Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies.

Diosmetin, a natural occurring flavonoid, is primarily found in citrus fruits, beans, and other plants. Diosmetin demonstrates a variety of pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antibacterial, metabolic regulation, cardiovascular function improvement, estrogenic effects, and others. The process of literature search was done using PubMed, Web of Science and ClinicalTrials databases with search terms containing Diosmetin, content, anticancer, anti-inflammatory, antioxidant, pharmacological activity, pharmacokinetics, in vivo, and in vitro. The aim of this review is to summarize the in vivo, in vitro and clinical studies of Diosmetin over the last decade, focusing on studies related to its anticancer, anti-inflammatory, and antioxidant activities. It is found that DIO has significant therapeutic effects on skin and cardiovascular system diseases, and its research in pharmacokinetics and toxicology is summarized. It provides the latest information for researchers and points out the limitations of current research and areas that should be strengthened in future research, so as to facilitate the relevant scientific research and clinical application of DIO.

Resveratrol promotes the differentiation of human umbilical cord mesenchymal stem cells into esophageal fibroblasts via AKT signaling pathway.

Objectives: Resveratrol has been implicated in the differentiation and development of human umbilical cord mesenchymal stem cells. The differentiation of into esophageal fibroblasts is a promising strategy for esophageal tissue engineering. However, the pharmacological effect and underlying mechanism of resveratrol on human umbilical cord mesenchymal stem cells differentiation are unknown. Here, we investigated the effects and mechanism of resveratrol on the differentiation of human umbilical cord mesenchymal stem cells. Methods: Using a transwell-membrane coculture system to culture human umbilical cord mesenchymal stem cells and esophageal fibroblasts, we examined how resveratrol act on the differentiation of human umbilical cord mesenchymal stem cells. Immunocytochemistry, Sirius red staining, quantitative real-time PCR, and Western blotting were performed to examine collagen synthesis and possible signaling pathways in human umbilical cord mesenchymal stem cells. Results: We found that resveratrol promoted collagen synthesis and AKT phosphorylation. However, co-treatment of cells with resveratrol and the PI3K inhibitor LY294002 inhibited collagen synthesis and AKT phosphorylation. We demonstrated that resveratrol down-regulated the expression of IL-6, TGF-ß, caspase-9, and Bax by activating the AKT pathway in human umbilical cord mesenchymal stem cell. Furthermore, resveratrol inhibited phosphorylated NF-ĸB in human umbilical cord mesenchymal stem cells. Conclusion: Our data suggest that resveratrol promotes the differentiation of human umbilical cord mesenchymal stem cells into fibroblasts. The underlying mechanism is associated with the downregulation of IL-6 and TGF-ß via the AKT pathway and by inhibiting the NF-ĸB pathway. Resveratrol may be useful for esophageal tissue engineering.

Developing Hypoxia-Sensitive System via Designing Tumor-Targeted Fullerene-Based Photosensitizer for Multimodal Therapy of Deep Tumor.

Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C70) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C70 consuming O2 for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C70-mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.

An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re-Epithelization and Skin Constriction for Enhancing Wound Closure.

Delayed re-epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large-scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active-shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re-epithelization and skin constriction to accelerate large-scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7-fold and ≈1.7-fold better re-epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.

Transcriptomic Analysis Reveals Candidate Genes in Response to Sorghum Mosaic Virus and Salicylic Acid in Sugarcane.

Sorghum mosaic virus (SrMV) is one of the most prevalent viruses deteriorating sugarcane production. Salicylic acid (SA) plays an essential role in the defense mechanism of plants and its exogenous application has been observed to induce the resistance against biotic and abiotic stressors. In this study, we set out to investigate the mechanism by which sorghum mosaic virus (SrMV) infected sugarcane responds to SA treatment in two sugarcane cultivars, i.e., ROC22 and Xuezhe. Notably, significantly low viral populations were observed at different time points (except for 28 d in ROC22) in response to post-SA application in both cultivars as compared to control based on qPCR data. Furthermore, the lowest number of population size in Xuezhe (20 copies/µL) and ROC22 (95 copies/µL) was observed in response to 1 mM exogenous SA application. A total of 2999 DEGs were identified, of which 731 and 2268 DEGs were up- and down-regulated, respectively. Moreover, a total of 806 DEGs were annotated to GO enrichment categories: 348 biological processes, 280 molecular functions, and 178 cellular components. GO functional categorization revealed that DEGs were mainly enriched in metabolic processes, extracellular regions, and glucosyltransferase activity, while KEGG annotation revealed that DEGs were mainly concentrated in phenylpropanoid biosynthesis and plant-pathogen interaction suggesting the involvement of these pathways in SA-induced disease resistance of sugarcane in response to SrMV infection. The RNA-seq dataset and qRT-PCR assay showed that the transcript levels of PR1a, PR1b, PR1c, NPR1a, NPR1b, PAL, ICS, and ABA were significantly up-regulated in response to SA treatment under SrMV infection, indicating their positive involvement in stress endorsement. Overall, this research characterized sugarcane transcriptome during SrMV infection and shed light on further interaction of plant-pathogen under exogenous application of SA treatment.

Self-Cascade Redox Modulator Trilogically Renovates Intestinal Microenvironment for Mitigating Endotoxemia.

Endotoxemia is a life-threatening multiple organ failure disease caused by bacterial endotoxin infection. Unfortunately, current single-target therapy strategies have failed to prevent the progression of endotoxemia. Here, we reported that alanine fullerene redox modulator (AFRM) remodeled the intestinal microenvironment for multiple targets endotoxemia mitigation by suppressing inflammatory macrophages, inhibiting macrophage pyroptosis, and repairing epithelial cell barrier integrity. Specifically, AFRM exhibited broad-spectrum and self-cascade redox regulation properties with superoxide dismutase (SOD)-like enzyme, peroxidase (POD)-like enzyme activity, and hydroxyl radical (•OH) scavenging ability. Guided by proteomics, we demonstrated that AFRM regulated macrophage redox homeostasis and down-regulated LPS/TLR4/NF-κB and MAPK/ERK signaling pathways to suppress inflammatory hyperactivation. Of note, AFRM could attenuate inflammation-induced macrophage pyroptosis via inhibiting the activation of gasdermin D (GSDMD). In addition, our results revealed that AFRM could restore extracellular matrix and cell-tight junction proteins and protect the epithelial cell barrier integrity by regulating extracellular redox homeostasis. Consequently, AFRM inhibited systemic inflammation and potentiated intestinal epithelial barrier damage repair during endotoxemia in mice. Together, our work suggested that fullerene based self-cascade redox modulator has the potential in the management of endotoxemia through synergistically remodeling the inflammation and epithelial barriers in the intestinal microenvironment.

Sweet Gradient matters: Designing consistent and efficient estimator for Zero-shot Architecture Search.

Zero-shot Neural Architecture Search has garnered attention due to its training-free nature and rapid search speed. However, existing zero-shot estimators commonly suffer from low consistency, which hampers their practicality. In this work, we theoretically analyze that network generalization and convergence are highly correlated with Sweet Gradient of Parameter, i.e., the number of parameters whose gradient absolute values are within a certain interval. Empirical results indicate that Sweet Gradient of Parameter brings a higher consistency than the overall number of parameters. Additionally, we demonstrate a positive correlation between the network depth and the proportion of parameters with sweet gradients in each layer. Based on the analysis, we propose a training-free method to find the Sweet Gradient interval and obtain an estimator, named Sweetimator. Furthermore, Sweet Gradient can be an effective and general approach to promote the consistency of zero-shot estimators. Experiments show that Sweetimator and Sweet-enhanced estimators have significant consistency improvement in multiple benchmarks. Our method achieves state-of-the-art performance with 256x speedup in NAS-Bench-201 and maintains high competitiveness in DARTS, MobileNet, and Transformer search spaces. The source code is available at https://github.com/xingxing-123/SweetGradient.

Cuproptosis and Immune-Related Gene Signature Predicts Immunotherapy Response and Prognosis in Lung Adenocarcinoma.

Cuproptosis and associated immune-related genes (IRG) have been implicated in tumorigenesis and tumor progression. However, their effects on lung adenocarcinoma (LUAD) have not been elucidated. Therefore, we investigated the impact of cuproptosis-associated IRGs on the immunotherapy response and prognosis of LUAD using a bioinformatical approach and in vitro experiments analyzing clinical samples. Using the cuproptosis-associated IRG signature, we classified LUAD into two subtypes, cluster 1 and cluster 2, and identified three key cuproptosis-associated IRGs, NRAS, TRAV38-2DV8, and SORT1. These three genes were employed to establish a risk model and nomogram, and to classify the LUAD cohort into low- and high-risk subgroups. Biofunctional annotation revealed that cluster 2, remarkably downregulating epigenetic, stemness, and proliferation pathways activity, had a higher overall survival (OS) and immunoinfiltration abundance compared to cluster 1. Real-time quantitative PCR (RT-qPCR) validated the differential expression of these three genes in both subgroups. scRNA-seq demonstrated elevated expression of NRAS and SORT1 in macrophages. Immunity and oncogenic and stromal activation pathways were dramatically enriched in the low-risk subgroup, and patients in this subgroup responded better to immunotherapy. Our data suggest that the cuproptosis-associated IRG signature can be used to effectively predict the immunotherapy response and prognosis in LUAD. Our work provides enlightenment for immunotherapy response assessment, prognosis prediction, and the development of potential prognostic biomarkers for LUAD patients.

Inhibiting redox-mediated endothelial migration by gadofullerenes for inducing tumor vascular normalization and improving chemotherapy.

Tumor vascular normalization (TVN) reverses abnormal tumor vasculatures, which could boost anti-cancer efficiency and especially increase drug intratumoral delivery. Endothelial cells play a vital role in angiogenesis, yet continuous modulating endothelial cell migration to improve TVN is ingenious but challenging. Here we propose a potential strategy for TVN based on inhibiting endothelial migration using antioxidative fullerene nanoparticles (FNPs). We demonstrate that FNPs inhibit cell migration upon their anti-oxidation effects in vitro. The optimized alanine-modified gadofullerene (GFA) exhibits superior TVN ability and inhibits tumor growth in vivo. Mechanically, facilitated with the protein microarray, we confirm that GFA could suppress the focal adhesion pathway to restrain endothelial migration. Subsequently, remarkable anti-tumor efficacy of chemotherapy synergy was obtained, which benefited from a more normalized vascular network by GFA. Together, our study introduces the potential of FNPs as promising TVN boosters to consider in cancer nanomedicine design.

Metal-Free Peroxidase-Mimetic Nanocatalysts for Chemodynamic Vascular-Disrupting Cancer Therapy.

Metal ion-facilitated chemodynamic therapy (CDT) is an emerging method for treating cancer. However, its potential is hindered by its low catalytic performance in weakly acidic tumor microenvironments (TMEs) and the severe toxicity of free metal ions. A new approach to tumor therapy, chemodynamic vascular disruption (CVD), is introduced using metal-free, peroxidase (POD)-mimetic multihydroxylated [70] fullerene (MHF) nanocatalysts. The research shows that MHF contains C···O active sites, as demonstrated by density functional theory (DFT) calculations, and converts H2 O2 into ∙OH across a pH range of 6.0-10.0. The generation of ∙OH and the dismantling of tumor blood vessels are observed in real-time using mouse dorsal skin-fold chamber (DSFC) models. Applying proteomics, it is discovered that the CVD mechanism involves the nanocatalytic MHF enhancing H2 O2 decomposition in the TME, producing ∙OH. This damages tumor vascular endothelial junction proteins, causing vascular leakage and subsequently cutting off the vascular supply to the tumor cells. This method deviates from the traditional CDT that targets tumor cells. Instead, the proficient MHF nanocatalysts aim to directly disrupt the tumor vasculature, enhancing anti-tumor efficiency without triggering harmful toxicity. The proposed CVD therapeutic strategy enhances the application of gentle carbon nanocatalysts in cancer therapy, offering new perspectives on nanocatalytic medicine.

Metastatic Colorectal Cancer Patient with Microsatellite Stability and Germline BRAC2 Mutation Shows a Complete Response to Olaparib in Combination with a PD-1 Inhibitor and Bevacizumab: A Case Report and Review of the Literature.

Metastatic colorectal cancer (mCRC) has a poor prognosis. Combining chemotherapy with targeted therapy constitutes a basic form of mCRC treatment. Immune checkpoint inhibitors have been recommended for microsatellite instability mCRC, while most patients harboring microsatellite stability (MSS) or proficient mismatch repair (pMMR) are less responsive to immunotherapy. Combinational targeted therapy, including poly-ADP ribose polymerase (PARP) inhibitors, has been considered a promising way to reverse immunotherapy resistance; however, there is no clear and consistent conclusions can be drawn from the current research. Here, we report the case of a 59-year-old woman diagnosed with stage IVB MSS mCRC who received three courses of capecitabine/oxaliplatin chemotherapy combined with bevacizumab as a first-line treatment, resulting in an overall evaluation of stable disease (-25.7%). However, the occurrence of adverse events of intolerable grade 3 diarrhea and vomiting forced the cessation of this therapy. A germline BRCA2 mutation was found by next-generation sequencing, and the patient further received a combination of olaparib, tislelizumab, and bevacizumab. This treatment regime resulted in a complete metabolic response and a partial response (-50.9%) after 3 months of treatment. Mild asymptomatic interstitial pneumonia and manageable hematologic toxicity were two adverse events associated with this combination therapy. This study provides new insights into the combination of PARP inhibitors and immunotherapy for MSS mCRC patients carrying germline BRCA2 mutations.

Biocontrol features of Pseudomonas syringae B-1 against Botryosphaeria dothidea in apple fruit.

Apple ring rot caused by Botryosphaeria dothidea is an important disease that leads to severe quality deterioration and yield loss at pre-harvest and postharvest stages. Therefore, it is urgent to develop safe and efficient measures to control this disease. The objective of the present study was to investigate the biocontrol features of Pseudomonas syringae B-1 against B. dothidea and explore its mechanism of action utilizing in vitro and in vivo assays. The results showed that P. syringae B-1 strongly reduced the incidence of apple ring rot and lesion diameter by 41.2 and 90.2%, respectively, in comparison to the control fruit. In addition, the control efficiency of strain B-1 against B. dothidea infection depended on its concentration and the interval time. P. syringae B-1 cells showed higher inhibitory activities than its culture filtrates on the mycelial growth and spore germination of B. dothidea. Moreover, P. syringae B-1 treatment alleviated electrolyte leakage, lipid peroxidation, and H2O2 accumulation in B. dothidea-infected apple fruit by increasing antioxidant enzyme activities, including peroxidase, catalase, superoxide dismutase, and ascorbate peroxidase. We also found that strain B-1 treatment enhanced four defense-related enzyme activities and stimulated the accumulation of three disease-resistant substances including phenolics, lignin, and salicylic acid (SA) in apple fruit. In addition, strain B-1 triggered the upregulated expression of defense-related genes such as PR genes (PR1, PR5, GLU, and CHI) and two genes involved in the biosynthesis of SA (SID2 and PAD4) to promote the resistance potential in apple fruit. Hence, our results suggest that P. syringae B-1 is a promising strategy against B. dothidea, mainly through reducing oxidative damage, activating defense-related enzymes, accumulating disease-resistant substances, and triggering the expression of resistance-correlated genes in apple fruit.

Efficiently Inhibiting Systemic Inflammatory Cascades by Fullerenes for Retarding HFD-Fueled Atherosclerosis.

Atherosclerosis accounts for major mortality of cardiac-cerebral vascular diseases worldwide. Pathologically, persistent inflammation dominates the progression of atherosclerosis, which can be accelerated by a high-fat diet (HFD), possibly through triggering local intestinal oxidative stress and ensuing gut barrier dysfunction. Current pharmacotherapy has been disappointing, ascribed to limited therapeutic efficacy and undesirable side effects. Hence it is compelling to explore novel efficient anti-atherosclerotic drugs with minimal toxicity. Herein, two fullerene-based therapies with exceptional antioxidant capacity, in the form of water-soluble injectable fullerene nanoparticles (IFNPs) and oral fullerene tablets (OFTs), are demonstrated to retard HFD-fueled atherosclerosis in ApoE-/- mice with favorable biosafety. Especially, OFTs afford robust anti-atherosclerotic therapeutic even against advanced plaques, besides stabilizing plaques with less lipid deposition and improved collagen expression. Specifically, it is identified that OFTs can ameliorate HFD-induced dysregulated intestinal redox homeostasis and restore gut barrier integrity, thereby restraining the translocation of luminal lipopolysaccharide (LPS) into the bloodstream. Furthermore, significantly reduced circulating LPS after OFTs treatment contributes to down-regulated LPS/TLR4/NF-κB signaling in aortic focal, which further mitigates local inflammation and disease development. Overall, this study confirms the universal anti-atherosclerotic effect of fullerenes and provides a novel therapeutic mechanism via modulating intestinal barrier to attenuate atherosclerosis.

Assessment of carbon emission reduction contribution of Chinese power grid enterprises based on MCS-GA-ELM method.

To achieve China's "double carbon" goal, it is necessary to make quantitative evaluation of the power grid enterprises' contribution to carbon emission reduction. This paper analyzes the contribution of power grid enterprises to carbon emission reduction from three points: power generation side, power grid side, and user side. Then, PLS-VIP method is used to screen the key influencing factors of carbon emission reduction contribution of power grid enterprises from three aspects: consumption of clean energy emission reduction, reduction of line loss emission reduction, and substitution of electric energy. Based on GA-ELM combined machine learning algorithm, we establish an intelligent evaluation model of power grid enterprises' carbon emission reduction contribution. Furthermore, according to the distribution law of key influencing factors, this paper uses Monte Carlo simulation method to calculate the contribution of power grid enterprises to carbon emission reduction by scenario, so as to evaluate the contribution of power grid enterprises to carbon emission reduction. Finally, combined with the relevant data of power grid enterprises from 2003 to 2019, this paper makes an empirical study on the completion of carbon emission reduction contribution and the promotion path.

Oral fullerene tablets for colorectal cancer therapy based on modulation of tumor inflammatory microenvironments.

The development and progression of colorectal cancer (CRC) are highly dependent on the long-term inflammatory microenvironment with immune dysregulation in the colorectum. However, effective therapeutics are limited to targeting CRC. Here, we developed oral fullerene tablets (OFTs) that can act directly on the colorectal site by oral administration and reduce the inflammatory state at the tumor site for effective CRC therapy. In detail, OFTs scavenged reactive oxygen species (ROS), restrained the mutation of the wild-type P53, inhibited the activation of the inflammatory pathway nuclear factor-κB (NF-κB) and the signal transducer and activator of transcription 3 (STAT3) in the colorectum of CRC mice. Subsequently, OFTs could greatly reduce the infiltration of pro-inflammatory M1 macrophages and neutrophils at the tumor site, restoring the inflammatory microenvironment and immune homeostasis in the colorectal region, and ultimately achieving the inhibition of CRC. In addition, there were no significant toxic side effects of the long-term administration of OFTs. Our work provides an effective oral therapeutic strategy for CRC therapy by modulating the colorectal tumor inflammatory microenvironment and sheds light on the route for oral nano-materials in the clinical treatment of CRC.

Multi-Scale Capsule Attention Network and Joint Distributed Optimal Transport for Bearing Fault Diagnosis under Different Working Loads.

In recent years, intelligent fault diagnosis methods based on deep learning have developed rapidly. However, most of the existing work performs well under the assumption that training and testing samples are collected from the same distribution, and the performance drops sharply when the data distribution changes. For rolling bearings, the data distribution will change when the load and speed change. In this article, to improve fault diagnosis accuracy and anti-noise ability under different working loads, a transfer learning method based on multi-scale capsule attention network and joint distributed optimal transport (MSCAN-JDOT) is proposed for bearing fault diagnosis under different loads. Because multi-scale capsule attention networks can improve feature expression ability and anti-noise performance, the fault data can be better expressed. Using the domain adaptation ability of joint distribution optimal transport, the feature distribution of fault data under different loads is aligned, and domain-invariant features are learned. Through experiments that investigate bearings fault diagnosis under different loads, the effectiveness of MSCAN-JDOT is verified; the fault diagnosis accuracy is higher than that of other methods. In addition, fault diagnosis experiment is carried out in different noise environments to demonstrate MSCAN-JDOT, which achieves a better anti-noise ability than other transfer learning methods.

A long non-coding RNA specifically expressed in early embryos programs the metabolic balance in adult mice.

Many Long non-coding RNAs (lncRNAs) are specifically expressed in early embryos, but the physiological functions of most of them remain largely unknown. Here, we show that deficiency of lncenc1, an early embryo-specific lncRNA, altering glucose and lipid balance in adult mice. Newly weaned lncenc1-deficient mice prefer to use lipids as a fuel source. When mice were fed a normal chow diet (NCD), glucose intolerance and insulin resistance were observed in adult lncenc1-deficient mice. Under high-fat diet (HFD) conditions, however, lncenc1-deficient mice became healthier and could resist food-induced obesity and metabolic disturbances. Furthermore, AKT/mTOR-regulated lipogenesis in liver was reduced in lncenc1-deficient mice fed a HFD. MEFs lacking lncenc1 showed impaired glycolysis and lipogenesis, suggesting that the metabolic defects may already exist in embryos. Our study demonstrated the essential roles of lncenc1 in adult metabolism, providing experimental data that support the "fetal origin" of adult metabolic disorders.

Gadofullerene inhibits the degradation of apolipoprotein B100 and boosts triglyceride transport for reversing hepatic steatosis.

Hepatic steatosis is a widespread metabolic disease characterized by excessive accumulation of triglyceride (TG) in liver. So far, effective approved drugs for hepatic steatosis are still in development, and removing the unnecessary TG from the hepatocytes is an enormous challenge. Here, we explore a promising anti-hepatic steatosis strategy by boosting hepatocellular TG transport using ß-alanine-modified gadofullerene (GF-Ala) nanoparticles. We confirm that GF-Ala could reverse hepatic steatosis in oleic acid-induced hepatocytes, fructose-induced mice, and obesity-associated transgenic ob/ob mice. Observably, GF-Ala improves hepatomegaly and hepatic lipid accumulation, reduces lipid peroxidation, and repairs abnormal mitochondria. Of note, we demonstrate that GF-Ala markedly inhibits the posttranslational degradation of apolipoprotein B100 (ApoB100) and boosts hepatocellular TG transport based on their superior antioxidant property. Together, we conclude that GF-Ala could potently ameliorate hepatic TG transport and maintain hepatic metabolic homeostasis without apparent toxicity, being beneficial for treatments of hepatic steatosis and other fatty liver diseases.

Gadofullerene nanoparticles for robust treatment of aplastic anemia induced by chemotherapy drugs.

Aplastic anemia (AA) is characterized as hypoplasia of bone marrow hematopoietic cells and hematopenia of peripheral blood cells. Though the supplement of exogenous erythropoietin (EPO) has been clinically approved for AA treatment, the side-effects hinder its further application. Here a robust treatment for AA induced by chemotherapy drugs is explored using gadofullerene nanoparticles (GFNPs). Methods: The gadofullerene were modified with hydrogen peroxide under alkaline conditions to become the water-soluble nanoparticles (GFNPs). The physicochemical properties, in vitro chemical construction, stability, hydroxyl radical scavenging ability, in vitro cytotoxicity, antioxidant activity, in vivo treatment efficacy, therapeutic mechanism and biological distribution, metabolism, toxicity of GFNPs were examined. Results: GFNPs with great stability and high-efficiency antioxidant activity could observably increase the number of red blood cells (RBC) in the peripheral blood of AA mice and relieve the abnormal pathological state of bone marrow. The erythropoiesis mainly includes hemopoietic stem cells (HSCs) differentiation, erythrocyte development in bone marrow and erythrocyte maturation in peripheral blood. The positive control-EPO promotes erythropoiesis by regulating HSCs differentiation and erythrocyte development in bone marrow. Different from the anti-AA mechanism of EPO, GFNPs have little impact on both the differentiation of HSCs and the myeloid erythrocyte development, but notably improve the erythrocyte maturation. Besides, GFNPs can notably decrease the excessive reactive oxygen species (ROS) and inhibit apoptosis of hemocytes in blood. In addition, GFNPs are mostly excreted from the living body and cause no serious toxicity. Conclusion: Our work provides an insight into the advanced nanoparticles to powerfully treat AA through ameliorating the erythrocyte maturation during erythropoiesis.

Functional Gadofullerene Nanoparticles Trigger Robust Cancer Immunotherapy Based on Rebuilding an Immunosuppressive Tumor Microenvironment.

Cancer immunotherapy as a novel cancer therapeutic strategy has shown enormous promise. However, the immunosuppressive tumor microenvironment (ITM) is a primary obstacle. Tumor-associated macrophages (TAMs) as a major component of immune cells in a tumor microenvironment are generally polarized to the M2 phenotype that not only accelerates tumor growth but also influences the infiltration of lymphocytes and leads to immunosuppression. Thus, rebuilding ITM by re-educating TAMs and increasing infiltration of lymphocytes is a promising strategy. Herein, gadofullerene (GF-Ala) nanoparticles are demonstrated to reprogram TAMs to M1-like and increase the infiltration of cytotoxic T lymphocytes (CTLs), achieving effective inhibition of tumor growth. Notably, the modulation of ITM by GF-Ala promotes the anticancer efficacy of anti-PD-L1 immune checkpoint inhibitor, achieving superior synergistic treatment. Additionally, GF-Ala nanoparticles can be mostly excreted from the body and cause no obvious toxicity. Together, this study provides an effective immunomodulation strategy using gadofullerene nanoparticles by rebuilding ITM and synergizing immune checkpoint blockade therapy.