Integrin Expression Research Articles

Suppression of Dad1 induces cardiomyocyte death by weakening cell adhesion.

As cardiomyocyte loss causes heart failure, inhibition of cardiomyocyte death may be a therapeutic strategy against heart failure. In this study, we have identified Defender against cell death 1 (Dad1) as a candidate regulator of cardiomyocyte death, using complementary DNA microarray and siRNA knockdown screening. Dad1 is a subunit of oligosaccharyltransferase (OST) complex that is responsible for protein N-glycosylation; however, its function in cardiomyocytes remains unknown. Importantly, the knockdown of Dad1 using siRNA reduced the viability of neonatal rat cardiomyocytes (NRCMs), accompanied by cleaved caspase3 expression, independent of endoplasmic reticulum stress. Dad1 knockdown impaired cell spreading and reduced myofibrillogenesis in NRCMs, suggesting that Dad1 knockdown induced anoikis, apoptosis by disrupting cell-matrix interactions. Consistently, knockdown of Dad1 impaired N-glycosylation of integrins α5 and β1, accompanied by inactivation of focal adhesion kinase. When cell adhesion was enhanced using adhesamine, fibronectin, or collagen type IV, cardiomyocyte death induced by Dad1 knockdown was reduced. Dad1 knockdown decreased the expression of staurosporine and temperature sensitive 3A (Stt3A), a catalytic subunit of OST complex. Interestingly, Stt3A knockdown using Stt3A siRNA reduced the expression of Dad1, indicating that both Dad1 and Stt3A were required for OST stabilization. In conclusion, Dad1 plays an important role in maintaining the expression of mature N-glycosylated integrins and their downstream signaling molecules to suppress cardiomyocyte anoikis.

Carnosic acid inhibits integrin expression and prevents pulmonary metastasis of melanoma.

Carnosic acid is a naturally occurring, plant-derived polyphenolic abietane diterpene with anti-tumor properties. However, its underlying mechanisms are still unclear. Therefore, we investigated the effects of carnosic acid on lung metastasis in a murine melanoma model. C57BL/6 mice were intravenously injected with B16-BL6 cells, followed by carnosic acid treatment. Lung weights were recorded, and tumor cell colonies were counted at the end of the experiment. Integrin expression was evaluated using flow cytometry and cell adhesion assays. Lung weights were significantly lower in the carnosic acid group than in the control group, indicating the suppression of metastasis. Carnosic acid suppressed α4 integrin expression in B16-BL6 cells and inhibited α4 and α9 integrin-dependent cell adhesion. Thus, our data suggest that carnosic acid prevents lung metastasis, possibly by suppressing integrin expression. Our findings support the clinical application of carnosic acid as a potential natural anti-tumor agent, offering a complementary approach to conventional therapies.

Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies.

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD-integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies.

Abstract B004: Identification of distinct subpopulations of cancer associated fibroblasts in oral squamous cell carcinoma by imaging mass cytometry

Abstract Background: Although cancer associated fibroblast (CAF) heterogeneity is recognized in oral squamous cell carcinoma (OSCC), the phenotype and role of CAF subpopulations in OSCC is still unknown. Objectives: This study aimed to dissect CAF heterogeneity and spatial location by using imaging mass cytometry on formalin fixed paraffin embedded (FFPE) tissues from primary OSCC. Methods: Imaging mass cytometry (Hyperion technology) was used to identify 24 markers (E-cadherin, EGFR, Ki-67, α-SMA, CD140β, FAP, FSP-1/S100A4, CD90/Thy-1, integrin α-11, collagen-1, tenascin-C, caveolin-1, CD4, CD8a, CD16, CD20, CD68, CD163, FoxP3, granzyme B, CD31, podoplanin, CD146, and YAP-1) in HPV-negative OSCC lesions (n=10). Tissue images were segmented employing the Steinbock framework. Unsupervised clustering of single-cell data was carried out using a bioinformatics pipeline developed in R language. Results: Unsupervised clustering identified several major cell types, with E-cadherin+ cells being the most abundant (30%) and CD146+ being the least abundant cell type (0.62%). Within the immune compartment CD4+ cells were most abundant (11.72%) followed by CD8+ cells (10.6%) and CD68+ cells (10.25%). Cells negative for other major lineage markers and positive for stromal markers were considered as CAFs and they clustered in 6 clusters defined as CAF1 to CAF6. CAF1-3 were high in FAP and CD140β while CAF 4-6 were low expressing FAP and CD140β. CAF1 and 6 expressed high αSMA, while CAF 3 and 5 expressed high collagen-1. CAF6 had high expression of integrin α-11. CAF1 and 3 subtypes were found closer to immune cells whereas CAF2 and 6 were closely located to cancer cells. Conclusions: We identified six distinct subpopulations of CAFs in OSCC by using imaging mass cytometry. Their clinical implications can be further revealed by using this method on larger patient cohorts with FFPE tissues available in diagnostic biobanks. Citation Format: Stian Tornaas, Siren Fromreide, Dimitrios Kleftogiannis, Hans Jørgen Aarstad, Olav K. Vintermyr, Lars Akslen, Harsh Dongre, Daniela Elena Costea. Identification of distinct subpopulations of cancer associated fibroblasts in oral squamous cell carcinoma by imaging mass cytometry [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B004.

Integrin β2 regulates titanium particle‑induced inflammation in macrophages: In vitro aseptic loosening model.

Aseptic loosening is a major complication of joint replacement surgery, characterized by periprosthetic osteolysis and chronic inflammation at the bone‑implant interface. Cells release chemokines, cytokines and other pro‑inflammatory substances that perpetuate inflammation reactions, while other particle‑stimulated macrophages promote osteoclastic bone resorption and impair bone formation. The present study investigated integrin and inflammatory cytokine expression patterns in RAW 264.7 cells treated with titanium (Ti) particles to elucidate the role of integrins in Ti particle‑mediated inflammatory osteolysis. Assessment was performed by reverse transcription‑quantitative PCR, western blotting, confocal immunofluorescence, flow cytometry and enzyme‑linked immunosorbent assays. Cell migration was evaluated by wound healing assay. It was found that Ti particles significantly induced integrin expression in RAW 264.7 cells, including upregulation of integrins β2 (CD18), aL (CD11a), aM (CD11b) and aX (CD11c). Ti particles also enhanced the expression of Toll‑like receptors (TLRs; TLR1, TLR2, TLR3 and TLR4) and triggered the release of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)‑1β, IL‑8 and IL‑12. Proteomics showed higher expression and activity levels of TLR2 and TLR4, along with their downstream signaling adaptors myeloid differentiation primary response protein 88 (MyD88) and Mal/TIR‑domain‑containing adapter protein (TIRAP), following Ti treatment. Additionally, Ti treatment significantly enhanced the migration rate of RAW 264.7 cells. The present findings indicated that Ti particles regulate the inflammatory response of RAW 264.7 cells in an in vitro aseptic loosening model by activating the TLR/TIRAP/MyD88 signaling pathway.

IMMU-31. DAMAGE RESPONSE FROM SYSTEMIC RNA VACCINATION RESTORES HUMORAL IMMUNITY IN GLIOBLASTOMA

Abstract Therapies against glioblastoma (GBM) remain stymied by poor penetration across the blood-brain barrier (BBB) and systemic immunotolerance. These outcomes necessitate development of therapies simultaneously targeted to tumors while engineering peripheral immunity to co-localize for synergistic responses. We developed RNA loaded lipid particles (LPs) to simultaneously function as inducers of cytotoxic responses in the GBM tumor microenvironment (TME) and as systemic activators of peripheral immunity. RNA-LP mediated response was studied in mice bearing KR158b tumors and in canines and humans with spontaneous glioma and glioblastoma respectively. We found that RNA-LPs could localize to the brain TME of animals bearing murine gliomas and rapidly upregulate damage associated signaling pathways including p53-CDKN2A. This correlates with increased gene signatures for complement and proteosome processing. Simultaneously, in the periphery, RNA-LPs increase integrin expression on activated T cells and ICAM expression in brain tumors helping steer T cell translocation across the BBB. In canines with malignant gliomas, response to RNA-LPs correlated with increasing tumor size suggesting pseudoprogression. Similar to murine glioma, canine gliomas harvested within 48h of vaccine administration demonstrated rapid increases in complement and p53 pathway activation. In one human patient treated with RNA-LPs per NCT04573140 (PNOC020 trial), we demonstrate biopsy confirmed pseudoprogression with increases in p53 pathway signaling and complement activation. In post-treatment tumor biopsy samples, there was increased hyperexpanded post-infusion intratumoral IgH clones. Systemic administration of RNA-LP elicits damage response in the TME that predisposes complement activation and humoral immunity. Coupled with peripheral recruitment of T cells that can translocate across the BBB, RNA-LPs elicit potent bi-directional adaptive immunotherapy against GBM.

Knockdown of ANO1 decreases TGF-β- and IL-6-induced adhesion and migration of cardiac fibroblasts by inhibiting the expression of integrin and focal adhesion kinase

Ischemic cardiac injury triggers a significant inflammatory response, activating and mobilizing cardiac fibroblasts (CFs), which ultimately contributes to myocardial fibrosis. In this study, we investigated the role of ANO1, a calcium-activated chloride channel (CaCC) protein, in regulating CFs migration and adhesion under inflammatory conditions. Our results demonstrated that ANO1 knockdown significantly attenuated TGF-β- and IL-6-induced adhesion and migration of CFs. This inhibitory effect was mediated through the downregulation of integrin expression and reduced activation of focal adhesion kinase (FAK), key components in cellular adhesion and motility pathways. This study provides new insights into the mechanisms underlying CFs migration and adhesion, highlighting the potential of ANO1 as a therapeutic target for mitigating adverse fibrotic remodeling following myocardial infarction.

Synthetic hydrogel substrate for human induced pluripotent stem cell definitive endoderm differentiation

Human induced pluripotent stem cells (hiPSCs) can give rise to multiple lineages derived from three germ layers, endoderm, mesoderm and ectoderm. Definitive endoderm (DE) cell types and tissues have great potential for regenerative medicine applications. Current hiPSC differentiation protocols focus on the addition of soluble factors; however, extracellular matrix properties are known to also play a role in dictating cell fate. Matrigel™ is the gold standard for DE differentiation, but this xenogeneic, poorly defined basement membrane extract limits the clinical translatability of DE-derived tissues. Here we present a fully defined PEG-based hydrogel substrate to support hiPSC-derived DE differentiation. We screened hydrogel formulations presenting different adhesive peptides and matrix stiffness. Our results demonstrate that presenting a short peptide, cyclic RGD, on the engineered PEG hydrogel supports the transition from undifferentiated hiPSCs to DE using a serum-free, commercially available kit. We show that increasing substrate stiffness (G’ = 1.0–4.0 kPa) results in an increased linear response in DE differentiation efficiency. We also include a temporal analysis of the expression of integrin and syndecan receptors as the hiPSCs undergo specification towards DE lineage. Finally, we show that focal adhesion kinase activity regulates hiPSC growth and DE differentiation efficiency. Overall, we present a fully defined matrix as a synthetic alternative for Matrigel™ supporting DE differentiation.

Innovative 3D-Printed Titanium Specimens Favor a Modulation of Inflammation in Dental Pulp Stem Cells During Liposome-Triggered Mineralization.

developing customized titanium specimens, with innovative surfaces, is a suitable strategy to overcome implant failure. Additionally, a faster and efficient osteogenic commitment assists tissue regeneration. To investigate the interplay between inflammation and differentiation upon implantation, Dental Pulp Stem Cells (DPSCs) were cultured on 3D-printed titanium owning an internal open cell form, administering osteogenic factors by a liposomal formulation (LipoMix) compared to traditional delivery of differentiation medium (DM). osteogenic differentiation was evaluated by western blot, by measuring β1 integrin expression, and by and real-time RT-PCR, by measuring SP7 and Collagen I gene expression; while.angiogenesis was characterized by measuring VEGF secretion levels. Matrix mineralization was assessed by means of Alizarin Red Staining, cell adhesion and inflammation responses through western blot, enzymatic and ELISA assays evaluating Nrf2 expression, catalase activity and Prostaglandin E2 secretion, respectively. LipoMix enhances cell proliferation and adhesion, as revealed by increased integrin β1 expression. Mineralized matrix deposition, SP7 gene expression, Collagen I release and Alkaline Phosphatase activity appear increased in LipoMix condition. Additionally, the redox-sensitive transcription factor Nrf2 is overexpressed at the earliest experimental times, triggering the catalase activity. data reported confirm that internal topography and post-production treatments on titanium surfaces dynamically and positively condition the DPSC progress towards the osteogenic phenotype, moreover, the combination with LipoMix fastens the positive modulation of inflammation under osteogenic conditions. Therefore, the development of customized surfaces along with the administration of differentiating factors enclosed in a liposomal delivery system, could represent a promising and innovative tool in regenerative dentistry.

Acute contact with profibrotic macrophages mechanically activates fibroblasts via αvβ3 integrin-mediated engagement of Piezo1.

Fibrosis-excessive scarring after injury-causes >40% of disease-related deaths worldwide. In this misguided repair process, activated fibroblasts drive the destruction of organ architecture by accumulating and contracting extracellular matrix. The resulting stiff scar tissue, in turn, enhances fibroblast contraction-bearing the question of how this positive feedback loop begins. We show that direct contact with profibrotic but not proinflammatory macrophages triggers acute fibroblast contractions. The contractile response depends on αvβ3 integrin expression on macrophages and Piezo1 expression on fibroblasts. The touch of macrophages elevates fibroblast cytosolic calcium within seconds, followed by translocation of the transcription cofactors nuclear factor of activated T cells 1 and Yes-associated protein, which drive fibroblast activation within hours. Intriguingly, macrophages induce mechanical stress in fibroblasts on soft matrix that alone suppresses their spontaneous activation. We propose that acute contact with suitable macrophages mechanically kick-starts fibroblast activation in an otherwise nonpermissive soft environment. The molecular components mediating macrophage-fibroblast mechanotransduction are potential targets for antifibrosis strategies.

ROCK Inhibitor Enhances Neurite Outgrowth In Vitro and Corneal Sensory Nerve Reinnervation In Vivo.

The intraepithelial corneal nerves are essential to corneal health. Rho kinase or ROCK inhibitors (RIs) have been reported to play a role in neuron survival after injury. Here we assess integrin and extracellular matrix expression in primary mouse neurons and determine whether treating cells with RI impacts neurite outgrowth in vitro and reinnervation after trephine and debridement injury in mice in vivo. Cocultures of human corneal limbal epithelial cells and E11.5 mouse trigeminal neurons and neurons alone were grown on glass coverslips. High-resolution imaging was performed to localize integrins and laminin on neurons and to determine whether RI impacts neurite outgrowth in vitro and in vivo after both 1.5-mm trephine and 1.5-mm debridement injuries. Several integrin α (α3, α6, αv) chains as well as β4 integrin are expressed on neuron axons and growth cones in cocultures. RI treatment of isolated neurons, cocultures, and in conditioned media increases neurite outgrowth. In vivo, RI positively impacts sensory nerve reinnervation after trephine and debridement injury. These studies are the first to demonstrate expression of β4 integrin on trigeminal sensory neurons and preferential adhesion of neurons to the laminin-enriched matrices found in footprints deposited by human corneal limbal epithelial cells. In addition, we also document for the first time the positive impact of RI on neurite outgrowth in vitro and reinnervation in vivo.

Insights into the metastatic bone marrow niche gained from fibronectin and β1 integrin transgenic mice

Tumor cells can migrate from a primary cancer and form metastases by localizing to niches within other organs including the bone marrow, where tumor cells may exploit the hematopoietic stem cell niche. The precise composition of the premetastatic and the hematopoietic niches and the degree of overlap between them remain elusive. Because the extracellular matrix protein fibronectin is expressed in the pre-metastatic lung microenvironment, we evaluated the implications of its loss, as well as those of loss of its primary receptor subunit, β1 integrin, in various bone marrow cell types both in breast cancer bone metastasis and hematopoiesis.Using eight transgenic mouse models, we established that fibronectin production by osterix-expressing marrow cells, or β1 integrin expression (on vav, mx, or leptin receptor expressing cells), affects MDA-MB-231 breast cancer cell numbers in the bone marrow. Additionally, we identified stromal subpopulations that modulate transmigration through blood vessel walls. Not the number of tumor cells, but rather the changes in the microenvironment dictated whether the tumor progresses. Furthermore, hematopoiesis, particularly myelopoiesis, was affected in some of the models showing changes in tumor homing.In conclusion, there is partial overlap between the pre-metastatic and the hematopoietic niches in the bone marrow. Moreover, we have delineated a cascade starting with fibronectin secreted by pre-osteoblastic cells, which potentially acts on β1 integrin in specific stromal cell subsets, thereby inhibiting the formation of new breast cancer lesions in the bone marrow. This work therefore sheds light on the role of various stromal cell subpopulations that influence tumor behavior and affect hematopoiesis.

Pleiotrophin Activates cMet- and mTORC1-Dependent Protein Synthesis through PTPRZ1-The Role of ανβ3 Integrin.

Pleiotrophin (PTN) is a secreted factor that regulates endothelial cell migration through protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) and αvβ3 integrin. Genetic deletion of Ptprz1 results in enhanced endothelial cell proliferation and migration, due to the decreased expression of β3 integrin and the subsequent, enhanced cMet phosphorylation. In the present study, we investigated the effect of PTN and PTPRZ1 on activating the mTORC1 kinase and protein synthesis and identified part of the implicated signaling pathway in endothelial cells. PTN or genetic deletion of Ptprz1 activates protein synthesis in a mTORC1-dependent manner, as shown by the enhanced phosphorylation of the mTORC1-downstream targets ribosomal protein S6 kinase 1 (SK61) and 4E-binding protein 1 (4EBP1) and the upregulation of HIF-1α. The cMet tyrosine kinase inhibitor crizotinib abolishes the stimulatory effects of PTN or PTPRZ1 deletion on mTORC1 activation and protein synthesis, suggesting that mTORC1 activation is downstream of cMet. The mTORC1 inhibitor rapamycin abolishes the stimulatory effect of PTN or PTPRZ1 deletion on endothelial cell migration, suggesting that mTORC1 is involved in the PTN/PTPRZ1-dependent cell migration. The αvβ3 integrin blocking antibody LM609 and the peptide PTN112-136, both known to bind to ανβ3 and inhibit PTN-induced endothelial cell migration, increase cMet phosphorylation and activate mTORC1, suggesting that cMet and mTORC1 activation are required but are not sufficient to stimulate cell migration. Overall, our data highlight novel aspects of the signaling pathway downstream of the PTN/PTPRZ1 axis that regulates endothelial cell functions.

Heterobivalent Dual-Target Peptide for Integrin-αvβ3 and Neuropeptide Y Receptors on Breast Tumor.

Background/Objectives: Heterodimer peptides targeting more than one receptor can be advantageous, as tumors can simultaneously express more than one receptor type. For human breast cancer, a promising biological target is tumor angiogenesis through αvβ3 integrin expression. Another promising target is Neuropeptide Y receptors, considering Y1R is overexpressed in 90% of human breast tumors. This article details the development and preclinical evaluation, both in vitro and in vivo, of a novel heterodimer peptide dual-receptor-targeting probe, [99mTc]HYNIC-cRGDfk-NPY, designed for imaging breast tumors. Methods: Female BALB/c healthy mice were used to perform biodistrubution studies and female SCID mice were subcutaneously injected with MCF-7 and MDA-MB-231 tumor cells. [99mTc]HYNIC-cRGDfk-NPY was intravenously administered to the mice, followed by ex vivo biodistribution studies and small-animal SPECT/CT imaging. Nonspecific tracer uptake in both models was determined by coinjecting an excess of unlabeled HYNIC-cRGDfk-NPY (100 µg) along with the radiolabeled tracer. Results: Imaging and biodistribution data demonstrate good uptake to estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) tumor models. The in vivo tumor uptakes of radiolabeled conjugate were 9.30 ± 3.25% and 4.93 ± 1.01% for MCF-7 and MDA-MB231, respectively. The tumor/muscle ratios were 5.65 ± 0.94 for the MCF-7 model and 7.78 ± 3.20 for MDA-MB231. Conclusions: [99mTc]HYNIC-cRGDfk-NPY demonstrated rapid blood clearance, renal excretion, and in vivo tumor uptake, highlighting its potential as a tumor imaging agent.

A-213 αEβ7 Integrin (CD103) expression in both early and advanced stage of Cutaneous T cell Lymphoma's (CTCL)

A-213 αEβ7 Integrin (CD103) expression in both early and advanced stage of Cutaneous T cell Lymphoma's (CTCL)

Modulation of αv integrins by lebecetin, a viper venom-derived molecule, in experimental neuroinflammation and demyelination models

Several neurodegenerative diseases, such as multiple sclerosis and Parkinson’s disease, are linked to alterations in myelin content or structure. Transmembrane receptors such as integrins could be involved in these alterations. In the present study, we investigated the role of αv-integrins in experimental models of neuroinflammation and demyelination with the use of lebecetin (LCT), a C-lectin protein purified from Macrovipera lebetina viper venom, as an αv-integrin modulator. In a model of neuroinflammation, LCT inhibited the upregulation of αv, β3, β5, α5, and β1 integrins, as well as the associated release of pro-inflammatory factor IL-6 and chemokine CXCL-10, and decreased the expression of phosphorylated NfκB. The subsequent “indirect culture” between reactive astrocytes and oligodendrocytes showed a down-regulation of αv and β3 integrins versus upregulation of β1 one, accompanied by a reduced expression of myelin basic protein (MBP). Treatment of oligodendrocytes with LCT rectified the changes in integrin and MBP expression. Through Western blot quantification, LCT was shown to upregulate the expression levels of PI3K and p-mTOR while downregulating expression levels of p-AKT in oligodendrocytes, suggesting the neuroprotective and pro-myelinating effects of LCT may be related to the PI3K/mTor/AKT pathway. Concomitantly, we found that LCT promoted remyelination by tracking the increased expression of MBP in the brains of cuprizone-intoxicated mice. These results point to an involvement of integrins in not only neuroinflammation but demyelination as well. Thus, targeting αv integrins could offer potential therapeutic avenues for the treatment of demyelinating diseases.

A Machine Learning-Based Investigation of Integrin Expression Patterns in Cancer and Metastasis.

Integrins, a family of transmembrane receptor proteins, play complex roles in cancer development and metastasis. These roles could be better delineated through machine learning of transcriptomic data to reveal relationships between integrin expression patterns and cancer. We collected publicly available RNA-Seq integrin expression from 8 healthy tissues and their corresponding tumors, along with data from metastatic breast cancer. We then used machine learning methods, including t-SNE visualization and Random Forest classification, to investigate changes in integrin expression patterns. Integrin expression varied across tissues and cancers, and between healthy and cancer samples from the same tissue, enabling the creation of models that classify samples by tissue or disease status. The integrins whose expression was important to these classifiers were identified. For example, ITGA7 was key to classification of breast samples by disease status. Analysis in breast tissue revealed that cancer rewires co-expression for most integrins, but the co-expression relationships of some integrins remain unchanged in healthy and cancer samples. Integrin expression in primary breast tumors differed from their metastases, with liver metastasis notably having reduced expression. Integrin expression patterns vary widely across tissues and are greatly impacted by cancer. Machine learning of these patterns can effectively distinguish samples by tissue or disease status.

αvβ3 integrin-targeted magnetic resonance imaging in a pancreatic cancer mouse model using RGD-modified liposomes encapsulated with Fe-deferoxamine.

Magnetic resonance (MR) imaging is a powerful imaging modality for obtaining anatomical information with high spatial and temporal resolution. In the drug delivery system (DDS) framework, nanoparticles such as liposomes are potential candidates for MR imaging. We validated that RGD peptides are possible targeting molecules for pancreatic cancer with αvβ3 integrin expression. This study aimed to evaluate RGD-modified liposomes loaded with ferrioxamine B for pancreatic cancer imaging. We synthesized four types of RGD-modified liposomes encapsulated with ferrioxamine B (SH-, H-, M-, and L-RGD-liposomes). The binding affinity of RGD-modified liposomes was evaluated in a competitive inhibition study using 125I-echistatin. To investigate the pharmacokinetics of RGD-modified liposomes, a biodistribution study using RGD-liposomes labeled with 111In was carried out in a human pancreatic cancer PANC-1 xenograft mouse model. Finally, MR was performed using ferrioxamine-B-loaded liposomes. RGD-liposomes inhibited the binding of 125I-echistatin to RGD. The biodistribution study revealed that 111In-RGD-liposomes accumulated significantly in the liver and spleen. Among the 111In-RGD-liposomes, 111In-H-RGD-liposomes showed the highest tumor-to-normal tissue ratio. In the MR study, H-RGD-liposomes loaded with ferrioxamine B showed higher tumor-to-muscle signal ratios than RKG-liposomes loaded with ferrioxamine B (control). We successfully synthesized RGD-liposomes that can target αvβ3 integrin.

Interleukin-33-activated basophils promote asthma by regulating Th2 cell entry into lung tissue.

Asthma is characterized by lung eosinophilia, remodeling, and mucus plugging, controlled by adaptive Th2 effector cells secreting IL-4, IL-5, and IL-13. Inhaled house dust mite (HDM) causes the release of barrier epithelial cytokines that activate various innate immune cells like DCs and basophils that can promote Th2 adaptive immunity directly or indirectly. Here, we show that basophils play a crucial role in the development of type 2 immunity and eosinophilic inflammation, mucus production, and bronchial hyperreactivity in response to HDM inhalation in C57Bl/6 mice. Interestingly, conditional depletion of basophils during sensitization did not reduce Th2 priming or asthma inception, whereas depletion during allergen challenge did. During the challenge of sensitized mice, basophil-intrinsic IL-33/ST2 signaling, and not FcεRI engagement, promoted basophil IL-4 production and subsequent Th2 cell recruitment to the lungs via vascular integrin expression. Basophil-intrinsic loss of the ubiquitin modifying molecule Tnfaip3, involved in dampening IL-33 signaling, enhanced key asthma features. Thus, IL-33-activated basophils are gatekeepers that boost allergic airway inflammation by controlling Th2 tissue entry.

Recoverability of zebrafish from decabromodiphenyl ether exposure: The persisted interference with extracellular matrix production and collagen synthesis and the enhancement of arrhythmias

As a widely used brominated flame retardant, the widespread presence of decabromodiphenyl ether (BDE-209) in the natural environment and the toxicity risks it poses are well established, but the recoverability of BDE-209-induced individual injuries remains unknown. Therefore, a 7-day depuration experiment following a 4-day exposure of zebrafish to BDE-209 was conducted to confirm the recoverability and its mode of action. Oxidative stress after depuration was significantly reduced compared with BDE-209 exposure as indicated by the decreased expression level of oxidative stress-related genes and the reduced MDA, Gpx, and GST in zebrafish, indicating a gradual recovery of antioxidant activity. However, BDE-209 inhibition of extracellular matrix (ECM) proteins worsened after depuration. Mechanistically, BDE-209 mediated ECM production and secretion by down-regulating integrin expression. Furthermore, BDE-209 inhibition of collagen synthesis worsened after depuration. Biochemical assays and histopathological observations revealed a same result in zebrafish. Mechanistically, lysine hydroxylation is inhibited thereby affecting collagen synthesis. Interestingly, zebrafish showed arrhythmia after depuration compared to BDE-209 exposure, and abnormal changes in ATPase levels indicated that disturbances in Ca2+ homeostasis contributed to arrhythmia. Collectively, BDE-209-induced interference with ECM production and collagen synthesis persisted after depuration, which will provide new insights for understanding the recovery patterns of individuals under BDE-209 stress.