Migration Activity Research Articles

Promising Pharmacological Interventions for Posterior Capsule Opacification: A Review

AbstractPhacoemulsification combined with intraocular lens implantation is the primary treatment for cataract. Although this treatment strategy benefits patients with cataracts, posterior capsule opacification (PCO) remains a common complication that impairs vision and affects treatment outcomes. The pathogenesis of PCO is associated with the proliferation, migration, and fibrogenesis activity of residual lens epithelial cells, with epithelial–mesenchymal transition (EMT) serving as a key mechanism underlying the condition. Transforming growth factor‐beta 2 (TGF‐β2) is a major promotor of EMT, thereby driving PCO development. Most studies have shown that drugs and miRNAs mitigate EMT by inhibiting, clearing, or eliminating LECs. In addition, targeting EMT–related signaling pathways in TGF‐β2–stimulated LECs has garnered attention as a research focus. This review highlights potential treatments for PCO and details the mechanisms by which drugs and miRNAs counter EMT.

Bilayer Scaffolds Synergize Immunomodulation and Rejuvenation via Layer-Specific Release of CK2.1 and the "Exercise Hormone" Lac-Phe for Enhanced Osteochondral Regeneration.

Repairing osteochondral defects necessitates the intricate reestablishment of the microenvironment. The cartilage layer consists of a porous gelatin methacryloyl hydrogel (PGelMA) covalently crosslinked with the chondroinductive peptide CK2.1 via a "linker" acrylate-PEG-N-hydroxysuccinimide (AC-PEG-NHS). This layer is optimized for remodeling the senescent microenvironment in the cartilage region, thereby establishing a regenerative microenvironment that supports chondrogenesis. For the bone layer, silk fibroin methacryloyl (SilMA) is coated onto a three dimensional (3D)-printed 45S5 bioactive glass scaffold (BG scaffold). The "exercise hormone" N-lactoyl-phenylalanine (Lac-Phe) is loaded onto the SilMA, endowing it with diversified functions to regulate the osteogenic microenvironment. Systematic analysis in vitro reveals that PGelMA-CK2.1 shifts the microenvironment from a pro-inflammatory into an anti-inflammatory condition, and alleviates cellular senescence, thus modifying the cartilage microenvironment to improve the recruitment, proliferation and chondral differentiation of bone marrow mesenchymal stem cells (BMSCs). The scaffold bone layer enhances microvascular endothelial cell proliferation, migration, and angiogenic activities, which, couple with increased BMSC recruitment and regulatory mechanisms directing BMSC differentiation, favor a shift in the "osteogenesis-adipogenesis" balance toward enhanced osteogenesis. In vivo, it is found that this biphasic biomimetic scaffold favors simultaneous dual tissue regeneration. This approach facilitates the development of bioactive regenerative scaffolds and holds great potential for clinical application.

Long-Term Dynamics of Different Avian Influenza Viruses in Mallard (Anas platyrhynchos) Population in Moscow City and Moscow Oblast: Dependence on the Migration Activity

Long-Term Dynamics of Different Avian Influenza Viruses in Mallard (Anas platyrhynchos) Population in Moscow City and Moscow Oblast: Dependence on the Migration Activity

Corynoxine suppresses lung adenocarcinoma proliferation and metastasis via inhibiting PI3K/AKT pathway and suppressing Cyclooxygenase-2 expression

BackgroundLung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer.MethodsThe impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice.ResultsIn this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis.ConclusionThis study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD.

Uncovering migration systems through spatio-temporal tensor co-clustering

A central problem in the study of human mobility is that of migration systems. Typically, migration systems are defined as a set of relatively stable movements of people between two or more locations over time. While these emergent systems are expected to vary over time, they ideally contain a stable underlying structure that could be discovered empirically. There have been some notable attempts to formally or informally define migration systems. However, they have been limited by being hard to operationalize and defining migration systems in ways that ignore origin/destination aspects and fail to account for migration dynamics over time. In this work, we propose to employ spatio-temporal tensor co-clustering—that stems from signal processing and machine learning theory—as a novel migration system analysis tool. Tensor co-clustering is designed to cluster entities exhibiting similar patterns across multiple modalities and thus suits our purpose of analyzing spatial migration activities across time. To demonstrate its effectiveness in describing stable migration systems, we first focus on domestic migration between counties in the US from 1990 to 2018. We conduct three case studies on domestic migration, namely, (i) US Metropolitan Areas, (ii) the state of California, and (iii) Louisiana, in which the last focuses on detecting exogenous events such as Hurricane Katrina in 2005. In addition, we also examine a case study at a larger scale, using worldwide international migration data from 200 countries between 1990 and 2015. Finally, we conclude with a discussion of this approach and its limitations.

TMEM206 Contributes to Cancer Hallmark Functions in Colorectal Cancer Cells and Is Regulated by p53 in a p21-Dependent Manner

Acid-induced ion flux plays a role in pathologies where tissue acidification is prevalent, including cancer. In 2019, TMEM206 was identified as the molecular component of acid-induced chloride flux. Localizing to the plasma membrane, TMEM206 contributes to cellular processes like acid-induced cell death. Since over 50% of human cancers carry loss of function mutations in the p53 gene, we aimed to analyze how TMEM206 is regulated by p53 and its role in cancer hallmark function and acid-induced cell death in HCT116 colorectal cancer (CRC) cells. We generated p53-deficient HCT116 cells and assessed TMEM206-mediated Cl− currents and transcriptional regulation using the patch-clamp and a dual-luciferase reporter assay, respectively. To investigate the contribution of TMEM206 to cancer hallmark functions, we performed migration and metabolic activity assays. The role of TMEM206 in p53-mediated acid-induced cell death was assessed with cell death assays. The TMEM206 mRNA level was significantly elevated in human primary CRC tumors. TMEM206 knockout increased acid-induced cell death and reduced proliferation and migration, indicating a role for TMEM206 in these cancer hallmark functions. Furthermore, we observed increased TMEM206 mRNA levels and currents in HCT116 p53 knockout cells. This phenotype can be rescued by transient overexpression of p53 but not by overexpression of dysfunctional p53. In addition, our data suggest that TMEM206 may mediate cancer hallmark functions within p53-associated pathways. TMEM206 promoter activity is not altered by p53 overexpression. Conversely, knockout of p21, a major target gene of p53, increased TMEM206-mediated currents, suggesting expression control of TMEM206 by p21 downstream signaling. Our results show that in colorectal cancer cells, TMEM206 expression is elevated, contributes to cancer hallmark functions, and its regulation is dependent on p53 through a p21-dependent mechanism.

Evaluation of methods to estimate nocturnal bird migration activity: C comparison of radar and nocturnal flight call monitoring in the American West

Evaluation of methods to estimate nocturnal bird migration activity: C comparison of radar and nocturnal flight call monitoring in the American West

Combination of Methotrexate and Resveratrol Reduces Pro-Inflammatory Chemokines in Human THP-1 Cells.

Methotrexate (MTX) is a widely used anti-metabolite drug in cancer therapy, but its efficacy is often hindered by reactive oxygen species (ROS)-induced cellular toxicity. Resveratrol, a natural polyphenol, possesses antioxidant and anticancer properties. Therefore, this in vitro study aimed to investigate the synergistic anti-proliferative and anti-inflammatory effects of MTX and resveratrol in human THP-1 cells. THP-1 cells were differentiated into macrophage-like cells using phorbol 12-myristate 13-acetate. In vitro experiments assessed the impact of various concentrations of MTX and resveratrol on cell viability and proliferation using the MTT assay. Concentration-effect curves were generated to elucidate their relationship. Gene expression was analyzed by RT-qPCR, while chemokine expression was measured via ELISA. Phagocytic and migratory activities were also evaluated. Differentiated THP-1 cells were treated with MTX and resveratrol and stimulated with dimethyl sulfoxide (DMSO) and lipopolysaccharide (LPS) as inflammatory stimuli. The combination of MTX and resveratrol exhibited an anti-proliferative effect in THP-1 cells (p = 0.03). The concentration-effect curve revealed IC50 values of 49.15 µg at 24hours (R = 0.8236) and 2.029e-005 µg at 48hours (R = 0.97) for MTX, and 20.17 µg at 48hours (R = 1.000) and 55.38 µg at 96hours (R = 0.9666) for resveratrol. Co-treatment with MTX and resveratrol significantly reduced mRNA and chemokine expression of CCL2, CCL3, CCL4, CCL5, and CXCL10 (p < 0.05). Moreover, decreased phagocytic and migratory activities were confirmed by phagocytosis and migration assays (p < 0.05). The combination of MTX and resveratrol effectively attenuated pro-inflammatory activity in THP-1 cells, as evidenced by the downregulation of mRNA and chemokine expression. These findings suggest that the synergistic effects of MTX and resveratrol hold promise for enhancing cancer therapeutics.

CD248 cleaved form in human colorectal cancer stroma: implications for tumor behavior and prognosis.

CD248 (Endosialin/TEM-1) is upregulated in cancer, including colorectal cancer (CRC), but its exact role in tumor progression remains to be elucidated. Previous studies have shown that the extracellular domain of CD248 mediates the interaction between tumor cells and extracellular matrix proteins and that interfering with this interaction may reduce tumor invasion and migration activities. We have examined the expression of CD248 in 117 human CRC samples by immunohistochemistry and investigated the association with various clinicopathological features, including the occurrence of metastasis intra-tumoral immune cell density, and overall survival. Out of the 117 specimens analyzed, 76.1% (89/117) exhibited CD248-high stromal expression, while 23.1% (28/117) demonstrated CD248-low stromal expression. Interestingly, we detected the presence of a cleaved form of CD248, which appears to accumulate in the stromal extracellular matrix. A higher metastasis rate (lymph node and distant) was observed in the CD248-low group (21/28, 75.0% versus 44/89, 49.4%, p=0.02). In addition, CD248-low tumors had fewer CD163-positive macrophages and FoxP3-positive regulatory T cells (p<0.05) with no significant difference in CD8-positive T-cell infiltration and PD-L1 expression between the groups (p>0.05). Finally, overall survival was lower in CD248-low tumors than in CD248-high tumors, with 5-year survival rates of 35.7% and 57.3%, respectively (p=0.01). In a multivariate analysis, the hazard ratio of CD248-low tumors versus CD248-high tumors was 1.93 (95% confidence interval: 1.09 - 3.40; p=0.02). Our findings suggest that CD248 stromal expression may influence the TME, impacting tumor behavior and prognosis, and can serve as a promising prognostic biomarker in CRC.

Zoledronate interrupts pre-osteoclast-induced angiogenesis via SDF-1/CXCR4 pathway

IntroductionIn this study, we tested the hypothesis that pre-osteoclast signaling is key in triggering post-traumatic angiogenesis in alveolar bone via the SDF-1/CXCR4 pathway. Interruption of osteoclast differentiation through zoledronate (Zol) disrupts the crosstalk between pre-osteoclasts and endothelial cells, hindering the initial angiogenic reaction following dental trauma. This disruption could therefore play a role in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ). MethodsThe effect of zoledronate on the expression of SDF1 was tested in pre-osteoclasts (POC) in vitro. Then, we tested the effect of pre-osteoclast conditioned medium on HUVEC cell differentiation, migration, tube-formation, and CXCR4 expression and activity in-vitro. Lastly, we quantified the effect of zoledronate treatment on post-traumatic vascular perfusion of alveolar bone, using microCT-angiography and immunohistochemistry. ResultsSDF-1 mRNA expression decreased in Zol-treated POCs (p = 0.02). Flow-Cytometry analysis showed a decrease in CXCL-12+ (SDF-1α) expressing POCs with Zol treatment (p = 0.0058). On the other hand, CXCR4 mRNA expression was significantly inhibited in Zol-treated HUVECs (p = 0.0063). CXCR4 protein expression and activity showed a corresponding dose-dependent downregulation HUVEC surface treated with conditioned media from POC treated with Zol (p = 0.008 and 0.03, respectively). Similar inhibition was observed of HUVEC migration (p = 0.0012), and tube formation (p < 0.0001), effects that were reversed with SDF-1. Finally, there was a significant reduction of CD31+ HUVECs in Alveolar bone of Zol-treated rats (p = 0.0071), confirmed by significantly lower percentage of blood vessel volume (p = 0.026), and marginally lower vessel number (p = 0.062) in the alveolar bone. ConclusionPre-osteoclasts play a crucial role in the initial angiogenic response in alveolar bone following dental extraction. Disruption of this process may be a predisposing factor to osteonecrosis.

Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells

While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation, and PGE2 blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE2-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.

Monocarboxylate transporter dependent mechanism is involved in proliferation, migration, and invasion of human glioblastoma cell lines via activation of PI3K/Akt signaling pathway.

Glioblastoma multiforme is one of the most common primary tumors of the central nervous system, with a very poor prognosis. Cancer cells have been observed to upregulate pH regulators, such as monocarboxylate transporters (MCTs), with an increase in MCT4 expression being observed in several malignancies. MCT4/ recombinant cluster of differentiation 147 (CD147) transporter complex was reported to stimulate vascular endothelial growth factor (VEGF) via the phosphatidylinositol 3 kinase (PI3K) /protein kinase B (Akt) pathway, which has been proven to mediate glioblastoma invasion and migration. The present study aimed to clarify the role of the MCT4/CD147 transporter complex in glioblastoma cell proliferation, migration, and invasion. In this work, lentiviral vectors were used to overexpress MCT4/CD147 and small interfering RNA (siRNA) was used to silence MCT4/CD147 in the human glioma cell lines U87 and U251, respectively. The effects on cell proliferation, migration and invasiveness, as well as the protein expression levels of MCT4 and CD147, extracellular lactate content and Akt activation were assessed by MTT, wound-healing and invasion assays, western blotting and colorimetric method, respectively. The analysis results suggested that cell proliferation, migration, invasion, and Akt activation were decreased by siRNA in all cell lines, but were increased by lentivirus-mediated MCT4 overexpression. These findings suggest that inhibiting the activity and expression of the MCT4/CD147 transporter complex via metabolic-targeting drugs, particularly in cells with a high rate of glycolysis, should be explored as a novel strategy for glioblastoma treatment.

In-situ engineering of native extracellular matrix to improve vascularization and tissue regeneration at the ischemic injury site

Ischemic injury causes dynamic damage to the native extracellular matrix (ECM), which plays a key role in tissue homeostasis and regeneration by providing structural support, facilitating force transmission, and transducing key signals to cells. The main approach aimed at repairing injury to ischemic tissues is restoration of vascular function. Due to their potential to form capillary niches, endothelial cells (ECs) are of greatest interest for vascular regeneration. Integrin binding to ECM is crucial for cell anchorage to the surrounding matrix, spreading, migration, and further activation of intracellular signaling pathways. In this study, we proposed to establish an in-situ engineering strategy to remodel the ECM at the ischemic site to guide EC endogenous binding and establish effective EC/ECM interactions to promote revascularization. We designed and constructed a dual-function molecule (LXW7)2-SILY, which is comprised of two functional domains: the first one (LXW7) binds to integrin αvβ3 expressed on ECs, and the second one (SILY) binds to collagen. In vitro, we confirmed (LXW7)2-SILY improved EC adhesion and survival. After in situ injection, (LXW7)2-SILY showed stable retention at the injured area and promoted revascularization, blood perfusion, and tissue regeneration in a mouse hindlimb ischemia model.Graphical

Exploring tumor endothelial cells heterogeneity in hepatocellular carcinoma: insights from single-cell sequencing and pseudotime analysis.

This study aimed to explore the heterogeneity of tumor endothelial cells (TECs) in hepatocellular carcinoma (HCC) and their role in tumor progression, with the goal of identifying new therapeutic targets and strategies to improve patient prognosis. Single-cell RNA sequencing data from nine primary liver cancer samples were analyzed, obtained from the Gene Expression Omnibus (GEO) database. Data preprocessing, normalization, dimensionality reduction, and batch effect correction were performed based on the Seurat package. HCC cell types were identified using uniform manifold approximation and projection (UMAP) and cluster analysis, and the different cell types were annotated using the CellMarker database. Pseudotime trajectory analysis was conducted with Monocle to explore the differentiation trajectory of TECs. MAPK signaling pathway activity and copy number variations (CNV) in TECs were analyzed in conjunction with data from The Cancer Genome Atlas (TCGA), the trans-well and wound healing assay was used for cell invasion and migration activity assessment. Two subgroups of TECs (TECs 1 and TECs 2) were identified, exhibiting distinct functional activities and signaling pathways. Specifically, TECs 1 may be involved in tumor cell proliferation and inflammatory responses, whereas TECs 2 is not only involved in cell proliferation pathways, but also enriched in pathways such as metabolic synthesis. Pseudotime analysis revealed dynamic changes in TECs subgroups during HCC progression, correlating specific gene expressions (such as PDGFRB, PGF, JUN, and NR4A1). Subsequently, the JUN gene was predicted by performing binding sites and was shown to act as a transcription factor that may regulate the expression of the PGF gene. CNV analysis highlighted key genes and pathways in TECs that might influence HCC progression, and the PGF as key regulatory factor mediated cell proliferation and migration. The study revealed the heterogeneity of TECs in HCC and their potential roles in tumor progression, offering new perspectives and potential therapeutic targets for HCC molecular mechanisms. The findings emphasize the importance of further exploring TECs heterogeneity for understanding HCC pathogenesis and developing personalized treatment strategies.

Unite and Conquer: Association of Two G-Quadruplex Aptamers Provides Antiproliferative and Antimigration Activity for Cells from High-Grade Glioma Patients

Background: High-grade gliomas remain a virtually incurable form of brain cancer. Current therapies are unable to completely eradicate the tumor, and the tumor cells that survive chemotherapy or radiation therapy often become more aggressive and resistant to further treatment, leading to inevitable relapses. While the antiproliferative effects of new therapeutic molecules are typically the primary focus of research, less attention is given to their influence on tumor cell migratory activity, which can play a significant role in recurrence. A potential solution may lie in the synergistic effects of multiple drugs on the tumor. Objectives: In this study, we investigated the effect of combined exposure to bi-(AID-1-T), an anti-proliferative aptamer, and its analog bi-(AID-1-C), on the migratory activity of human GBM cells. Results: We examined the effects of various sequences of adding bi-(AID-1-T) and bi-(AID-1-C) on five human GBM cell cultures. Our findings indicate that certain sequences significantly reduced the ability of tumor cells to migrate and proliferate. Additionally, the expression of Nestin, PARP1, L1CAM, Caveolin-1, and c-Myc was downregulated in human GBM cells that survived exposure, suggesting that the treatment had a persistent antitumor effect on these cells.

Immune system dysfunction in personnel of chemical hazard facilities: purpose and effectiveness of immunotherapeutic drugs

Clinical signs of the presence of immune dysfunction/insufficiency, identified by questioning workers at the landfill for the storage and destruction of industrial toxic waste, were the basis for performing a screening study of immune status. This included a clinical blood test with determination of the leukocyte formula, assessment of the phenotypic status of lymphocytes for the main subpopulations, determination of the concentration in serum immunoglobulins of various classes, assessment of the migration activity of leukocytes, assessment of the microbicidal capacity of neutrophils and their ability to phagocytosis. When the examined employees were found to have more than 20% changes in the normative range of immune status parameters and the presence of combined disorders in different parts of immunoreactivity, in particular combined disorders in the cellular part of the immune system, it was the basis for conducting an in-depth stage of immunoepidemiological examination. This included determination of functional activity cellular elements of the adaptive component of immunity, assessment of the severity of autosensitization, assessment of the severity and specificity of atopic hypersensitization, assessment of cytokine status in normal conditions and in response to mitogen. When assessing the phenotypic status of immunoreactivity cells, it turned out that the absolute number of T lymphocytes (CD3+ phenotype), helper T lymphocytes (CD3+CD4+ phenotype) and killer T lymphocytes (CD3+CD8+ phenotype) was significantly reduced in the peripheral blood of test site employees (p ≤ 0.05, compared with similar indicators in the control group). On the contrary, the content of NK cells (CD3-CD56+ phenotype) tended to increase (both the absolute number and the proportion among other lymphocyte populations). Dysfunction of the cellular component of humoral immunoreactivity (a significant decrease in the absolute number of lymphocytes with the CD3-CD20+ phenotype [B lymphocytes] in the peripheral blood), as well as a significant increase in the concentration of serum IgA-class immunoglobulin and pronounced disimmunoglobulinemia in the serum of the examined individuals (compared to individuals in the control group ) indicated a predominantly inhalation method of exposure to immunotoxic industrial toxicants from the landfill on the immune system. Pathogenetically targeted immune-oriented therapy for the personnel of the test site was carried out with drugs that have thymomimetic activity (cytovir-3, thymogen) and are a means of replacement immunocorrection with a cytokine drug (genetically engineered recombinant yeast IL-2 [roncoleukin]). The established effectiveness of the immunotherapy, in particular the reduction in the incidence rate of various nosological forms of immune-related pathology among the site employees who received immunotherapy and the presence of an immunocorrective effect in the immunoactive drugs used for therapy, indicate the advisability of carrying out preventive medical measures in persons professionally exposed to xenobiotic influences as a component of improving medical provision.

Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma.

DAOY (SHH driven/tp53 mutant) and D425 (non-SHH group 3) were treated with BT9. For in vitro analysis, cell proliferation, death, migration, invasion, and metabolic activity were assessed using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. A D425 orthotopic xenograft mouse model was used to evaluate BT9 efficacy in vivo. BT9 treatment resulted in a significant decrease in cell proliferation (DAOY, 24 hours IC50: 3.6 μM, 48 hours IC50: 2.3 μM, 72 hours IC50: 2.1 μM; D425 24 hours IC50: 3.4 μM, 48 hours IC50: 2.2 μM, 72 hours IC50: 2.1 μM) and a significant increase in cell death (DAOY, 24 hours p = 0.0004, 48 hours p<0.0001; D425, 24 hours p = 0.0001, 48 hours p = 0.02). In DAOY cells, 3 μM BT9 delayed migration and significantly reduced DAOY and D425 cell invasion (p < 0.0001). It also modified mitochondrial respiratory function in both medulloblastoma cell lines. Compared to control, however, BT9 administration did not improve survival in a D425 orthotopic xenograft mouse model. Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines, suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

CircRNA_SLC8A1 alleviates hypertrophic scar progression by mediating the Nrf2-ARE pathway.

Hypertrophic scar (HS) is associated with cosmetic defects, mobility, and functional impairments, pruritus, and pain. Previous circRNA microarray analysis identified reduced expression of circRNA_SLC8A1 in HS tissues. Therefore, this study aims to investigate the role of circRNA_SLC8A1 in modulating the abnormal behavior of HS-derived fibroblasts (HSFs) in vitro. RT-qPCR and FISH assays were used to assess the differential expression and localization of circRNA_SLC8A1 in normal and HS tissues. Following modulation of circRNA_SLC8A1 expression, CCK-8, flow cytometry, Transwell, and wound healing assays were employed to evaluate the effects of circRNA_SLC8A1 on the biological behaviors of HSFs. The Starbase database, dual-luciferase reporter assays, and Ago2-RIP assays were utilized to predict and validate the interaction between circRNA_SLC8A1 and downstream miRNAs. CircRNA_SLC8A1 was found to be downregulated in HS tissues and was primarily localized in the cytoplasm. Overexpression of circRNA_SLC8A1 reduced cell viability, cell invasion, wound healing, and the expression of Vimentin, N-cadherin, Col I, and Col III, while enhancing apoptosis and E-cadherin expression in HSFs. CircRNA_SLC8A1 activates the Nrf2-ARE pathway by competitively binding to miRNA-27a-3p. miRNA-27a-3p and Nrf2 exhibited high and low expression, respectively in HS tissues, with an inverse correlation between their levels. Overexpression of miRNA-27a-3p counteracted the effects of circRNA_SLC8A1 in HSF proliferation, apoptosis, migration, EMT, collagen deposition, and Nrf2-ARE pathway activity. CircRNA_SLC8A1 inhibits the proliferation, migration, EMT, and collagen deposition of HSF through competitive binding with miRNA-27a-3p, thereby activating the Nrf2-ARE pathway. The circRNA_SLC8A1/miRNA-27a-3p/Nrf2-ARE axis may offer a promising molecular target for HS therapy.

Structural insights into the mechanism of DNA branch migration during homologous recombination in bacteria.

Some DNA helicases play central and specific roles in genome maintenance and plasticity through their branch migration activity in different pathways of homologous recombination. RadA is a highly conserved bacterial helicase involved in DNA repair throughout all bacterial species. In Gram-positive Firmicutes, it also has a role in natural transformation, while in Gram-negative bacteria, ComM is the canonical transformation-specific helicase. Both RadA and ComM helicases form hexameric rings and use ATP hydrolysis as an energy source to propel themselves along DNA. In this study, we present the cryoEM structures of RadA and ComM interacting with DNA and ATP analogs. These structures reveal important molecular interactions that couple ATP hydrolysis and DNA binding in RadA, as well as the role of the Lon protease-like domain, shared by RadA and ComM, in this process. Taken together, these results provide new molecular insights into the mechanisms of DNA branch migration in different pathways of homologous recombination.

Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates Toxoplasma dissemination.

Intracellular pathogens can hijack the cellular functions of infected host cells to their advantage, for example, for intracellular survival and dissemination. However, how microbes orchestrate the hijacking of complex cellular processes, such as host cell migration, remains poorly understood. As such, the common parasite Toxoplasma gondii actively invades the immune cells of humans and other vertebrates and modifies their migratory properties. Here, we show that the concerted action of a number of secreted effector proteins from the parasite, principally GRA15 and GRA24, acts on host cell signaling pathways to activate chemotaxis. Furthermore, the protein effector GRA28 selectively acted on chromatin accessibility in the host cell nucleus to selectively boost host gene expression. The joint activities of GRA effectors culminated in pro-migratory signaling within the infected phagocyte. We provide a molecular framework delineating how T. gondii can orchestrate a complex biological phenotype, such as the migratory activation of phagocytes to boost dissemination.