Resilience of weighted networks with dynamical behavior against multi-node removal.

In many real-world networks, interactions between nodes are weighted to reflect their strength, such as predator-prey interactions in the ecological network and passenger numbers in airline networks. These weighted networks are prone to cascading effects caused by minor perturbations, which can lead to catastrophic outcomes. This vulnerability highlights the importance of studying weighted network resilience to prevent system collapses. However, due to many variables and weight parameters coupled together, predicting the behavior of such a system governed by a multi-dimensional rate equation is challenging. To address this, we propose a dimension reduction technique that simplifies a multi-dimensional system into a one-dimensional state space. We applied this methodology to explore the impact of weights on the resilience of four dynamics whose weights are assigned by three weight assignment methods. The four dynamical systems are the biochemical dynamical system (B), the epidemic dynamical system (E), the regulatory dynamical system (R), and the birth-death dynamical system (BD). The results show that regardless of the weight distribution, for B, the weights are negatively correlated with the activities of the network, while for E, R, and BD, there is a positive correlation between the weights and the activities of the network. Interestingly, for B, R, and BD, the change in the weights of the system has little impact on the resilience of the system. However, for the E system, the greater the weights the more resilient the system. This study not only simplifies the complexity inherent in weighted networks but also enhances our understanding of their resilience and response to perturbations.

Fraxetin pretreatment alleviates cisplatin-induced kidney injury by antagonizing autophagy and apoptosis via mTORC1 activation.

Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC. bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on apoptosis and autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In  summary, fraxetin pretreatment alleviates CKI by antagonizing autophagy and apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.

Facile Synthesis of Helicene-Containing Arenes for Optical Limiting Devices.

A helicene-containing arene and its linear analogue have been successfully synthesized and characterized, where the single-crystal X-ray diffraction analysis indicates that the former can arrange in an offset packing style with a π-π overlap. The introduction of pentagon-rings into the parent skeletons in the resulting compounds can boost the stability, and such helicene-containing molecule possesses higher solubility in organic solvent than the linear analogue. The structural difference has significantly influenced the optical limiting performance. The former in solution and in doped gel glass presents higher optical limiting response towards 532 nm laser than the latter. This study can enrich the functionalization of helicene, which can possess a positive effect in terms of nonlinear optical property.

Effect of Annulation Mode of Twistarene on the Physical Property and Self-Assembly Behavior of Functionalized Curved Aromatic Molecules.

Four novel curved polycyclic aromatic hydrocarbons 3 a, 5, 8, 15 a have been synthesized and characterized, where molecules 3 a and 15 a bear [5]carbohelicene units. X-ray single crystal analyses indicate that compound 3 a shows offset packing arrangements of (P5 )- and (M5 )-isomers, and 15 a has a symmetrical plane and looks like a butterfly. In comparison, 8 exhibits a slightly curved structure, in which the significant convex-to-convex π-overlap with the shortest distance of 3.42 Šoccurs. In addition, the effect of annulation mode of twistarenes on the physical properties, self-assembly behaviors, and switchable photoconductivity of the as-prepared curved aromatic compounds were further examined in a comparative manner.

Identification of a novel histone acetylation-related long non-coding RNA model combined with qRT-PCR experiments for prognosis and therapy in gastric cancer.

Gastric cancer (GC) is considered a global health crisis due to the scarcity of early diagnostic methods. Numerous studies have substantiated the involvement of histone acetylation imbalance in the progression of diverse tumor types. The potential roles of long non-coding RNA (lncRNA) in improving prognostic, predictive as well as therapeutic approaches in cancers have made it a major hotspot in recent years. Nevertheless, existent studies have never concerned the prognostic and clinical value of histone acetylation-related lncRNAs (HARlncs) in GC. Based on the aforementioned rationale, we developed a prognostic model incorporating four HARlncs-AC114730.1, AL445250.1, LINC01778, and AL163953.1-which demonstrated potential as an independent predictor of prognosis. Subsequently, GC patients were stratified into high-risk and low-risk groups. The low-risk group exhibited significantly higher overall survival (OS) compared to the high-risk group. Based on the analyses of the tumor microenvironment (TME) and immune responses, significant differences were observed between the two risk groups in terms of immune cell infiltration, immune checkpoint (ICP) expression, and other TME alterations. Furthermore, the sensitivity of GC patients to some chemotherapeutic drugs and the discrepant biological behaviors of three tumor clusters were studied in this model. In summary, we developed an effective HARlncs model with the objective of offering novel prognostic prediction methods and identifying potential therapeutic targets for GC patients.

Characterization of a predictive signature for tumor microenvironment and immunotherapy response in hepatocellular carcinoma involving neutrophil extracellular traps.

Neutrophil extracellular traps (NETs) and other factors play a significant role in impacting the prognosis of patients with Hepatocellular carcinoma (HCC). Nevertheless, further research is warranted to fully elucidate the prognostic implications of NETs in patients with HCC. We employed a hierarchical clustering technique to examine the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) data and identified subtypes associated with NETs. Subsequently, we utilized LASSO regression analysis to identify a distinct gene expression pattern within these subtypes. The strength of this signature was further validated through analysis of TCGA-LIHC and International Cancer Genome Consortium-Liver Cancer (ICGC-LIRI-JP) data. Our findings resulted in the construction of a six-gene signature related to NETs, which can predict survival outcomes in HCC patients. To enhance the predictive accuracy of our tool, we developed a nomogram that integrates the NETs signature with clinicopathological characteristics. We validated the significance of NETs in HCC patients using qRT-PCR and immunohistochemistry assays, along with in vitro experiments targeting high-risk genes. Furthermore, our exploration of the immune microenvironment uncovered augmented immune-specific metrics within the low-risk cohort, implying potential disparities in immune-related attributes between the high-risk and low-risk contingents. In summary, the NETs signature we discovered serves as a valuable biomarker and provides guidance for personalized therapy in HCC patients.

Glucose-6-phosphate dehydrogenase alleviates epileptic seizures by repressing reactive oxygen species production to promote signal transducer and activator of transcription 1-mediated N-methyl-d-aspartic acid receptors inhibition.

The pathogenesis of epilepsy remains unclear; however, a prevailing hypothesis suggests that the primary underlying cause is an imbalance between neuronal excitability and inhibition. Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway, which is primarily involved in deoxynucleic acid synthesis and antioxidant defense mechanisms and exhibits increased expression during the chronic phase of epilepsy, predominantly colocalizing with neurons. G6PD overexpression significantly reduces the frequency and duration of spontaneous recurrent seizures. Furthermore, G6PD overexpression enhances signal transducer and activator of transcription 1 (STAT1) expression, thus influencing N-methyl-d-aspartic acid receptors expression, and subsequently affecting seizure activity. Importantly, the regulation of STAT1 by G6PD appears to be mediated primarily through reactive oxygen species signaling pathways. Collectively, our findings highlight the pivotal role of G6PD in modulating epileptogenesis, and suggest its potential as a therapeutic target for epilepsy.

Erratum to "Characterization of a predictive signature for tumor microenvironment and immunotherapy response in hepatocellular carcinoma involving neutrophil extracellular traps" [Heliyon Volume 10, issue 10, May 2024, article e30827].

[This corrects the article DOI: 10.1016/j.heliyon.2024.e30827.].

Smad4 regulates TGF-ß1-mediated hedgehog activation to promote epithelial-to-mesenchymal transition in pancreatic cancer cells by suppressing Gli1 activity.

Pancreatic cancer (PC) is an aggressive and metastatic gastrointestinal tumor with a poor prognosis. Persistent activation of the TGF-ß/Smad signaling induces PC cell (PCC) invasion and infiltration via epithelial-to-mesenchymal transition (EMT). Hedgehog signaling is a crucial pathway for the development of PC via the transcription factors Gli1/2/3. This study aimed to investigate the underlying molecular mechanisms of action of hedgehog activation in TGF-ß1-triggered EMT in PCCs (PANC-1 and BxPc-3). In addition, overexpression and shRNA techniques were used to evaluate the role of Smad4 in TGF-ß1-treated PCCs. Our data showed that TGF-ß1 promoted PCC invasion and infiltration via Smad2/3-dependent EMT. Hedgehog-Gli signaling axis in PCCs was activated upon TGF-ß1 stimulation. Inhibition of hedgehog with cyclopamine effectively antagonized TGF-ß1-induced EMT, thereby suggesting that the hedgehog signaling may act as a downstream cascade signaling of TGF-ß1. As a key protein that assists the nuclear translocation of Smad2/3, Smad4 was highly expressed in PANC-1 cells, but not in BxPc-3 cells. Conversely, Gli1 expression was low in PANC-1 cells, but high in BxPc-3 cells. Furthermore, knockdown of Smad4 in PANC-1 cells by shRNA inhibited TGF-ß1-mediated EMT and collagen deposition. Overexpression of Smad4 did not affect TGF-ß1-mediated EMT due to the lack of significant increase in nuclear expression of Smad4. Importantly, Gli1 activity was upregulated by Smad4 knockdown in PANC-1 cells and downregulated by Smad4 overexpression in BxPc-3 cells, indicating that Gli1 may be a negative target protein downstream of Smad4. Thus, Smad4 regulates TGF-ß1-mediated hedgehog activation to promote EMT in PCCs by suppressing Gli1 activity.

Investigating the impact of inflammatory response-related genes on renal fibrosis diagnosis: a machine learning-based study with experimental validation.

Renal fibrosis plays a crucial role in the progression of renal diseases, yet the lack of effective diagnostic markers poses challenges in scientific and clinical practices. In this study, we employed machine learning techniques to identify potential biomarkers for renal fibrosis. Utilizing two datasets from the GEO database, we applied LASSO, SVM-RFE and RF algorithms to screen for differentially expressed genes related to inflammatory responses between the renal fibrosis group and the control group. As a result, we identified four genes (CCL5, IFITM1, RIPK2, and TNFAIP6) as promising diagnostic indicators for renal fibrosis. These genes were further validated through in vivo experiments and immunohistochemistry, demonstrating their utility as reliable markers for assessing renal fibrosis. Additionally, we conducted a comprehensive analysis to explore the relationship between these candidate biomarkers, immunity, and drug sensitivity. Integrating these findings, we developed a nomogram with a high discriminative ability, achieving a concordance index of 0.933, enabling the prediction of disease risk in patients with renal fibrosis. Overall, our study presents a predictive model for renal fibrosis and highlights the significance of four potential biomarkers, facilitating clinical diagnosis and personalized treatment. This finding presents valuable insights for advancing precision medicine approaches in the management of renal fibrosis.Communicated by Ramaswamy H. Sarma.

Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4/MyD88-mediated NF-κB p65 and JNK/FoxO1 activation.

BACKGROUND: Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an isoflavone derivative isolated from Pueraria lobata, has been proven to possess exceptional effectiveness in reducing inflammation. However, the effects and underlying mechanisms of puerarin on AKI remain uncertain. PURPOSE: This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism. STUDY DESIGN AND METHODS: The effects of puerarin on AKI and macrophage polarization were investigated in lipopolysaccharide (LPS)-induced or unilateral ureteral obstruction (UUO)-induced mouse models in vivo and LPS-treated macrophages (Raw264.7) in vitro. Additionally, the effects of puerarin on inflammation-related signaling pathways were analyzed. RESULTS: Administration of puerarin effectively alleviated kidney dysfunction and reduced inflammatory response in LPS-induced and UUO-induced AKI. In vitro, puerarin treatment inhibited the polarization of M1 macrophages and the release of inflammatory factors in Raw264.7 cells stimulated by LPS. Mechanistically, puerarin downregulated the activities of NF-κB p65 and JNK/FoxO1 signaling pathways. The application of SRT1460 to activate FoxO1 or anisomycin to activate JNK eliminated puerarin-mediated inhibition of JNK/FoxO1 signaling, leading to suppression of macrophage M1 polarization and reduction of inflammatory factors. Further studies showed that puerarin bound to Toll/interleukin-1 receptor (TIR) domain of MyD88 protein, hindering its binding with TLR4, ultimately resulting in downstream NF-κB p65 and JNK/FoxO1 signaling inactivation. CONCLUSIONS: Puerarin antagonizes NF-κB p65 and JNK/FoxO1 activation via TLR4/MyD88 pathway, thereby suppressing macrophage polarization towards M1 phenotype and alleviating renal inflammatory damage.

Thrombectomy for delayed thromboembolism in a recurrent cerebral aneurysm previously treated with coiling: A case report.

RATIONALE: Giant intracranial aneurysms pose a significant threat due to high mortality rates upon rupture, prompting interventions such as neurosurgical clipping or endovascular coiling. PATIENT CONCERNS: We present a rare case involving a 47-year-old female with a history of successfully treated ruptured giant intracranial aneurysms. Six months post-surgical clipping, she developed symptoms of acute ischemic stroke, prompting the decision for neurosurgical coiling and stent-assisted aneurysm coil embolization due to recurrent intracranial aneurysms. DIAGNOSES: Subsequently, occlusion occurred at the previously implanted stent site during embolization, necessitating exploration of alternative therapeutic options. Digital subtraction angiography confirmed stent occlusion in the right middle cerebral artery. INTERVENTIONS: Despite an initial unsuccessful attempt using a direct aspiration first-pass technique, the patient underwent successful mechanical thrombectomy with a retrievable stent, leading to successful reperfusion. This study aims to highlight the challenges and therapeutic strategies in managing delayed cerebral vascular occlusion following stent-assisted coil embolization, emphasizing the significance of exploring alternative interventions to enhance patient outcomes. OUTCOMES: The patient achieved successful reperfusion, and the study underscores the importance of recognizing and addressing delayed cerebral vascular occlusion after stent-assisted coil embolization for recurrent cerebral aneurysms. LESSONS: Our findings suggest that retrievable stent mechanical thrombectomy may serve as a viable therapeutic option in challenging scenarios, emphasizing the need for further exploration of alternative interventions to enhance patient care.

Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling exerts a vital effect on the growth and progression of PDAC. While dietary flavonoid phloretin has anti-inflammatory and antioxidant activities, it remains unclear whether phloretin has anti-tumor effects on PDAC. PURPOSE: The focus of the present study is to elucidate the effects of phloretin on PDAC and investigate its underlying molecular mechanisms. STUDY DESIGN AND METHODS: Effect of phloretin were assessed in the pancreatic cancer cells (PCCs) by colony formation assay, real-time cell analysis, flow cytometry, Immunofluorescence staining, and cell migration assay. The expressions of mRNA and protein were respectively analyzed by quantitative PCR and Western blotting. A xenograft model was used to appraise the antitumor efficacy of phloretin. RESULTS: Phloretin treatment significantly restrained cell viability and metastasis, induced DNA injury and ROS accumulation, and triggered mitochondrial-dependent apoptosis in PCCs. Mechanistically, phloretin exhibits anti-tumor potential via inactivating STAT3 signaling and enhancing Nrf2 activity. STAT3 overexpression and Nrf2 silencing partially relieved phloretin-induced inhibition on cell growth and metastasis in PCCs. Phloretin remarkably blocked pancreatic tumor growth and metastasis in vivo. CONCLUSIONS: Phloretin suppresses pancreatic cancer growth and progression through inhibition of STAT3 mediated by enhancing Nrf2 activity. Phloretin may serve as a promising therapeutic agent for PDAC.

STAT3 inhibition enhances gemcitabine sensitivity in pancreatic cancer by suppressing EMT, immune escape and inducing oxidative stress damage.

Pancreatic cancer (PC) is a highly-malignant tumor of the digestive system with a very poor prognosis and high mortality. Chemotherapy and PD-1/PD-L1 immune checkpoint blockade are important treatment strategies for advanced PC. However, chemotherapy resistance and poor therapeutic effect of immune checkpoint inhibitors is are the main clinical problems to be solved urgently at present. The effects of combined application of gemcitabine and STAT3 inhibition on the proliferation, apoptosis, migration, and invasion of PC cells (PCCs) were investigated. In addition, oxidative stress (OS), ferroptosis, immune escape, and the epithelial-mesenchymal transition (EMT) were evaluated. STAT3 inhibition with Stattic enhanced the inhibitory activity of gemcitabine on PCC proliferation by regulating the cell cycle. STAT3 inhibition enhanced mitochondrial-dependent apoptosis in gemcitabine-treated PCCs, but did not induce autophagy and ferroptosis. Further study showed that the anti-proliferative and pro-apoptotic effects may be associated with increased OS damage by inactivating Nrf2-HO-1 signaling, as well as DNA damage by inducing the imbalance between ATM andATR-Chk1 pathway. In addition, STAT3 inhibition strengthened gemcitabine-mediated suppression in PCC invasion and migration by antagonizing Smad2/3-dependent EMT. Moreover, the anti-tumorimmuneresponse of gemcitabine was upregulated by Stattic through reducing the expression of PD-L1 and CD47. Mechanistically, combined application of gemcitabine and Stattic suppressed the phosphorylation and nuclear expression of STAT3. Interestingly, the activities of AKT and ß-catenin signaling were also regulated, suggesting that drug combination has a broad-spectrum signal regulation effect. STAT3 inhibition enhanced the sensitivity of PCCs to the chemotherapy drug gemcitabine by suppressing EMT and immune escape and inducing OS damage.

S100A2 induces epithelial-mesenchymal transition and metastasis in pancreatic cancer by coordinating transforming growth factor ß signaling in SMAD4-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor and is associated with a poor prognosis. Treatment strategies for PDAC are largely ineffective primarily because of delay in its diagnosis and limited efficacy of systematic treatment. S100A2 is associated with the proliferation, migration, and differentiation of several tumors; however, its effects on PDAC and the associated molecular mechanisms remain to be explored. We studied the mechanisms underlying the effect of S100A2 on epithelial-mesenchymal transition (EMT) and metastasis in PDAC cells. We found that the level of S100A2 remarkably increased and was associated with poor PDAC prognosis. The overexpression of S100A2 in PANC-1 cells also induced EMT, in addition to increasing the invasion and migration of PDAC cells, whereas the knockdown of S100A2 markedly inhibited cell metastasis. Furthermore, S100A2 was found to enhance metastatic abilities in vivo. The overexpression of S100A2 increased SMAD4 expression, whereas the knockdown of S100A2 reduced SMAD4 expression. SMAD4 overexpression could effectively rescue the effects of S100A2 knockdown on EMT. S100A2 mechanistically activated the transforming growth factor (TGF)-ß/Smad2/3 signaling pathway, upregulated SMAD4 expression, induced EMT, and increased PANC-1 cell metastasis. In conclusion, the S100A2/SMAD4 axis modulates EMT to accelerate PDAC development. Our results supplement and enrich the understanding of the pathogenesis underlying PDAC and provide a new theoretical basis and strategy targeting S100A2 for the diagnosis and treatment of PDAC.

Diagnostic model constructed by five EMT-related genes for renal fibrosis and reflecting the condition of immune-related cells.

Background: Renal fibrosis is a physiological and pathological characteristic of chronic kidney disease (CKD) to end-stage renal disease. Since renal biopsy is the gold standard for evaluating renal fibrosis, there is an urgent need for additional non-invasive diagnostic biomarkers. Methods: We used R package "limma" to screen out differently expressed genes (DEGs) based on Epithelial-mesenchymal transformation (EMT), and carried out the protein interaction network and GO, KEGG enrichment analysis of DEGs. Secondly, the least absolute shrinkage and selection operator (LASSO), random forest tree (RF), and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to identify candidate diagnostic genes. ROC curves were plotted to evaluate the clinical diagnostic value of these genes. In addition, mRNA expression levels of candidate diagnostic genes were analyzed in control samples and renal fibrosis samples. CIBERSORT algorithm was used to evaluate immune cells level. Additionally, gene set enrichment analysis (GSEA) and drug sensitivity were conducted. Results: After obtaining a total of 24 DEGs, we discovered that they were mostly involved in several immunological and inflammatory pathways, including NF-KappaB signaling, AGE-RAGE signaling, and TNF signaling. Five genes (COL4A2, CXCL1, TIMP1, VCAM1, and VEGFA) were subsequently identified as biomarkers for renal fibrosis through machine learning, and their expression levels were confirmed by validation cohort data sets and in vitro RT-qPCR experiment. The AUC values of these five genes demonstrated significant clinical diagnostic value in both the training and validation sets. After that, CIBERSORT analysis showed that these biomarkers were strongly associated with immune cell content in renal fibrosis patients. GSEA also identifies the potential roles of these diagnostic genes. Additionally, diagnostic candidate genes were found to be closely related to drug sensitivity. Finally, a nomogram for diagnosing renal fibrosis was developed. Conclusion: COL4A2, CXCL1, TIMP1, VCAM1, and VEGFA are promising diagnostic biomarkers of tissue and serum for renal fibrosis.

Trans-cinnamaldehyde attenuates renal ischemia/reperfusion injury through suppressing inflammation via JNK/p38 MAPK signaling pathway.

Inflammation is the major contributor to the mechanisms of acute kidney injury due to renal ischemia-reperfusion injury (IRI). Trans-cinnamaldehyde (TCA) is a main bioactive component extracted from the bark of cinnamon and has been proved to have good anti-inflammatory properties. The current study was to demonstrate the effect of TCA on renal IRI and explore its specific mechanism. C57BL/6J mice were injected prophylactically intraperitoneally for TCA 3 days, and IRI for 24 h. In parallel, Human Kidney-2 (HK-2) cells were prophylactically treated with TCA, and then exposed to oxygen glucose deprivation/reperfusion (OGD/R) and cobalt chloride (CoCl2). TCA was found to significantly attenuate renal pathological changes and renal dysfunction, and inhibit gene and protein expression of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, TCA significantly suppressed the expression of TNF-α, IL-6, IL-1ß, COX-2, iNOS, and MCP-1. Mechanistically, the activation of the JNK/p38 MAPK signaling pathway was inhibited by TCA in renal IRI as well as in OGD/R and CoCl2-stimulated cells. However, following pretreatment with anisomycin before OGD/R treatment, we found that the activation of the JNK/p38 MAPK signaling pathway was significantly enhanced, and concomitant abrogation of the TCA inhibitory effect on the JNK/p38 MAPK signaling pathway, which was followed by a worsening of cell injury that was characterized by an increased number of cell necrosis and an increase in the expression of Kim-1, NGAL as well as proinflammatory factors (IL-6, IL-1ß, iNOS). In summary, TCA inhibited renal inflammation via the JNK/p38 MAPK signaling pathway and attenuated renal IRI.

The anthelmintic drug niclosamide induces GSK-ß-mediated ß-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression.

Niclosamide, a cell-permeable salicylanilide, was approved by the Food and Drug Administration for its anthelmintic efficiency. A growing body of evidence in recent years suggests that niclosamide exhibits potential tumor-suppressive activity. However, the role and molecular mechanism of niclosamide in pancreatic cancer remain unclear. In this study, niclosamide inhibited proliferation of pancreatic cancer cells (PCCs), induced apoptosis via the mitochondrial-mediated pathway, and suppressed cell migration and invasion by antagonizing epithelial-to-mesenchymal transition. Also, niclosamide inhibited tumor growth and metastasis in pancreatic cancer xenograft mouse models. Mechanistically, niclosamide exerted these therapeutic effects via targeting ß-catenin. Niclosamide did not reduce ß-catenin mRNA expression in PCCs, but significantly downregulated its protein level. Moreover, niclosamide induced ß-catenin phosphorylation and protein degradation. Interestingly, niclosamide also induced GSK-3ß phosphorylation, which is involved in the ubiquitination degradation of ß-catenin. Pharmacological activation of ß-catenin by methyl vanillate and ß-catenin overexpression abolished the inhibitory effects of niclosamide. Furthermore, niclosamide potentiated the antitumor effect of the chemotherapy drug gemcitabine and reduced the ability of cancer immune evasion by downregulating the expression levels of PD-L1, which is involved in T cell immunity. Thus, our study indicated that niclosamide induces GSK-ß-mediated ß-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability, and suppress pancreatic cancer progression. Niclosamide may be a potential therapeutic candidate for pancreatic cancer.

Targeted delivery of a STING agonist to brain tumors using bioengineered protein nanoparticles for enhanced immunotherapy.

Immunotherapy is emerging as a powerful tool for combating many human diseases. However, the application of this life-saving treatment in serious brain diseases, including glioma, is greatly restricted. The major obstacle is the lack of effective technologies for transporting therapeutic agents across the blood-brain barrier (BBB) and achieving targeted delivery to specific cells once across the BBB. Ferritin, an iron storage protein, traverses the BBB via receptor-mediated transcytosis by binding to transferrin receptor 1 (TfR1) overexpressed on BBB endothelial cells. Here, we developed bioengineered ferritin nanoparticles as drug delivery carriers that enable the targeted delivery of a small-molecule immunomodulator to achieve enhanced immunotherapeutic efficacy in an orthotopic glioma-bearing mouse model. We fused different glioma-targeting moieties on self-assembled ferritin nanoparticles via genetic engineering, and RGE fusion protein nanoparticles (RGE-HFn NPs) were identified as the best candidate. Furthermore, RGE-HFn NPs encapsulating a stimulator of interferon genes (STING) agonist (SR717@RGE-HFn NPs) maintained stable self-assembled structure and targeting properties even after traversing the BBB. In the glioma-bearing mouse model, SR717@RGE-HFn NPs elicited a potent local innate immune response in the tumor microenvironment, resulting in significant tumor growth inhibition and prolonged survival. Overall, this biomimetic brain delivery platform offers new opportunities to overcome the BBB and provides a promising approach for brain drug delivery and immunotherapy in patients with glioma.

Rational design of engineered H-ferritin nanoparticles with improved siRNA delivery efficacy across an in vitro model of the mouse BBB.

Gene therapy holds tremendous potential for the treatment of incurable brain diseases including Alzheimer's disease (AD), stroke, glioma, and Parkinson's disease. The main challenge is the lack of effective gene delivery systems traversing the blood-brain barrier (BBB), due to the complex microvessels present in the brain which restrict substances from the circulating blood passing through. Recently, increasing efforts have been made to develop promising gene carriers for brain-related disease therapies. One such development is the self-assembled heavy chain ferritin (HFn) nanoparticles (NPs). HFn NPs have a unique hollow spherical structure that can encapsulate nucleic acid drugs (NADs) and specifically bind to cancer cells and BBB endothelial cells (BBB ECs) via interactions with the transferrin receptor 1 (TfR1) overexpressed on their surfaces, which increases uptake through the BBB. However, the gene-loading capacity of HFn is restricted by its limited interior volume and negatively charged inner surface; therefore, these drawbacks have prompted the demand for strategies to remould the structure of HFn. In this work, we analyzed the three-dimensional (3D) structure of HFn using Chimera software (v 1.14) and developed a class of internally cationic HFn variants (HFn+ NPs) through arginine mutation on the lumenal surface of HFn. These HFn+ NPs presented powerful electrostatic forces in their cavities, and exhibited higher gene encapsulation efficacy than naive HFn. The top-performing candidate, HFn2, effectively delivered siRNA to glioma cells after traversing the BBB and achieved the highest silencing efficacy among HFn+ NPs. Overall, our findings demonstrate that HFn+ NPs obtained by this genetic engineering method provide critical insights into the future development of nucleic acid delivery carriers with BBB-crossing ability.