Tannic acid-poloxamer self-assembled nanoparticles for advanced atherosclerosis therapy by regulation of macrophage polarization.

Atherosclerosis (AS) is a significant contributor to cardiovascular events. Advanced AS is particularly concerning, as it leads to the formation of high-risk vulnerable plaques. Current treatments for AS focus on antithrombotic and lipid-lowering interventions, which are effective in treating early-stage AS. Recent studies have shown that macrophage polarization plays a crucial role in the development of AS. This study presents a new biomedical application of natural tannic acid as an anti-inflammatory nanoplatform for advanced AS. Tannic acid-poloxamer nanoparticles (TPNP) are fabricated through self-assembly of tannic acid (TA) and poloxamer. TPNP has the potential to provide effective treatment for advanced AS. According to in vitro studies, TPNP has been found to suppress the inflammatory response in lipopolysaccharide-stimulated macrophages by scavenging reactive oxygen species (ROS), downregulating the expression levels of inflammatory cytokines (such as interleukin-10 and tumor necrosis factor-α) and regulating polarization of macrophages. In vivo studies further reveal that TPNP can retard the development of advanced atherosclerotic plaques by reducing ROS production and promoting M2 macrophage polarization in the aorta of ApoE-/- mice. Overall, these findings suggest that TPNP could be used to develop natural multifunctional nanoplatforms for molecular therapy of AS and other inflammation-related diseases.

Nano-Drug Delivery Systems Targeting CAFs: A Promising Treatment for Pancreatic Cancer.

Currently, pancreatic cancer (PC) is one of the most lethal malignant tumors. PC is typically diagnosed at a late stage, exhibits a poor response to conventional treatment, and has a bleak prognosis. Unfortunately, PC's survival rate has not significantly improved since the 1960s. Cancer-associated fibroblasts (CAFs) are a key component of the pancreatic tumor microenvironment (TME). They play a vital role in maintaining the extracellular matrix and facilitating the intricate communication between cancer cells and infiltrated immune cells. Exploring therapeutic approaches targeting CAFs may reverse the current landscape of PC therapy. In recent years, nano-drug delivery systems have evolved rapidly and have been able to accurately target and precisely release drugs with little or no toxicity to the whole body. In this review, we will comprehensively discuss the origin, heterogeneity, potential targets, and recent advances in the nano-drug delivery system of CAFs in PC. We will also propose a novel integrated treatment regimen that utilizes a nano-drug delivery system to target CAFs in PC, combined with radiotherapy and immunotherapy. Additionally, we will address the challenges that this regimen currently faces.

Nrf2-mediated redox balance alleviates LPS-induced vascular endothelial cell inflammation by inhibiting endothelial cell ferroptosis.

Ferroptosis plays an important role in inflammation and oxidative stress. Whether ferroptosis is involved in the inflammation of vascular endothelial cells and its regulation mechanism remains unclear. We estimated the correlation between serum iron ion levels and the inflammation index of 33 patients with arteriosclerosis. In vitro, HUVECs with or without ferrostatin-1 were exposed to Lipopolysaccharide. Corresponding cell models to verify the target signaling pathway. The results showed that serum iron ion levels had a significant positive correlation with N ratio, N/L, LDL level, and LDL/HDL (P < 0.05), and a negative correlation with L ratio (P < 0.05) in the arteriosclerosis patients. In vitro, ferroptosis is involved in HUVECs inflammation. Ferrostatin-1 can rescue LPS-induced HUVECs inflammation by decreasing HMGB1/IL-6/TNF-α expression. Nrf2 high expression could protect HUVECs against ferroptosis by activating the GPX4/GSH system, inhibiting ferritinophagy, and alleviating inflammation in HUVECs by inhibiting HMGB1/IL-6/TNF-α expression. It also found that Nrf2 is a key adaptive regulatory factor in the oxidative damage of HUVECs induced by NOX4 activation. These findings indicated that ferroptosis contributed to the pathogenesis of vascular endothelial cell damage by mediating endothelial cell inflammation. Nrf2-mediated redox balance in vascular inflammation may be a therapeutic strategy in vascular diseases.

The transcription factor GATA3 positively regulates NRP1 to promote radiation-induced pulmonary fibrosis.

Radiation-Induced Pulmonary Fibrosis (RIPF) frequently arises as a delayed complication following radiation therapy for thoracic cancers, encompassing lung, breast, and esophageal malignancies. Characterized by a relentless and irreversible accumulation of extracellular matrix (ECM) proteins within the lung parenchyma, RIPF presents a significant clinical challenge. While the modulation of gene expression by transcription factors is a recognized aspect in various pathologies, their specific role in the context of RIPF has been less clear. This study elucidates that ionizing radiation prompts the translocation of the transcription factor GATA3 into the nucleus. This translocation facilitates GATA3's binding to the NRP1 promoter, thereby enhancing the transcription and subsequent translation of NRP1. Further investigations demonstrate that the TGF-ß pathway agonist, SRI-011381, can mitigate the effects of NRP1 knockdown on epithelial-mesenchymal transition (EMT) and ECM deposition, suggesting a pivotal role of the GATA3/NRP1/TGF-ß axis in the pathogenesis of RIPF. In conclusion, our findings not only underscore the critical involvement of GATA3 in RIPF but also highlight the GATA3/NRP1/TGF-ß signaling pathway as a promising target for therapeutic intervention in RIPF management.

CDC123 promotes Hepatocellular Carcinoma malignant progression by regulating CDKAL1.

The cell proliferation protein 123 (CDC123) is involved in the synthesis of the eukaryotic initiation factor 2 (eIF2), which regulates eukaryotic translation. Although CDC123 is considered a candidate oncogene in breast cancer, its expression and role in Hepatocellular Carcinoma (HCC) remain unknown. Herein, we obtained the CDC123 RNA-seq and clinical prognostic data from the TCGA database. The mRNA level revealed that CDC123 was highly expressed in HCC patients, and Kaplan-Meier analysis implied better prognoses in HCC patients with low CDC123 expression (P < 0.001). The multivariate Cox analysis revealed that the CDC123 level was an independent prognostic factor (P < 0.001). We further confirmed a high CDC123 expression in HCC cell lines. Additionally, we found that CDC123 knockdown in HCC cell lines significantly inhibited cellular proliferation, invasion, and migration. Moreover, CDC123 was co-expressed with the CDK5 Regulatory Subunit-Associated Protein 1 Like 1 (CDKAL1), whose mRNA level was decreased after silencing CDC123. Therefore, we hypothesized that CDC123 promotes HCC progression by regulating CDKAL1.

ZDHHC5-mediated S-palmitoylation of FAK promotes its membrane localization and epithelial-mesenchymal transition in glioma.

BACKGROUND: Abnormal activation of FAK is associated with tumor development and metastasis. Through interactions with other intracellular signalling molecules, FAK influences cytoskeletal remodelling, modulation of adhesion signalling, and activation of transcription factors, promoting migration and invasion of tumor cells. However, the exact mechanism that regulates these processes remains unresolved. Herein, our findings indicate that the S-palmitoylation of FAK is crucial for both its membrane localization and activation. METHODS: The palmitoylation of FAK in U251 and T98G cells was assessed by an acyl-PEG exchange (APE) assay and a metabolic incorporation assay. Cellular palmitoylation was inhibited using 2-bromopalmitate, and the palmitoylation status and cellular localization of FAK were determined. A metabolic incorporation assay was used to identify the potential palmitoyl acyltransferase and the palmitoylation site of FAK. Cell Counting Kit-8 (CCK8) assays, colony formation assays, and Transwell assays were conducted to assess the impact of ZDHHC5 in GBM. Additionally, intracranial GBM xenografts were utilized to investigate the effects of genetically silencing ZDHHC5 on tumor growth. RESULTS: Inhibiting FAK palmitoylation leads to its redistribution from the membrane to the cytoplasm and a decrease in its phosphorylation. Moreover, ZDHHC5, a protein-acyl-transferase (PAT), catalyzes this key modification of FAK at C456. Knockdown of ZDHHC5 abrogates the S-palmitoylation and membrane distribution of FAK and impairs cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). Taken together, our research reveals the crucial role of ZDHHC5 as a PAT responsible for FAK S-palmitoylation, membrane localization, and activation. CONCLUSIONS: These results imply that targeting the ZDHHC5/FAK axis has the potential to be a promising strategy for therapeutic interventions for glioblastoma (GBM). Video Abstract.

How we do it: the double keyhole micro-endoscopic combined complex pituitary adenoma surgery.

BACKGROUND: Surgical removal of complex pituitary adenomas (PA) is a technically challenging procedure. To ensure safe and efficient surgery, we employ the micro-endoscopic combination technique. METHOD: In this study, we present our approach to the removal of a complex PA using the micro-endoscopic combination strategy. We describe our surgical setup and workflow in detail. CONCLUSION: Our experience with this case highlights the effectiveness of the micro-endoscopic combination technique in the management of complicated skull base surgeries with good teamwork and cooperation.

Laser additive manufacturing of shape memory biopolymer bone scaffold: 3D conductive network construction and electrically driven mechanism.

INTRODUCTION: The electro-actuated shape memory polymer scaffold has gained increasing attentions on the utilization of minimally invasive surgery for bone defect repair, which requires to construct an efficient conductive network to accomplish electrical-to-thermal conversion from conductive fillers to the entire matrix evenly. OBJECTIVES: In this study, multiwall carbon nanotube (MWCNT) was convective self-assembled on the ZnO tetrapod (t-ZnO) template, where MWCNT was controlled to disperse uniformly and regulated to contact with each other effectively due to the immersion capillary force during the evaporation loss of the convective self-assembly process, leading to an interwoven layer on the t-ZnO surface. METHODS: The prepared t-ZnO@MWCNT assembly was embedded in the poly(L-lactic acid)/thermoplastic polyurethane (PLLA/TPU) scaffold fabricated via selective laser sintering to construct a 3D conductive MWCNT network for improving the electro-actuated shape memory properties. RESULTS: It was observed that the interconnected MWCNT formed a 3D conductive network in the matrix without significant aggregation, which boosted the electrical-to-thermal properties of the scaffold, and the scaffold containing t-ZnO@MWCNT assembly possessed better electro-actuated shape memory properties with shape fixity of 98.0% and shape recovery of 98.8%. CONCLUSION: The scaffold exhibited improved electro-actuated shape memory properties and mechanical properties and the osteogenic inductivity was promoted with the combined effect of t-ZnO and electrical stimulation.

Co-Intercalation-Free Ether-Based Weakly Solvating Electrolytes Enable Fast-Charging and Wide-Temperature Lithium-Ion Batteries.

Ether-based electrolytes are competitive choices to meet the growing requirements for fast-charging and low-temperature lithium-ion batteries (LIBs) due to the low viscosity and low melting point of ether solvents. Unfortunately, the graphite (Gr) electrode is incompatible with commonly used ether solvents due to their irreversible co-intercalation into Gr interlayers. Here, we propose cyclopentyl methyl ether (CPME) as a co-intercalation-free ether solvent, which contains a cyclopentane group with large steric hindrance to obtain weakly solvating power with Li+ and a wide liquid-phase temperature range (-140 to +106 °C). A weakly solvating electrolyte (WSE) based on CPME and fluoroethylene carbonate (FEC) cosolvents can simultaneously achieve fast desolvation ability and high ionic conductivity, which also induces a LiF-rich solid electrolyte interphase (SEI) on the Gr anode. Therefore, the Gr/Li half-cell with this WSE can deliver outstanding rate capability, stable cycling performance, and high specific capacity (319 mAh g-1) at an ultralow temperature of -60 °C. Furthermore, a practical LiFePO4 (loading ≈25 mg cm-2)/Gr (loading ≈12 mg cm-2) pouch cell with this WSE also reveals outstanding rate capability and stable long-term cycling performance above 1000 cycles with a high Coulombic efficiency (≈99.9%) and achieves an impressive low-temperature application potential at -60 °C.

Liposomal Resveratrol Alleviates Platelet Storage Lesion via Antioxidation and the Physical Buffering Effect.

Platelet transfusion is essential in the treatment of platelet-related diseases and the prevention of bleeding in patients with surgical procedures. Platelet transfusion efficacy and shelf life are limited mainly by the development of platelet storage lesion (PSL). Mitigating PSL is the key to prolonging the platelet shelf life and reducing wastage. Excess intracellular reactive oxygen species (ROS) are one of the main factors causing PSL. In this study, we explored a nanomedicine strategy to improve the quality and functions of platelets in storage. Resveratrol (Res), a natural plant product, is known for its antioxidative effect. However, medical applications of Res are limited due to its low water solubility and stability. Therefore, we used a resveratrol-loaded liposomal system (Res-Lipo) to better utilize the antioxidant effect of the drug. This study aimed to evaluate the effect of Res-Lipo on platelet oxidative stress and alleviation of PSL during the storage time. Res-Lipo scavenged intracellular ROS and inhibited platelet apoptosis and activation during storage. Res-Lipo not only maintained mitochondrial function but also improved platelet aggregation in response to adenosine 5'-diphosphate. These results revealed that Res-Lipo ameliorated PSL and prolonged the platelet survival time in vivo. The strategy provides a potential method for extending the platelet storage time and might be considered a potential and safe additive to alleviate PSL.

MDSCs in breast cancer: an important enabler of tumor progression and an emerging therapeutic target.

Women worldwide are more likely to develop breast cancer (BC) than any other type of cancer. The treatment of BC depends on the subtype and stage of the cancer, such as surgery, radiotherapy, chemotherapy, and immunotherapy. Although significant progress has been made in recent years, advanced or metastatic BC presents a poor prognosis, due to drug resistance and recurrences. During embryonic development, myeloid-derived suppressor cells (MDSCs) develop that suppress the immune system. By inhibiting anti-immune effects and promoting non-immune mechanisms such as tumor cell stemness, epithelial-mesenchymal transformation (EMT) and angiogenesis, MDSCs effectively promote tumor growth and metastasis. In various BC models, peripheral tissues, and tumor microenvironments (TME), MDSCs have been found to amplification. Clinical progression or poor prognosis are strongly associated with increased MDSCs. In this review, we describe the activation, recruitment, and differentiation of MDSCs production in BC, the involvement of MDSCs in BC progression, and the clinical characteristics of MDSCs as a potential BC therapy target.

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain.

Ex vivo-loaded white blood cells (WBC) can transfer cargo to pathological foci in the central nervous system (CNS). Here we tested affinity ligand driven in vivo loading of WBC in order to bypass the need for ex vivo WBC manipulation. We used a mouse model of acute brain inflammation caused by local injection of tumor necrosis factor alpha (TNF-α). We intravenously injected nanoparticles targeted to intercellular adhesion molecule 1 (anti-ICAM/NP). We found that (A) at 2 h, >20% of anti-ICAM/NP were localized to the lungs; (B) of the anti-ICAM/NP in the lungs >90% were associated with leukocytes; (C) at 6 and 22 h, anti-ICAM/NP pulmonary uptake decreased; (D) anti-ICAM/NP uptake in brain increased up to 5-fold in this time interval, concomitantly with migration of WBCs into the injured brain. Intravital microscopy confirmed transport of anti-ICAM/NP beyond the blood-brain barrier and flow cytometry demonstrated complete association of NP with WBC in the brain (98%). Dexamethasone-loaded anti-ICAM/liposomes abrogated brain edema in this model and promoted anti-inflammatory M2 polarization of macrophages in the brain. In vivo targeted loading of WBC in the intravascular pool may provide advantages of coopting WBC predisposed to natural rapid mobilization from the lungs to the brain, connected directly via conduit vessels.

How we do it? Performing a protective superficial temporal artery-middle cerebral artery bypass with endoscopic transnasal cavernous sinus lesion operation.

BACKGROUND: To describe the concept of a protective superficial temporal artery-middle cerebral artery (STA-MCA) bypass performed prior to endoscopic transnasal cavernous sinus (CS) lesion resection in order to reduce the risk of perioperative cerebral ischemia due to internal carotid artery (ICA) vasospasm, occlusion, and even injury. METHOD: We illustrated the procedure of a 14-year-old female accepting a protective STA-MCA bypass with endoscopic transnasal CS lesion resection. CONCLUSION: A protective bypass may be a prophylactic strategy in selected endoscopic transnasal CS surgery cases, particularly where the diagnosis is uncertain, or the risk of ICA injury or occlusion is high.

Unveiling the secrets of non-coding RNA-encoded peptides in plants: A comprehensive review of mining methods and research progress.

Non-coding RNAs (ncRNAs) are not conventionally involved in protein encoding. However, recent findings indicate that ncRNAs possess the capacity to code for proteins or peptides. These ncRNA-encoded peptides (ncPEPs) are vital for diverse plant life processes and exhibit significant potential value. Despite their importance, research on plant ncPEPs is limited, with only a few studies conducted and less information on the underlying mechanisms, and the field remains in its nascent stage. This manuscript provides a comprehensive overview of ncPEPs mining methods in plants, focusing on prediction, identification, and functional analysis. We discuss the strengths and weaknesses of various techniques, identify future research directions in the ncPEPs domain, and elucidate the biological functions and agricultural application prospects of plant ncPEPs. By highlighting the immense potential and research value of ncPEPs, we aim to lay a solid foundation for more in-depth studies in plant science.

How I do it? Surgical removal of a corpus callosum arteriovenous malformation using a robotic digital microscope.

BACKGROUND: This report described the surgical nuance of a challenging deep-seated corpus callosum arteriovenous malformation (AVM) using a novel robotic digital microscope. METHOD: A 64-year-old male was admitted to treat a ruptured corpus callosum AVM. In order to facilitate surgical manipulation under the robotic digital microscope, a gravity-assisted supine position was utilized. Intraoperatively, identifying and preserving the transit and bystander artery is important while skeletonizing the anterior cerebral artery. The nidus was totally resected and the patient was discharged without sequella. CONCLUSION: It is feasible to perform complicated AVM resection under the robotic digital microscope with a rigorous surgical plan.

Gut microbiota: A novel and potential target for radioimmunotherapy in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate, and is a major burden on human health worldwide. Gut microbiota regulate human immunity and metabolism through producing numerous metabolites, which act as signaling molecules and substrates for metabolic reactions in various biological processes. The importance of host-gut microbiota interactions in immunometabolic mechanisms in CRC is increasingly recognized, and interest in modulating the microbiota to improve patient's response to therapy has been raising. However, the specific mechanisms by which gut microbiota interact with immunotherapy and radiotherapy remain incongruent. Here we review recent advances and discuss the feasibility of gut microbiota as a regulatory target to enhance the immunogenicity of CRC, improve the radiosensitivity of colorectal tumor cells and ameliorate complications such as radiotoxicity. Currently, great breakthroughs in the treatment of non-small cell lung cancer and others have been achieved by radioimmunotherapy, but radioimmunotherapy alone has not been effective in CRC patients. By summarizing the recent preclinical and clinical evidence and considering regulatory roles played by microflora in the gut, such as anti-tumor immunity, we discuss the potential of targeting gut microbiota to enhance the efficacy of radioimmunotherapy in CRC and expect this review can provide references and fresh ideas for the clinical application of this novel strategy.

Modulation of Enzyme Cascade Activity by Local Substrate Enrichment and Exclusion on DNA Nanostructures.

Substrate confinement and channeling play a critical role in multienzyme pathways and are considered to impact the catalytic efficiency and specificity of biomimetic and artificial nanoreactors. Here we reported a modulation of a multienzyme system with the cascade activity impacted by the surface affinity binding to substrate molecules. A DNA origami modified with aptamers was used to bind and enrich ATP molecules in the local area of immobilized enzymes, thereby enhancing the activity of an enzyme cascade by more than 2-fold. Alternatively, DNA nanostructure modified with blocked aptamers does not bind with ATP, thereby reducing the activity of the enzyme cascade. The Michaelis-Menten kinetics showed decreased apparent KM values (∼3-fold lower) for enzyme nanostructures modified with aptamers, suggesting the higher effective substrate concentration near enzymes due to the local enrichment of substrates. Conversely, increased apparent KM values (∼2-fold higher) were observed for enzyme nanostructures modified with blocked aptamers, possibly due to the exclusion of substrates approaching the surface. The similar concept of this modified surface-substrate interaction should be applicable to other multienzyme systems immobilized on nanostructures, which could be useful in the development of biomimetic nanoreactors.

Multi-Omics Analysis Reveals the Unexpected Immune Regulatory Effects of Arsenene Nanosheets in Tumor Microenvironment.

Arsenene, a two-dimensional (2D) monoelemental layered nanosheet composed of arsenic, was recently reported to feature outstanding anticancer activities. However, the specific biological mechanism of action remains unknown. In this work, we extensively analyzed the mechanism of arsenene in vivo and in vitro and discovered the unexpected immune regulatory capability of arsenene for the first time. Analysis of cell phenotypes in tumor microenvironment by single-cell RNA sequencing revealed that arsenene remodeled the tumor microenvironment by recruiting a high proportion of anticancer immune cells to eliminate the tumor. Mechanistically, arsenene significantly activated T cell receptor signaling pathways to produce antitumor immune cells while inhibiting DNA replication and TCA cycle pathways of tumor cells in vivo. Further proteomic analysis on tumor cells revealed that arsenene induced reactive oxygen species production and oxidative stress damage by targeting thioredoxin TXNL1. The overloaded reactive oxygen species (ROS) further triggered endoplasmic reticulum stress responses to release damage-associated molecular patterns (DAMPs) and "eat-me" signals from dying tumor cells, leading to the activation of antigen-presenting processes to induce the subsequent effector tumor-specific CD8+ T cell immune responses. This unexpected discovery indicated for the first time that 2D inorganic nanomaterials could effectively activate direct anticancer immune responses, suggesting arsenene as a promising candidate nanomedicine for future cancer immunotherapy.

Construction of magnetic drug delivery system and its potential application in tumor theranostics.

Magnetic nanoparticles(NPs) are characterized by a rich variety of properties. Because of their excellent physical and chemical properties, they have come to the fore in biomedicine and other fields. The magnetic NPs were extensively studied in magnetic separation of cells, targeted drug delivery, tumor hyperthermia, chemo-photothermal therapy, magnetic resonance imaging (MRI) and other biomedical fields. Magnetic NPs are increasingly used in magnetic resonance imaging (MRI) based on their inherent magnetic targeting, superparamagnetic enzyme-like catalytic properties and nanoscale size. Poly(lactic-co-glycolic acid) (PLGA) is a promising biodegradable material approved by FDA and EU for drug delivery. Currently, PLGA-based magnetic nano-drug delivery systems have attracted the attention of researchers. Herein, we achieved the effective encapsulation of sized-controlled polyethylene glycol-3,4-dihydroxy benzyl-amine-coated superparamagnetic iron oxide nanoparticles (SPIO NPs) and euphorbiasteroid into PLGA nanospheres via a modified multiple emulsion solvent evaporation method (W1/O2/W2). NPs with narrow size distribution and acceptable magnetic properties were developed that are very useful for applications involving cancer therapy and MRI. Furthermore, SPIO-PLGA NPs enhanced the MRI T2 relaxation properties of tumor sites.The prepared SPIO NPs and magnetic PLGA nanospheres can be promising magnetic drug delivery systems for tumor theranostics. This study has successfully constructed a tumor-targeting and magnetic-targeting smart nanocarrier with enhanced permeability and retention, multimodal anti-cancer therapeutics and biodegradability, which could be a hopeful candidate for anti-tumor therapy in the future.