Structural basis of membrane skeleton organization in red blood cells.

The spectrin-based membrane skeleton is a ubiquitous membrane-associated two-dimensional cytoskeleton underneath the lipid membrane of metazoan cells. Mutations of skeleton proteins impair the mechanical strength and functions of the membrane, leading to several different types of human diseases. Here, we report the cryo-EM structures of the native spectrin-actin junctional complex (from porcine erythrocytes), which is a specialized short F-actin acting as the central organizational unit of the membrane skeleton. While an α-/ß-adducin hetero-tetramer binds to the barbed end of F-actin as a flexible cap, tropomodulin and SH3BGRL2 together create an absolute cap at the pointed end. The junctional complex is strengthened by ring-like structures of dematin in the middle actin layers and by patterned periodic interactions with tropomyosin over its entire length. This work serves as a structural framework for understanding the assembly and dynamics of membrane skeleton and offers insights into mechanisms of various ubiquitous F-actin-binding factors in other F-actin systems.

25-hydroxycholesterol promotes proliferation and metastasis of lung adenocarcinoma cells by regulating ERß/TNFRSF17 axis.

Lung adenocarcinoma is the main type of lung cancer in women. Our previous findings have evidenced that 25-hydroxycholesterol (25-HC) promotes migration and invasion of lung adenocarcinoma cells (LAC), during which LXR as a 25-HC receptor plays an important role. Estrogen receptor beta (ERß) is a receptor of 27-hydroxycholesterol that is structurally analogous to 25-HC, but its role in the functional actions of 25-HC remained largely unknown. In this study, we demonstrated that 25-HC treatment triggered ERß expression in LAC. Knockdown of ERß inhibited 25-HC-mediated proliferation, migration and invasion, and reduced 25-HC-induced LAC metastasis in vivo. Further investigation revealed that ERß knockdown restrained the expression of TNFRSF17 (BCMA). In vivo experiments also confirmed that ERß knockdown blocked 25-HC-induced TNFRSF17 expression. TNFRSF17 knockdown also restrained 25-HC-induced proliferation, migration and invasion. Bioinformatic analysis showed that the levels of ERß and TNFRSF17 were elevated in lung adenocarcinoma, and were closely related to tumor stages and nodal metastasis status. These results suggested that 25-HC promoted the proliferation and metastasis of LAC by regulating ERß/TNFRSF17 axis.

FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice. METHODS: KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected. RESULTS: Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue. CONCLUSION: Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.

Co-inoculation of Soybean Seedling with Trichoderma asperellum and Irpex laceratus Promotes the Absorption of Nitrogen and Phosphorus.

Soybean are one of the main oil crops in the world. The study demonstrated that co-inoculation with Trichoderma asperellum (Sordariomycetes, Hypocreomycetidae) and Irpex laceratus (Basidiomycota, Polyporales) isolated from Kosteletzkya virginica can promote the growth of soybean seedlings. The two fungi were found to produce various enzymes, including cellulase, amylase, laccase, protease, and urease. Upon inoculation, T. asperellum mainly colonized within the phloem of the roots in soybean seedlings, while I. laceratus mainly in the xylem and phloem of the roots. Physiological parameters, such as plant height, root length, and fresh weight, were significantly increased in soybean seedlings co-inoculated with T. asperellum and I. laceratus. Moreover, the expression of key genes related to N and P absorption and metabolism was also increased, leading to improved N and P utilization efficiency in soybean seedlings. These results indicate that the two fungi may have complementary roles in promoting plant growth, co-inoculation with T. asperellum and I. laceratus can enhance the growth and nutrient uptake of soybean. These findings suggest that T. asperellum and I. laceratus have the potential to be used as bio-fertilizers to improve soybean growth and yield.

Hsa_circ_0006260 Mediates Trophoblast Function by Fibronectin Type III Domains Containing Protein 5 via Interacting with miR-770-5p.

A series of studies have confirmed the relationship between circular RNAs (circRNAs) and metabolic diseases. Hsa_circ_0006260 has been reported to be lowly expressed in the placenta of gestational diabetes mellitus (GDM) patients, but the underlying mechanism and its biological functions remain obscure. Placental tissues were collected from 37 pregnant women with normal glucose tolerance (NGT) and 37 pregnant women with GDM. Expression changes of hsa_circ_0006260 in placentas and high glucose (HG)-stimulated HTR-8/SVneo cells were detected using real-time quantitative polymerase chain reaction. Cell viability and migration were determined by cell counting and transwell assays, respectively. Measurement of cytokines was done by enzyme-linked immunosorbent assay. Cell apoptosis was estimated by flow cytometry assay. The molecular mechanisms were identified using dual-luciferase reporter and RNA-binding protein immunoprecipitation assays. Hsa_circ_0006260 expression was remarkably lowered in GDM patient-derived placentas and HG-stimulated HTR-8/SVneo cells. Functionally, hsa_circ_0006260 overexpression weakened HG-mediated repression of HTR-8/SVneo cell viability and migration, as well as promotion of HTR-8/SVneo cell inflammatory response and apoptosis. Mechanistically, hsa_circ_0006260 functioned as a miR-770-5p decoy to mediate fibronectin type III domains containing protein 5 (FNDC5) expression. Ectopic expression of miR-770-5p weakened hsa_circ_0006260 overexpression-mediated repression of HG-induced HTR-8/SVneo cell dysfunction. Also, FNDC5 knockdown lessened miR-770-5p overexpression-mediated promotion of HG-induced HTR-8/SVneo cell dysfunction. Our findings manifested a novel mechanism by which hsa_circ_0006260 could lower HG-induced HTR-8/SVneo cell dysfunction by upregulating FNDC5 via binding to miR-770-5p, which shed new light on circRNA mediated GDM pathogenesis.

Is repeat sentinel lymph node biopsy possible for surgical axillary staging among patients with ipsilateral breast tumor recurrence?

BACKGROUND: There is a lack of studies assessing the survival of repeat sentinel lymph node biopsy (rSLNB) versus axillary lymph node dissection (ALND) for surgical axillary staging among patients with ipsilateral breast tumor recurrence (IBTR). METHODS: We retrospectively identified patients with IBTR from the Surveillance, Epidemiology, and End Results database from 2000 to 2017. The primary outcome was overall survival (OS) between the rSLNB and ALND groups. RESULTS: Of the 2141 women with IBTR after lumpectomy and SLNB, 524 did not receive surgical axillary staging (nonsurgery group) and 1617 patients who did undergo axilla surgery received either rSLNB or ALND as axillary staging (1268 with rSLNB and 349 with ALND). The 10-year OS rates were 61.9% for the nonsurgery and 73.8% for axilla surgery groups (p = .001). In the 1:1 matched cohorts, the 10-year OS rates were 61.4% for the nonsurgery and 69.1% for axilla surgery groups (p = .072). After adjusting for other factors, axillary surgery treatment of IBTR was an independent favorable factor for OS (hazard ratio [HR], 0.71; 95% CI, 0.56-0.90; p = .004). Within the axilla surgery group, rSLNB presented a comparable 10-year OS to the ALND cohort (log-rank test p = .054). Multivariate Cox analysis, as well as subgroup analysis, showed that rSLNB had a similar benefit to ALND (10-year OS; HR, 1.18; 95% CI, 0.88-1.58; p = .268). CONCLUSIONS: The results of this cohort study suggested that receiving surgical axillary staging was associated with better survival of IBTR patients, and rSLNB had a similar long-term survival outcome as ALND. rSLNB might be considered for surgical axillary staging among patients with IBTR after lumpectomy and initial SLNB.

Vacancy-Rich Bismuth-Based Nanosheets for Mitochondrial Destruction via CO Poisoning, Ca2+ Dyshomeostasis, and Oxidative Damage.

Mitochondria are core regulators of tumor cell homeostasis, and their damage has become an arresting therapeutic modality against cancer. Despite the development of many mitochondrial-targeted pharmaceutical agents, the exploration of more powerful and multifunctional medications is still underway. Herein, oxygen vacancy-rich BiO2-x wrapped with CaCO3 (named BiO2-x @CaCO3 /PEG, BCP) is developed for full-fledged attack on mitochondrial function. After endocytosis of BCP by tumor cells, the CaCO3 shell can be decomposed in the acidic lysosomal compartment, leading to immediate Ca2+ release and CO2 production in the cytoplasm. Near-infrared irradiation enhances the adsorption of CO2 onto BiO2-x defects, which enables highly efficient photocatalysis of CO2 -to-CO. Meanwhile, such BiO2-x nanosheets possess catalase-, peroxidase- and oxidase-like catalytic activities under acidic pH conditions, allowing hypoxia relief and the accumulation of diverse reactive oxygen species (ROS) in the tumor microenvironment. Ca2+ overload-induced ion dyshomeostasis, CO-mediated respiratory chain poisoning, ROS-triggered oxidative stress aggravation, and cytosolic hyperoxia can cause severe mitochondrial disorders, which further lead to type I cell death in carcinoma. Not only does BCP cause irreversible apoptosis, but immunogenic cell death is simultaneously triggered to activate antitumor immunity for metastasis inhibition. Collectively, this platform promises high benefits in malignant tumor therapy and may expand the medical applications of bismuth-based nanoagents.

Ultrasound-Activatable g-C3 N4 -Anchored Titania Heterojunction as an Intracellular Redox Homeostasis Perturbator for Augmented Oncotherapy.

Energy band structure of inorganic nano-sonosensitizers is usually optimized by surface decoration with noble metals or metal oxide semiconductors, aiming to enhance interfacial charge transfer, augment spin-flip and promote radical generation. To avoid potential biohazards of metallic elements, herein, metal-free graphitic carbon nitride quantum dots (g-C3 N4 QDs) are anchored onto hollow mesoporous TiO2 nanostructure to formulate TiO2 @g-C3 N4 heterojunction. The direct Z-scheme charge transfer significantly improves the separation/recombination dynamics of electron/hole (e- /h+ ) pairs upon ultrasound (US) stimulation, which promotes the yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH). The conjugated g-C3 N4 QDs with peroxidase-mimic activity further react with the elevated endogenous H2 O2 and aggravate oxidative stress. After loading prodrug romidepsin (RMD) in TiO2 @g-C3 N4 , stimulus-responsive drug delivery can be realized by US irradiation. The disulfide bridge of the released RMD tends to be reduced by glutathione (GSH) into a monocyclic dithiol, which arrests cell cycle in G2/M phase and evokes apoptosis through enhanced histone acetylation. Importantly, reactive oxygen species accumulation accompanied by GSH depletion is devoted to deleterious redox dyshomeostasis, leading to augmented systemic oncotherapy by eliciting antitumor immunity. Collectively, this paradigm provides useful insights in optimizing the performance of TiO2 -based nano-sonosensitizers for tackling critical diseases.

Rfd1, a restorer to the Aegilops juvenalis cytoplasm, functions in fertility restoration of wheat cytoplasmic male sterility.

Cytoplasmic male sterility (CMS) is a crucial means for the utilization of heterosis, which is of great significance for improving the yield and quality of hybrids. Currently, fertility restoration has been extensively investigated in crops, but fertility restoration of CMS wheat with Aegilops juvenalis cytoplasm is poorly understood. Here, a backcross population BC1F1 derived from a cross between the male-sterile line Ju706A, its maintainer line 706B, and restorer line LK783 was used to map the Rfd1 locus by bulked segregant analysis and wheat 660K single nucleotide polymorphism genotyping. Ju706A displayed complete male sterility, and its fertility can be restored by LK783 with a pair of dominant genes Rfd1Rfd1. The locus was located to a 2.4 Mb region on chromosome 1BS by markers AX-174254104 and AX-111201011. Combined with transcriptomic analysis and quantitative real-time PCR assay, TraesCS1B02G197400LC, the most likely candidate gene for Rfd1, was found to encode a pectinesterase that was localized in the cell wall, and was highly expressed in fertile anthers. The silencing of Rfd1 resulted in decreased fertility, and heterogeneous expression of Rfd1 promoted pollen germination and affected vegetative growth. This implies that Rfd1 is required for anther or pollen development and male fertility in CMS wheat with Ae. juvenalis cytoplasm. Furthermore, a 7 bp deletion in Ju706A was employed to develop a specific marker, Xnwafu1, for molecular marker-assisted selection of restorers. This study provides a new understanding for exploring the fertility restoration mechanism of CMS.

Developmental toxicity of bromoacetamide via the thyroid hormone receptors-mediated disruption of thyroid hormone homeostasis in zebrafish embryos.

Bromoacetamide (BAcAm) is a nitrogenous disinfection by-product. We previously found that BAcAm induced developmental toxicity in zebrafish embryos, but the underlying mechanisms remain to be elucidated. Since thyroid hormones (THs) homeostasis is crucial to development, we hypothesized that disruption of THs homeostasis may play a role in the developmental toxicity of BAcAm. In this study, we found BAcAm exposure significantly increased mortality and malformation rate, decreased hatching rate and body length, inhibited the locomotor capacity in zebrafish embryos. BAcAm elevated TSH, T3 and T4 levels, down-regulated T3/T4 ratios, and up-regulated mRNA expression changes of THs related genes (trh, tsh, tg, nis, tpo, dio1, dio2, ugt1ab，klf9 and rho), but down-regulated mRNA expression changes of TH receptors (tr α and tr ß). Up-regulated tr α and tr ß mRNAs by rescue treatment confirmed that both tr α and tr ß were involved in the developmental toxicity of BAcAm. In conclusion, our study indicates disruption of THs homeostasis via the thyroid hormone receptors was responsible for the developmental toxicity of BAcAm.

A nanozyme-based competitive electrochemical immunosensor for the determination of E-selectin.

A nanozyme-based competitive electrochemical immunosensor has been developed for the quantitative determination of E-selectin, a common adhesion molecule expressed by activated endothelial cells. A glassy carbon electrode modified with poly(azure A) and E-selectin antibody (GCE/PAA/Ab) was prepared. Au-CuO nanocomposite-labeled E-selectin, CD62E-Au-CuO, was synthetized, and it could be captured on GCE/PAA/Ab owing to the immunoreaction. The immobilized nanocomposites on GCE/PAA/Ab/CD62E-Au-CuO acted as nanozymes and were involved in the electrocatalytic process that caused the high cathodic peak current. The assembly of GCE/PAA/Ab/CD62E-Au-CuO was inhibited by E-selectin due to the competitive immunoreaction, which resulted in a decrease of the current signal. The cathodic peak current difference at - 0.35 V vs SCE was proportional to the concentration of E-selectin in the range 0.500-500 ng mL-1, and the limit of detection was estimated to be 226 pg mL-1. The cell morphology observation, the cell viability test, and the electrochemical measurement indicate that the injury of human umbilical vein endothelial cells was aggravated, and the release of E-selectin from the injured cells was gradually accelerated when the NaCl content in the growth medium increased.

Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation.

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat pain, inflammation, and other central nervous system disorders. Herein, a series of novel heterocyclic carbohydrazide derivatives were firstly designed by the classic scaffold-hopping strategy. Then, multi-steps synthesis and human FAAH enzyme inhibiting activity assays were conducted. Among them, compound 26 showedstrong inhibition against human FAAH with IC50 of 2.8 µM. Corresponding docking studies revealed that the acyl hydrazide group of compound 26 well-occupied the acyl-chain binding pocket. It also exhibited high selectivity towards FAAH when comparing with CES2 and MAGL. Additionally, compound 26 effectively suppressed the LPS-induced neuroinflammation of microglial cells (BV2) via the reduction of interleukin-1ß and tumor necrosis factor-α. Our results provided significative lead compounds for the further discovery of novel selective and safe FAAH inhibitors with potent anti-neuroinflammation activity.

Role of the gene Phlda1 in fenvalerate-induced apoptosis and testicular damage in Sprague-Dawley rats.

Fenvalerate (FEN), a pyrethroid insecticide used worldwide, has been shown to produce a potentially adverse effect on male reproduction. However the mechanisms are not completely understood. Thus this study aimed to (1) determine whether cellular apoptosis was involved in FEN-induced testicular damage in rats, and (2) identify the potential mechanism involved in FEN-induced apoptosis in testes. Data demonstrated that FEN markedly decreased serum testosterone levels, increased the inner diameter of seminiferous tubules, decreased the layers of spermatogenic cells, disturbed spermatogenesis and increased the number of apoptotic cells. Further, bioinformatic analysis of gene microarray in rat testis tissue showed that FEN significantly altered the expressions of genes (Krt8, Mal, Cd24, Lcn2, Phlda1, Arg2) related to apoptotic related processes. The expression pattern of these 6 genes was upregulated in FEN-treated rat testicular tissue. qRT-PCR analysis demonstrated that Phlda1, a well-documented pro-apoptotic factor, was significantly elevated by FEN. The expression of PHLDA1 testicular protein was also elevated following FEN exposure. In conclusion, our results suggest that FEN exposure induced deleterious effects on rat testes associated with Phlda1-mediated apoptosis which may act as a molecular mechanism underlying FEN induced rat testicular damage.

Analysis on the accident casualties influenced by several economic factors based on the traffic-related data in China from 2004 to 2016.

PURPOSE: By studying the economic data related to road traffic accidents in recent 10 years, this paper explores the impact of various economic factors on the number of casualties in traffic accidents in China, and puts forward related prevention and management measures. METHODS: Based on five economic factors including the number of new health institutions, health investment, transportation investment and disposable income per capita, this paper collects the data of traffic accidents in 31 provinces and municipalities of China from 2004 to 2016 and estimates the parameters using fixed effect model. RESULTS: The number of health institutions, health investment, transportation investment and disposable income per capita are negatively correlated with the number of traffic accident casualties; the number of new health institutions is positively correlated with the number of traffic accident casualties; health investment and transportation investment have a great impact on the number of road traffic accident casualties. CONCLUSION: Economic development has a positive impact on improving traffic conditions, but the increase in the number of new health institutions does not reduce the number of casualties in accidents. The irrational layout of health institutions and imperfect road traffic management mechanism should be taken into account.

Road traffic safety: An analysis of the cross-effects of economic, road and population factors.

PURPOSE: Through the study of economic, traffic and population data related to road traffic accidents from 2004 to 2016, this paper analyzed the impact of various factors on road traffic casualties in China, and provided theoretical basis and suggestions for the road traffic safety management in China. METHODS: Based on three aspects (economy, road, population) with five factors (gross domestic product (GDP), traffic investment, new vehicle ownership, new road mileage and newly increased population), this paper collected the relevant data of road traffic accidents in 31 provinces and cities in China, from 2004 to 2016. A panel model was established to carry out empirical analysis. RESULTS: All factors have a significant impact on the number of road traffic accident casualties. When other factors remain unchanged, the number of road traffic casualties decreased by an average of 0.19 for every 100 million CNY increased in GDP. For every 100 million CNY increased in traffic investment, the number of road traffic casualties is reduced by an average of 13.93, indicating that economic development can improve road traffic safety to a certain extent. On the contrary, the growth in road mileage, new motor vehicles and population has increased the number of road traffic casualties. For every 10, 000 km of new road mileage, the number of traffic accident casualties has increased by 284.04. For every 10,000 newborns, the number of road traffic casualties increased by 7.33; as the number of new motor vehicles increases by 10,000, the number of road traffic casualties increased by an average of 21.77. CONCLUSION: The increase of GDP and traffic investment can significantly reduce the number of road traffic casualties in China, which shows that economic development is essential to improve road traffic safety. The numbers of new road mileage, newly increased population and the new motor vehicles are positively correlated with the number of traffic accident casualties in traffic accidents, which reflects the existing problems in road design, distribution of road resources, and traffic management in China. Therefore, it is necessary to improve the economic and road related aspects to improve road traffic safety.

[In vitro anticoagulant activity of different processed products of Whitmania pigra by water extraction and bionic extraction].

In order to determine the scientificalness of traditionally processed Whitmania pigra, water extraction method and bionic extraction method were used respectively to extract the anticoagulating active components in W. pigra hanging dry products, talcum powder fried products and wine immersing-baked products. Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and antithrombin activity were selected as the activity indexes to evaluate the anticoagulant activities of different processed W. pigra. Then the contents of protein in different processed W. pigra were measured by Coomassie brilliant blue method to preliminarily explain the reason of anticoagulant activity changes. When water extraction method was used, the results of APTT, PT, TT and antithrombin activity showed that the anticoagulant activities of W. pigra were decreased both in talcum powder fried products and wine immersing-baked products, and the activity order was as follows: hanging dried products> wine immersing-baked products>talcum powder fried products. This order was same as the protein content order. While when bionic extraction was used, APTT was shortened in talcum powder fried products, but all the other results indicated the anticoagulant activities of W. pigra processed products were increased, and the activity order was as follows: wine immersing-baked products>talcum powder fried products>hanging dry products. As compared with water extraction, the bionic extraction was more similar to the absorption process of W. pigra in human digestive system after oral administration and was more scientific. Therefore, the traditional processing method can not only modify the taste and smell, but also enhance the anticoagulant activity of W. pigra.

Porous boron-doped graphitic carbon nitride-based label-free electrochemical immunoassay of vascular endothelial cadherin.

As a main connecting protein between endothelial cells, vascular endothelial cadherin (CD144) is involved in regulating vascular remodeling and maintaining vascular integrity. It is regarded as a marker of endothelial dysfunction and injury. Quantitative determination of CD144 is of importance in pathology research, diagnosis and treatment of vascular diseases. A label-free electrochemical method for the immunoassay of CD144 was developed in this work. CD144 antibodies were assembled on a glassy carbon electrode modified with porous boron-doped carbon nitride (B-GCN) and gold nanoparticles (AuNPs) in the presence of protein A. The binding of CD144 on the antibody-modified electrode induced serious steric hindrance, inhibiting the diffusion of ferri-/ferrocyanide from the bulk electrolyte to the electrode interface. The change of the differential pulse voltammetric response displayed a linear relationship with the concentration of CD144 between 0.500 and 400 ng mL-1. The new electrochemical sensor showed some good performances including good selectivity, high stability and satisfactory reproducibility. The cellular morphology observation and activity measurement showed that the dysfunction of vascular endothelial cells appeared in the presence of high-content NaCl. The electrochemical analysis reveals a positive correlation between the release amount of CD144 from the dysfunctional cells and the NaCl concentration in the growth medium.

Nitrogen vacancy-rich carbon nitride anchored with iron atoms for efficient redox dyshomeostasis under ultrasound actuation.

Traditional Fe-based Fenton reaction for inducing oxidative stress is restricted by random charge transfer without oriental delivery, and the resultant generation of reactive oxygen species (ROS) is always too simplistic to realize a satisfactory therapeutic outcome. Herein, FeNv/CN nanosheets rich in nitrogen vacancies are developed for high-performance redox dyshomeostasis therapy after surface conjugation with polyethylene glycol (PEG) and cyclic Arg-Gly-Asp (cRGD). Surface defects in FeNv/CN serve as electron traps to drive the directional transfer of the excited electrons to Fe atom sites under ultrasound (US) actuation, and the highly elevated electron density promote the catalytic conversion of H2O2 into ·OH. Meanwhile, energy band edges of FeNv/CN favor the production of 1O2 upon interfacial redox chemistry, which is enhanced by the optimal separation/recombination dynamics of electron/hole pairs. Moreover, intrinsic peroxidase-like activity of FeNv/CN contributes to the depletion of reductant glutathione (GSH). Under the anchoring effect of cRGD, PEGylated FeNv/CN can be efficiently enriched in the tumorous region, which is ultrasonically activated for concurrent ROS accumulation and GSH consumption in cytosolic region. The deleterious redox dyshomeostasis not only eradicates primary tumor but also suppresses distant metastasis via antitumor immunity elicitation. Collectively, this study could inspire more facile designs of chalybeates for medical applications.

Bimetallic PtPd Atomic Clusters as Apoptosis/Ferroptosis Inducers for Antineoplastic Therapy through Heterogeneous Catalytic Processes.

Active polymetallic atomic clusters can initiate heterogeneous catalytic reactions in the tumor microenvironment, and the products tend to cause manifold damage to cell metabolic functions. Herein, bimetallic PtPd atomic clusters (BAC) are constructed by the stripping of Pt and Pd nanoparticles on nitrogen-doped carbon and follow-up surface PEGylation, aiming at efficacious antineoplastic therapy through heterogeneous catalytic processes. After endocytosed by tumor cells, BAC with catalase-mimic activity can facilitate the decomposition of endogenous H2O2 into O2. The local oxygenation not only alleviates hypoxia to reduce the invasion ability of cancer cells but also enhances the yield of •O2- from O2 catalyzed by BAC. Meanwhile, BAC also exhibit peroxidase-mimic activity for •OH production from H2O2. The enrichment of reactive oxygen species (ROS), including the radicals of •OH and •O2-, causes significant oxidative cellular damage and triggers severe apoptosis. In another aspect, intrinsic glutathione (GSH) peroxidase-like activity of BAC can indirectly upregulate the level of lipid peroxides and promote ferroptosis. Such deleterious redox dyshomeostasis caused by ROS accumulation and GSH consumption also results in immunogenic cell death to stimulate antitumor immunity for metastasis suppression. Collectively, this paradigm is expected to inspire more facile designs of polymetallic atomic clusters in disease therapy.

Hepatic arterial infusion chemotherapy, lenvatinib plus programmed cell death protein-1 inhibitors: A promising treatment approach for high-burden hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has demonstrated remarkable local therapeutic efficacy in treating patients with large unresectable hepatocellular carcinoma (HCC). Additionally, the combination of lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has demonstrated promising antitumor effects in unresectable HCC. Therefore, we conducted a retrospective analysis to evaluate the efficacy and safety of combining HAIC with lenvatinib and PD-1 inhibitors as a first-line therapeutic approach in high-burden HCC patients. METHODS: We conducted a retrospective analysis on patients diagnosed with high-burden HCC who had major portal vein tumor thrombosis (Vp3 and Vp4) or tumor occupancy exceeding 50% of the liver. These patients received a first-line treatment consisting of HAIC with a combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), along with lenvatinib and PD-1 inhibitors between November 2020 and June 2023. The primary endpoints of this study included progression-free survival (PFS) and overall survival (OS), while the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). RESULTS: Ninety-one patients were enrolled in this study, with a median PFS of 8.8 months (95% confidence interval [CI]: 5.75-11.78) and a median OS of 14.3 months (95% CI: 11.23-17.31). According to RECIST 1.1 criteria, the ORR was 52.7%, and DCR was 95.6%. According to the mRECIST criteria, the ORR was 72.5%, and the DCR was 96.5%. Among all patients, 86 (94.5%) experienced TRAEs, and there were no instances of treatment-related deaths. CONCLUSION: The combination of HAIC-FOLFOX with lenvatinib and PD-1 inhibitors as a first-line therapy has exhibited notable therapeutic efficacy and well-tolerated adverse events among patients with high-burden HCC.