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.

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.

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.

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.

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.

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 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.

R237 and h238 are key amino acids in the rubella virus E1 neutralization epitope.

Residues 221-239 of rubella virus E1 glycoprotein contain antibody neutralization domains, and the solvent-exposed charged amino acids at the binding interface may be crucial for binding ability. However, the role of charged amino acid residues on the E1 epitope in peptide-antibody binding is unknown. To investigate the role of single amino acid substitutions on the important neutralizing epitope, biolayer interferometry and serological tests were performed. There are three charged residues in the neutralizing epitope: D229, R237, and H238. Substitution of D229 for amino acid A had no influence on the binding activity of the antibody to the peptide. However, substitutions of R237 or H238 for charged amino acid H or R were found to abolish the binding activity. Furthermore, substitution of an uncharged amino acid Q236 for a charged amino acid D was found to reduce the binding activity significantly. Thus, R237 and H238 are key amino acids in the rubella virus E1 neutralization epitope.