SIRT5 Regulates Ferroptosis through the Nrf2/HO-1 Signaling Axis to Participate in Ischemia-Reperfusion Injury in Ischemic Stroke.

This work aimed to study the role and mechanism of SIRT5 regulation of ferroptosis in cerebral ischemia-reperfusion (I/R) injury. A model of middle cerebral artery occlusion in rats was prepared using the method of thread occlusion. The ferroptosis inhibitor was injected intraperitoneally while the SIRT5 interfering lentivirus were injected into the brain, and neurological disorders were scored in the rats. TTC staining was used to detect infarct volume, and immunohistochemistry was used to detect the expression of SIRT5 in tissues. Rat hippocampal neuronal cells H19-7 were transduced with SIRT5 interfering lentivirus and ferroptosis was induced using erastin. The CCK8 detection kit was used to detect cell viability. Commercial kits were used to detect levels of iron ions, ROS, MDA, SOD, and inflammatory factor (TNF-α and IL-6) in brain tissue or cell supernatant. Western blot was used to detect the expression changes of ferroptosis related proteins GPX4, Nrf2, and HO-1 in tissues or cells. Compared with the sham group, the MCAO model group showed higher levels of neurological impairment score, increased cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. Compared with the MCAO group, the MCAO + fer-1 group exhibited lower levels of neurological impairment scores, cerebral infarction volume, decreased iron ions, inflammatory factors, and oxidative stress levels in rats. Meanwhile, compared with the MCAO + DMSO/LV-shRNA group, the MCAO + fer-1/LV-shSIRT5 group showed a significant decrease in neurological impairment scores, cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. In vitro experiments have found that LV-shSIRT5 can prevent erastin-induced cell ferroptosis. In summary, SIRT5 regulates ferroptosis through the Nrf2/HO-1 signaling axis to participate in ischemia-reperfusion injury in ischemic stroke.

Differential reinforcement of cGAS-STING pathway-involved immunotherapy by biomineralized bacterial outer membrane-sensitized EBRT and RNT.

Radiotherapy (RT), including external beam radiation therapy (EBRT) and radionuclide therapy (RNT), realizes physical killing of local tumors and activates systemic anti-tumor immunity. However, these effects need to be further strengthened and the difference between EBRT and RNT should be discovered. Herein, bacterial outer membrane (OM) was biomineralized with manganese oxide (MnO2) to obtain OM@MnO2-PEG nanoparticles for enhanced radio-immunotherapy via amplifying EBRT/RNT-induced immunogenic cell death (ICD) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. OM@MnO2-PEG can react with H2O2 and then gradually produce O2, Mn2+ and OM fragments in the tumor microenvironment. The relieved tumor hypoxia improves the radio-sensitivity of tumor cells, resulting in enhanced ICD and DNA damage. Mn2+ together with the DNA fragments in the cytoplasm activate the cGAS-STING pathway, further exhibiting a positive role in various aspects of innate immunity and adaptive immunity. Besides, OM fragments promote tumor antigen presentation and anti-tumor macrophages polarization. More importantly, our study reveals that OM@MnO2-PEG-mediated RNT triggers much stronger cGAS-STING pathway-involved immunotherapy than that of EBRT, owing to the duration difference of RT. Therefore, this study develops a powerful sensitizer of radio-immunotherapy and uncovers some differences between EBRT and RNT in the activation of cGAS-STING pathway-related anti-tumor immunity.

Systematic Proteomics Study on the Embryonic Development of Danio rerio.

The early development of zebrafish (Danio rerio) is a complex and dynamic physiological process involving cell division, differentiation, and movement. Currently, the genome and transcriptome techniques have been widely used to study the embryonic development of zebrafish. However, the research of proteomics based on proteins that directly execute functions is relatively vacant. In this work, we apply label-free quantitative proteomics to explore protein profiling during zebrafish's embryogenesis, and a total of 5961 proteins were identified at 10 stages of zebrafish's early development. The identified proteins were divided into 11 modules according to weighted gene coexpression network analysis (WGCNA), and the characteristics between modules were significantly different. For example, mitochondria-related functions enriched the early development of zebrafish. Primordial germ cell-related proteins were identified at the 4-cell stage, while the eye development event is dominated at 5 days post fertilization (dpf). By combining with published transcriptomics data, we discovered some proteins that may be involved in activating zygotic genes. Meanwhile, 137 novel proteins were identified. This study comprehensively analyzed the dynamic processes in the embryonic development of zebrafish from the perspective of proteomics. It provided solid data support for further understanding of the molecular mechanism of its development.

Tumor Vascular Destruction and cGAS-STING Activation Induced by Single Drug-Loaded Nano-Micelles for Multiple Synergistic Therapies of Cancer.

Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS-STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic-co-glycolic) acid co-polymer (PLGA-PEG), obtaining PLGA-PEG/DMXAA (PPD) nanoparticles to induce the tumor-specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD-mediated therapies could trigger potent systemic anti-tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS-STING pathway. Together with anti-PD-L1, PPD-mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug-loaded nano-micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.

Ceramide d18:1/24:1 as a potential biomarker to differentiate obesity subtypes with unfavorable health outcomes.

BACKGROUND: The criteria for metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) remain controversial. This research aimed to identify a potential biomarker to differentiate the subtypes of obesity. METHODS: The study conducted a lipidomic evaluation of ceramide in the serum of 77 Chinese adults who had undergone hyperinsulinemic-euglycemic clamps. These adults were divided into three groups according to the clinical data: normal weight control group (N = 21), MHO (N = 20), and MUO (N = 36). RESULTS: The serum Cer d18:1/24:1 level in the MHO group was lower than that in the MUO group. As the Cer d18:1/24:1 level increased, insulin sensitivity decreased, and the unfavorable parameters increased in parallel. Multivariate logistic regression analysis revealed that serum Cer d18:1/24:1 levels were independently correlated with MUO in obesity. Individuals with higher levels of Cer d18:1/24:1 also had an elevated risk of cardiovascular disease. Most ceramide subtype levels increased in obesity compared to normal-weight individuals, but the levels of serum Cer d18:0/18:0 and Cer d18:1/16:0 decreased in obesity. CONCLUSIONS: The relationships between ceramide subtypes and metabolic profiles might be heterogeneous in populations with different body weights. Cer d18:1/24:1 could be a biomarker that can be used to differentiate MUO from MHO, and to better predict who will develop unfavorable health outcomes among obese individuals. TRIAL REGISTRATION: The First Affiliated Hospital of Nanjing Medical University's Institutional Review Board authorized this study protocol, and all participants provided written informed consent (2014-SR-003) prior to study entry.

Differences in neuromuscular junctions between intrinsic muscles of the forepaw and biceps muscles in rats.

Motor endplates of the interossei muscles become destabilized, whereas those of the biceps muscles remain stable in a rat model of obstetric brachial plexus palsy. However, it is unclear whether the morphology of the motor endplates of the interossei muscles is different from that of the biceps muscles in normal rat. We hypothesized that the motor endplates in the interossei muscles have specific characteristics different from those in the biceps muscles. The motor endplates were labeled with α-bungarotoxin and synaptophysin. The cross-sectional areas of the muscle fibers, the morphologies of the motor endplates, and the absolute and normalized areas (corrected by muscle fiber diameter) of the motor endplates of the interossei muscles and the biceps muscles were compared in rats at 1, 3, and 5 weeks after birth. The cross-sectional area of the interossei muscles and biceps muscle fibers were found to have increased gradually at 1, 3, and 5 weeks, but that of the biceps muscles was larger than that of the interossei muscles. The motor endplates of the interossei muscles and the biceps muscles gradually develop from crescent to pretzel shape after birth, and those of the interossei muscles have a smaller area. At 1, 3, and 5 weeks postnatally, the area of postnatal normalized motor endplates of the interossei muscles was much smaller than that of the biceps muscles. A better understanding of the morphological differences of the motor endplates between the interossei muscles and the biceps muscles may help to understand their physiological and pathological changes.

Association Between Diverse Cell Death Patterns Related Gene Signature and Prognosis, Drug Sensitivity, and Immune Microenvironment in Glioblastoma.

Glioblastoma (GBM) is the most invasive type of glioma and is difficult to treat. Diverse programmed cell death (PCD) patterns have a significant association with tumor initiation and progression. A novel prognostic model based on PCD genes may serve as an effective tool to predict the prognosis of GBM. The study incorporated 11 PCD patterns, namely apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis, to develop the model. To construct and validate the model, both bulk and single-cell transcriptome data, along with corresponding clinical data from GBM cases, were obtained from the TCGA-GBM, REMBRANDT, CGGA, and GSE162631 datasets. A cell death-related signature containing 14 genes was constructed with the TCGA-GBM cohort and validated in the REMBRANDT and CGGA datasets. GBM patients with a higher cell death index (CDI) were significantly associated with poorer survival outcomes. Two separate clusters associated with clinical outcomes emerged from unsupervised analysis. A multivariate Cox regression analysis was conducted to examine the association of CDI with clinical characteristics, and a prognostic nomogram was developed. Drug sensitivity analysis revealed high-CDI GBM patients might be resistant to carmustine while sensitive to 5-fluorouracil. Less abundance of natural killer cells was found in GBM cases with high CDI and bulk transcriptome data. A cell death-related prognostic model that could predict the prognosis of GBM patients with good performance was established, which could discriminate between the prognosis and drug sensitivity of GBM.

Dysregulation of LINC00324 promotes poor prognosis in patients with glioma.

BACKGROUND: LINC00324 is a long-stranded non-coding RNA, which is aberrantly expressed in various cancers and is associated with poor prognosis and clinical features. It involves multiple oncogenic molecular pathways affecting cell proliferation, migration, invasion, and apoptosis. However, the expression, function, and mechanism of LINC00324 in glioma have not been reported. MATERIAL AND METHODS: We assessed the expression of LINC00324 of LINC00324 in glioma patients based on data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to identify pathways involved in LINC00324-related glioma pathogenesis. RESULTS: Based on our findings, we observed differential expression of LINC00324 between tumor and normal tissues in glioma patients. Our analysis of overall survival (OS) and disease-specific survival (DSS) indicated that glioma patients with high LINC00324 expression had a poorer prognosis compared to those with low LINC00324 expression. By integrating clinical data and genetic signatures from TCGA patients, we developed a nomogram to predict OS and DSS in glioma patients. Gene set enrichment analysis (GSEA) revealed that several pathways, including JAK/STAT3 signaling, epithelial-mesenchymal transition, STAT5 signaling, NF-κB activation, and apoptosis, were differentially enriched in glioma samples with high LINC00324 expression. Furthermore, we observed significant correlations between LINC00324 expression, immune infiltration levels, and expression of immune checkpoint-related genes (HAVCR2: r = 0.627, P = 1.54e-77; CD40: r = 0.604, P = 1.36e-70; ITGB2: r = 0.612, P = 6.33e-7; CX3CL1: r = -0.307, P = 9.24e-17). These findings highlight the potential significance of LINC00324 in glioma progression and suggest avenues for further research and potential therapeutic targets. CONCLUSION: Indeed, our results confirm that the LINC00324 signature holds promise as a prognostic predictor in glioma patients. This finding opens up new possibilities for understanding the disease and may offer valuable insights for the development of targeted therapies.

Capped L21-norm-based common spatial patterns for EEG signals classification applicable to BCI systems.

The common spatial patterns (CSP) technique is an effective strategy for the classification of multichannel electroencephalogram (EEG) signals. However, the objective function expression of the conventional CSP algorithm is based on the L2-norm, which makes the performance of the method easily affected by outliers and noise. In this paper, we consider a new extension to CSP, which is termed capped L21-norm-based common spatial patterns (CCSP-L21), by using the capped L21-norm rather than the L2-norm for robust modeling. L21-norm considers the L1-norm sum which largely alleviates the influence of outliers and noise for the sake of robustness. The capped norm is further used to mitigate the effects of extreme outliers whose signal amplitude is much higher than that of the normal signal. Moreover, a non-greedy iterative procedure is derived to solve the proposed objective function. The experimental results show that the proposed method achieves the highest average recognition rates on the three real data sets of BCI competitions, which are 91.67%, 85.07%, and 82.04%, respectively. Capped L21-norm-based common spatial patterns-a robust model for EEG signals classification.

Hyperoside, a natural flavonoid compound, attenuates Triptolide-induced testicular damage by activating the Keap1-Nrf2 and SIRT1-PGC1α signalling pathway.

OBJECTIVES: Hyperoside (Hyp), as the main ingredient from Semen Cuscutae, Abelmoschus moschatus, Acanthopanax senticosus, its protective effect in testicular dysfunction and mechanisms have not been studied. Here, we explored the action of Hyp in preventing oxidative stress-induced testicular damage and underlying mechanisms. METHODS: The testicular injury model caused by oxidative stress was successfully built via Triptolide (TP) intraperitoneal injection in male mice. After Hyp (12.5, 25 and 50 mg/kg/day) treatment, testes weights, sperm count and morphology, histological changes, oxidative stress biomarkers from testicular tissue were detected. Also, the molecular mechanism was investigated by western blotting and immunohistochemistry assay. KEY FINDINGS: These data suggested that Hyp significantly ameliorated TP-induced testicular atrophy, microstructural injury and spermatogenic dysfunction. Besides, it was shown that apoptosis-related proteins (cleaved caspase-3 and cleaved PARP) were prominently suppressed. The mechanical results indicated that Hyp significantly promoted Nrf2 translocation and elevated antioxidant enzymes expression in the testicular tissue. Meanwhile, this study also found that Hyp could improve TP-induced mitochondrial dysfunction via the SIRT1-PGC-1α signalling pathway. CONCLUSIONS: The present study indicated that Hyp exerted a potent ameliorative effect against testicular injury caused by oxidative stress via stimulating Keap1-Nrf2 and SIRT1-PGC1a signalling pathway.

In Vitro Digestion and Colonic Fermentation of UHT Treated Faba Protein Emulsions: Effects of Enzymatic Hydrolysis and Thermal Processing on Proteins and Phenolics.

Faba bean (Vicia faba L.) protein is a new plant protein alternative source with high nutrient content especially protein and phenolic compounds. The present study investigated physicochemical properties, phenolic content, antioxidant potential, and short chain fatty acids (SCFAs) production during in vitro digestion and colonic fermentation of faba bean hydrolysates and oil-in-water (O/W) emulsions. Results indicate that the enzymic hydrolysates of faba proteins exhibited higher protein solubility, increased electronegativity, and decreased surface hydrophobicity than native faba protein. O/W emulsions showed improved colloidal stability for the faba protein hydrolysates after ultra-high temperature processing (UHT). Furthermore, UHT processing preserved total phenolic content, DPPH and ABTS radical scavenging abilities while decreasing total flavonoid content and ferric reducing power. Besides, the release of phenolic compounds in faba bean hydrolysates (FBH) and emulsions (FBE) improved after intestinal digestion by 0.44 mg GAE/g and 0.55 mg GAE/g, respectively. For colonic fermentation, FBH demonstrated an approximately 10 mg TE/g higher ABTS value than FBE (106.45 mg TE/g). Total SCFAs production of both FBH and FBE was only 0.03 mM. The treatment of FBH with 30 min enzymatic hydrolysis displayed relatively higher antioxidant capacities and SCFAs production, indicating its potential to bring more benefits to gut health. Overall, this study showed that enzymic hydrolysis of faba proteins not only improved the colloidal emulsion stability, but also released antioxidant capacity during in vitro digestibility and colonic fermentation. Colonic fermentation metabolites (SCFAs) were related to the degree of hydrolysis for both FBH and FBE. Additional studies are required to further elucidate and differentiate the role of phenolics during faba protein processing and digestion stages in comparison to contributions of peptides, amino acids and microelements to digestion rates, antioxidant capacities and colonial SCFA production.

SARS-CoV-2 Pattern Provides a New Scoring System and Predicts the Prognosis and Immune Therapeutic Response in Glioma.

OBJECTIVE: Glioma is the most common primary malignancy of the adult central nervous system (CNS), with a poor prognosis and no effective prognostic signature. Since late 2019, the world has been affected by the rapid spread of SARS-CoV-2 infection. Research on SARS-CoV-2 is flourishing; however, its potential mechanistic association with glioma has rarely been reported. The aim of this study was to investigate the potential correlation of SARS-CoV-2-related genes with the occurrence, progression, prognosis, and immunotherapy of gliomas. METHODS: SARS-CoV-2-related genes were obtained from the human protein atlas (HPA), while transcriptional data and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Glioma samples were collected from surgeries with the knowledge of patients. Differentially expressed genes were then identified and screened, and seven SARS-CoV-2 related genes were generated by LASSO regression analysis and uni/multi-variate COX analysis. A prognostic SARS-CoV-2-related gene signature (SCRGS) was then constructed based on these seven genes and validated in the TCGA validation cohort and CGGA cohort. Next, a nomogram was established by combining critical clinicopathological data. The correlation between SCRGS and glioma related biological processes was clarified by Gene set enrichment analysis (GSEA). In addition, immune infiltration and immune score, as well as immune checkpoint expression and immune escape, were further analyzed to assess the role of SCRGS in glioma-associated immune landscape and the responsiveness of immunotherapy. Finally, the reliability of SCRGS was verified by quantitative real-time polymerase chain reaction (qRT-PCR) on glioma samples. RESULTS: The prognostic SCRGS contained seven genes, REEP6, CEP112, LARP4B, CWC27, GOLGA2, ATP6AP1, and ERO1B. Patients were divided into high- and low-risk groups according to the median SARS-CoV-2 Index. Overall survival was significantly worse in the high-risk group than in the low-risk group. COX analysis and receiver operating characteristic (ROC) curves demonstrated excellent predictive power for SCRGS for glioma prognosis. In addition, GSEA, immune infiltration, and immune scores indicated that SCRGS could potentially predict the tumor microenvironment, immune infiltration, and immune response in glioma patients. CONCLUSIONS: The SCRGS established here can effectively predict the prognosis of glioma patients and provide a potential direction for immunotherapy.

Construction and Validation of a Necroptosis-Related lncRNA Signature in Prognosis and Immune Microenvironment for Glioma.

Background: Glioma is the most common primary brain tumor, representing approximately 80.8% of malignant tumors. Necroptosis triggers and enhances antitumor immunity and is expected to be a new target for tumor immunotherapy. The effectiveness of necroptosis-related lncRNAs as potential therapeutic targets for glioma has not been elucidated. Methods: We acquired RNA-seq data sets from LGG and GBM samples, and the corresponding clinical characteristic information is from TCGA. Normal brain tissue data is from GTEX. Based on TCGA and GTEx, we used univariate Cox regression to sort out survival-related lncRNAs. Lasso regression models were then built. Then, we performed a separate Kaplan-Meier analysis of the lncRNAs used for modeling. We validated different risk groups via OS, DFS, enrichment analysis, comprehensive immune analysis, and drug sensitivity. Results: We constructed a 12 prognostic lncRNAs model after bioinformatic analysis. Subsequently, the risk score of every glioma patient was calculated based on correlation coefficients and expression levels, and the patients were split into low- and high-risk groups according to the median value of the risk score. A nomogram was established for every glioma patient to predict prognosis. Besides, we found significant differences in OS, DFS, immune infiltration and checkpoints, and immune therapy between different risk subgroups. Conclusion: Predictive models of 12 necroptosis-related lncRNAs can facilitate the assessment of the prognosis and molecular characteristics of glioma patients and improve treatment modalities.

Phytochemicals, Nutrition, Metabolism, Bioavailability, and Health Benefits in Lettuce-A Comprehensive Review.

Lettuce is one of the most famous leafy vegetables worldwide with lots of applications from food to other specific uses. There are different types in the lettuce group for consumers to choose from. Additionally, lettuce is an excellent source of bioactive compounds such as polyphenols, carotenoids, and chlorophyll with related health benefits. At the same time, nutrient composition and antioxidant compounds are different between lettuce varieties, especially for green and red lettuce types. The benefit of lettuce consumption depends on its composition, particularly antioxidants, which can function as nutrients. The health benefits rely on their biochemical effect when reaching the bloodstream. Some components can be released from the food matrix and altered in the digestive system. Indeed, the bioaccessibility of lettuce is measuring the quantity of these compounds released from the food matrix during digestion, which is important for health-promoting features. Extraction of bioactive compounds is one of the new trends observed in lettuce and is necessarily used for several application fields. Therefore, this review aims to demonstrate the nutritional value of lettuce and its pharmacological properties. Due to their bioaccessibility and bioavailability, the consumer will be able to comprehensively understand choosing a healthier lettuce diet. The common utilization pattern of lettuce extracted nutrients will also be summarized for further direction.

Personalized antiplatelet therapy guided by clopidogrel pharmacogenomics in acute ischemic stroke and transient ischemic attack: A prospective, randomized controlled trial.

Background: Clopidogrel is frequently used in patients with ischemic stroke or transient ischemic attack (TIA), but its efficacy is hampered by inter-individual variability, due to genetic differences associated with clopidogrel metabolism. We conducted this randomized controlled trial to validate whether the personalized antiplatelet therapy based on clopidogrel pharmacogenomics and clinical characteristics leads to better clinical outcomes compared with standard treatment. Methods: Patients were randomly divided into the standard group or pharmacogenetic group, in which the pharmacogenetic group required the detection of the genotyping of CYP2C19*2, CYP2C19*3, and CYP2C19*17. Patients were followed up for 90 days for the primary efficacy endpoint of new stroke events, secondary efficacy endpoint of individual or composite outcomes of the new clinical vascular events, and the incidence of disability. The primary safety outcome was major bleeding. Results: A total of 650 patients underwent randomization, among which 325 were in the pharmacogenomics group while 325 were in the standard group. Our study found after a 90-day follow-up, the risk of stroke and composite vascular events in the pharmacogenomics group was lower than that in the standard group. The incidence of disability significantly decreased in the pharmacogenomics group. In addition, no statistically significant differences were observed in bleeding events between the two groups. Conclusion: The present study demonstrates that personalized antiplatelet therapy guided by clopidogrel pharmacogenomics and clinical characteristics can significantly improve the net clinical benefit of ischemic stroke or TIA patients during the 90-day treatment period without increasing bleeding risk.

Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles.

OBJECTIVE: To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODS: In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. RESULTS: All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; ß = -0.335, P = 0.004) and taurodeoxycholic acid (TDCA; ß = -0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (ß = 0.335, P = 0.002) was positively correlated with insulin clearance. CONCLUSIONS: Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.

Emerging strategies based on nanomaterials for ionizing radiation-optimized drug treatment of cancer.

Drug-radiotherapy is a common and effective combinational treatment for cancer. This study aimed to explore the ionizing radiation-optimized drug treatment based on nanomaterials so as to improve the synergistic efficacy of drug-radiotherapy against cancer and limit the adverse effect on healthy organs. In this review, these emerging strategies were divided into four parts. First, the delivery of the drug-loaded nanoparticles was optimized owing to the strengthened passive targeting process, active targeting process, and cell targeting process of nanoparticles after ionizing radiation exposure. Second, nanomaterials were designed to respond to the ionizing radiation, thus leading to the release of the loading drugs controllably. Third, radiation-activated pro-drugs were loaded onto nanoparticles for radiation-triggered drug therapy. In particular, nontoxic nanoparticles with radiosensitization capability and innocuous radio-dynamic contrast agents can be considered as radiation-activated drugs, which were discussed in this review. Fourth, according to the various synergetic mechanisms, radiotherapy could improve the drug response of cancer, obtaining optimized drug-radiotherapy. Finally, relative suggestions were provided to further optimize these aforementioned strategies. Therefore, a novel topic was selected and the emerging strategies in this region were discussed, aiming to stimulate the inspiration for the development of ionizing radiation-optimized drug treatment based on nanomaterials.

Diagnostic Radionuclides Labeled on Biomimetic Nanoparticles for Enhanced Follow-Up Photothermal Therapy of Cancer.

Imaging-guided local therapy is the most effective strategy to treat primary cancers in patients. However, the local therapeutic effect should be further improved under the premise of absence of induction of additional side effects. It would be meaningful to analyze the potential assistance of nuclear imaging to the follow-up treatments. In this study,cancer-targeted copper sulfide nanoparticles with 99m Tc labeling (99m Tc-M-CuS-PEG) are prepared using-cancer cell membranes as a synthesis reactor and applied for the potential single-photon emission computed tomography/photoacoustic imaging-guided and 99m Tc-amplified photothermal therapy of cancer. Owing to the homologous targeting capability of the cancer cell membrane, M-CuS-PEG selectively accumulates in homologous tumor sites. After labeling with 99m Tc, M-CuS-PEG with a high near-infrared light absorbance can realize bimodal imaging-guided photothermal therapy of cancer. Furthermore, the labeled 99m Tc significantly enhances the cell uptake of M-CuS-PEG by inducing G2/M arrest of the cell cycle, further improving the photothermal antitumor effect, which is positively correlated with endocytosis of the photothermal conversion reagent. Therefore, a novel cancer-targeted theranostic nanoplatform is developed and it is revealed that the labeled 99m Tc can not only guide but also amplify the subsequent therapy of cancer, providing a conceptual strategy for cancer theranostics with a high biosafety.

Photo-Driven Delivery of 125I-Labeled Nanomicelles for Nucleus-Targeted Internal Conversion Electron-Based Cancer Therapy.

As a kind of high linear energy transfer (LET) radiation, internal conversion electrons are emitted from some radionuclides, such as 125I, triggering severe DNA damage to tumor cells when transported into the nucleus. Herein, we develop a curcumin-loaded nanomicelle composed of a photosensitizer chlorin e6 (Ce6) and amphiphilic poly(ethylene glycol) (poly(maleic anhydride-alt-1-octadecene)-poly(ethylene glycol) (C18-PMH-PEG)) to deliver 125I into the nucleus under 660 nm laser irradiation, leading to the optimized imaging-guided internal conversion electron therapy of cancer. Ce6-containing nanomicelles (Ce6-C18-PEG) self-assemble with nucleus-targeted curcumin (Cur), obtaining Ce6-C18-PEG/Cur nanoparticles. After labeling Cur with 125I, Ce6-C18-PEG/Cur enables single-photon emission computed tomography and fluorescence imaging of the tumor, serving as a guide for follow-up laser irradiation. Notably, the 660 nm laser-triggered photodynamic reaction of Ce6 optimizes the delivery of Ce6-C18-PEG/125I-Cur at various stages, including tumor accumulation, cellular uptake, and lysosome escape, causing plenty of 125I-Cur to enter the nucleus. By this strategy, Ce6-C18-PEG/125I-Cur showed optimal antitumor efficacy and high biosafety in mice treated with local 660 nm laser irradiation using efficient energy deposition of internally converted electrons over short distances. Therefore, our work provides a novel strategy to optimize 125I delivery for tumor treatment.

Quantitative proteomic analysis of glycosylated proteins enriched from urine samples with magnetic ConA nanoparticles identifies potential biomarkers for small cell lung cancer.

Lung cancer has high morbidity and mortality and small cell lung cancer (SCLC) is a highly invasive malignant tumor with a very unfavorable survival rate. Early diagnosis and treatment can result in better prognosis for the SCLC patients but current diagnostic methods are either invasive or incapable for large-scale screen. Therefore, discovering biomarkers for early diagnosis of SCLC is of importance. In this work, we covalently coupled Concanavalin A (ConA) to functionalized magnetic nanoparticles to obtain magnetic ConA-nanoparticles (ConA-NPs) for the enrichment of glycosylated proteins. We then purified glycosylated proteins in 36 urine samples from 9 healthy controls, 9 SCLC patients, 9 lung adenocarcinoma (LUAD) patients, and 9 lung squamous cell carcinoma (LUSC) patients. The purified glycosylated proteins were digested and analyzed by LC-MS/MS for identification and quantification. Among the 398 identified proteins, 20, 15, and 1 glycosylated protein(s), respectively, were upregulated in the urine of SCLC, LUAD, and LUSC patients. Immunoblotting experiments further demonstrated that cathepsin C and transferrin were significantly upregulated in the ConA-NP purified urine of SCLC patients. This work suggests that glycosylated cathepsin C and transferrin might be able to serve as potential biomarkers for the noninvasive diagnosis of SCLC patients.