lrp5^−/− mouse brains. Tissue-specific alternative splicing of Lrp5 in Lrp5^−/− mice supports that the expression of LRP5 in the brain is needed for the correct synthesis of vitamins and fatty acids, and it is indispensable for correct brain development. Full article

Saliva plays a crucial role in shaping the compatibility of piercing–sucking insects with their host plants. Understanding the complex composition of leafhopper saliva is important for developing effective and eco-friendly control strategies for the tea green leafhopper, Empoasca flavescens Fabrecius, a major piercing–sucking pest in Chinese tea plantations. This study explored the saliva proteins of tea green leafhopper adults using a custom collection device, consisting of two layers of Parafilm stretched over a sucrose diet. A total of 152 proteins were identified using liquid chromatography–tandem mass spectrometry (LC-MS/MS) following the filter-aided sample preparation (FASP). These proteins were categorized into six groups based on their functions, including enzymes, transport proteins, regulatory proteins, cell structure proteins, other proteins, and unknown proteins. Bioinformatics analyses predicted 16 secreted proteins, which were successfully cloned and transcriptionally analyzed across various tissues and developmental stages. Genes encoding putative salivary secretory proteins, including Efmucin1, EfOBP1, EfOBP2, EfOBP3, Efmucin2, low-density lipoprotein receptor-related protein (EfLRP), EFVg1, and EFVg2, exhibited high expressions in salivary gland (SG) tissues and feeding-associated expressions at different developmental stages. These findings shed light on the potential elicitors or effectors mediating the leafhopper feeding and defense responses in tea plants, providing insights into the coevolution of tea plants and leafhoppers. The study’s conclusions open avenues for the development of innovative leafhopper control technologies that reduce the reliance on pesticides in the tea industry. Full article

Oral cancer ranks fourth among malignancies among Taiwanese men and is the eighth most common cancer among men worldwide in terms of general diagnosis. The purpose of the current study was to investigate how low-density lipoprotein receptor-related protein 1B (LDL receptor related protein 1B; LRP1B) gene polymorphisms affect oral squamous cell carcinoma (OSCC) risk and progression in individuals with diabetes mellitus (DM). Three LRP1B single-nucleotide polymorphisms (SNPs), including rs10496915, rs431809, and rs6742944, were evaluated in 311 OSCC cases and 300 controls. Between the case and control groups, we found no evidence of a significant correlation between the risk of OSCC and any of the three specific SNPs. Nevertheless, in evaluating the clinicopathological criteria, individuals with DM who possess a minimum of one minor allele of rs10496915 (AC + CC; p = 0.046) were significantly associated with tumor size compared with those with homozygous major alleles (AA). Similarly, compared to genotypes homologous for the main allele (GG), rs6742944 genotypes (GA + AA; p = 0.010) were more likely to develop lymph node metastases. The tongue and the rs6742944 genotypes (GA + AA) exhibited higher rates of advanced clinical stages (p = 0.024) and lymph node metastases (p = 0.007) when compared to homozygous alleles (GG). LRP1B genetic polymorphisms appear to be prognostic and diagnostic markers for OSCC and DM, as well as contributing to genetic profiling research for personalized medicine. Full article

Background: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. Methods: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II–III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. Results: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28–5.14, p = 0.008). The Kaplan–Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4⁺ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4⁺ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4⁺ T cells, CD8⁺ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10–0.93, p = 0.042). Conclusions: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits. Full article

The blood–brain barrier (BBB) is a unique and selective feature of the central nervous system’s vasculature. BBB dysfunction has been observed as an early sign of Alzheimer’s Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB’s role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform ε4 of apolipoprotein E (ApoEε4), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD’s pathogenesis. In this comprehensive review, we endeavor to shed light on the intricate pathogenic and therapeutic connections between AD and the BBB. We also delve into the latest developments and pioneering strategies targeting the BBB for therapeutic interventions, addressing its potential as a barrier and a carrier. By providing an integrative perspective, we anticipate paving the way for future research and treatments focused on exploiting the BBB’s role in AD pathogenesis and therapy. Full article

Carbon nanodots present resistance to photobleaching, bright photoluminescence, and superior biocompatibility, making them highly promising for bioimaging applications. Herein, nanoprobes were caged with four-armed oligomers and subsequently modified with a novel DBCO–PEG-modified retro-enantio peptide ligand reL57, enhancing cellular uptake into U87MG glioma cells highly expressing low-density lipoprotein receptor-related protein 1 (LRP1). A key point in the development of the oligomers was the incorporation of ε-amino-linked lysines instead of standard α-amino-linked lysines, which considerably extended the contour length per monomer. The four-armed oligomer 1696 was identified as the best performer, spanning a contour length of ~8.42 nm for each arm, and was based on an altering motive of two cationic ε-amidated lysine tripeptides and two tyrosine tripeptides for electrostatic and aromatic stabilization of the resulting formulations, cysteines for disulfide-based caging, and N-terminal azidolysines for click-modification. This work highlights that well-designed four-armed oligomers can be used for noncovalent coating and covalent caging of nanoprobes, and click modification using a novel LRP1-directed peptide ligand facilitates delivery into receptor-expressing target cells. Full article